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dd62af59ca32a131c762e984f7b7e1a39147fb8e	nice	Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis when surgery is not an option	Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis when surgery is not an option Evidence-based recommendations on endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis when surgery is not an option. This involves inserting a stent through an endoscope into the gallbladder. # Recommendations Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis can be used when surgery is not an option, if standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. For auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). This technically challenging procedure should only be done in specialist centres by clinicians trained and experienced in using this procedure for gallbladder drainage. Why the committee made these recommendations Standard treatment for acute cholecystitis is keyhole (laparoscopic) or open surgery to remove the gallbladder (cholecystectomy). But for some people, surgery is too risky, or they may not be able to have it because they have other conditions that make surgery unsuitable. There is good evidence to show that this procedure is effective in treating acute cholecystitis and is an alternative when surgery is not an option. A disadvantage of this procedure, when compared with cholecystectomy, is that cholecystitis may reoccur.# The condition, current treatments and procedure # The condition Acute cholecystitis is inflammation of the gallbladder. The most common cause of acute cholecystitis is gallstones (calculous cholecystitis) blocking the duct that drains the gallbladder (cystic duct). This means bile cannot drain from the gallbladder, causing pain, nausea, vomiting and fever. Acalculous cholecystitis is a less common, but usually more serious, cause of acute cholecystitis. It usually develops as a complication of a serious illness, infection or injury that damages the gallbladder. It can be caused by accidental damage to the gallbladder during major surgery, serious injuries or burns, sepsis, severe malnutrition, or HIV or AIDS. # Current treatments Initial treatment usually involves fasting, pain relief, and antibiotics if there is an infection. The gallbladder can be surgically removed (open or laparoscopic cholecystectomy) to prevent acute cholecystitis re-occurring, and to reduce the risk of developing complications, such as gangrenous cholecystitis and peritonitis. People who cannot have surgery may be able to have percutaneous cholecystostomy. This involves inserting a drainage catheter in the gallbladder through a small entry hole made in the abdominal wall. Endoscopic transpapillary gallbladder drainage is a less common alternative. It involves inserting a plastic stent through the ampulla and cystic duct into the gallbladder endoscopically. # The procedure Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis is typically done under sedation or general anaesthesia using a specialist endoscope with an ultrasound probe and fluoroscopic guidance. Imaging is used before the procedure to determine its feasibility. An anastomotic tract is created into the gallbladder through either the wall of the antrum of the stomach (cholecystogastrostomy) or the wall of the duodenum (cholecystoduodenostomy). A stent is inserted to establish biliary drainage into the gut and relieve the gallbladder obstruction. Occasionally, the anastomotic tract may be created between the gallbladder and jejunum (cholecystojejunostomy) if the anatomy has been altered by previous surgery. Different technologies are used to create the anastomotic tract and deploy the stent, and stents can be made of different materials. Single-step devices allow for single-step delivery of the stent without the need to change instruments for track dilation. Multistep devices need track dilation with a cystotome and a biliary balloon. The aim is to drain bile from the gallbladder and avoid the need for emergency cholecystectomy, particularly in people for whom surgery poses a high risk.	{'Recommendations': "Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis can be used when surgery is not an option, if standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nFor auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nThis technically challenging procedure should only be done in specialist centres by clinicians trained and experienced in using this procedure for gallbladder drainage.\n\nWhy the committee made these recommendations\n\nStandard treatment for acute cholecystitis is keyhole (laparoscopic) or open surgery to remove the gallbladder (cholecystectomy). But for some people, surgery is too risky, or they may not be able to have it because they have other conditions that make surgery unsuitable.\n\nThere is good evidence to show that this procedure is effective in treating acute cholecystitis and is an alternative when surgery is not an option. A disadvantage of this procedure, when compared with cholecystectomy, is that cholecystitis may reoccur.", 'The condition, current treatments and procedure': '# The condition\n\nAcute cholecystitis is inflammation of the gallbladder. The most common cause of acute cholecystitis is gallstones (calculous cholecystitis) blocking the duct that drains the gallbladder (cystic duct). This means bile cannot drain from the gallbladder, causing pain, nausea, vomiting and fever.\n\nAcalculous cholecystitis is a less common, but usually more serious, cause of acute cholecystitis. It usually develops as a complication of a serious illness, infection or injury that damages the gallbladder. It can be caused by accidental damage to the gallbladder during major surgery, serious injuries or burns, sepsis, severe malnutrition, or HIV or AIDS.\n\n# Current treatments\n\nInitial treatment usually involves fasting, pain relief, and antibiotics if there is an infection. The gallbladder can be surgically removed (open or laparoscopic cholecystectomy) to prevent acute cholecystitis re-occurring, and to reduce the risk of developing complications, such as gangrenous cholecystitis and peritonitis.\n\nPeople who cannot have surgery may be able to have percutaneous cholecystostomy. This involves inserting a drainage catheter in the gallbladder through a small entry hole made in the abdominal wall. Endoscopic transpapillary gallbladder drainage is a less common alternative. It involves inserting a plastic stent through the ampulla and cystic duct into the gallbladder endoscopically.\n\n# The procedure\n\nEndoscopic ultrasound-guided gallbladder drainage for acute cholecystitis is typically done under sedation or general anaesthesia using a specialist endoscope with an ultrasound probe and fluoroscopic guidance. Imaging is used before the procedure to determine its feasibility. An anastomotic tract is created into the gallbladder through either the wall of the antrum of the stomach (cholecystogastrostomy) or the wall of the duodenum (cholecystoduodenostomy). A stent is inserted to establish biliary drainage into the gut and relieve the gallbladder obstruction. Occasionally, the anastomotic tract may be created between the gallbladder and jejunum (cholecystojejunostomy) if the anatomy has been altered by previous surgery.\n\nDifferent technologies are used to create the anastomotic tract and deploy the stent, and stents can be made of different materials. Single-step devices allow for single-step delivery of the stent without the need to change instruments for track dilation. Multistep devices need track dilation with a cystotome and a biliary balloon.\n\nThe aim is to drain bile from the gallbladder and avoid the need for emergency cholecystectomy, particularly in people for whom surgery poses a high risk.'}	https://www.nice.org.uk/guidance/ipg764	Evidence-based recommendations on endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis when surgery is not an option. This involves inserting a stent through an endoscope into the gallbladder.
b83a365b9ce7efe1855441ae3b13517adbe85ba7	nice	Minimally invasive fusionless posterior-approach surgery to correct idiopathic scoliosis in children and young people	Minimally invasive fusionless posterior-approach surgery to correct idiopathic scoliosis in children and young people Evidence-based recommendations on minimally invasive fusionless posterior-approach surgery to correct idiopathic scoliosis in children and young people. This involves inserting a rod along the spine through a small cut in the back. # Recommendations Minimally invasive fusionless posterior-approach surgery to correct idiopathic scoliosis in children and young people should be used only in research. Find out what only in research means on the NICE interventional procedures guidance page. Further research should include: patient selection in terms of age, skeletal maturity, and site and degree of scoliosis the technique and device (including version) used patient-reported outcomes potential damage from local inflammatory processes (including metallosis) and systemic metal poisoning long-term movement in the thoracic spine long-term complications for the lifetime of the device. Why the committee made these recommendations The evidence on efficacy and safety for the procedure is limited. There are only a few studies, which are small and provide no long-term data. The procedure aims to preserve movement in the spine but there is no evidence about whether this is beneficial. Also, different versions of the device have been used in different studies, and there is limited evidence for the current version. There are also safety concerns about: potential build-up of metal in the body (metallosis) and metal poisoning from titanium in the device bone destruction (osteolysis) where the device is attached to the spine.This procedure is only recommended for use in research because, overall, there is not enough good quality evidence on its safety and efficacy.# The condition, current treatments and procedure # The condition Scoliosis is a 3‑dimensional change to the spine in the coronal, sagittal and axial planes. It causes the bones of the spine to twist or rotate so that the spine curves sideways. Scoliosis curves most commonly occur in the thoracic spine, but can also occur in the lumbar spine. Occasionally, they occur in both the thoracic and lumbar spine. Adolescent idiopathic scoliosis (AIS) is the most common type of scoliosis in children and young people. It is progressive and the exact cause is unknown. Mild to moderate spinal curvature does not cause any health problems but can cause cosmetic concerns. Severe spinal curvature with secondary rib changes can also cause significant pain and lung problems. # Current treatments Treatment of AIS depends on several factors, including skeletal maturity, location of the spinal curve, speed of curve progression and size of the curve. Conservative treatments for mild to moderate AIS include routine surveillance (spinal imaging to monitor progression) and physical therapy. For severe AIS, interventions include casting or bracing (for curves of more than 25 degrees) or spinal fusion surgery (for curves of more than 40 degrees) with various instrumented metallic fixation techniques and grafting to fuse vertebrae. Minimally invasive growth modulating and fusionless surgical techniques to correct idiopathic scoliosis include vertebral body stapling, vertebral body tethering, magnetically controlled growing rods and sublaminar polyester bands. These are also used for AIS in some people. The aim is to correct the scoliosis, prevent progression, restore balance, and reduce pain and morbidity. # The procedure Minimally invasive fusionless posterior-approach surgery to correct idiopathic scoliosis is intended to treat AIS in selected people aged 8 years to 17 years whose bones have not fully matured. It is mainly used to correct flexible single curves (a thoracic major curve, or a thoracolumbar or lumbar major curve) with a Cobb angle of up to 60 degrees that reduces to 30 degrees or less on lateral side-bending radiographs, and thoracic kyphosis of less than 55 degrees (as measured from T5 to T12). The procedure is done under general anaesthesia and fluoroscopic guidance using a posterior unilateral approach. The concave side of the spinal curve is exposed through an incision around the apex of the curve. Two pedicle screws are inserted into the vertebral bodies through the pedicle above and below the apex of the spinal curvature to serve as anchor points. A ratchet rod with an extender and 2 polyaxial joints (that allow a degree of spinal motion) is then fixed to the spine with pedicle screws that are implanted around the apex of the curve. Distraction during surgery is applied with a manual instrument to expand the rod and to straighten the spine. After the procedure, people are allowed to weight bear during everyday activities. About 2 to 3 weeks after surgery, people are advised to exercise daily. This is to allow the rod additional unilateral elongation so there may be further gradual straightening of the spine while the person continues to grow. Because the procedure does not involve any spinal fusion, spinal motion is preserved. This minimises length of hospital stay and recovery time.	{'Recommendations': 'Minimally invasive fusionless posterior-approach surgery to correct idiopathic scoliosis in children and young people should be used only in research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include:\n\npatient selection in terms of age, skeletal maturity, and site and degree of scoliosis\n\nthe technique and device (including version) used\n\npatient-reported outcomes\n\npotential damage from local inflammatory processes (including metallosis) and systemic metal poisoning\n\nlong-term movement in the thoracic spine\n\nlong-term complications for the lifetime of the device.\n\nWhy the committee made these recommendations\n\nThe evidence on efficacy and safety for the procedure is limited. There are only a few studies, which are small and provide no long-term data.\n\nThe procedure aims to preserve movement in the spine but there is no evidence about whether this is beneficial. Also, different versions of the device have been used in different studies, and there is limited evidence for the current version.\n\nThere are also safety concerns about:\n\npotential build-up of metal in the body (metallosis) and metal poisoning from titanium in the device\n\nbone destruction (osteolysis) where the device is attached to the spine.This procedure is only recommended for use in research because, overall, there is not enough good quality evidence on its safety and efficacy.', 'The condition, current treatments and procedure': '# The condition\n\nScoliosis is a 3‑dimensional change to the spine in the coronal, sagittal and axial planes. It causes the bones of the spine to twist or rotate so that the spine curves sideways. Scoliosis curves most commonly occur in the thoracic spine, but can also occur in the lumbar spine. Occasionally, they occur in both the thoracic and lumbar spine.\n\nAdolescent idiopathic scoliosis (AIS) is the most common type of scoliosis in children and young people. It is progressive and the exact cause is unknown. Mild to moderate spinal curvature does not cause any health problems but can cause cosmetic concerns. Severe spinal curvature with secondary rib changes can also cause significant pain and lung problems.\n\n# Current treatments\n\nTreatment of AIS depends on several factors, including skeletal maturity, location of the spinal curve, speed of curve progression and size of the curve. Conservative treatments for mild to moderate AIS include routine surveillance (spinal imaging to monitor progression) and physical therapy. For severe AIS, interventions include casting or bracing (for curves of more than 25\xa0degrees) or spinal fusion surgery (for curves of more than 40\xa0degrees) with various instrumented metallic fixation techniques and grafting to fuse vertebrae. Minimally invasive growth modulating and fusionless surgical techniques to correct idiopathic scoliosis include vertebral body stapling, vertebral body tethering, magnetically controlled growing rods and sublaminar polyester bands. These are also used for AIS in some people. The aim is to correct the scoliosis, prevent progression, restore balance, and reduce pain and morbidity.\n\n# The procedure\n\nMinimally invasive fusionless posterior-approach surgery to correct idiopathic scoliosis is intended to treat AIS in selected people aged 8\xa0years to 17\xa0years whose bones have not fully matured. It is mainly used to correct flexible single curves (a thoracic major curve, or a thoracolumbar or lumbar major curve) with a Cobb angle of up to 60\xa0degrees that reduces to 30\xa0degrees or less on lateral side-bending radiographs, and thoracic kyphosis of less than 55\xa0degrees (as measured from\xa0T5 to\xa0T12).\n\nThe procedure is done under general anaesthesia and fluoroscopic guidance using a posterior unilateral approach. The concave side of the spinal curve is exposed through an incision around the apex of the curve. Two pedicle screws are inserted into the vertebral bodies through the pedicle above and below the apex of the spinal curvature to serve as anchor points. A ratchet rod with an extender and 2\xa0polyaxial joints (that allow a degree of spinal motion) is then fixed to the spine with pedicle screws that are implanted around the apex of the curve. Distraction during surgery is applied with a manual instrument to expand the rod and to straighten the spine. After the procedure, people are allowed to weight bear during everyday activities.\n\nAbout 2\xa0to 3\xa0weeks after surgery, people are advised to exercise daily. This is to allow the rod additional unilateral elongation so there may be further gradual straightening of the spine while the person continues to grow. Because the procedure does not involve any spinal fusion, spinal motion is preserved. This minimises length of hospital stay and recovery time.'}	https://www.nice.org.uk/guidance/ipg765	Evidence-based recommendations on minimally invasive fusionless posterior-approach surgery to correct idiopathic scoliosis in children and young people. This involves inserting a rod along the spine through a small cut in the back.
1655d167ddd1d9999927e8cd08959a18af6238da	nice	Dapagliflozin for treating chronic heart failure with preserved or mildly reduced ejection fraction	Dapagliflozin for treating chronic heart failure with preserved or mildly reduced ejection fraction Evidence-based recommendations on dapagliflozin (Forxiga) for treating chronic heart failure with preserved or mildly reduced ejection fraction in adults. # Recommendations Dapagliflozin is recommended, within its marketing authorisation, as an option for treating symptomatic chronic heart failure with preserved or mildly reduced ejection fraction in adults. Why the committee made this recommendation Current standard care for heart failure with preserved or mildly reduced ejection fraction is loop diuretics and treatment for other conditions the person may have. These manage symptoms, but do not reduce hospitalisations for heart failure. Clinical trial evidence shows that dapagliflozin plus standard care reduces the combined risk of dying from cardiovascular causes or likelihood of first hospitalisation for heart failure compared with placebo plus standard care. Evidence suggests that dapagliflozin could reduce the chance of dying from cardiovascular or other causes. The cost-effectiveness estimates are below what NICE considers an acceptable use of NHS resources. So, dapagliflozin is recommended.# Information about dapagliflozin # Marketing authorisation indication Dapagliflozin (Forxiga, AstraZeneca) is indicated in adults for 'the treatment of symptomatic chronic heart failure'. Dapagliflozin is recommended for treating chronic heart failure with reduced ejection fraction in adults (NICE technology appraisal guidance 679). # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for dapagliflozin. # Price The list price of 10 mg dapagliflozin is £36.59 per 28‑tablet pack (excluding VAT; BNF online accessed April 2023). The annual treatment cost is £477.30.# Committee discussion The evaluation committee considered evidence submitted by AstraZeneca, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Details of condition Heart failure is a chronic condition that occurs when the heart is unable to pump enough blood to meet the body's needs. Left ventricular ejection fraction, the amount of blood pumped by the left ventricle during each heartbeat, is 1 measure used to classify the different types of chronic heart failure, with: % or less defined as heart failure with reduced ejection fraction % to 49% defined as heart failure with mildly reduced ejection fraction % or more defined as heart failure with preserved ejection fraction.The clinical experts noted that chronic heart failure with reduced ejection fraction and chronic heart failure with preserved or mildly reduced ejection fraction should not necessarily be considered as 2 separate conditions, and that they exist on a continuum. Dapagliflozin already has a marketing authorisation for chronic heart failure with reduced ejection fraction and is recommended by NICE for this population (see NICE's technology appraisal guidance on dapagliflozin ). The committee noted that the population in the NICE scope for this appraisal is 'adults with symptomatic chronic heart failure with a left ventricular ejection fraction of 40% or more'. There is also a group of people with chronic heart failure whose left ventricular ejection fraction is initially below 40% but then improves to above 40%; these were included as a subgroup in the DELIVER clinical trial (see section 3.5). This evaluation is relevant to people with chronic heart failure with preserved or mildly reduced ejection fraction (left ventricular ejection fraction of more than 40%). ## Impact on quality of life Symptoms of heart failure with preserved or mildly reduced ejection fraction include difficulty breathing, tiredness and ankle swelling. While treatments are available for heart failure with reduced ejection fraction (see TA679 and NICE's technology appraisal guidance on empagliflozin for treating chronic heart failure with reduced ejection fraction ), there are no disease-modifying treatments available for heart failure with preserved or mildly reduced ejection fraction. The patient experts described how the symptoms, disease severity and impact on daily life of heart failure with preserved or mildly reduced ejection fraction are similar to those experienced by people with heart failure with reduced ejection fraction. In addition, the lack of hope because of the lack of research and available treatments impacts the quality of life and mental health of people with heart failure with preserved or mildly reduced ejection fraction. The patient experts considered both improvement in quality of life and survival to be important for this group. They explained that because there are no disease-modifying treatments, there is a lack of familiarity with this group in clinical practice, and so they tend to be offered less clinical support. The clinical experts also noted that hospitalisations for heart failure with preserved or mildly reduced ejection fraction place a substantial burden on the NHS. So, a treatment that could reduce the number and duration of hospital stays would be beneficial. The committee concluded that there is an unmet need for people with heart failure with preserved or mildly reduced ejection fraction and a new treatment option for this group would be welcome. # Clinical management ## Treatment options NICE's guideline on chronic heart failure in adults: diagnosis and management recommends low- to medium-dose loop diuretics (such as furosemide and bumetanide) for people with heart failure with preserved ejection fraction. Specialist treatment advice is recommended for people whose heart failure does not respond to treatment. Symptomatic treatments for comorbidities are also offered to people with heart failure with preserved ejection fraction, including angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers, beta blockers or mineralocorticoid receptor antagonists. ## Comparators Dapagliflozin would be used with standard care for people with heart failure with preserved or mildly reduced ejection fraction. The final scope for this evaluation listed the comparators as established clinical management without dapagliflozin, including but not limited to loop diuretics and symptomatic treatments for comorbidities. The company defined standard care in its model as loop diuretics (furosemide and bumetanide). The EAG noted that the company did not include symptomatic treatments for comorbidities in its economic modelling. But, it considered that this was unlikely to impact the cost-effectiveness estimates and said that the company's choice of comparators was appropriate. The committee agreed that the appropriate comparator in this evaluation was standard care, and it was appropriate to model standard care as loop diuretics. # Clinical effectiveness ## Data sources and generalisability The company submitted clinical evidence from a randomised, double-blind, phase 3 clinical trial (DELIVER). This compared dapagliflozin plus standard care and placebo plus standard care in adults (40 years and over) with heart failure with preserved or mildly reduced ejection fraction. The study was done in 20 countries across Europe, Asia and North America but did not include people from the UK. The study completed in March 2022. In the trial, the mean age was 72 years, about 44% of people were female and about 45% of people had a history of type 2 diabetes. About one-fifth of people in the trial had been previously diagnosed with heart failure with reduced ejection fraction (left ventricular ejection fraction of 40% or less) which had improved (left ventricular ejection fraction over 40%). Participants in DELIVER had not had a sodium-glucose-co-transporter 2 (SGLT2) inhibitor, such as dapagliflozin, for at least 4 weeks before randomisation. The clinical experts noted that the trial population was about 10 years younger than they would expect in clinical practice, but overall they considered the trial to be generalisable to NHS clinical practice. The committee questioned whether DELIVER would be generalisable to UK clinical practice because it did not include anyone from the UK. The clinical experts noted that the North American population in DELIVER is likely generalisable to UK clinical practice. They noted that, because there are no disease-modifying treatments available for heart failure with preserved or mildly reduced ejection fraction, the standard care treatment arms would be similar across the countries included in the trial. The committee concluded that the results from DELIVER were broadly generalisable to NHS clinical practice. ## Trial outcomes The primary outcome in DELIVER was the composite outcome of time to cardiovascular death or first heart failure event (hospitalisation caused by heart failure or urgent heart failure visit). Compared with placebo plus standard care, dapagliflozin plus standard care reduced the time to cardiovascular death or first heart failure event (hazard ratio 0.82, 95% confidence interval 0.73 to 0.92). The committee concluded that dapagliflozin significantly reduced the combined risk of cardiovascular death or first heart failure event. ## Impact of treatment on cardiovascular and all-cause mortality In DELIVER, dapagliflozin reduced all-cause mortality (hazard ratio 0.94, 95% confidence interval 0.83 to 1.07) and cardiovascular mortality (hazard ratio 0.88, 95% confidence interval 0.74 to 1.05) compared with placebo, but these results were not statistically significant. For both all-cause and cardiovascular mortality the confidence intervals crossed 1. This means that it is uncertain whether dapagliflozin significantly improved all-cause or cardiovascular mortality compared with placebo. The clinical experts noted that the clinical trial was not powered to assess the impact of dapagliflozin on all-cause or cardiovascular mortality. They highlighted a pre-specified analysis (DAPA-HF) which pooled results from DELIVER with trial results from people with reduced ejection fraction. This pooled analysis showed that dapagliflozin significantly reduced cardiovascular mortality compared with placebo (hazard ratio 0.86, 95% confidence interval 0.76 to 0.96; Jhund et al. ). In this pooled analysis there was no evidence that the effect of dapagliflozin differed by level of ejection fraction. The committee noted that evidence from the pooled analysis was not incorporated into the economic model. The clinical experts considered that it was plausible that dapagliflozin could reduce cardiovascular mortality by reducing hospitalisation for heart failure, which is associated with a substantial quality of life burden (see section 3.2) and risk of infection. One clinical expert proposed that reducing hospitalisations may be associated with a reduction in the overall decline in heart function and quality of life that people with chronic heart failure typically experience over time. The clinical experts also noted that the trial population was younger than would be expected in clinical practice (see section 3.5), and that it is possible that an impact on cardiovascular mortality may be seen in an older population. The committee acknowledged that it is plausible that dapagliflozin may reduce all-cause and cardiovascular mortality. But, the committee concluded that this is uncertain from the DELIVER data. This is because, for both all-cause and cardiovascular mortality as individual endpoints, the confidence intervals cross 1, meaning these results are not statistically significant. ## Trial outcomes in people with heart failure with improved ejection fraction DELIVER included a subgroup of people whose left ventricular ejection fraction was initially below 40% but had improved to above 40% (heart failure with improved ejection fraction; see section 3.5). To further understand the impact of dapagliflozin on cardiovascular and all-cause deaths, the EAG requested subgroup analyses for people with heart failure with improved ejection fraction and people who had consistent left ventricular ejection fraction of 40% or more. It noted that the treatment effect of dapagliflozin on survival was different in the 2 groups. The magnitude of difference is deemed academic in confidence by the company and cannot be reported here. The EAG considered whether any benefits in survival could be driven by the impact in the heart failure with improved ejection fraction group. Clinical expert opinion sought by the EAG suggested that, in clinical practice, people with heart failure with reduced ejection fraction would be eligible for SGLT2 inhibitors (including dapagliflozin) and would be unlikely to stop treatment when their left ventricular ejection fraction increased to above 40% (heart failure with improved ejection fraction). The company highlighted that DELIVER only included people who had not had an SGLT2 inhibitor within 4 weeks before randomisation. It also noted that DELIVER included people with heart failure with improved ejection fraction to understand the treatment effect of dapagliflozin in this subgroup because there were no previous studies for this subgroup. The committee acknowledged the company's and EAG's perspectives and concluded that it would take both into account in its decision making. # Economic model ## Model structure The company modelled the cost effectiveness of dapagliflozin using a Markov cohort model with health states defined by Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ‑TSS) quartiles. KCCQ-TSS is a disease-specific measure of quality of life, with higher scores reflecting better health outcomes (less frequent and less severe symptoms). Disease progression was modelled by transition between KCCQ quartiles (KCCQ‑TSS of 0 to below 55, quartile 1; 55 to below 73, quartile 2; 73 to below 88, quartile 3; 88 to 100, quartile 4). The model also captured hospitalisation for heart failure as a transient event, and captured death because of cardiovascular and non-cardiovascular causes using parametric survival equations. It used a monthly cycle length, with a lifetime horizon (to 101 years), and discounted costs and quality-adjusted life-years (QALYs) at a rate of 3.5% per year. The committee questioned the appropriateness of using health states defined by KCCQ‑TSS. The committee noted that older cost-effectiveness models of chronic heart failure had used health states defined by New York Heart Association score. But, the model structure in this evaluation was similar to those used in previous NICE technology appraisals in chronic heart failure which used health states defined by KCCQ score (see TA679 and TA773). The clinical experts explained that the KCCQ is the most used questionnaire for assessing quality of life in people with chronic heart failure in clinical trials. Published data has shown that KCCQ score is closely correlated with likelihood of hospitalisation for heart failure and cardiovascular death. The committee concluded that the model was similar to those used in previous NICE technology appraisals in chronic heart failure. But, it noted that there are some uncertainties about the validity of the survival modelling approach (see section 3.13). ## Health state transition In the company's model, disease progression was modelled by transition between health states defined by KCCQ-TSS quartile. EQ‑5D‑5L data was collected in DELIVER at baseline, 8 months and at the final visit. This data was mapped to the EQ‑5D‑3L and used to derive utility values for each KCCQ‑TSS quartile. The company estimated transition probabilities between the KCCS‑TSS quartiles from the raw count KCCQ data collected in DELIVER over 2 time periods (baseline to month 4 and month 5 onwards). Transition probabilities from month 5 onwards were used for the rest of the model time horizon. The transition probabilities were different depending on the treatment arm, and people having dapagliflozin were more likely to remain in the higher KCCQ states. The company used monthly transition count data from DELIVER to obtain transition probabilities between health states. For the months that KCCQ data was unavailable, the company used a last observation carried forward (LOCF) approach. That is, people remained in the same KCCQ quartile until further data showing they had moved to a different health state became available. At the clarification stage, the company noted that LOCF was not used for people whose data was missing at the scheduled assessment, and the data was not imputed in that situation. It noted that the same modelling approach was applied in TA679. The EAG considered that using LOCF is reasonable if it is not used after people in the trial have missed one of the scheduled KCCQ‑TSS measurements, because this could lead to bias. The committee concluded that the company's imputation method was appropriate. ## Modelling of treatment effect on cardiovascular and all-cause mortality The company fitted parametric survival curves to all-cause mortality and to cardiovascular-related mortality Kaplan–Meier data from DELIVER, separately. In the company base case, risk equations for all-cause and cardiovascular mortality were adjusted for: treatment effect of dapagliflozin KCCQ‑TSS health state (time-updated covariate) age sex body mass index race left ventricular ejection fraction N-terminal pro-B-type natriuretic peptide (NT‑proBNP) systolic blood pressure type 2 diabetes atrial fibrillation history of hospitalisation for heart failure heart failure duration. The risk of non-cardiovascular death was applied as the maximum risk of non-cardiovascular death from DELIVER (that is, the difference between all-cause and cardiovascular deaths) or the risk of non-cardiovascular deaths in the general population (whichever was greater). General population risk was calculated by adjusting data in the Office for National Statistics 2017 to 2019 life tables for England and Wales with cardiovascular mortality risk data reported by the World Health Organization. The EAG noted that including KCCQ‑TSS as a predictor of all-cause and cardiovascular mortality generates an indirect survival benefit for dapagliflozin. This is because people having dapagliflozin are more likely to remain in better KCCQ‑TSS states than people having standard care (see section 3.15), and therefore would have reduced risk of all-cause or cardiovascular death. The EAG did scenario analyses which assessed the impact of including a direct treatment effect (by including a dapagliflozin treatment effect coefficient in the survival model) and/or an indirect treatment effect (by including a KCCQ‑TSS treatment effect coefficient) of dapagliflozin on cardiovascular and all-cause survival. The EAG did this by setting the dapagliflozin treatment effect coefficient and/or the KCCQ coefficient in the model to zero. The committee noted that it is not methodologically appropriate to remove a coefficient from a risk equation without refitting the equation and adjusting the other coefficients. In its first meeting, the committee considered that it may be appropriate to include a direct and/or indirect treatment effect of dapagliflozin on cardiovascular and all-cause mortality, but noted that the model should be able to replicate the observed trial data (see section 3.13). The committee concluded that it would have preferred additional scenarios exploring the impact of a direct and/or indirect treatment effect of dapagliflozin on cardiovascular and all-cause mortality which refitted the survival model when parameters were excluded (for example, coefficient for treatment effect and impact of KCCQ state). After consultation, the company provided 2 scenarios which removed the treatment effect of dapagliflozin from the analysis. The first scenario removed the direct treatment effect of dapagliflozin on all-cause and cardiovascular mortality by removing the dapagliflozin treatment effect coefficient in the survival model. The second removed both the direct and indirect treatment effect of dapagliflozin on all-cause and cardiovascular mortality by also removing the effect of KCCQ state on survival. The company considered these scenarios inappropriate for decision making. It said that because its base case uses the full dataset of cardiovascular and all-cause mortality data from DELIVER, it would provide the most robust method for estimating survival. The company also provided mortality extrapolation plots for each treatment effect scenario compared with Kaplan–Meier data from DELIVER. The committee noted that the scenario that excluded the direct and indirect treatment effect of dapagliflozin on cardiovascular and all-cause mortality was likely pessimistic. The most plausible scenario would include a dapagliflozin treatment effect on all-cause and cardiovascular mortality (see section 3.13), but uncertainty was still present. ## Survival extrapolations To model cardiovascular and all-cause survival beyond the observed data in DELIVER, the company used a piecewise modelling approach with an inflection point at 1 year. The company considered DELIVER survival data too complex for a single fully parametric model to be applied and noted that there was a clear separation of the dapagliflozin and placebo curves, beginning at 1 year. Taking into account visual and statistical fit, the company selected the adjusted Weibull model for both cardiovascular and all-cause survival extrapolation for its base case. The company provided scenario analyses using alternative parametric models to extrapolate cardiovascular and all-cause mortality. The EAG raised concerns about the choice of survival curves, noting that the adjusted Gompertz model was the only clinically plausible model for fitting cardiovascular survival data, and that the other models produced optimistic results (that is, underestimated cardiovascular mortality). The EAG considered the adjusted Weibull and Gompertz models to both be clinically plausible for estimating all-cause survival. The company attempted to externally validate its survival extrapolation by comparing it to 2 published studies which reported 5- and 10‑year survival in people with heart failure (Jones et al. ) and Shahim et al. , respectively). For the analyses, it reweighted the baseline characteristics for people having placebo treatment in DELIVER and compared all-cause mortality in this group to the published data. The EAG noted that the validation with Shahim et al. (2021) produced inconsistent results because the Gompertz model fitted best at year 5 while the Weibull model fitted best at year 10. It also highlighted that neither of the published studies reported data beyond 10 years. The EAG explored a scenario using the Gompertz model for cardiovascular and all-cause mortality, which increased the incremental cost-effectiveness ratio (ICER). In addition, the EAG considered that the company did not provide a clinically plausible rationale for the inflection point and noted that the piecewise approach may have contributed to the poor model fit. It would have preferred the use of a single fully fitted parametric model for extrapolating survival. The committee noted that using the Gompertz model to extrapolate both all-cause and cardiovascular mortality increased the ICER, but it considered that the Gompertz model was likely overly pessimistic. It noted that there is uncertainty about the method used to incorporate treatment effect on survival in the model (see section 3.11) but concluded that the company's approach was sufficient for decision making. ## Ability of the model to replicate observed all-cause and cardiovascular survival outcomes The committee noted that including a time-updated model covariate and a treatment effect coefficient (see section 3.11) is not a standard modelling approach and could affect model validity. While this approach was used in previous NICE appraisals of SGLT2 inhibitors (see TA679 and TA773), it is not commonly used in other disease areas. The committee noted that a multi-state simulation model may have been more appropriate because it considers competing risks and can account for patient history. At its first meeting, the committee noted that survival extrapolations of all-cause and cardiovascular mortality had been provided, but that these were the outputs of the regression analysis, rather than the economic model survival outcomes (including the indirect impact of changes in KCCQ‑TSS state over time). It also noted that a model that does not replicate the trial data to an appropriate level of accuracy would cause considerable uncertainty around the plausibility of the model results. In its response to consultation, the company compared the survival outputs from its base-case model and each treatment effect scenario (see section 3.11) with the Kaplan–Meier curve from DELIVER. The EAG provided a numerical comparison of observed mortality data from DELIVER with predicted mortality from the company's base-case model and each treatment effect scenario (see section 3.11). The EAG noted that the comparison suggested the model overestimated mortality compared with DELIVER. It raised concerns about the model's prediction of mortality which continually increased over a long-term time horizon. The company noted that the model estimates produced by the EAG did not account for patient censoring (that is, people who were not present for the full study duration) in DELIVER. The committee acknowledged the EAG's and the company's perspectives. It noted that analysis of all-cause mortality would be less affected by censoring because it includes cardiovascular and non-cardiovascular deaths. The committee concluded that the company's base case (which includes direct and indirect treatment effect) and the scenario which only includes an indirect treatment effect were most suitable for decision making. ## Modelling of treatment effect on heart failure events The company modelled hospitalisation for heart failure and urgent hospitalisation for heart failure by applying generalised estimating equations to DELIVER data. It derived 2 sets of equations, one fully adjusted for patient characteristics and treatment effect (referred to as adjusted) and another which was only adjusted for treatment effect (referred to as unadjusted). The adjusted model was used in the company's base case. The company's approach assumed a constant risk of hospitalisation for heart failure and did not differentiate between initial and subsequent hospitalisations. The EAG noted that DELIVER data did not convincingly support a benefit of dapagliflozin in reducing urgent hospitalisation for heart failure. At its first meeting, the committee concluded that a comparison of the hospitalisation for heart failure predictions from the economic model (including the impact of changes in KCCQ‑TSS state over time) and the observed data from DELIVER is needed to determine whether the modelling approach was appropriate. After consultation, the company provided further data on heart failure events in DELIVER. The EAG believed this data convincingly shows that dapagliflozin did not substantially reduce urgent hospitalisations for heart failure. So, the EAG excluded a dapagliflozin treatment effect on urgent hospitalisation for heart failure in its base case. The committee noted that the impact from this assumption was small, increasing the ICER by no more than £210 per QALY gained. The committee concluded that a dapagliflozin treatment effect on urgent hospitalisation for heart failure should be excluded. ## Long-term treatment effect The company estimated transition probabilities between KCCQ‑TSS quartiles from trial data for 2 time periods. On discontinuation of dapagliflozin, transition probabilities for standard care were used from then onwards. The company and clinical experts said that they would not expect a sustained treatment effect of dapagliflozin after discontinuation. The EAG noted that the model structure results in a sustained treatment effect over time. This is because there is a low probability of moving health states from month 5 onwards, and at month 4 a higher percentage of people having dapagliflozin were in higher KCCQ-TSS states. The committee concluded that the model structure may contribute to a sustained treatment effect for dapagliflozin, which may bias the cost-effectiveness results in favour of dapagliflozin. # Utility values ## Source of utility values and use in the model EQ‑5D‑5L data collected in DELIVER was mapped to EQ‑5D‑3L and used to derive utility values for each KCCQ‑TSS quartile (see section 3.10). The EAG questioned the company's method for deriving utility estimates, noting that an additive approach was used rather than the preferred multiplicative approach outlined in NICE's Decision Support Unit technical support document 12. It noted that the mean utility applied for quartile 4 (the least severe quartile) in the company's economic model was higher than the general population utility of the same age. Additionally, the EAG highlighted that the company did not include the impact of age on utility because it considered this to be negligible. The EAG highlighted clinical expert opinion which considered it implausible for people with symptomatic heart failure with preserved or mildly reduced ejection fraction to have a better quality of life than the general population of the same age. So, for its base case, the EAG used the multiplicative approach to derive its utility, adjusting for age impact and setting quartile 4 utility to equal the general population. After consultation, the company used the EAG's approach for deriving utility estimates in its revised base case. The committee concluded that the EAG's approach for deriving utility estimates is more appropriate. ## Duration of impact of heart failure events on quality of life The company used a disutility period of 1 month for heart failure events in its base case; that is, being hospitalised for heart failure would reduce people's quality of life for 1 month. The EAG's clinical experts suggested that the average hospital stay for a heart failure event was about 11 days. It considered that being hospitalised for 1 day would impact quality of life for 1 week, with a maximum duration of impact on quality of life of 6 months after discharge. So, the company did scenario analyses assuming a disutility period of 2.75 months (11 weeks) and 6 months, which improved its cost-effectiveness estimates. The EAG base case used a disutility period of 11 weeks. The clinical experts said that a hospitalisation for heart failure has a substantial impact on quality of life and that for older people a hospital stay can impact on frailty, mobility and risk of falls. They considered that a disutility period of 11 weeks was an underestimate and that heart failure impacted quality of life for around 6 months. After consultation, the company applied a disutility period of 6 months in its revised base case. The committee concluded that it was reasonable to assume that a hospitalisation for heart failure impacted quality of life for 6 months. # Costs ## Non-elective care costs The company estimated the costs of non-elective care, including hospitalisation for heart failure and inpatient care for adverse events, using NHS reference costs from 2020/2021. The EAG noted that the cost of non-elective care was markedly higher in 2020/2021 compared with recent years and considered that COVID‑19 may have influenced the cost. So, the EAG asked the company to provide a scenario in which non-elective inpatient care was costed using NHS reference costs from 2019/2020, inflated to 2020/2021, which increased the cost-effectiveness estimates. The EAG preferred the use of the inflated values and applied this in its base case. After consultation, the EAG provided a sample of NHS reference costs for non-elective care from 2016 to 2021. The EAG noted that costs appear to be inflated for the 2020/2021 period across all areas compared with previous years. The committee concluded that NHS reference costs from 2019/2020 inflated to 2021 values were preferred. ## Resource use estimate for hospitalisation for heart failure events The company estimated the acute costs of hospitalisation for heart failure based on NHS reference costs from 2020/2021 for non-elective long inpatient stay. These were calculated as the weighted average of reference costs for healthcare resource group (HRG) codes EB03A to EB03E. The EAG's clinical experts considered that the average length of hospital stay for heart failure was 11 days. The company did not provide data on the average duration of hospital stay in DELIVER, noting that there were regional differences in the clinical trial which could introduce uncertainty. The EAG noted that the company had included more severe cost codes in its weighted average, for example, EB03A is associated with a 53‑day hospital stay. The EAG preferred the scenario using the HRG code EB03E only, which is associated with a 13‑day hospital stay, and used this in its base-case cost-effectiveness estimates. This led to a small increase in the ICER. At the second committee meeting, a clinical expert noted that length of hospital stay can vary and only a very small number of people (below 3%) hospitalised for heart failure are in the group associated with the shorter 13-day hospital stay. They explained that this meant the weighted average approach to costing was more appropriate. The committee acknowledged the clinical expert's opinion and concluded that it is more appropriate to use the weighted average to estimate costs for heart failure hospitalisation. ## Cost of cardiovascular deaths The company estimated the cost of cardiovascular death based on a regression analysis presented in Alva et al. (2014) that predicted the added inpatient costs for type 2 diabetes complications from a UK cohort. The company used the cost associated with a myocardial infarction, because this was the lowest cost of the available fatal cardiovascular events. This was then inflated to the 2020/2021 cost year to give a cost of £1,763 per cardiovascular event. This approach aligned with TA679. The EAG noted that sudden cardiovascular deaths might be associated with a lower cost per event. But because only a small proportion of people in DELIVER had sudden cardiovascular deaths the EAG used the company's estimate in its base case. The EAG did a scenario analysis using £1,452 as the total cost for cardiovascular deaths, which assumes no cost for sudden cardiovascular deaths. The scenario showed that using the lower cost had negligible impact on the cost-effectiveness estimates. The committee concluded that the EAG's scenario analysis included the most appropriate costs for cardiovascular deaths. ## Estimation of annual GP visits The company's model assumed that people with heart failure with preserved or mildly reduced ejection fraction would have a total of 23.14 GP visits or other contacts per year. The company clarified that the number of GP visits or contacts in the model included other primary care visits, but that it had conservatively costed these all as GP visits. The EAG noted that because of fewer treatments being available for this group (see section 3.3), about 6 GP or other primary care visits would be expected per year. It asked the company to explore a scenario with 6 GP visits per year, which improved the cost-effectiveness estimates. The committee noted that GPs may not frequently see people with heart failure with preserved or mildly reduced ejection fraction because there are no disease-modifying treatments available for this population (see section 3.3). It noted that other healthcare professionals, such as specialist pharmacists and nurses, may also be involved in the care pathway. After consultation, the company's revised base case assumed 6 annual GP or other primary care visits. The committee concluded that 6 primary care visits per year was a reasonable estimate. # Adverse events ## Inclusion of amputation as an adverse event The company's base case included adverse events reported in DELIVER which occurred with a frequency of over 1%. Amputation occurred with a frequency of less than 1% in DELIVER but was also included in the model. The company took this approach because amputation is an adverse event of interest based on the historical link between SGLT2 inhibitors and risk of amputation. The company also noted that a recent meta-analysis on SGLT2 inhibitors and the risk of amputation suggested that this link is not statistically significant. The EAG highlighted that clinical expert opinion suggests that dapagliflozin is not expected to be associated with increased risk of amputation. So, it considered any increased risk of amputation to be confounded by the presence of type 2 diabetes. The EAG requested that the company stratify the amputation events in DELIVER based on type 2 diabetes status, also noting that in UK clinical practice, people with type 2 diabetes are eligible for treatment with dapagliflozin. The EAG noted that the requested analysis did not support the inclusion of amputation in the cost-effectiveness modelling. Given the potential for confounding results, the EAG's preference was to exclude amputation as an adverse event in its base-case assumptions. The committee heard from clinical experts that there is unlikely to be a link between SGLT2 inhibitors and amputation. Patient experts also noted that they were unfamiliar with this risk. After consultation, the company removed amputation as an adverse event from its base case. The committee considered that dapagliflozin was unlikely to be associated with an increased risk of amputation and concluded that amputation should be excluded as an adverse event in the modelling. ## Estimation of adverse event probabilities The company derived adverse event probabilities based on data from DELIVER. The EAG noted that the adverse event probabilities used in the company's model were higher than those seen in TA679 and lacked external validity. While it expected some differences in the adverse event probabilities because people in DELIVER were about 5 years older, and therefore had more comorbidities, the size of difference was higher than expected. The company considered that comparing DELIVER and DAPA‑HF (which included people with heart failure with reduced ejection fraction) introduces uncertainty because both trials had different populations and median trial follow-up periods. The EAG considered the adverse event probabilities from DAPA‑HF appeared more generalisable to people with heart failure with preserved or mildly reduced ejection fraction. But, it maintained the company's approach of using adverse event probabilities from DELIVER in its base case because the data is available. The committee acknowledged the concerns raised by the EAG but concluded that adverse events probability estimates from DELIVER should be used. # Severity NICE's health technology evaluations manual notes that when considering overall benefits, the committee can consider decision-making modifiers. The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company's absolute (3.31) and proportional (0.40) QALY shortfalls were below the cut-offs required for the severity weighting. So, the company did not consider it appropriate to apply a severity modifier for heart failure with preserved or mildly reduced ejection fraction. The committee agreed with the company's approach not to include a severity modifier in this population. # Cost-effectiveness estimates ## Company and EAG cost-effectiveness estimates The company's revised (after consultation) base-case deterministic ICER was £8,975 per QALY gained. The EAG applied the following assumptions to the company's base case: non-elective inpatient costs taken from NHS reference costs 2019/2020 and inflated to the 2020/2021 cost year (see section 3.18) removal of dapagliflozin treatment effects from urgent heart failure visit event (see section 3.14).The company's revised base-case deterministic ICER with the EAG's preferred assumptions was £9,250 per QALY gained. Scenario analyses on the treatment effect of dapagliflozin resulted in ICER estimates of £20,068 per QALY gained (excluding direct treatment effect of dapagliflozin on all-cause and cardiovascular deaths) and £27,665 per QALY gained (assuming no treatment effect of dapagliflozin on all-cause and cardiovascular deaths). The committee considered that assuming dapagliflozin had no effect on cardiovascular and all-cause deaths was likely pessimistic. It preferred scenarios which included a direct and/or an indirect treatment effect on cardiovascular and all-cause deaths. ## Committee's preferred assumptions The committee's preferred assumptions were to use the company's revised (after consultation) base-case with the following changes: weighted average HRG cost codes (EB03A to EB03E) associated with severe and less severe hospitalisation for heart failure (see section 3.19) unit cost for cardiovascular death of £1,452, including cost of sudden cardiovascular death as £0 (see section 3.20) removal of dapagliflozin treatment effects from urgent heart failure visit event (see section 3.14) non-elective inpatient costs taken from NHS reference costs 2019/2020 and inflated to the 2020/2021 cost year (see section 3.18).The committee considered that there was uncertainty about the treatment effect of dapagliflozin on cardiovascular and all-cause deaths (see section 3.11). But, it concluded that the most plausible scenario would include a direct and/or indirect treatment effect on cardiovascular and all-cause mortality (see section 3.13). ## Committee cost-effectiveness estimates The committee noted that with its preferred assumptions to modelling survival (see section 3.26), the cost-effectiveness estimates were below £20,000 per QALY gained. Including only an indirect treatment effect on cardiovascular and all-cause deaths resulted in an ICER of £18,537 per QALY gained. Using the complete model survival data without any exclusion (that is, including both direct and indirect treatment effect on cardiovascular and all-cause deaths) resulted in an ICER of £8,715 per QALY gained. # Other factors ## Equality issues The committee noted that previous NICE technology appraisals in chronic heart failure had identified that people from Black or South Asian family backgrounds may have a higher risk of developing heart failure. In addition, a meta-analysis of data from people with chronic heart failure with reduced ejection fraction (Zannad et al. ) suggested that SGLT2 inhibitors were more effective in people from Black or Asian family backgrounds. The committee noted that the results from DELIVER did not suggest dapagliflozin was more effective at treating chronic heart failure with preserved or mildly reduced ejection fraction in people from Black or Asian family backgrounds. But, it noted that clinical trials were not usually powered to detect differences by family background. The committee concluded that there was not enough evidence to determine whether dapagliflozin was more effective or less effective in people from Black or Asian family backgrounds. The committee noted that its recommendation applied to all people, regardless of family background. The committee concluded that differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal. ## Prescribing setting NICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team should work in collaboration with the primary care team to start new medicines that need specialist supervision. Dapagliflozin is currently prescribed for heart failure with reduced ejection fraction in primary care, according to the advice of a heart failure specialist. The company noted that socioeconomic deprivation is a strong risk factor for developing heart failure and experiencing adverse heart failure outcomes. The company suggested that inequality in access to specialist care across the UK may contribute to these health inequalities. So, broad prescribing of dapagliflozin in primary and secondary care may reduce health inequalities. Also, the requirement for advice from a heart failure specialist may delay access to treatment and contribute to resource constraints. The patient experts explained that many GPs are not familiar with heart failure with preserved or mildly reduced ejection fraction, because there are currently no disease-modifying treatments available for this population. The committee noted that GPs are experienced in prescribing dapagliflozin for chronic heart failure with reduced ejection fraction and for type 2 diabetes. The committee also noted that clinicians have experience in treating chronic heart failure with reduced ejection fraction and type 2 diabetes across primary and secondary care. The committee discussed the capacity challenges facing GPs around the diagnosis of heart failure with preserved or mildly reduced ejection fraction, and noted that NICE's guideline on chronic heart failure in adults recommends the measurement of NT‑proBNP in people with suspected heart failure, followed by specialist assessment and transthoracic echocardiography. The committee concluded that dapagliflozin would be started on the advice of a heart failure specialist who can determine the most appropriate treatment. # Conclusion ## Recommendation The committee concluded that when its preferred assumptions are incorporated, dapagliflozin is a cost-effective use of NHS resources. Therefore, the committee recommended dapagliflozin for treating symptomatic chronic heart failure with preserved or mildly reduced ejection fraction.	{'Recommendations': 'Dapagliflozin is recommended, within its marketing authorisation, as an option for treating symptomatic chronic heart failure with preserved or mildly reduced ejection fraction in adults.\n\nWhy the committee made this recommendation\n\nCurrent standard care for heart failure with preserved or mildly reduced ejection fraction is loop diuretics and treatment for other conditions the person may have. These manage symptoms, but do not reduce hospitalisations for heart failure.\n\nClinical trial evidence shows that dapagliflozin plus standard care reduces the combined risk of dying from cardiovascular causes or likelihood of first hospitalisation for heart failure compared with placebo plus standard care. Evidence suggests that dapagliflozin could reduce the chance of dying from cardiovascular or other causes.\n\nThe cost-effectiveness estimates are below what NICE considers an acceptable use of NHS resources. So, dapagliflozin is recommended.', 'Information about dapagliflozin': "# Marketing authorisation indication\n\nDapagliflozin (Forxiga, AstraZeneca) is indicated in adults for 'the treatment of symptomatic chronic heart failure'.\n\nDapagliflozin is recommended for treating chronic heart failure with reduced ejection fraction in adults (NICE technology appraisal guidance\xa0679).\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for dapagliflozin.\n\n# Price\n\nThe list price of 10\xa0mg dapagliflozin is £36.59 per 28‑tablet pack (excluding VAT; BNF online accessed April 2023). The annual treatment cost is £477.30.", 'Committee discussion': "The evaluation committee considered evidence submitted by AstraZeneca, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Details of condition\n\nHeart failure is a chronic condition that occurs when the heart is unable to pump enough blood to meet the body's needs. Left ventricular ejection fraction, the amount of blood pumped by the left ventricle during each heartbeat, is 1\xa0measure used to classify the different types of chronic heart failure, with:\n\n% or less defined as heart failure with reduced ejection fraction\n\n% to 49% defined as heart failure with mildly reduced ejection fraction\n\n% or more defined as heart failure with preserved ejection fraction.The clinical experts noted that chronic heart failure with reduced ejection fraction and chronic heart failure with preserved or mildly reduced ejection fraction should not necessarily be considered as 2\xa0separate conditions, and that they exist on a continuum. Dapagliflozin already has a marketing authorisation for chronic heart failure with reduced ejection fraction and is recommended by NICE for this population (see NICE's technology appraisal guidance on dapagliflozin [TA679]). The committee noted that the population in the NICE scope for this appraisal is 'adults with symptomatic chronic heart failure with a left ventricular ejection fraction of 40% or more'. There is also a group of people with chronic heart failure whose left ventricular ejection fraction is initially below 40% but then improves to above 40%; these were included as a subgroup in the DELIVER clinical trial (see section\xa03.5). This evaluation is relevant to people with chronic heart failure with preserved or mildly reduced ejection fraction (left ventricular ejection fraction of more than 40%).\n\n## Impact on quality of life\n\nSymptoms of heart failure with preserved or mildly reduced ejection fraction include difficulty breathing, tiredness and ankle swelling. While treatments are available for heart failure with reduced ejection fraction (see TA679 and NICE's technology appraisal guidance on empagliflozin for treating chronic heart failure with reduced ejection fraction [TA773]), there are no disease-modifying treatments available for heart failure with preserved or mildly reduced ejection fraction. The patient experts described how the symptoms, disease severity and impact on daily life of heart failure with preserved or mildly reduced ejection fraction are similar to those experienced by people with heart failure with reduced ejection fraction. In addition, the lack of hope because of the lack of research and available treatments impacts the quality of life and mental health of people with heart failure with preserved or mildly reduced ejection fraction. The patient experts considered both improvement in quality of life and survival to be important for this group. They explained that because there are no disease-modifying treatments, there is a lack of familiarity with this group in clinical practice, and so they tend to be offered less clinical support. The clinical experts also noted that hospitalisations for heart failure with preserved or mildly reduced ejection fraction place a substantial burden on the NHS. So, a treatment that could reduce the number and duration of hospital stays would be beneficial. The committee concluded that there is an unmet need for people with heart failure with preserved or mildly reduced ejection fraction and a new treatment option for this group would be welcome.\n\n# Clinical management\n\n## Treatment options\n\nNICE's guideline on chronic heart failure in adults: diagnosis and management recommends low- to medium-dose loop diuretics (such as furosemide and bumetanide) for people with heart failure with preserved ejection fraction. Specialist treatment advice is recommended for people whose heart failure does not respond to treatment. Symptomatic treatments for comorbidities are also offered to people with heart failure with preserved ejection fraction, including angiotensin-converting enzyme inhibitors, angiotensin\xa02 receptor blockers, beta blockers or mineralocorticoid receptor antagonists.\n\n## Comparators\n\nDapagliflozin would be used with standard care for people with heart failure with preserved or mildly reduced ejection fraction. The final scope for this evaluation listed the comparators as established clinical management without dapagliflozin, including but not limited to loop diuretics and symptomatic treatments for comorbidities. The company defined standard care in its model as loop diuretics (furosemide and bumetanide). The EAG noted that the company did not include symptomatic treatments for comorbidities in its economic modelling. But, it considered that this was unlikely to impact the cost-effectiveness estimates and said that the company's choice of comparators was appropriate. The committee agreed that the appropriate comparator in this evaluation was standard care, and it was appropriate to model standard care as loop diuretics.\n\n# Clinical effectiveness\n\n## Data sources and generalisability\n\nThe company submitted clinical evidence from a randomised, double-blind, phase\xa03 clinical trial (DELIVER). This compared dapagliflozin plus standard care and placebo plus standard care in adults (40\xa0years and over) with heart failure with preserved or mildly reduced ejection fraction. The study was done in 20\xa0countries across Europe, Asia and North America but did not include people from the UK. The study completed in March\xa02022. In the trial, the mean age was 72\xa0years, about 44% of people were female and about 45% of people had a history of type\xa02 diabetes. About one-fifth of people in the trial had been previously diagnosed with heart failure with reduced ejection fraction (left ventricular ejection fraction of 40% or less) which had improved (left ventricular ejection fraction over 40%). Participants in DELIVER had not had a sodium-glucose-co-transporter\xa02 (SGLT2) inhibitor, such as dapagliflozin, for at least 4\xa0weeks before randomisation. The clinical experts noted that the trial population was about 10\xa0years younger than they would expect in clinical practice, but overall they considered the trial to be generalisable to NHS clinical practice. The committee questioned whether DELIVER would be generalisable to UK clinical practice because it did not include anyone from the UK. The clinical experts noted that the North American population in DELIVER is likely generalisable to UK clinical practice. They noted that, because there are no disease-modifying treatments available for heart failure with preserved or mildly reduced ejection fraction, the standard care treatment arms would be similar across the countries included in the trial. The committee concluded that the results from DELIVER were broadly generalisable to NHS clinical practice.\n\n## Trial outcomes\n\nThe primary outcome in DELIVER was the composite outcome of time to cardiovascular death or first heart failure event (hospitalisation caused by heart failure or urgent heart failure visit). Compared with placebo plus standard care, dapagliflozin plus standard care reduced the time to cardiovascular death or first heart failure event (hazard ratio 0.82, 95% confidence interval 0.73 to 0.92). The committee concluded that dapagliflozin significantly reduced the combined risk of cardiovascular death or first heart failure event.\n\n## Impact of treatment on cardiovascular and all-cause mortality\n\nIn DELIVER, dapagliflozin reduced all-cause mortality (hazard ratio 0.94, 95% confidence interval 0.83 to 1.07) and cardiovascular mortality (hazard ratio 0.88, 95% confidence interval 0.74 to 1.05) compared with placebo, but these results were not statistically significant. For both all-cause and cardiovascular mortality the confidence intervals crossed 1. This means that it is uncertain whether dapagliflozin significantly improved all-cause or cardiovascular mortality compared with placebo. The clinical experts noted that the clinical trial was not powered to assess the impact of dapagliflozin on all-cause or cardiovascular mortality. They highlighted a pre-specified analysis (DAPA-HF) which pooled results from DELIVER with trial results from people with reduced ejection fraction. This pooled analysis showed that dapagliflozin significantly reduced cardiovascular mortality compared with placebo (hazard ratio 0.86, 95% confidence interval 0.76 to 0.96; Jhund et al. ). In this pooled analysis there was no evidence that the effect of dapagliflozin differed by level of ejection fraction. The committee noted that evidence from the pooled analysis was not incorporated into the economic model. The clinical experts considered that it was plausible that dapagliflozin could reduce cardiovascular mortality by reducing hospitalisation for heart failure, which is associated with a substantial quality of life burden (see section\xa03.2) and risk of infection. One clinical expert proposed that reducing hospitalisations may be associated with a reduction in the overall decline in heart function and quality of life that people with chronic heart failure typically experience over time. The clinical experts also noted that the trial population was younger than would be expected in clinical practice (see section\xa03.5), and that it is possible that an impact on cardiovascular mortality may be seen in an older population. The committee acknowledged that it is plausible that dapagliflozin may reduce all-cause and cardiovascular mortality. But, the committee concluded that this is uncertain from the DELIVER data. This is because, for both all-cause and cardiovascular mortality as individual endpoints, the confidence intervals cross 1, meaning these results are not statistically significant.\n\n## Trial outcomes in people with heart failure with improved ejection fraction\n\nDELIVER included a subgroup of people whose left ventricular ejection fraction was initially below 40% but had improved to above 40% (heart failure with improved ejection fraction; see section\xa03.5). To further understand the impact of dapagliflozin on cardiovascular and all-cause deaths, the EAG requested subgroup analyses for people with heart failure with improved ejection fraction and people who had consistent left ventricular ejection fraction of 40% or more. It noted that the treatment effect of dapagliflozin on survival was different in the 2\xa0groups. The magnitude of difference is deemed academic in confidence by the company and cannot be reported here. The EAG considered whether any benefits in survival could be driven by the impact in the heart failure with improved ejection fraction group. Clinical expert opinion sought by the EAG suggested that, in clinical practice, people with heart failure with reduced ejection fraction would be eligible for SGLT2 inhibitors (including dapagliflozin) and would be unlikely to stop treatment when their left ventricular ejection fraction increased to above 40% (heart failure with improved ejection fraction). The company highlighted that DELIVER only included people who had not had an SGLT2 inhibitor within 4\xa0weeks before randomisation. It also noted that DELIVER included people with heart failure with improved ejection fraction to understand the treatment effect of dapagliflozin in this subgroup because there were no previous studies for this subgroup. The committee acknowledged the company's and EAG's perspectives and concluded that it would take both into account in its decision making.\n\n# Economic model\n\n## Model structure\n\nThe company modelled the cost effectiveness of dapagliflozin using a Markov cohort model with health states defined by Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ‑TSS) quartiles. KCCQ-TSS is a disease-specific measure of quality of life, with higher scores reflecting better health outcomes (less frequent and less severe symptoms). Disease progression was modelled by transition between KCCQ quartiles (KCCQ‑TSS of 0 to below 55, quartile\xa01; 55 to below 73, quartile\xa02; 73 to below 88, quartile\xa03; 88 to 100, quartile\xa04). The model also captured hospitalisation for heart failure as a transient event, and captured death because of cardiovascular and non-cardiovascular causes using parametric survival equations. It used a monthly cycle length, with a lifetime horizon (to 101\xa0years), and discounted costs and quality-adjusted life-years (QALYs) at a rate of 3.5% per year. The committee questioned the appropriateness of using health states defined by KCCQ‑TSS. The committee noted that older cost-effectiveness models of chronic heart failure had used health states defined by New York Heart Association score. But, the model structure in this evaluation was similar to those used in previous NICE technology appraisals in chronic heart failure which used health states defined by KCCQ score (see TA679 and TA773). The clinical experts explained that the KCCQ is the most used questionnaire for assessing quality of life in people with chronic heart failure in clinical trials. Published data has shown that KCCQ score is closely correlated with likelihood of hospitalisation for heart failure and cardiovascular death. The committee concluded that the model was similar to those used in previous NICE technology appraisals in chronic heart failure. But, it noted that there are some uncertainties about the validity of the survival modelling approach (see section\xa03.13).\n\n## Health state transition\n\nIn the company's model, disease progression was modelled by transition between health states defined by KCCQ-TSS quartile. EQ‑5D‑5L data was collected in DELIVER at baseline, 8\xa0months and at the final visit. This data was mapped to the EQ‑5D‑3L and used to derive utility values for each KCCQ‑TSS quartile. The company estimated transition probabilities between the KCCS‑TSS quartiles from the raw count KCCQ data collected in DELIVER over 2\xa0time periods (baseline to month\xa04 and month\xa05 onwards). Transition probabilities from month\xa05 onwards were used for the rest of the model time horizon. The transition probabilities were different depending on the treatment arm, and people having dapagliflozin were more likely to remain in the higher KCCQ states. The company used monthly transition count data from DELIVER to obtain transition probabilities between health states. For the months that KCCQ data was unavailable, the company used a last observation carried forward (LOCF) approach. That is, people remained in the same KCCQ quartile until further data showing they had moved to a different health state became available. At the clarification stage, the company noted that LOCF was not used for people whose data was missing at the scheduled assessment, and the data was not imputed in that situation. It noted that the same modelling approach was applied in TA679. The EAG considered that using LOCF is reasonable if it is not used after people in the trial have missed one of the scheduled KCCQ‑TSS measurements, because this could lead to bias. The committee concluded that the company's imputation method was appropriate.\n\n## Modelling of treatment effect on cardiovascular and all-cause mortality\n\nThe company fitted parametric survival curves to all-cause mortality and to cardiovascular-related mortality Kaplan–Meier data from DELIVER, separately. In the company base case, risk equations for all-cause and cardiovascular mortality were adjusted for:\n\ntreatment effect of dapagliflozin\n\nKCCQ‑TSS health state (time-updated covariate)\n\nage\n\nsex\n\nbody mass index\n\nrace\n\nleft ventricular ejection fraction\n\nN-terminal pro-B-type natriuretic peptide (NT‑proBNP)\n\nsystolic blood pressure\n\ntype\xa02 diabetes\n\natrial fibrillation\n\nhistory of hospitalisation for heart failure\n\nheart failure duration. The risk of non-cardiovascular death was applied as the maximum risk of non-cardiovascular death from DELIVER (that is, the difference between all-cause and cardiovascular deaths) or the risk of non-cardiovascular deaths in the general population (whichever was greater). General population risk was calculated by adjusting data in the Office for National Statistics 2017 to 2019 life tables for England and Wales with cardiovascular mortality risk data reported by the World Health Organization. The EAG noted that including KCCQ‑TSS as a predictor of all-cause and cardiovascular mortality generates an indirect survival benefit for dapagliflozin. This is because people having dapagliflozin are more likely to remain in better KCCQ‑TSS states than people having standard care (see section\xa03.15), and therefore would have reduced risk of all-cause or cardiovascular death. The EAG did scenario analyses which assessed the impact of including a direct treatment effect (by including a dapagliflozin treatment effect coefficient in the survival model) and/or an indirect treatment effect (by including a KCCQ‑TSS treatment effect coefficient) of dapagliflozin on cardiovascular and all-cause survival. The EAG did this by setting the dapagliflozin treatment effect coefficient and/or the KCCQ coefficient in the model to zero. The committee noted that it is not methodologically appropriate to remove a coefficient from a risk equation without refitting the equation and adjusting the other coefficients. In its first meeting, the committee considered that it may be appropriate to include a direct and/or indirect treatment effect of dapagliflozin on cardiovascular and all-cause mortality, but noted that the model should be able to replicate the observed trial data (see section\xa03.13). The committee concluded that it would have preferred additional scenarios exploring the impact of a direct and/or indirect treatment effect of dapagliflozin on cardiovascular and all-cause mortality which refitted the survival model when parameters were excluded (for example, coefficient for treatment effect and impact of KCCQ state). After consultation, the company provided 2\xa0scenarios which removed the treatment effect of dapagliflozin from the analysis. The first scenario removed the direct treatment effect of dapagliflozin on all-cause and cardiovascular mortality by removing the dapagliflozin treatment effect coefficient in the survival model. The second removed both the direct and indirect treatment effect of dapagliflozin on all-cause and cardiovascular mortality by also removing the effect of KCCQ state on survival. The company considered these scenarios inappropriate for decision making. It said that because its base case uses the full dataset of cardiovascular and all-cause mortality data from DELIVER, it would provide the most robust method for estimating survival. The company also provided mortality extrapolation plots for each treatment effect scenario compared with Kaplan–Meier data from DELIVER. The committee noted that the scenario that excluded the direct and indirect treatment effect of dapagliflozin on cardiovascular and all-cause mortality was likely pessimistic. The most plausible scenario would include a dapagliflozin treatment effect on all-cause and cardiovascular mortality (see section 3.13), but uncertainty was still present.\n\n## Survival extrapolations\n\nTo model cardiovascular and all-cause survival beyond the observed data in DELIVER, the company used a piecewise modelling approach with an inflection point at 1\xa0year. The company considered DELIVER survival data too complex for a single fully parametric model to be applied and noted that there was a clear separation of the dapagliflozin and placebo curves, beginning at 1\xa0year. Taking into account visual and statistical fit, the company selected the adjusted Weibull model for both cardiovascular and all-cause survival extrapolation for its base case. The company provided scenario analyses using alternative parametric models to extrapolate cardiovascular and all-cause mortality. The EAG raised concerns about the choice of survival curves, noting that the adjusted Gompertz model was the only clinically plausible model for fitting cardiovascular survival data, and that the other models produced optimistic results (that is, underestimated cardiovascular mortality). The EAG considered the adjusted Weibull and Gompertz models to both be clinically plausible for estimating all-cause survival. The company attempted to externally validate its survival extrapolation by comparing it to 2\xa0published studies which reported 5- and 10‑year survival in people with heart failure (Jones et al. ) and Shahim et al. , respectively). For the analyses, it reweighted the baseline characteristics for people having placebo treatment in DELIVER and compared all-cause mortality in this group to the published data. The EAG noted that the validation with Shahim et al. (2021) produced inconsistent results because the Gompertz model fitted best at year\xa05 while the Weibull model fitted best at year\xa010. It also highlighted that neither of the published studies reported data beyond 10\xa0years. The EAG explored a scenario using the Gompertz model for cardiovascular and all-cause mortality, which increased the incremental cost-effectiveness ratio (ICER). In addition, the EAG considered that the company did not provide a clinically plausible rationale for the inflection point and noted that the piecewise approach may have contributed to the poor model fit. It would have preferred the use of a single fully fitted parametric model for extrapolating survival. The committee noted that using the Gompertz model to extrapolate both all-cause and cardiovascular mortality increased the ICER, but it considered that the Gompertz model was likely overly pessimistic. It noted that there is uncertainty about the method used to incorporate treatment effect on survival in the model (see section\xa03.11) but concluded that the company's approach was sufficient for decision making.\n\n## Ability of the model to replicate observed all-cause and cardiovascular survival outcomes\n\nThe committee noted that including a time-updated model covariate and a treatment effect coefficient (see section\xa03.11) is not a standard modelling approach and could affect model validity. While this approach was used in previous NICE appraisals of SGLT2 inhibitors (see TA679 and TA773), it is not commonly used in other disease areas. The committee noted that a multi-state simulation model may have been more appropriate because it considers competing risks and can account for patient history. At its first meeting, the committee noted that survival extrapolations of all-cause and cardiovascular mortality had been provided, but that these were the outputs of the regression analysis, rather than the economic model survival outcomes (including the indirect impact of changes in KCCQ‑TSS state over time). It also noted that a model that does not replicate the trial data to an appropriate level of accuracy would cause considerable uncertainty around the plausibility of the model results. In its response to consultation, the company compared the survival outputs from its base-case model and each treatment effect scenario (see section\xa03.11) with the Kaplan–Meier curve from DELIVER. The EAG provided a numerical comparison of observed mortality data from DELIVER with predicted mortality from the company's base-case model and each treatment effect scenario (see section\xa03.11). The EAG noted that the comparison suggested the model overestimated mortality compared with DELIVER. It raised concerns about the model's prediction of mortality which continually increased over a long-term time horizon. The company noted that the model estimates produced by the EAG did not account for patient censoring (that is, people who were not present for the full study duration) in DELIVER. The committee acknowledged the EAG's and the company's perspectives. It noted that analysis of all-cause mortality would be less affected by censoring because it includes cardiovascular and non-cardiovascular deaths. The committee concluded that the company's base case (which includes direct and indirect treatment effect) and the scenario which only includes an indirect treatment effect were most suitable for decision making.\n\n## Modelling of treatment effect on heart failure events\n\nThe company modelled hospitalisation for heart failure and urgent hospitalisation for heart failure by applying generalised estimating equations to DELIVER data. It derived 2 sets of equations, one fully adjusted for patient characteristics and treatment effect (referred to as adjusted) and another which was only adjusted for treatment effect (referred to as unadjusted). The adjusted model was used in the company's base case. The company's approach assumed a constant risk of hospitalisation for heart failure and did not differentiate between initial and subsequent hospitalisations. The EAG noted that DELIVER data did not convincingly support a benefit of dapagliflozin in reducing urgent hospitalisation for heart failure. At its first meeting, the committee concluded that a comparison of the hospitalisation for heart failure predictions from the economic model (including the impact of changes in KCCQ‑TSS state over time) and the observed data from DELIVER is needed to determine whether the modelling approach was appropriate. After consultation, the company provided further data on heart failure events in DELIVER. The EAG believed this data convincingly shows that dapagliflozin did not substantially reduce urgent hospitalisations for heart failure. So, the EAG excluded a dapagliflozin treatment effect on urgent hospitalisation for heart failure in its base case. The committee noted that the impact from this assumption was small, increasing the ICER by no more than £210 per QALY gained. The committee concluded that a dapagliflozin treatment effect on urgent hospitalisation for heart failure should be excluded.\n\n## Long-term treatment effect\n\nThe company estimated transition probabilities between KCCQ‑TSS quartiles from trial data for 2\xa0time periods. On discontinuation of dapagliflozin, transition probabilities for standard care were used from then onwards. The company and clinical experts said that they would not expect a sustained treatment effect of dapagliflozin after discontinuation. The EAG noted that the model structure results in a sustained treatment effect over time. This is because there is a low probability of moving health states from month\xa05 onwards, and at month 4 a higher percentage of people having dapagliflozin were in higher KCCQ-TSS states. The committee concluded that the model structure may contribute to a sustained treatment effect for dapagliflozin, which may bias the cost-effectiveness results in favour of dapagliflozin.\n\n# Utility values\n\n## Source of utility values and use in the model\n\nEQ‑5D‑5L data collected in DELIVER was mapped to EQ‑5D‑3L and used to derive utility values for each KCCQ‑TSS quartile (see section\xa03.10). The EAG questioned the company's method for deriving utility estimates, noting that an additive approach was used rather than the preferred multiplicative approach outlined in NICE's Decision Support Unit technical support document\xa012. It noted that the mean utility applied for quartile\xa04 (the least severe quartile) in the company's economic model was higher than the general population utility of the same age. Additionally, the EAG highlighted that the company did not include the impact of age on utility because it considered this to be negligible. The EAG highlighted clinical expert opinion which considered it implausible for people with symptomatic heart failure with preserved or mildly reduced ejection fraction to have a better quality of life than the general population of the same age. So, for its base case, the EAG used the multiplicative approach to derive its utility, adjusting for age impact and setting quartile\xa04 utility to equal the general population. After consultation, the company used the EAG's approach for deriving utility estimates in its revised base case. The committee concluded that the EAG's approach for deriving utility estimates is more appropriate.\n\n## Duration of impact of heart failure events on quality of life\n\nThe company used a disutility period of 1\xa0month for heart failure events in its base case; that is, being hospitalised for heart failure would reduce people's quality of life for 1\xa0month. The EAG's clinical experts suggested that the average hospital stay for a heart failure event was about 11\xa0days. It considered that being hospitalised for 1\xa0day would impact quality of life for 1\xa0week, with a maximum duration of impact on quality of life of 6\xa0months after discharge. So, the company did scenario analyses assuming a disutility period of 2.75\xa0months (11\xa0weeks) and 6\xa0months, which improved its cost-effectiveness estimates. The EAG base case used a disutility period of 11\xa0weeks. The clinical experts said that a hospitalisation for heart failure has a substantial impact on quality of life and that for older people a hospital stay can impact on frailty, mobility and risk of falls. They considered that a disutility period of 11\xa0weeks was an underestimate and that heart failure impacted quality of life for around 6\xa0months. After consultation, the company applied a disutility period of 6\xa0months in its revised base case. The committee concluded that it was reasonable to assume that a hospitalisation for heart failure impacted quality of life for 6\xa0months.\n\n# Costs\n\n## Non-elective care costs\n\nThe company estimated the costs of non-elective care, including hospitalisation for heart failure and inpatient care for adverse events, using NHS reference costs from 2020/2021. The EAG noted that the cost of non-elective care was markedly higher in 2020/2021 compared with recent years and considered that COVID‑19 may have influenced the cost. So, the EAG asked the company to provide a scenario in which non-elective inpatient care was costed using NHS reference costs from 2019/2020, inflated to 2020/2021, which increased the cost-effectiveness estimates. The EAG preferred the use of the inflated values and applied this in its base case. After consultation, the EAG provided a sample of NHS reference costs for non-elective care from 2016 to 2021. The EAG noted that costs appear to be inflated for the 2020/2021 period across all areas compared with previous years. The committee concluded that NHS reference costs from 2019/2020 inflated to 2021 values were preferred.\n\n## Resource use estimate for hospitalisation for heart failure events\n\nThe company estimated the acute costs of hospitalisation for heart failure based on NHS reference costs from 2020/2021 for non-elective long inpatient stay. These were calculated as the weighted average of reference costs for healthcare resource group (HRG) codes EB03A to EB03E. The EAG's clinical experts considered that the average length of hospital stay for heart failure was 11\xa0days. The company did not provide data on the average duration of hospital stay in DELIVER, noting that there were regional differences in the clinical trial which could introduce uncertainty. The EAG noted that the company had included more severe cost codes in its weighted average, for example, EB03A is associated with a 53‑day hospital stay. The EAG preferred the scenario using the HRG code EB03E only, which is associated with a 13‑day hospital stay, and used this in its base-case cost-effectiveness estimates. This led to a small increase in the ICER. At the second committee meeting, a clinical expert noted that length of hospital stay can vary and only a very small number of people (below 3%) hospitalised for heart failure are in the group associated with the shorter 13-day hospital stay. They explained that this meant the weighted average approach to costing was more appropriate. The committee acknowledged the clinical expert's opinion and concluded that it is more appropriate to use the weighted average to estimate costs for heart failure hospitalisation.\n\n## Cost of cardiovascular deaths\n\nThe company estimated the cost of cardiovascular death based on a regression analysis presented in Alva et al. (2014) that predicted the added inpatient costs for type\xa02 diabetes complications from a UK cohort. The company used the cost associated with a myocardial infarction, because this was the lowest cost of the available fatal cardiovascular events. This was then inflated to the 2020/2021 cost year to give a cost of £1,763 per cardiovascular event. This approach aligned with TA679. The EAG noted that sudden cardiovascular deaths might be associated with a lower cost per event. But because only a small proportion of people in DELIVER had sudden cardiovascular deaths the EAG used the company's estimate in its base case. The EAG did a scenario analysis using £1,452 as the total cost for cardiovascular deaths, which assumes no cost for sudden cardiovascular deaths. The scenario showed that using the lower cost had negligible impact on the cost-effectiveness estimates. The committee concluded that the EAG's scenario analysis included the most appropriate costs for cardiovascular deaths.\n\n## Estimation of annual GP visits\n\nThe company's model assumed that people with heart failure with preserved or mildly reduced ejection fraction would have a total of 23.14\xa0GP visits or other contacts per year. The company clarified that the number of GP visits or contacts in the model included other primary care visits, but that it had conservatively costed these all as GP visits. The EAG noted that because of fewer treatments being available for this group (see section\xa03.3), about 6\xa0GP or other primary care visits would be expected per year. It asked the company to explore a scenario with 6\xa0GP visits per year, which improved the cost-effectiveness estimates. The committee noted that GPs may not frequently see people with heart failure with preserved or mildly reduced ejection fraction because there are no disease-modifying treatments available for this population (see section\xa03.3). It noted that other healthcare professionals, such as specialist pharmacists and nurses, may also be involved in the care pathway. After consultation, the company's revised base case assumed 6\xa0annual GP or other primary care visits. The committee concluded that 6 primary care visits per year was a reasonable estimate.\n\n# Adverse events\n\n## Inclusion of amputation as an adverse event\n\nThe company's base case included adverse events reported in DELIVER which occurred with a frequency of over 1%. Amputation occurred with a frequency of less than 1% in DELIVER but was also included in the model. The company took this approach because amputation is an adverse event of interest based on the historical link between SGLT2 inhibitors and risk of amputation. The company also noted that a recent meta-analysis on SGLT2 inhibitors and the risk of amputation suggested that this link is not statistically significant. The EAG highlighted that clinical expert opinion suggests that dapagliflozin is not expected to be associated with increased risk of amputation. So, it considered any increased risk of amputation to be confounded by the presence of type\xa02 diabetes. The EAG requested that the company stratify the amputation events in DELIVER based on type\xa02 diabetes status, also noting that in UK clinical practice, people with type\xa02 diabetes are eligible for treatment with dapagliflozin. The EAG noted that the requested analysis did not support the inclusion of amputation in the cost-effectiveness modelling. Given the potential for confounding results, the EAG's preference was to exclude amputation as an adverse event in its base-case assumptions. The committee heard from clinical experts that there is unlikely to be a link between SGLT2 inhibitors and amputation. Patient experts also noted that they were unfamiliar with this risk. After consultation, the company removed amputation as an adverse event from its base case. The committee considered that dapagliflozin was unlikely to be associated with an increased risk of amputation and concluded that amputation should be excluded as an adverse event in the modelling.\n\n## Estimation of adverse event probabilities\n\nThe company derived adverse event probabilities based on data from DELIVER. The EAG noted that the adverse event probabilities used in the company's model were higher than those seen in TA679 and lacked external validity. While it expected some differences in the adverse event probabilities because people in DELIVER were about 5\xa0years older, and therefore had more comorbidities, the size of difference was higher than expected. The company considered that comparing DELIVER and DAPA‑HF (which included people with heart failure with reduced ejection fraction) introduces uncertainty because both trials had different populations and median trial follow-up periods. The EAG considered the adverse event probabilities from DAPA‑HF appeared more generalisable to people with heart failure with preserved or mildly reduced ejection fraction. But, it maintained the company's approach of using adverse event probabilities from DELIVER in its base case because the data is available. The committee acknowledged the concerns raised by the EAG but concluded that adverse events probability estimates from DELIVER should be used.\n\n# Severity\n\nNICE's health technology evaluations manual notes that when considering overall benefits, the committee can consider decision-making modifiers. The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company's absolute (3.31) and proportional (0.40) QALY shortfalls were below the cut-offs required for the severity weighting. So, the company did not consider it appropriate to apply a severity modifier for heart failure with preserved or mildly reduced ejection fraction. The committee agreed with the company's approach not to include a severity modifier in this population.\n\n# Cost-effectiveness estimates\n\n## Company and EAG cost-effectiveness estimates\n\nThe company's revised (after consultation) base-case deterministic ICER was £8,975 per QALY gained. The EAG applied the following assumptions to the company's base case:\n\nnon-elective inpatient costs taken from NHS reference costs 2019/2020 and inflated to the 2020/2021 cost year (see section\xa03.18)\n\nremoval of dapagliflozin treatment effects from urgent heart failure visit event (see section\xa03.14).The company's revised base-case deterministic ICER with the EAG's preferred assumptions was £9,250 per QALY gained. Scenario analyses on the treatment effect of dapagliflozin resulted in ICER estimates of £20,068 per QALY gained (excluding direct treatment effect of dapagliflozin on all-cause and cardiovascular deaths) and £27,665 per QALY gained (assuming no treatment effect of dapagliflozin on all-cause and cardiovascular deaths). The committee considered that assuming dapagliflozin had no effect on cardiovascular and all-cause deaths was likely pessimistic. It preferred scenarios which included a direct and/or an indirect treatment effect on cardiovascular and all-cause deaths.\n\n## Committee's preferred assumptions\n\nThe committee's preferred assumptions were to use the company's revised (after consultation) base-case with the following changes:\n\nweighted average HRG cost codes (EB03A to EB03E) associated with severe and less severe hospitalisation for heart failure (see section\xa03.19)\n\nunit cost for cardiovascular death of £1,452, including cost of sudden cardiovascular death as £0 (see section\xa03.20)\n\nremoval of dapagliflozin treatment effects from urgent heart failure visit event (see section\xa03.14)\n\nnon-elective inpatient costs taken from NHS reference costs 2019/2020 and inflated to the 2020/2021 cost year (see section\xa03.18).The committee considered that there was uncertainty about the treatment effect of dapagliflozin on cardiovascular and all-cause deaths (see section\xa03.11). But, it concluded that the most plausible scenario would include a direct and/or indirect treatment effect on cardiovascular and all-cause mortality (see section\xa03.13).\n\n## Committee cost-effectiveness estimates\n\nThe committee noted that with its preferred assumptions to modelling survival (see section\xa03.26), the cost-effectiveness estimates were below £20,000 per QALY gained. Including only an indirect treatment effect on cardiovascular and all-cause deaths resulted in an ICER of £18,537 per QALY gained. Using the complete model survival data without any exclusion (that is, including both direct and indirect treatment effect on cardiovascular and all-cause deaths) resulted in an ICER of £8,715 per QALY gained.\n\n# Other factors\n\n## Equality issues\n\nThe committee noted that previous NICE technology appraisals in chronic heart failure had identified that people from Black or South Asian family backgrounds may have a higher risk of developing heart failure. In addition, a meta-analysis of data from people with chronic heart failure with reduced ejection fraction (Zannad et al. ) suggested that SGLT2 inhibitors were more effective in people from Black or Asian family backgrounds. The committee noted that the results from DELIVER did not suggest dapagliflozin was more effective at treating chronic heart failure with preserved or mildly reduced ejection fraction in people from Black or Asian family backgrounds. But, it noted that clinical trials were not usually powered to detect differences by family background. The committee concluded that there was not enough evidence to determine whether dapagliflozin was more effective or less effective in people from Black or Asian family backgrounds. The committee noted that its recommendation applied to all people, regardless of family background. The committee concluded that differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal.\n\n## Prescribing setting\n\nNICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team should work in collaboration with the primary care team to start new medicines that need specialist supervision. Dapagliflozin is currently prescribed for heart failure with reduced ejection fraction in primary care, according to the advice of a heart failure specialist. The company noted that socioeconomic deprivation is a strong risk factor for developing heart failure and experiencing adverse heart failure outcomes. The company suggested that inequality in access to specialist care across the UK may contribute to these health inequalities. So, broad prescribing of dapagliflozin in primary and secondary care may reduce health inequalities. Also, the requirement for advice from a heart failure specialist may delay access to treatment and contribute to resource constraints. The patient experts explained that many GPs are not familiar with heart failure with preserved or mildly reduced ejection fraction, because there are currently no disease-modifying treatments available for this population. The committee noted that GPs are experienced in prescribing dapagliflozin for chronic heart failure with reduced ejection fraction and for type\xa02 diabetes. The committee also noted that clinicians have experience in treating chronic heart failure with reduced ejection fraction and type\xa02 diabetes across primary and secondary care. The committee discussed the capacity challenges facing GPs around the diagnosis of heart failure with preserved or mildly reduced ejection fraction, and noted that NICE's guideline on chronic heart failure in adults recommends the measurement of NT‑proBNP in people with suspected heart failure, followed by specialist assessment and transthoracic echocardiography. The committee concluded that dapagliflozin would be started on the advice of a heart failure specialist who can determine the most appropriate treatment.\n\n# Conclusion\n\n## Recommendation\n\nThe committee concluded that when its preferred assumptions are incorporated, dapagliflozin is a cost-effective use of NHS resources. Therefore, the committee recommended dapagliflozin for treating symptomatic chronic heart failure with preserved or mildly reduced ejection fraction."}	https://www.nice.org.uk/guidance/ta902	Evidence-based recommendations on dapagliflozin (Forxiga) for treating chronic heart failure with preserved or mildly reduced ejection fraction in adults.
6ff7f53557e9bd542bac67bc295708cc4d079619	nice	Darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer	Darolutamide with androgen deprivation therapy and docetaxel for treating hormone-sensitive metastatic prostate cancer Evidence-based recommendations on darolutamide (Nubeqa) with androgen deprivation therapy and docetaxel for hormone-sensitive metastatic prostate cancer in adults. # Recommendations Darolutamide with docetaxel is recommended, within its marketing authorisation, as an option for treating hormone-sensitive metastatic prostate cancer in adults. Darolutamide is only recommended if the company provides it according to the commercial arrangement. Why the committee made these recommendations Usual treatment for hormone-sensitive metastatic prostate cancer always includes androgen deprivation therapy (ADT), which may be given alone, or with docetaxel or enzalutamide. Darolutamide plus ADT and docetaxel would be another treatment option. Clinical trial evidence shows that, compared with taking placebo plus ADT and docetaxel, people taking darolutamide plus ADT and docetaxel live longer, and have longer before their cancer gets worse or stops responding to ADT. There is also an indirect comparison comparing darolutamide plus ADT and docetaxel with usual treatment. The results suggest that darolutamide increases how long people live, and how long they have before their cancer gets worse or stops responding to ADT. The cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So, darolutamide is recommended.# Information about darolutamide # Marketing authorisation indication Darolutamide (Nubeqa, Bayer) is indicated for 'the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for darolutamide. # Price The list price of darolutamide is £4,040.00 for a 28‑day supply of 112 tablets, each containing 300 mg (excluding VAT, BNF online accessed March 2023). The company has a commercial arrangement. This makes darolutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Bayer, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Need for treatment options The patient and clinical experts would welcome an additional treatment option for hormone-sensitive metastatic prostate cancer. The patient experts stated that an increasing number of people have metastatic prostate cancer at the initial diagnosis, which is associated with a worse prognosis. They also stated that the approach of adding darolutamide to ADT and docetaxel is new and innovative in prostate cancer. They added that many younger people with hormone-sensitive metastatic prostate cancer would be willing to have darolutamide plus ADT and docetaxel if it meant that they have more years of life in better health. A patient expert explained that, apart from feeling weak for a few days after each docetaxel dose, darolutamide plus ADT and docetaxel was well tolerated and did not otherwise affect usual daily activities. A clinical expert explained that darolutamide plus ADT and docetaxel will be beneficial across the whole patient population. They noted the importance of this treatment for people of Black, African and Caribbean family backgrounds. This was because, depending on the geographical region, there may be more people from these backgrounds, who may have more aggressive disease and so may benefit more. The committee concluded that darolutamide plus ADT and docetaxel would be an important treatment option for people with hormone-sensitive metastatic prostate cancer. # Clinical management ## Treatment pathway The company positioned darolutamide plus ADT and docetaxel in the hormone-sensitive metastatic part of the prostate cancer pathway, where the treatment options include: ADT alone (see NICE's guideline on prostate cancer) docetaxel with ADT (see NICE's guideline on prostate cancer) enzalutamide with ADT (see NICE's technology appraisal guidance on enzalutamide for treating hormone-sensitive metastatic prostate cancer) apalutamide with ADT when docetaxel is unsuitable (see NICE's technology appraisal guidance on apalutamide with ADT for treating hormone-sensitive metastatic prostate cancer).The clinical experts agreed with the treatment options and the positioning of darolutamide plus ADT and docetaxel in the treatment pathway for people with hormone-sensitive metastatic prostate cancer. A clinical expert noted that having darolutamide plus ADT and docetaxel in the hormone-sensitive metastatic stage limits treatment options in the hormone-relapsed metastatic stage. This is because an anti-androgen (apalutamide, darolutamide or enzalutamide) would have already been used in the hormone-sensitive metastatic stage, and NHS practice is to only use an anti-androgen once in the treatment pathway. The clinical expert noted that more people are expected to have an anti-androgen in the hormone-sensitive metastatic stage than in the hormone-relapsed metastatic stage. The clinical expert estimated that between 10% to 15% of people have ADT with docetaxel in the hormone-sensitive metastatic stage. The clinical experts explained that some younger people with hormone-sensitive metastatic prostate cancer may prefer to have ADT with docetaxel rather than an anti-androgen (enzalutamide) because treatment is shorter, unlike the more prolonged treatment with an anti-androgen. Some reasons people may not have enzalutamide are contraindications, drug–drug interactions, epilepsy, or intolerance to or toxicity of an anti-androgen. A clinical expert added that improved progression-free survival is valuable to people because of the difficult consequences of progression to the hormone-relapsed disease stage. NHS England's clinical lead for the Cancer Drugs Fund stated that in national clinical practice, 50% of anti-androgen use is in the hormone-sensitive setting, and 50% is in the hormone-relapsed setting. In addition, 85% to 90% of people having enzalutamide are eligible to have chemotherapy, but around 1.0% to 1.5% of people have chemotherapy followed by ADT with enzalutamide. The clinical expert explained that 50% of people having an anti-androgen in the hormone-relapsed setting is a legacy effect of introducing anti-androgens earlier in the treatment pathway during COVID, so is expected to decrease over time, in addition to general changes to the treatment pathway over time. The committee concluded that darolutamide plus ADT and docetaxel is positioned appropriately in the treatment pathway. ## Comparators The NICE scope for this evaluation lists ADT alone, ADT with docetaxel, and ADT with enzalutamide as comparators for darolutamide plus ADT and docetaxel. The clinical experts agreed with the company and EAG that monotherapy with bicalutamide (a standard non-steroidal anti-androgen, a component of ADT) is not a relevant comparator because it is not used in standard care. Additionally, apalutamide with ADT is not a relevant comparator because it is only recommended by NICE as an option for treating hormone-sensitive metastatic prostate cancer if docetaxel is not suitable. Abiraterone with ADT is not a relevant comparator because it is not recommended by NICE. The committee concluded that ADT alone, ADT with docetaxel, and ADT with enzalutamide are all relevant comparators, but that most people have ADT with enzalutamide (see section 3.2). ## Subgroups The NICE scope included high-risk and newly diagnosed metastatic prostate cancer as subgroups. But the company noted that these definitions were used inconsistently in the hormone-sensitive metastatic prostate cancer trials. After technical engagement, the company presented comparative efficacy estimates for overall survival and time to 'castration-resistant prostate cancer or death' (CROD), representing progression-free survival, for darolutamide plus ADT and docetaxel compared with placebo plus ADT and docetaxel, for: the intention-to-treat population the population with metastatic disease at diagnosis the population with high-risk disease. The effectiveness of darolutamide was similar across the intention-to-treat population and subgroups. But the subgroups were not included in the network meta-analysis (see section 3.8) or model (see section 3.12) because of limited data and inconsistencies across the network. The EAG agreed with the company's reasoning. The clinical experts explained that a different benefit would not be expected for the different subgroups. The committee concluded that it was appropriate to consider the effectiveness of darolutamide plus ADT and docetaxel for the whole marketing authorisation population. # Clinical evidence ## ARASENS trial generalisability The clinical-effectiveness evidence for darolutamide plus ADT and docetaxel compared with ADT and docetaxel was from the ARASENS trial. This was an international, phase 3, double-blind, placebo-controlled, randomised controlled trial in metastatic hormone-sensitive prostate cancer. It compared darolutamide plus ADT and docetaxel, and placebo plus ADT and docetaxel. There were 1,306 adults enrolled in the intention-to-treat population, and 29 of these were from the UK across 8 centres. The trial grouped people according to: extent of disease alkaline phosphatase level.The ARASENS trial design included an active follow up, in which assessments were done every 12 weeks for up to 1 year, and a long-term survival follow up, in which assessments were done until the end of the study. After treatment was stopped, people could either end the study with no follow up, enter the active follow up and subsequently the long-term survival follow up, or enter directly from stopping treatment to the long-term survival follow up. The EAG noted that most people in the trial had metastatic disease at baseline diagnosis. The clinical experts agreed that the high percentage of people with metastatic disease at diagnosis was generalisable to the NHS population in which double or triple treatment regimens such as darolutamide would be considered. They noted that the proportion of people with metastatic disease at diagnosis was consistent with other trials in hormone-sensitive metastatic prostate cancer (ARCHES and TITAN). The EAG also noted that most of the people in the trial had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0, which is associated with better prognosis and outcomes, but at the same time, most people in the trial had metastatic disease at diagnosis, which is associated with worse prognosis and outcomes than hormone-sensitive metastatic prostate cancer that has progressed after localised disease. The clinical experts explained high numbers of people with an ECOG PS score of 0 in the trial was expected, because a clinical judgement is made to ensure chemotherapy is safe and appropriate. The EAG noted that there were fewer people of Black or African American family background (who tend to have worse outcomes, see section 3.1) in the trial than in NHS clinical practice. The clinical experts explained that the demographics are applicable to the overall NHS population, but noted that some geographical areas where there are more diverse populations may be under-represented. The committee concluded that overall, ARASENS is generalisable to NHS clinical practice. # Clinical effectiveness ## Overall survival benefit with darolutamide The primary outcome in ARASENS was overall survival. The company presented results that showed a treatment benefit of darolutamide compared with placebo (hazard ratio 0.68, 95% confidence interval 0.57 to 0.80). The company did not adjust the overall survival results for subsequent treatments with a second anti-androgen, which was possible in the ARASENS trial but not in clinical practice. But the EAG and clinical experts agreed that a second anti-androgen is unlikely to have a clinical benefit. The committee noted that overall survival results from ARASENS suggests a treatment benefit of darolutamide plus ADT and docetaxel compared with placebo plus ADT and docetaxel. ## Time to CROD as a proxy for progression-free survival Progression-free survival was measured through the composite outcome time to CROD. There was a treatment benefit of darolutamide compared with placebo (the company considers the exact numbers to be confidential, so they cannot be reported here). Time to CROD was defined as the time from randomisation to a 'castration-resistant prostate cancer event' (either radiological, or biochemical with prostate-specific antigen progression) or death. This outcome was used as a proxy for progression-free survival in the economic model (see section 3.12). Time to developing hormone-relapsed prostate cancer (a synonym for castration-resistant prostate cancer) was a secondary endpoint in the ARASENS trial. The company explained that this better reflects clinical practice than radiographic progression-free survival, which is measured on a fixed schedule. Imaging for time to developing hormone-relapsed prostate cancer was done yearly after the end of docetaxel treatment, or at the investigator's discretion in response to clinical factors (for example, prostate-specific antigen progression, symptomatic progressive disease, or a change of antineoplastic therapy). The EAG agreed that time to developing hormone-relapsed prostate cancer was an appropriate outcome, and time to CROD was an appropriate proxy for progression-free survival in the model. The clinical experts explained that time to CROD may be more clinically relevant, because imaging was done based on clinically relevant events such as increasing prostate-specific antigen levels, rather than at set intervals for radiological progression-free survival, so it may be possible to detect progression earlier. The committee noted that it was important to consider how similar or different time to CROD was to radiological progression-free survival, but the company did not have any data on this comparison because ARASENS was not designed to measure radiological progression-free survival at set intervals. The committee acknowledged the heterogeneity in the definitions of progression-free survival across studies of hormone-sensitive metastatic prostate cancer. It agreed that time to CROD was an appropriate outcome to use for decision making, and that the results suggested a treatment benefit of darolutamide plus ADT and docetaxel compared with placebo plus ADT and docetaxel. # Indirect treatment comparison ## Studies included in the network meta-analysis The company's network meta-analysis indirectly compared darolutamide plus ADT and docetaxel with its comparators (see section 3.3). It included 6 trials and produced a network of: darolutamide plus ADT and docetaxel compared with placebo plus ADT and docetaxel (ARASENS) enzalutamide plus ADT compared with ADT alone (ARCHES) docetaxel plus ADT compared with ADT alone (CHAARTED; GETUG‑AFU15) abiraterone plus prednisolone and ADT compared with ADT alone (LATITUDE; STAMPEDE‑2) docetaxel plus ADT compared with ADT alone (STAMPEDE‑3) abiraterone plus ADT compared with ADT alone (STAMPEDE‑4).Although abiraterone was not a relevant comparator (because is not recommended by NICE), it provided a source of indirect evidence. The company did not find any statistically significant inconsistencies between the direct and indirect evidence in the network. The EAG's scenario analysis removed abiraterone from the network meta-analysis and assumed STAMPEDE‑4 was a subset of STAMPEDE‑2 and STAMPEDE‑3, rather than separate trials, because the populations may have overlapped. The committee considered it appropriate to explore the impact on the cost effectiveness of removing abiraterone from the network. A further analysis by the EAG on the individual residual deviance for each trial in the network suggested that STAMPEDE‑4 contributed more to the total residual deviance than the other trials, and that there was inconsistency in the network. The committee noted that the definitions of progression-free survival used across the trials differed. The base-case network meta-analysis used time to CROD (ARASENS), and the closest matching definitions from the other trials (time to clinical progression , radiological progression-free survival , and failure-free survival ) were used. The company also did an alternative network meta-analysis, in which the progression-free survival definition did not need to include death. This was to explore the uncertainty of the different progression-free survival definitions. Here, time to developing hormone-relapsed prostate cancer was used as a measure for progression-free survival in ARASENS, and the closest matching definition was used from the other trials. The company stated that using the alternative definition of progression had only a limited impact on the results. In terms of baseline characteristics across the populations included in the trials, 17.8% of people in the ARCHES trial had had docetaxel previously. But the company used the hazard ratio for the overall population because it was similar to that of the group who did not have previous docetaxel. Comparing the baseline characteristics across the studies included in the network suggested similarities across the trials in terms of age, ECOG PS score, Gleason score and prostate-specific antigen level. But there were proportionally more people with stage 4 prostate cancer in ARASENS than in the other trials. The company's subgroup analysis using data from ARASENS did not show that age, ECOG PS score, Gleason score, prostate-specific antigen level or prostate cancer stage were treatment-effect modifiers for overall survival because they had overlapping confidence intervals. The committee acknowledged that subgroup analyses would be unlikely to be appropriately powered to detect differences in potential treatment-effect modifiers. But it concluded that the studies included in the company's network meta-analysis were appropriate for decision making, but there was uncertainty about the consistency between the direct and indirect evidence included. ## Types of network meta-analysis In its base case, the company used a fixed-effects network meta-analysis, assuming no heterogeneity between studies, to model overall survival. The fixed-effects network meta-analysis for overall survival had a lower deviance information criterion score than the random-effects model, indicating a better model fit. The company used a random-effects network meta-analysis for progression-free survival because of potential heterogeneity from the different outcome definitions used across the studies (see section 3.8). The random-effects network meta-analysis for progression-free survival had a lower deviance information criterion score than the fixed-effects model, indicating a better model fit. The committee concluded that the network meta-analysis was appropriate for decision making. ## Treatment switching in the network meta-analysis The ARCHES and LATITUDE trials in the network meta-analysis allowed treatment switching after the primary data analysis and unblinding. In the ARCHES trial, treatment switching from placebo to the intervention arm was 31%, and in the LATITUDE trials it was 12%. The company did not adjust for treatment switching. It considered that adjusted hazard ratios may not reflect clinical practice because they would assume people in the control arm did not subsequently have an anti-androgen. But unadjusted hazard ratios may not reflect clinical practice if people have an anti-androgen earlier than they would in clinical practice, because treatment switching was after unblinding rather than disease progression. The EAG did a scenario analysis that adjusted the hazard ratios for treatment switching. This suggested an improved treatment effect for enzalutamide (ARCHES) and abiraterone (LATITUDE) compared with darolutamide plus ADT and docetaxel (the exact numbers are confidential and cannot be reported here). The EAG noted that because there was treatment switching in the comparator trials, using unadjusted hazard ratios may mean that the relative treatment effect of darolutamide plus ADT and docetaxel was overestimated. So, it suggested that separately adjusting for treatment switching in ARCHES and LATITUDE may be appropriate. The company argued that adjusted hazard ratios may underestimate the treatment efficacy of darolutamide, because after adjustment, the proportion of subsequent treatment with a first anti-androgen was disproportionally greater in ARASENS compared with the unadjusted hazard ratios. This would favour the comparators (enzalutamide and abiraterone) because of a greater impact on survival for the placebo arm from having a first anti-androgen. The committee acknowledged that using unadjusted hazard ratios may better reflect clinical practice because people in the placebo arm would subsequently have a first anti-androgen, and a second anti-androgen is not likely to add clinical benefit. The committee concluded that unadjusted hazard ratios may better reflect clinical practice, and so would be appropriate to use in the model. ## Progression-free survival estimates for comparators in the network meta-analysis The latest progression-free survival estimates from ARCHES and STAMPEDE‑2 were not available for the company's original submission. At technical engagement the company updated its network meta-analysis with the most recent radiological progression-free survival estimates from ARCHES and failure-free survival estimates from STAMPEDE‑2, and applied these to progression-free survival and time-on-treatment because the hazard ratios in the model were interdependent. It noted that the updated results from ARCHES were consistent with overall survival in the network meta-analysis, and it closely matched the ARASENS follow up. The EAG did not use the updated progression-free survival estimates in its base case because of unexplained notable differences in the hazard ratios (HR 0.63 ) compared with the original estimate (HR 0.39 ). It noted that the original radiological progression-free survival estimate from ARCHES used centralised independent review, whereas the updated radiological progression-free survival estimate used investigator assessment. The EAG added that the difference in assessment method may explain the difference in hazard ratios, but that the centralised assessment is usually conservative. A clinical expert said that a greater treatment effect using centralised assessments was plausible because it was driven by meeting the Response Evaluation Criteria In Solid Tumours (RECIST) criteria, so people would be more likely to continue the trial treatment. A clinical expert added that conventional imaging (that is, CT or bone scans) tend to show progression later than indicators such as prostate-specific antigen levels. The clinical experts explained that individual investigator assessments reflect decision making in NHS clinical practice. But it was unclear to the committee whether the investigators were blinded for either the centralised assessment or investigator assessment. On balance, the committee noted a general preference for more mature data, where available, and it preferred to use the latest progression-free survival estimates from ARCHES and STAMPEDE‑2. # Economic model ## Company model In its submission, the company presented a 3‑state partitioned survival model to estimate the cost effectiveness of darolutamide plus ADT and docetaxel compared with enzalutamide plus ADT, ADT plus docetaxel, and ADT alone, for adults with hormone-sensitive metastatic prostate cancer who can have chemotherapy. The 3 health states were pre-progression (hormone-sensitive metastatic prostate cancer), post-progression (hormone-relapsed metastatic prostate cancer), and death. In the pre-progression health state, people could be on or off treatment (ADT only), and post-progression, people could have up to 3 lines of treatment. Darolutamide and enzalutamide continued until disease progression or unacceptable toxicity; docetaxel continued for 6 cycles; and ADT continued indefinitely as a background therapy. The model cycle was 28 days, with a half-cycle correction, and had a 34‑year lifetime time horizon. Overall survival and time to CROD from the ARASENS trial were included in the network meta-analysis. The efficacy of darolutamide plus ADT and docetaxel, and the comparator treatments (enzalutamide with ADT, and ADT alone) were derived by applying the network meta-analysis hazard ratios to extrapolated docetaxel data. The efficacy of docetaxel with ADT was from ARASENS. The committee noted that the quality-adjusted life years (QALYs) were accrued from people living longer, with a better quality of life from delayed progression to the hormone-relapsed metastatic prostate cancer state. The committee concluded that the model was suitable for decision making. ## Overall survival and progression-free survival extrapolations In its original submission, the company modelled overall survival using a log-normal distribution. It compared the extrapolations to the CHAARTED and STAMPEDE‑3 (considered more representative of NHS clinical practice) survival estimates over 9 years for docetaxel. After technical engagement, the company aligned with the EAG's preference of using a log-logistic distribution. This was because clinical advice to the EAG suggested that the overall survival estimates for darolutamide over 30 years were optimistic. The log-logistic distribution fitted the observed overall survival data from ARASENS and STAMPEDE‑3 and was more conservative than the log-normal distribution. The company modelled time to CROD using the generalised gamma distribution in its original submission, but after technical engagement, updated this to align with the EAG's choice of the log-normal distribution to account for potential optimistic predictions. The committee had concerns about the clinical plausibility of the overall and progression-free survival estimates for darolutamide plus ADT and docetaxel and its comparators extrapolated over 30 years. After the committee meeting, the clinical experts agreed that for overall survival and time to CROD, the estimates up to 10 years were consistent with evidence from the STAMPEDE‑3 trial. Beyond this, the progression-free survival estimates were above the level expected in clinical practice. The clinical experts added that it is unlikely that people would be progression free over 20 and 30 years. For the time-on-treatment extrapolation, the clinical experts agreed more people were on treatment at 20 years than would be expected in clinical practice. The committee concluded that the optimistic extrapolations for darolutamide and the comparators added to the uncertainties. # Health-related quality of life ## Docetaxel disutility The ARASENS trial did not collect EQ‑5D data, so the company used the EAG's preferred utilities from NICE's technology appraisal guidance on enzalutamide. These utilities were from the ARCHES and AFFIRM trials and included all the relevant comparators for darolutamide plus ADT and docetaxel. The EAG preferred to add a 0.02 disutility for docetaxel use for 6 months. This was in line with NICE's technology appraisal guidance on apalutamide, in which a 0.02 disutility was added for 12 months, because a generally lower health-related quality of life is expected. After technical engagement, the company used a 0.02 disutility for docetaxel for 6 months, and also adjusted the disutility to account for the proportion of people alive during the 6 months. The EAG noted that the company's additional adjustment had a negligible impact on the cost-effectiveness estimates. The committee concluded that the utility values used by the company and EAG were appropriate for decision making. # Treatment-effect waning ## Darolutamide plus ADT and docetaxel treatment effect over time The committee wanted to explore whether, on a population level, the benefit of treatment with darolutamide is likely to stay the same or change over time. The company did not explore treatment-effect waning for darolutamide plus ADT and docetaxel, but previous NICE technology appraisal guidance explored treatment-effect waning in scenarios (NICE's technology appraisal guidance on abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer, apalutamide and enzalutamide). The clinical experts questioned the clinical plausibility of treatment-effect waning and noted that because ARASENS was a more mature trial with longer follow up, and the comparator included docetaxel, minimal treatment-effect waning would be expected. The clinical lead for the Cancer Drugs Fund highlighted that, because darolutamide is continued until disease progression rather than for a fixed period of time, any waning is likely to be captured in the modelling. The company added that there was less uncertainty in the survival extrapolations in its model because ARASENS was a more mature trial, and the general population mortality eventually merged. In addition, time spent in the hormone-relapsed metastatic prostate cancer setting was lower in the intervention arm, which could have been because of fewer treatment options being available at this stage. The committee acknowledged that the model and its extrapolations may already capture a gradual loss in treatment effect at an individual level. But it also agreed that scenarios exploring further impacts on treatment effect in the extrapolated part of the model would be useful to explore the extent to which the cost-effectiveness estimates depend on the assumption of constant treatment benefit. The committee concluded that the potential impact of treatment-effect waning was not known and added to the uncertainties. # Cost-effectiveness estimates ## Company and EAG cost-effectiveness estimates NICE's guide to the methods of health technology evaluation notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, decisions about the acceptability of a technology as an effective use of NHS resources will specifically consider the degree of uncertainty around the ICER, and aspects that relate to uncaptured benefits and non-health factors. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the confidential commercial arrangements for darolutamide, its comparators, and other treatments after progression, the cost-effectiveness estimates cannot be reported here. The committee noted that the main differences in the company and EAG modelling was around modelling docetaxel disutility, and the latest data source for progression-free survival from ARCHES and STAMPEDE‑2. It concluded that: adjusting docetaxel disutility for the proportion of people alive during 6 months (see section 3.14) had a negligible impact on the ICER, but the company's modelling approach was appropriate it preferred the latest progression-free survival estimates from ARCHES and STAMPEDE‑2, but the reason for the large difference in treatment effectiveness between the interim and final assessments was uncertain.The committee also noted the uncertainty in the cost-effectiveness results around: the impact of removing abiraterone from the network meta-analysis the potential impact of treatment-effect waning the clinical plausibility of modelled overall and progression-free survival estimates. ## Acceptable ICER The committee considered that a maximum acceptable ICER would be close to £20,000 per QALY gained, to take into account the impact of the uncertainties in the clinical plausibility of the modelled overall and progression-free survival, and the unknown impact of treatment-effect waning. Because of the confidential discounts, the cost-effectiveness results cannot be reported here. Applying confidential discounts for darolutamide plus ADT and docetaxel, its comparators and other treatments after progression, and considering its preferences, the committee noted that the cost-effectiveness estimates were within the maximum acceptable ICER range. That is, it considered darolutamide plus ADT and docetaxel to be an acceptable use of NHS resources. So, the committee recommended it for routine use in the NHS. # Other factors ## Equality issues The committee noted that people from Black, African and Caribbean family backgrounds are more likely to have an aggressive form of hormone-sensitive metastatic prostate cancer. But it concluded that its recommendation for darolutamide plus ADT and docetaxel would not have an effect on people protected by equality legislation different from the effect on the wider population. ## Severity The company did not consider that the severity weighting applied in this appraisal, and NICE's advice about conditions with a high degree of severity did not apply. ## Innovation The committee considered if darolutamide plus ADT and docetaxel was innovative. It did not identify any additional benefits not captured in the economic modelling. So, it concluded that all additional benefits of darolutamide plus ADT and docetaxel had already been taken into account. # Conclusion ## Recommendation The committee agreed that its preferred cost-effectiveness estimates for darolutamide plus ADT and docetaxel were within the range considered an acceptable use of NHS resources. So, the committee concluded that it is recommended for treating hormone-sensitive metastatic prostate cancer.	{'Recommendations': 'Darolutamide with docetaxel is recommended, within its marketing authorisation, as an option for treating hormone-sensitive metastatic prostate cancer in adults. Darolutamide is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nUsual treatment for hormone-sensitive metastatic prostate cancer always includes androgen deprivation therapy (ADT), which may be given alone, or with docetaxel or enzalutamide. Darolutamide plus ADT and docetaxel would be another treatment option.\n\nClinical trial evidence shows that, compared with taking placebo plus ADT and docetaxel, people taking darolutamide plus ADT and docetaxel live longer, and have longer before their cancer gets worse or stops responding to ADT. There is also an indirect comparison comparing darolutamide plus ADT and docetaxel with usual treatment. The results suggest that darolutamide increases how long people live, and how long they have before their cancer gets worse or stops responding to ADT.\n\nThe cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So, darolutamide is recommended.', 'Information about darolutamide': "# Marketing authorisation indication\n\nDarolutamide (Nubeqa, Bayer) is indicated for 'the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for darolutamide.\n\n# Price\n\nThe list price of darolutamide is £4,040.00 for a 28‑day supply of 112\xa0tablets, each containing 300\xa0mg (excluding VAT, BNF online accessed March 2023).\n\nThe company has a commercial arrangement. This makes darolutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Bayer, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Need for treatment options\n\nThe patient and clinical experts would welcome an additional treatment option for hormone-sensitive metastatic prostate cancer. The patient experts stated that an increasing number of people have metastatic prostate cancer at the initial diagnosis, which is associated with a worse prognosis. They also stated that the approach of adding darolutamide to ADT and docetaxel is new and innovative in prostate cancer. They added that many younger people with hormone-sensitive metastatic prostate cancer would be willing to have darolutamide plus ADT and docetaxel if it meant that they have more years of life in better health. A patient expert explained that, apart from feeling weak for a few days after each docetaxel dose, darolutamide plus ADT and docetaxel was well tolerated and did not otherwise affect usual daily activities. A clinical expert explained that darolutamide plus ADT and docetaxel will be beneficial across the whole patient population. They noted the importance of this treatment for people of Black, African and Caribbean family backgrounds. This was because, depending on the geographical region, there may be more people from these backgrounds, who may have more aggressive disease and so may benefit more. The committee concluded that darolutamide plus ADT and docetaxel would be an important treatment option for people with hormone-sensitive metastatic prostate cancer.\n\n# Clinical management\n\n## Treatment pathway\n\nThe company positioned darolutamide plus ADT and docetaxel in the hormone-sensitive metastatic part of the prostate cancer pathway, where the treatment options include:\n\nADT alone (see NICE's guideline on prostate cancer)\n\ndocetaxel with ADT (see NICE's guideline on prostate cancer)\n\nenzalutamide with ADT (see NICE's technology appraisal guidance on enzalutamide for treating hormone-sensitive metastatic prostate cancer)\n\napalutamide with ADT when docetaxel is unsuitable (see NICE's technology appraisal guidance on apalutamide with ADT for treating hormone-sensitive metastatic prostate cancer).The clinical experts agreed with the treatment options and the positioning of darolutamide plus ADT and docetaxel in the treatment pathway for people with hormone-sensitive metastatic prostate cancer. A clinical expert noted that having darolutamide plus ADT and docetaxel in the hormone-sensitive metastatic stage limits treatment options in the hormone-relapsed metastatic stage. This is because an anti-androgen (apalutamide, darolutamide or enzalutamide) would have already been used in the hormone-sensitive metastatic stage, and NHS practice is to only use an anti-androgen once in the treatment pathway. The clinical expert noted that more people are expected to have an anti-androgen in the hormone-sensitive metastatic stage than in the hormone-relapsed metastatic stage. The clinical expert estimated that between 10% to 15% of people have ADT with docetaxel in the hormone-sensitive metastatic stage. The clinical experts explained that some younger people with hormone-sensitive metastatic prostate cancer may prefer to have ADT with docetaxel rather than an anti-androgen (enzalutamide) because treatment is shorter, unlike the more prolonged treatment with an anti-androgen. Some reasons people may not have enzalutamide are contraindications, drug–drug interactions, epilepsy, or intolerance to or toxicity of an anti-androgen. A clinical expert added that improved progression-free survival is valuable to people because of the difficult consequences of progression to the hormone-relapsed disease stage. NHS England's clinical lead for the Cancer Drugs Fund stated that in national clinical practice, 50% of anti-androgen use is in the hormone-sensitive setting, and 50% is in the hormone-relapsed setting. In addition, 85% to 90% of people having enzalutamide are eligible to have chemotherapy, but around 1.0% to 1.5% of people have chemotherapy followed by ADT with enzalutamide. The clinical expert explained that 50% of people having an anti-androgen in the hormone-relapsed setting is a legacy effect of introducing anti-androgens earlier in the treatment pathway during COVID, so is expected to decrease over time, in addition to general changes to the treatment pathway over time. The committee concluded that darolutamide plus ADT and docetaxel is positioned appropriately in the treatment pathway.\n\n## Comparators\n\nThe NICE scope for this evaluation lists ADT alone, ADT with docetaxel, and ADT with enzalutamide as comparators for darolutamide plus ADT and docetaxel. The clinical experts agreed with the company and EAG that monotherapy with bicalutamide (a standard non-steroidal anti-androgen, a component of ADT) is not a relevant comparator because it is not used in standard care. Additionally, apalutamide with ADT is not a relevant comparator because it is only recommended by NICE as an option for treating hormone-sensitive metastatic prostate cancer if docetaxel is not suitable. Abiraterone with ADT is not a relevant comparator because it is not recommended by NICE. The committee concluded that ADT alone, ADT with docetaxel, and ADT with enzalutamide are all relevant comparators, but that most people have ADT with enzalutamide (see section\xa03.2).\n\n## Subgroups\n\nThe NICE scope included high-risk and newly diagnosed metastatic prostate cancer as subgroups. But the company noted that these definitions were used inconsistently in the hormone-sensitive metastatic prostate cancer trials. After technical engagement, the company presented comparative efficacy estimates for overall survival and time to 'castration-resistant prostate cancer or death' (CROD), representing progression-free survival, for darolutamide plus ADT and docetaxel compared with placebo plus ADT and docetaxel, for:\n\nthe intention-to-treat population\n\nthe population with metastatic disease at diagnosis\n\nthe population with high-risk disease. The effectiveness of darolutamide was similar across the intention-to-treat population and subgroups. But the subgroups were not included in the network meta-analysis (see section\xa03.8) or model (see section\xa03.12) because of limited data and inconsistencies across the network. The EAG agreed with the company's reasoning. The clinical experts explained that a different benefit would not be expected for the different subgroups. The committee concluded that it was appropriate to consider the effectiveness of darolutamide plus ADT and docetaxel for the whole marketing authorisation population.\n\n# Clinical evidence\n\n## ARASENS trial generalisability\n\nThe clinical-effectiveness evidence for darolutamide plus ADT and docetaxel compared with ADT and docetaxel was from the ARASENS trial. This was an international, phase\xa03, double-blind, placebo-controlled, randomised controlled trial in metastatic hormone-sensitive prostate cancer. It compared darolutamide plus ADT and docetaxel, and placebo plus ADT and docetaxel. There were 1,306\xa0adults enrolled in the intention-to-treat population, and 29\xa0of these were from the UK across 8\xa0centres. The trial grouped people according to:\n\nextent of disease\n\nalkaline phosphatase level.The ARASENS trial design included an active follow\xa0up, in which assessments were done every 12\xa0weeks for up to 1\xa0year, and a long-term survival follow up, in which assessments were done until the end of the study. After treatment was stopped, people could either end the study with no follow\xa0up, enter the active follow\xa0up and subsequently the long-term survival follow\xa0up, or enter directly from stopping treatment to the long-term survival follow\xa0up. The EAG noted that most people in the trial had metastatic disease at baseline diagnosis. The clinical experts agreed that the high percentage of people with metastatic disease at diagnosis was generalisable to the NHS population in which double or triple treatment regimens such as darolutamide would be considered. They noted that the proportion of people with metastatic disease at diagnosis was consistent with other trials in hormone-sensitive metastatic prostate cancer (ARCHES and TITAN). The EAG also noted that most of the people in the trial had an Eastern Cooperative Oncology Group performance status (ECOG\xa0PS) score of 0, which is associated with better prognosis and outcomes, but at the same time, most people in the trial had metastatic disease at diagnosis, which is associated with worse prognosis and outcomes than hormone-sensitive metastatic prostate cancer that has progressed after localised disease. The clinical experts explained high numbers of people with an ECOG\xa0PS score of 0 in the trial was expected, because a clinical judgement is made to ensure chemotherapy is safe and appropriate. The EAG noted that there were fewer people of Black or African American family background (who tend to have worse outcomes, see section\xa03.1) in the trial than in NHS clinical practice. The clinical experts explained that the demographics are applicable to the overall NHS population, but noted that some geographical areas where there are more diverse populations may be under-represented. The committee concluded that overall, ARASENS is generalisable to NHS clinical practice.\n\n# Clinical effectiveness\n\n## Overall survival benefit with darolutamide\n\nThe primary outcome in ARASENS was overall survival. The company presented results that showed a treatment benefit of darolutamide compared with placebo (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.57 to 0.80). The company did not adjust the overall survival results for subsequent treatments with a second anti-androgen, which was possible in the ARASENS trial but not in clinical practice. But the EAG and clinical experts agreed that a second anti-androgen is unlikely to have a clinical benefit. The committee noted that overall survival results from ARASENS suggests a treatment benefit of darolutamide plus ADT and docetaxel compared with placebo plus ADT and docetaxel.\n\n## Time to CROD as a proxy for progression-free survival\n\nProgression-free survival was measured through the composite outcome time to CROD. There was a treatment benefit of darolutamide compared with placebo (the company considers the exact numbers to be confidential, so they cannot be reported here). Time to CROD was defined as the time from randomisation to a 'castration-resistant prostate cancer event' (either radiological, or biochemical with prostate-specific antigen progression) or death. This outcome was used as a proxy for progression-free survival in the economic model (see section\xa03.12). Time to developing hormone-relapsed prostate cancer (a synonym for castration-resistant prostate cancer) was a secondary endpoint in the ARASENS trial. The company explained that this better reflects clinical practice than radiographic progression-free survival, which is measured on a fixed schedule. Imaging for time to developing hormone-relapsed prostate cancer was done yearly after the end of docetaxel treatment, or at the investigator's discretion in response to clinical factors (for example, prostate-specific antigen progression, symptomatic progressive disease, or a change of antineoplastic therapy). The EAG agreed that time to developing hormone-relapsed prostate cancer was an appropriate outcome, and time to CROD was an appropriate proxy for progression-free survival in the model. The clinical experts explained that time to CROD may be more clinically relevant, because imaging was done based on clinically relevant events such as increasing prostate-specific antigen levels, rather than at set intervals for radiological progression-free survival, so it may be possible to detect progression earlier. The committee noted that it was important to consider how similar or different time to CROD was to radiological progression-free survival, but the company did not have any data on this comparison because ARASENS was not designed to measure radiological progression-free survival at set intervals. The committee acknowledged the heterogeneity in the definitions of progression-free survival across studies of hormone-sensitive metastatic prostate cancer. It agreed that time to CROD was an appropriate outcome to use for decision making, and that the results suggested a treatment benefit of darolutamide plus ADT and docetaxel compared with placebo plus ADT and docetaxel.\n\n# Indirect treatment comparison\n\n## Studies included in the network meta-analysis\n\nThe company's network meta-analysis indirectly compared darolutamide plus ADT and docetaxel with its comparators (see section\xa03.3). It included 6 trials and produced a network of:\n\ndarolutamide plus ADT and docetaxel compared with placebo plus ADT and docetaxel (ARASENS)\n\nenzalutamide plus ADT compared with ADT alone (ARCHES)\n\ndocetaxel plus ADT compared with ADT alone (CHAARTED; GETUG‑AFU15)\n\nabiraterone plus prednisolone and ADT compared with ADT alone (LATITUDE; STAMPEDE‑2)\n\ndocetaxel plus ADT compared with ADT alone (STAMPEDE‑3)\n\nabiraterone plus ADT compared with ADT alone (STAMPEDE‑4).Although abiraterone was not a relevant comparator (because is not recommended by NICE), it provided a source of indirect evidence. The company did not find any statistically significant inconsistencies between the direct and indirect evidence in the network. The EAG's scenario analysis removed abiraterone from the network meta-analysis and assumed STAMPEDE‑4 was a subset of STAMPEDE‑2 and STAMPEDE‑3, rather than separate trials, because the populations may have overlapped. The committee considered it appropriate to explore the impact on the cost effectiveness of removing abiraterone from the network. A further analysis by the EAG on the individual residual deviance for each trial in the network suggested that STAMPEDE‑4 contributed more to the total residual deviance than the other trials, and that there was inconsistency in the network. The committee noted that the definitions of progression-free survival used across the trials differed. The base-case network meta-analysis used time to CROD (ARASENS), and the closest matching definitions from the other trials (time to clinical progression [CHAARTRED], radiological progression-free survival [ARCHES, GETUG‑AFU15, LATITUDE], and failure-free survival [STAMPEDE‑2, STAMPEDE‑3, STAMPEDE‑4]) were used. The company also did an alternative network meta-analysis, in which the progression-free survival definition did not need to include death. This was to explore the uncertainty of the different progression-free survival definitions. Here, time to developing hormone-relapsed prostate cancer was used as a measure for progression-free survival in ARASENS, and the closest matching definition was used from the other trials. The company stated that using the alternative definition of progression had only a limited impact on the results. In terms of baseline characteristics across the populations included in the trials, 17.8% of people in the ARCHES trial had had docetaxel previously. But the company used the hazard ratio for the overall population because it was similar to that of the group who did not have previous docetaxel. Comparing the baseline characteristics across the studies included in the network suggested similarities across the trials in terms of age, ECOG\xa0PS score, Gleason score and prostate-specific antigen level. But there were proportionally more people with stage 4\xa0prostate cancer in ARASENS than in the other trials. The company's subgroup analysis using data from ARASENS did not show that age, ECOG\xa0PS score, Gleason score, prostate-specific antigen level or prostate cancer stage were treatment-effect modifiers for overall survival because they had overlapping confidence intervals. The committee acknowledged that subgroup analyses would be unlikely to be appropriately powered to detect differences in potential treatment-effect modifiers. But it concluded that the studies included in the company's network meta-analysis were appropriate for decision making, but there was uncertainty about the consistency between the direct and indirect evidence included.\n\n## Types of network meta-analysis\n\nIn its base case, the company used a fixed-effects network meta-analysis, assuming no heterogeneity between studies, to model overall survival. The fixed-effects network meta-analysis for overall survival had a lower deviance information criterion score than the random-effects model, indicating a better model fit. The company used a random-effects network meta-analysis for progression-free survival because of potential heterogeneity from the different outcome definitions used across the studies (see section\xa03.8). The random-effects network meta-analysis for progression-free survival had a lower deviance information criterion score than the fixed-effects model, indicating a better model fit. The committee concluded that the network meta-analysis was appropriate for decision making.\n\n## Treatment switching in the network meta-analysis\n\nThe ARCHES and LATITUDE trials in the network meta-analysis allowed treatment switching after the primary data analysis and unblinding. In the ARCHES trial, treatment switching from placebo to the intervention arm was 31%, and in the LATITUDE trials it was 12%. The company did not adjust for treatment switching. It considered that adjusted hazard ratios may not reflect clinical practice because they would assume people in the control arm did not subsequently have an anti-androgen. But unadjusted hazard ratios may not reflect clinical practice if people have an anti-androgen earlier than they would in clinical practice, because treatment switching was after unblinding rather than disease progression. The EAG did a scenario analysis that adjusted the hazard ratios for treatment switching. This suggested an improved treatment effect for enzalutamide (ARCHES) and abiraterone (LATITUDE) compared with darolutamide plus ADT and docetaxel (the exact numbers are confidential and cannot be reported here). The EAG noted that because there was treatment switching in the comparator trials, using unadjusted hazard ratios may mean that the relative treatment effect of darolutamide plus ADT and docetaxel was overestimated. So, it suggested that separately adjusting for treatment switching in ARCHES and LATITUDE may be appropriate. The company argued that adjusted hazard ratios may underestimate the treatment efficacy of darolutamide, because after adjustment, the proportion of subsequent treatment with a first anti-androgen was disproportionally greater in ARASENS compared with the unadjusted hazard ratios. This would favour the comparators (enzalutamide and abiraterone) because of a greater impact on survival for the placebo arm from having a first anti-androgen. The committee acknowledged that using unadjusted hazard ratios may better reflect clinical practice because people in the placebo arm would subsequently have a first anti-androgen, and a second anti-androgen is not likely to add clinical benefit. The committee concluded that unadjusted hazard ratios may better reflect clinical practice, and so would be appropriate to use in the model.\n\n## Progression-free survival estimates for comparators in the network meta-analysis\n\nThe latest progression-free survival estimates from ARCHES and STAMPEDE‑2 were not available for the company's original submission. At technical engagement the company updated its network meta-analysis with the most recent radiological progression-free survival estimates from ARCHES and failure-free survival estimates from STAMPEDE‑2, and applied these to progression-free survival and time-on-treatment because the hazard ratios in the model were interdependent. It noted that the updated results from ARCHES were consistent with overall survival in the network meta-analysis, and it closely matched the ARASENS follow\xa0up. The EAG did not use the updated progression-free survival estimates in its base case because of unexplained notable differences in the hazard ratios (HR\xa00.63 [95%\xa0CI 0.52 to 0.76]) compared with the original estimate (HR\xa00.39 [95%\xa0CI 0.30 to 0.50]). It noted that the original radiological progression-free survival estimate from ARCHES used centralised independent review, whereas the updated radiological progression-free survival estimate used investigator assessment. The EAG added that the difference in assessment method may explain the difference in hazard ratios, but that the centralised assessment is usually conservative. A clinical expert said that a greater treatment effect using centralised assessments was plausible because it was driven by meeting the Response Evaluation Criteria In Solid Tumours (RECIST) criteria, so people would be more likely to continue the trial treatment. A clinical expert added that conventional imaging (that is, CT or bone scans) tend to show progression later than indicators such as prostate-specific antigen levels. The clinical experts explained that individual investigator assessments reflect decision making in NHS clinical practice. But it was unclear to the committee whether the investigators were blinded for either the centralised assessment or investigator assessment. On balance, the committee noted a general preference for more mature data, where available, and it preferred to use the latest progression-free survival estimates from ARCHES and STAMPEDE‑2.\n\n# Economic model\n\n## Company model\n\nIn its submission, the company presented a 3‑state partitioned survival model to estimate the cost effectiveness of darolutamide plus ADT and docetaxel compared with enzalutamide plus ADT, ADT plus docetaxel, and ADT alone, for adults with hormone-sensitive metastatic prostate cancer who can have chemotherapy. The 3\xa0health states were pre-progression (hormone-sensitive metastatic prostate cancer), post-progression (hormone-relapsed metastatic prostate cancer), and death. In the pre-progression health state, people could be on or off treatment (ADT only), and post-progression, people could have up to 3\xa0lines of treatment. Darolutamide and enzalutamide continued until disease progression or unacceptable toxicity; docetaxel continued for 6\xa0cycles; and ADT continued indefinitely as a background therapy. The model cycle was 28\xa0days, with a half-cycle correction, and had a 34‑year lifetime time horizon. Overall survival and time to CROD from the ARASENS trial were included in the network meta-analysis. The efficacy of darolutamide plus ADT and docetaxel, and the comparator treatments (enzalutamide with ADT, and ADT alone) were derived by applying the network meta-analysis hazard ratios to extrapolated docetaxel data. The efficacy of docetaxel with ADT was from ARASENS. The committee noted that the quality-adjusted life years (QALYs) were accrued from people living longer, with a better quality of life from delayed progression to the hormone-relapsed metastatic prostate cancer state. The committee concluded that the model was suitable for decision making.\n\n## Overall survival and progression-free survival extrapolations\n\nIn its original submission, the company modelled overall survival using a log-normal distribution. It compared the extrapolations to the CHAARTED and STAMPEDE‑3 (considered more representative of NHS clinical practice) survival estimates over 9\xa0years for docetaxel. After technical engagement, the company aligned with the EAG's preference of using a log-logistic distribution. This was because clinical advice to the EAG suggested that the overall survival estimates for darolutamide over 30\xa0years were optimistic. The log-logistic distribution fitted the observed overall survival data from ARASENS and STAMPEDE‑3 and was more conservative than the log-normal distribution. The company modelled time to CROD using the generalised gamma distribution in its original submission, but after technical engagement, updated this to align with the EAG's choice of the log-normal distribution to account for potential optimistic predictions. The committee had concerns about the clinical plausibility of the overall and progression-free survival estimates for darolutamide plus ADT and docetaxel and its comparators extrapolated over 30\xa0years. After the committee meeting, the clinical experts agreed that for overall survival and time to CROD, the estimates up to 10\xa0years were consistent with evidence from the STAMPEDE‑3 trial. Beyond this, the progression-free survival estimates were above the level expected in clinical practice. The clinical experts added that it is unlikely that people would be progression free over 20\xa0and 30\xa0years. For the time-on-treatment extrapolation, the clinical experts agreed more people were on treatment at 20\xa0years than would be expected in clinical practice. The committee concluded that the optimistic extrapolations for darolutamide and the comparators added to the uncertainties.\n\n# Health-related quality of life\n\n## Docetaxel disutility\n\nThe ARASENS trial did not collect EQ‑5D data, so the company used the EAG's preferred utilities from NICE's technology appraisal guidance on enzalutamide. These utilities were from the ARCHES and AFFIRM trials and included all the relevant comparators for darolutamide plus ADT and docetaxel. The EAG preferred to add a 0.02 disutility for docetaxel use for 6\xa0months. This was in line with NICE's technology appraisal guidance on apalutamide, in which a 0.02 disutility was added for 12\xa0months, because a generally lower health-related quality of life is expected. After technical engagement, the company used a 0.02 disutility for docetaxel for 6\xa0months, and also adjusted the disutility to account for the proportion of people alive during the 6 months. The EAG noted that the company's additional adjustment had a negligible impact on the cost-effectiveness estimates. The committee concluded that the utility values used by the company and EAG were appropriate for decision making.\n\n# Treatment-effect waning\n\n## Darolutamide plus ADT and docetaxel treatment effect over time\n\nThe committee wanted to explore whether, on a population level, the benefit of treatment with darolutamide is likely to stay the same or change over time. The company did not explore treatment-effect waning for darolutamide plus ADT and docetaxel, but previous NICE technology appraisal guidance explored treatment-effect waning in scenarios (NICE's technology appraisal guidance on abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer, apalutamide and enzalutamide). The clinical experts questioned the clinical plausibility of treatment-effect waning and noted that because ARASENS was a more mature trial with longer follow up, and the comparator included docetaxel, minimal treatment-effect waning would be expected. The clinical lead for the Cancer Drugs Fund highlighted that, because darolutamide is continued until disease progression rather than for a fixed period of time, any waning is likely to be captured in the modelling. The company added that there was less uncertainty in the survival extrapolations in its model because ARASENS was a more mature trial, and the general population mortality eventually merged. In addition, time spent in the hormone-relapsed metastatic prostate cancer setting was lower in the intervention arm, which could have been because of fewer treatment options being available at this stage. The committee acknowledged that the model and its extrapolations may already capture a gradual loss in treatment effect at an individual level. But it also agreed that scenarios exploring further impacts on treatment effect in the extrapolated part of the model would be useful to explore the extent to which the cost-effectiveness estimates depend on the assumption of constant treatment benefit. The committee concluded that the potential impact of treatment-effect waning was not known and added to the uncertainties.\n\n# Cost-effectiveness estimates\n\n## Company and EAG cost-effectiveness estimates\n\nNICE's guide to the methods of health technology evaluation notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, decisions about the acceptability of a technology as an effective use of NHS resources will specifically consider the degree of uncertainty around the ICER, and aspects that relate to uncaptured benefits and non-health factors. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the confidential commercial arrangements for darolutamide, its comparators, and other treatments after progression, the cost-effectiveness estimates cannot be reported here. The committee noted that the main differences in the company and EAG modelling was around modelling docetaxel disutility, and the latest data source for progression-free survival from ARCHES and STAMPEDE‑2. It concluded that:\n\nadjusting docetaxel disutility for the proportion of people alive during 6\xa0months (see section\xa03.14) had a negligible impact on the ICER, but the company's modelling approach was appropriate\n\nit preferred the latest progression-free survival estimates from ARCHES and STAMPEDE‑2, but the reason for the large difference in treatment effectiveness between the interim and final assessments was uncertain.The committee also noted the uncertainty in the cost-effectiveness results around:\n\nthe impact of removing abiraterone from the network meta-analysis\n\nthe potential impact of treatment-effect waning\n\nthe clinical plausibility of modelled overall and progression-free survival estimates.\n\n## Acceptable ICER\n\nThe committee considered that a maximum acceptable ICER would be close to £20,000 per QALY gained, to take into account the impact of the uncertainties in the clinical plausibility of the modelled overall and progression-free survival, and the unknown impact of treatment-effect waning. Because of the confidential discounts, the cost-effectiveness results cannot be reported here. Applying confidential discounts for darolutamide plus ADT and docetaxel, its comparators and other treatments after progression, and considering its preferences, the committee noted that the cost-effectiveness estimates were within the maximum acceptable ICER range. That is, it considered darolutamide plus ADT and docetaxel to be an acceptable use of NHS resources. So, the committee recommended it for routine use in the NHS.\n\n# Other factors\n\n## Equality issues\n\nThe committee noted that people from Black, African and Caribbean family backgrounds are more likely to have an aggressive form of hormone-sensitive metastatic prostate cancer. But it concluded that its recommendation for darolutamide plus ADT and docetaxel would not have an effect on people protected by equality legislation different from the effect on the wider population.\n\n## Severity\n\nThe company did not consider that the severity weighting applied in this appraisal, and NICE's advice about conditions with a high degree of severity did not apply.\n\n## Innovation\n\nThe committee considered if darolutamide plus ADT and docetaxel was innovative. It did not identify any additional benefits not captured in the economic modelling. So, it concluded that all additional benefits of darolutamide plus ADT and docetaxel had already been taken into account.\n\n# Conclusion\n\n## Recommendation\n\nThe committee agreed that its preferred cost-effectiveness estimates for darolutamide plus ADT and docetaxel were within the range considered an acceptable use of NHS resources. So, the committee concluded that it is recommended for treating hormone-sensitive metastatic prostate cancer."}	https://www.nice.org.uk/guidance/ta903	Evidence-based recommendations on darolutamide (Nubeqa) with androgen deprivation therapy and docetaxel for hormone-sensitive metastatic prostate cancer in adults.
28459938c342b6532769cb8fd6b159e86b3d1a26	nice	Pembrolizumab with lenvatinib for previously treated advanced or recurrent endometrial cancer	Pembrolizumab with lenvatinib for previously treated advanced or recurrent endometrial cancer Evidence-based recommendations on pembrolizumab (Keytruda) with lenvatinib (Lenvima) for treating advanced or recurrent endometrial cancer in adults. # Recommendations Pembrolizumab plus lenvatinib is recommended, within its marketing authorisation, for treating advanced or recurrent endometrial cancer in adults: whose cancer has progressed on or after platinum-based chemotherapy and who cannot have curative surgery or radiotherapy.Pembrolizumab plus lenvatinib is recommended only if the companies provide them according to the commercial arrangements. Why the committee made these recommendations There is no standard treatment for previously treated advanced or recurrent endometrial cancer. But people would usually have non-platinum-based chemotherapy. Evidence from a clinical trial suggests that pembrolizumab plus lenvatinib increases the time until the cancer gets worse and how long people live compared with non-platinum-based chemotherapy. But, the results are uncertain because treatments not used in the NHS were used after non-platinum-based chemotherapy in the trial. So, the results may not apply to UK clinical practice. Pembrolizumab plus lenvatinib meets NICE's criteria to be considered a life-extending treatment at the end of life. There is some uncertainty in the economic model about how long the effect of treatment lasts after people stop taking pembrolizumab at 2 years. But the cost-effectiveness estimates are within the range considered acceptable for an end of life treatment. So, pembrolizumab plus lenvatinib is recommended.# Information about pembrolizumab with lenvatinib # Marketing authorisation indication Pembrolizumab (Keytruda, MSD), in combination with lenvatinib (Lenvima, Eisai), is indicated for 'the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for pembrolizumab and lenvatinib. # Price The price of pembrolizumab is £2,630 per 100 mg per 4‑ml vial (excluding VAT; BNF online accessed October 2022). The price of lenvatinib is £1,437 per 30 4‑mg or 10‑mg capsules (excluding VAT; BNF online accessed October 2022). The companies have commercial arrangements. These make pembrolizumab and lenvatinib available to the NHS with discounts. The sizes of the discounts are commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of the discounts.# Committee discussion The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # New treatment option ## People with advanced or recurrent endometrial cancer would welcome a new treatment option that is well tolerated Endometrial cancer has a devastating impact on life expectancy and quality of life. Recurrent or advanced endometrial cancer has a reported prognosis of 12 months or less and 5‑year net survival rates of about 20%, compared with 89% for non-recurrent disease. Physical symptoms can be debilitating and include bleeding, pain, discomfort, reduced appetite, nausea and fatigue. There can also be long-term physical effects after treatment affecting quality of life, including ongoing pain, discomfort and incontinence. Patient experts emphasised the devastating impact of the disease on a person's quality of life. The impact is not just limited to physical health, but also mental health and wellbeing. Repeated intimate examinations can psychologically affect sexual function and intimacy, and lead to distance in relationships. People also experience reduced confidence going to social events because of tiredness, access to a toilet and fear of urinary leakage. Limited mobility and pain resulting in being unable to leave home or work (or work less than full-time) can lead to additional concerns and anxiety about finances. Patient experts highlighted the impact of feeling vulnerable while having chemotherapy, such as the fear of neutropenic sepsis. They also noted how it limits normal activities like seeing family and friends, because of the need to be near a hospital in case of a crisis. The lack of available treatment options other than chemotherapy can lead to a lack of hope for the future and fear of relapse. A patient expert described the importance of hope with the availability of a treatment that could offer a longer and fuller life. The committee heard that since taking pembrolizumab their quality of life had improved dramatically with them being able to take part in sports, have an active social life again and focus on their career. The committee concluded that people with advanced or recurrent endometrial cancer would welcome a new treatment option. # Current clinical management ## There is no standard second-line treatment for advanced or recurrent endometrial cancer The marketing authorisation for pembrolizumab with lenvatinib states that it is indicated for use after platinum-based chemotherapy. The committee noted that this could be when a person has advanced or recurrent disease after having neoadjuvant or adjuvant platinum-based chemotherapy, or has had platinum-based chemotherapy as first-line treatment for advanced disease. Clinical experts noted that there are no standard second-line treatment options for endometrial cancer when it has progressed or recurred. Options depend on the time interval from previous chemotherapy, previous response and toxicities to chemotherapy, and patient preference. After neoadjuvant platinum-based treatment, people could then have retreatment with platinum-based doublet chemotherapy. Clinical experts noted that possible options include carboplatin with paclitaxel (as retreatment), but they stated that retreatment with platinum-based chemotherapy is infrequently used in the advanced setting. This is because many people do not want to go through hair loss and risk neutropenic sepsis again and some people would be too frail at this point to have chemotherapy again. Pegylated doxorubicin, and weekly paclitaxel monotherapies, are more commonly used as second-line chemotherapies. The clinical experts noted that the response rate with current second-line chemotherapy is only 10% to 15%. One of the clinical experts stated that weekly paclitaxel may have a slightly higher response rate, but overall the 2 drugs have similar efficacies and are used equally, noting that neither option was good. The EAG highlighted that dostarlimab (see NICE technology appraisal guidance on dostarlimab for previously treated advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency, from now TA779) was recently appraised but could not be considered as a comparator because it was recommended for use in the Cancer Drugs Fund. Hormone therapy, such as high-dose progesterone, may be considered if chemotherapy cannot be tolerated, but it is usually part of palliative care or a 'holding measure' to improve wellbeing for people who are more unwell or less fit. The company noted that best supportive care, which had been included in the scope as a comparator, is used for people not well enough for active treatment so is not a relevant comparator. The EAG noted that people for whom active treatment is suitable may choose best supportive care, but noted that the aims are different so excluding this as a comparator is appropriate. The committee acknowledged that platinum-based chemotherapy retreatment may be the relevant comparator when neoadjuvant platinum-based chemotherapy was used in the previous 12 months. However, it noted the comments from the clinical experts about the minimal use in this setting and noted that the company's scenario has a minor impact on the cost-effectiveness estimates. The committee concluded that there is no standard second-line treatment for advanced or recurrent endometrial cancer after platinum-based chemotherapy. But, for the purposes of this appraisal, doxorubicin or paclitaxel monotherapy are appropriate comparators. # Clinical evidence ## Key evidence for pembrolizumab with lenvatinib comes from the KEYNOTE-775 trial, which is generalisable to the NHS The company presented evidence from the KEYNOTE‑775 trial, an open-label randomised controlled trial in advanced or recurrent endometrial cancer that had progressed after platinum-based chemotherapy in adults who could not have surgery or radiotherapy. The trial compared pembrolizumab plus lenvatinib (n=411) with treatment chosen by physicians (either paclitaxel or doxorubicin monotherapy; n=416). The trial stratified people by mismatch repair status, with about 16% with mismatch repair deficiency (dMMR) or high microsatellite instability, and 84% with proficient mismatch repair (pMMR). The EAG noted, based on clinical input, that people in UK clinical practice are likely to be older and weigh more (and therefore need larger doses of pembrolizumab) than those in the trial. But it noted that both changes had a relatively small impact on the incremental cost-effectiveness ratio (ICER), particularly weight. The company disagreed with the EAG that higher age and weight would be seen in UK practice. It cited 2 real-world evidence studies that reported only a slightly greater age than people in KEYNOTE‑775 from the UK (none of these proportions can be reported here because they are marked as confidential by the company). The first study, ECHO, is a retrospective multicentre chart review of advanced or recurrent endometrial cancer that has progressed after a previous systemic therapy commissioned by the company. The number of people included is marked as confidential by the company. The second is Heffernan (2022; n=999), a retrospective review of the English National Cancer Registration and Analysis Service covering people whose cancer progressed to second-line chemotherapy (meaning those who had previous neoadjuvant platinum-based chemotherapy were not included). The clinical experts explained that people in the trial were a bit younger than in clinical practice, but because the drug combination is suitable for older people and those with a poor performance status, it was unlikely to affect the generalisability of the treatment to clinical practice. They noted that the age reported in the real-world studies was more representative of UK clinical practice. The committee acknowledged that there are often some differences between people selected for trials and those in clinical practice because of stringent selection criteria. The committee concluded that the trial was generalisable to NHS clinical practice for the purposes of this appraisal. ## Pembrolizumab plus lenvatinib improves overall and progression-free survival compared with doxorubicin or paclitaxel monotherapy The primary endpoints in the trial were progression-free survival and overall survival. The company presented evidence from an interim data cut (October 2020) from KEYNOTE‑775 in its original submission. At technical engagement the company presented the results from the final data cut (March 2022) but was not able to incorporate the final data cut in the economic model in time for the first committee meeting. In response to consultation on the draft guidance, the company incorporated the final data cut in the model. The final data cut had median 14.7 months follow up. Progression-free survival reached 7.3 months in the pembrolizumab plus lenvatinib arm compared with 3.8 months in the paclitaxel or doxorubicin monotherapy arm. This resulted in a statistically significant improvement in progression-free survival for pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy (hazard ratio 0.56, 95% confidence interval 0.48 to 0.66). At the final data cut, overall survival was 18.7 months with pembrolizumab plus lenvatinib compared with 11.9 months with paclitaxel or doxorubicin monotherapy. This resulted in a statistically significant improvement in overall survival for pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy (HR 0.65, 95% CI 0.55 to 0.77). The committee concluded that pembrolizumab plus lenvatinib improved both overall and progression-free survival compared with doxorubicin or paclitaxel monotherapy. ## Pembrolizumab plus lenvatinib may be better in dMMR disease than in pMMR disease but there is not enough evidence to conclude this The trial had stratified people based on MMR status and reported separate results for pMMR and dMMR disease from the interim data cut. The EAG noted a differential result by MMR status, with the dMMR population having a better response. For the dMMR group, the HR for overall survival was 0.37 (95% CI 0.22 to 0.62) compared with 0.68 (95% CI 0.56 to 0.84) in the pMMR group. Progression-free survival was 0.36 (95% CI 0.23 to 0.57) in the dMMR group compared with 0.60 (95% CI 0.50 to 0.72) in the pMMR group. The EAG acknowledged that the trial was not powered to explore differences and there was limited follow up, so it considered these subgroup analyses exploratory. However, the EAG's clinical expert noted that prognosis and treatment likely differs between these groups. They also noted that there was no separate cost-effectiveness analyses or model functionality to explore a scenario examining these groups separately. While the EAG noted that the impact on the ICER was unknown, pembrolizumab plus lenvatinib may have a lower ICER in dMMR because of the improved overall survival hazard ratio compared with the pMMR group. The company highlighted that it is not clear if the results are clinically or statistically meaningful because the trial was not powered for subgroups; the focus should be on the whole population as per the scope and the marketing authorisation. The company noted that there was a benefit of pembrolizumab plus lenvatinib over doxorubicin or paclitaxel monotherapy in both groups and that there was unmet need in both groups. It also noted that requiring mismatch repair status for treatment may limit access if biopsy or testing is delayed. The clinical experts noted that dMMR cancer may be more likely to relapse after surgery, but that the treatments offered have not differed until the recent guidance on dostarlimab for dMMR disease. They noted that some people with dMMR disease may have dostarlimab (though this is through the Cancer Drugs Fund; see section 3.2) so there is currently more unmet need for the pMMR group. The committee noted that, because dostarlimab is not recommended for routine commissioning, dostarlimab and pembrolizumab plus levantinib cannot be compared for this appraisal. The committee concluded that the study was not powered to consider subgroups based on MMR status and that the treatment pathways for routinely commissioned treatments for both subgroups are the same. It further concluded that both subgroups have had benefit from pembrolizumab plus lenvatinib compared with doxorubicin or paclitaxel monotherapy. # Economic model ## The model structure is suitable for decision making The company used a partitioned-survival economic model that included 3 health states: progression-free, progressed disease and death. The time horizon was 40 years with a 1‑week cycle length. There was a 24‑month stopping rule for pembrolizumab, as in KEYNOTE‑775. The EAG considered that the model structure was reasonable. The committee concluded that the model structure was generally appropriate. ## A one-knot spline model for extrapolating progression-free and overall survival is appropriate The company originally considered standard parametric and two‑piece parametric curves for the extrapolation of overall and progression-free survival. However, the EAG noted that the hazards were not well tracked with these curves, and that the breakpoint was arbitrary and not determined in an appropriate way. The EAG felt that the company should have considered more sophisticated flexible models (such as cubic splines) because they may better fit the evidence and better track the hazards from the trial. The committee agreed that more sophisticated curves may have a better fit. This was particularly important given the uncertainty and substantial impact on the ICER of the overall survival extrapolation curve and treatment waning assumption. In response to consultation, the company used more flexible spline models and selected the one-knot spline model using an odds scale for the extrapolation of both overall and progression-free survival in both arms over time. The EAG considered the company's new approach to be more defensible and that the results had greater credibility. However, it noted that the justification for the placement of the knot was not clear, which leads to some uncertainty. At the committee meeting, the company advised that it used the default placement for the knot applied by the statistical package used. The EAG noted that the odds scale appears appropriate for the extrapolation of overall survival for the pembrolizumab plus lenvatinib arm, but all extrapolations predicted higher than observed hazards at the end of the observation period. The EAG did an additional scenario using a two‑knot spline for the comparator arm but this had minimal impact on the ICER. The EAG expressed some concerns about the extrapolation of progression-free survival, noting that a comparison of survival estimates was not provided between models for progression-free survival. It also noted that spline models fit the comparator arm better than the pembrolizumab plus lenvatinib arm and odds scale models better fit the pembrolizumab plus lenvatinib arm, but this was less clear for the comparator. The EAG would have liked to test alternative types of models but the company model only allows for the odds scale to be used. The committee concluded that, given the EAG scenarios having minimal impact on the ICER, the one-knot spline model was an appropriate choice for the extrapolation of both overall and progression-free survival in both arms. ## Adjusting for the relative treatment effect to account for people having non-NHS treatments after paclitaxel or doxorubicin monotherapy gives the most optimistic estimate of the benefits of the technology At the first committee meeting, the committee noted that the impact of having immunotherapies as subsequent therapy after paclitaxel or doxorubicin monotherapy in KEYNOTE‑775 on the resulting effect estimate had not been explored. In its response to consultation, the company noted that a proportion of people who had paclitaxel or doxorubicin monotherapy had later switched to pembrolizumab plus lenvatinib or other PD1/PD‑L1 or VEGF/VEGFR inhibitor therapies not available in this line in the UK. The proportion cannot be reported here because the company considered it to be confidential. It noted that the trial estimates therefore likely overestimate overall survival for paclitaxel or doxorubicin monotherapy and so underestimate the benefit of pembrolizumab plus lenvatinib compared with the comparator. The company explored different treatment switching methods, noting that all methods improve the benefit of pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy. However, it considered the two-stage estimation (TSE) method to be the least biased and used the adjusted data resulting from using this method in its updated base case. The EAG noted that the committee did not request treatment switching in its preferred base case as the company had done, it just noted that it had not been explored. The EAG noted that the company preferred the TSE method without recensoring, but the reason for excluding recensoring was not stated. However, the EAG acknowledged that differences in the hazard ratios are small and that the more conservative result (with a lower treatment estimate) was chosen. The EAG noted that the TSE method assumes the same treatment effect for all treatments after switching. But, that may not be appropriate because there were a variety of treatments that people switched to after paclitaxel or doxorubicin monotherapy and they may have different effectiveness. The EAG considers that the true effect likely lies between the adjusted and unadjusted values. The committee also noted that the TSE method uses a new baseline at progression, assuming all those who progressed have the same prognostic factors. However, the committee agreed that it is unlikely that all will have the same prognostic factors at the new baseline. It also noted that switching does not necessarily happen immediately after progression. The company had reported the time to progression (the exact value is marked as confidential by the company so cannot be reported here). The committee considered that this could have an impact in the model. The company responded that current treatment has limited impact on overall survival, so people are unlikely to benefit from subsequent therapies if their disease has not responded to current first-line treatments. It also noted that adjusting for specific treatments is more complicated. The committee agreed that a result that was adjusted for treatment switching was likely to be less biased than an unadjusted result but was also likely to be an overly optimistic assumption. So, it concluded that the true result was likely to be between the adjusted and unadjusted values. ## It is appropriate to assume some treatment waning in the model KEYNOTE‑775 used a 2‑year stopping rule for pembrolizumab while lenvatinib was continued until clinical progression. The company's model assumed a continuing treatment effect after pembrolizumab is stopped at 2 years with no treatment effect waning for the duration of the model's 40‑year time horizon. At the first committee meeting, the committee concluded that it preferred the EAG scenario that included treatment waning from years 3 to 5 after starting treatment, but would prefer to see alternative treatment waning scenarios. In response to consultation, the company maintained its position that treatment waning was not appropriate because there is no evidence to substantiate a treatment effect waning. But it explored several scenarios with waning of different proportions of patients from years 5 to 7 after starting treatment. The company argued that there is no evidence of treatment effect waning in KEYNOTE‑775, noting that both data cuts show a sustained longer-term benefit of pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy. It noted that the biological rationale of no waning is supported by the fact that pembrolizumab and lenvatinib work synergistically. It considered that lenvatinib may continue to benefit people when pembrolizumab stops by helping to shift tumour environment to immune-stimulatory state by inhibiting VEGFR and FGFR. The company's clinical experts confirmed that some people will have a durable response. The company also reported that a small proportion of people in KEYNOTE‑775 were still taking lenvatinib at the last recorded time point of 3 years after starting treatment. The company cited several studies noting that waning was implausible and inappropriate. It noted that multiple pembrolizumab trials in other disease areas (melanoma and non-small cell carcinoma) with 5‑year follow up showed a sustained treatment effect. Hazard plots of pembrolizumab from 2 trials in melanoma showed no structural difference in hazards between the trial that had 2‑year stopping criteria and the trial that had no stopping criteria. The company also noted long-term durability of the treatment effect for CTLA4 agents in advanced melanoma from year 3 up to year 10 and stated that these work similarly to PD‑1 agents. So, the company considered that a similar plateau would likely occur with pembrolizumab plus lenvatinib in this population. It also noted a plateau for overall survival in KEYNOTE‑146, the longest-term data of the treatment in this population, with 30% survival reported at 5 years. KEYNOTE‑146 was a multicentre, open-label arm phase 1b/2 basket trial of people with selected solid tumours who had pembrolizumab plus lenvatinib. It included 108 women with pre-treated endometrial cancer with a median follow-up 34.7 months (95% CI 30.9 to 41.2). The company also noted that in the recent appraisal of the same drug combination in renal cell carcinoma, waning was not included as a preferred assumption. The committee acknowledged that this was because no scenarios incorporating waning had been presented to that committee and its conclusion was not that no waning had been accepted but that treatment waning was plausible but uncertain. The EAG for that topic had acknowledged that there is uncertainty in the long-term treatment effect of pembrolizumab and, because lenvatinib continues after pembrolizumab stops, it is not possible to plausibly separate out any potential waning of treatment effect. The EAG for this topic noted that there is some evidence to support some duration of effect after stopping pembrolizumab, but it is not sufficient to conclude that there is no waning over time. It noted that it is difficult to generalise findings from studies in different disease areas to advanced or recurrent endometrial cancer because previous treatments, patient characteristics and disease severity differed. The EAG noted that the modelled 5‑year overall survival for pembrolizumab plus lenvatinib in KEYNOTE‑775 showed some evidence of a sustained response (the exact value cannot be reported because it is considered confidential). But this was lower than the 30% response reported in KEYNOTE‑146. It also noted that there was uncertainty in the survival rate reported in KEYNOTE‑146 because there was considerable censoring and few patients at risk at 28 months. Clinical experts considered that the treatment effect of pembrolizumab plus lenvatinib was likely durable, but it must be assumed that there would be some treatment waning. NHS England's clinical lead noted that it is not appropriate to apply conclusions made for renal cell carcinoma to this appraisal. This is because tyrosine kinase inhibitors (TKI) are in routine commissioning for that disease but, for this indication, it is the first time a TKI would be seen in an established role. The committee noted that waning scenarios had not been explored in the renal cell carcinoma appraisal and so the conclusion in the renal cell carcinoma appraisal was not applicable to this appraisal. It agreed that this assumption should be explored based on evidence for this specific technology appraisal. The committee concluded that there was unlikely to be a continuing effect with no waning so it preferred some treatment waning in the model. ## There is likely to be a period with a sustained treatment effect before waning starts The committee acknowledged that levantinib could continue for some people for a period of time after pembrolizumab had been stopped. But it noted that data presented showed that only a small proportion of people were still on levantinib at 3‑year follow up. It noted that it was unclear how lenvatinib alone (or the synergistic effect of both) could impact a continued benefit from the immunotherapy after it had been stopped. But the committee agreed that it was likely there was a period with a sustained treatment effect before waning was likely to start. So, the committee reconsidered its previously preferred assumption of waning from year 3 to 5 after starting treatment as likely to be pessimistic (this was the EAG's preferred assumption, which was consistent with waning assumptions preferred by NICE in other immunotherapies). However, it was difficult to conclude an appropriate time when waning would start. The committee noted that the company's 3 scenarios examining waning from year 5 (the maximum follow up of KEYNOTE‑146) to year 7 after starting treatment had been applied to 60%, 70% and 80% of people. The committee acknowledged that there may be some people who have a durable response to treatment. But it agreed that the company's approach was unusual and it was likely that a more appropriate methodology such as a mixture cure model would be needed when taking this approach. The committee therefore agreed to consider all patients in any waning scenario. It concluded that the company's scenario of waning at 5 to 7 years after starting treatment was plausible. But it used the EAG's scenario of all patients waning at 5 to 7 years after starting treatment for decision making because it considered waning of all patients. ## Using progression status to derive utilities is appropriate The company used a time to death approach to derive utilities in the model. The EAG preferred an approach of deriving utilities using progression status because it is more consistent with the model structure. It considered that the company's approach 'divorced health-related quality of life from disease status' in the model. The company noted that the time to death approach is becoming more common and allows finer gradations in utility because it distinguishes between multiple health states not just 2. It considered that the limited utility assessments in immunotherapy trials after disease progression means that the time to death approach is more comprehensive because it captures patient utilities across the full spectrum of the disease, including being close to death. The committee noted that the dostarlimab appraisal (TA779) used a time-to-death utility approach but included disease progression as a covariate to predict utility. The committee noted that the company's approach in this appraisal limits the amount of information informing health states. So while the approach may provide more granular information than the progression status approach, the increased uncertainty in the utility estimates obscures differences between each of the time-to-death categories. In response to consultation, the company updated its base case and used an approach similar to that taken for TA779, except it used 6 time to death (TTD) categories (less than 30 days, 30 to 89 days, 90 to 179 days, 180 to 269 days, 270 to 359 days, 360 days and longer) for both the pre- and post-progressed health states rather than the 2 time to death categorise used in TA779 (TTD less than 180 days and TTD 180 days and longer). The EAG noted that the committee concerns about data required and associated uncertainty are still relevant. The EAG conducted a scenario using the approach used in TA779, which made a small to moderate impact on the ICER. The committee appreciated the company trying an alternative method to incorporate progression status. The committee was unclear of the reason for the cut-offs for the 6 TTD categories chosen by the company. The committee and clinical expert looked at the utilities estimated using the company's approach for the health states by the 6 TTD categories. They concluded that it was difficult to know which method was most appropriate given the information that was provided from the company on its scenarios. The committee maintained its conclusion from the first committee meeting that the EAG's approach to deriving utilities using progression status is more appropriate. ## People included in the model should be slightly older than reported in KEYNOTE-775 but younger than used by the EAG As discussed in section 3.3, clinical experts felt KEYNOTE‑775 was generalisable to UK clinical practice. But, they felt that the average age would be slightly higher than that used by the company and less than that used by the EAG. The experts thought that the most accurate age was likely be around 67, which is between the trial and EAG's estimate and is close to what was reported in the real-world studies. While changing age in the model did not have a very large influence on the results, the committee felt that it was appropriate to include the more applicable average age in the model, as reported in ECHO. Both the company and EAG incorporated a mean age of 67 in their revised base cases. The committee concluded that the age now used in the model is most appropriate. # End of life ## Pembrolizumab with lenvatinib meets the end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Life expectancy for people with previously treated advanced or recurrent endometrial cancer is typically less than 24 months. The company noted that, at the interim data cut, the paclitaxel or doxorubicin monotherapy arm of KEYNOTE‑775 reported mean survival of 11.4 months at the interim data cut and 11.9 months at the final data cut. It also noted that survival was less than 12 months in both ECHO (the exact value is confidential so cannot be reported) and Heffernan (2022), in which median survival was 10.3 months. This was consistent with the company's model (the exact value is confidential so cannot be reported) as well as the clinical expectations reported to the company of life expectancy being less than 12 months. The EAG noted that survival in the EAG base-case model was around 24 months. But it received clinical input that average life expectancy was plausibly less than 24 months so was satisfied it met this criterion. Pembrolizumab with lenvatinib appears to extend life longer than 3 months. The company noted that, at both the interim and final data cuts, the pembrolizumab with lenvatinib arm extended life by 6.9 months over the paclitaxel or doxorubicin monotherapy arm. This was consistent with the company's modelled mean survival which cannot be reported here because it is marked as confidential. The EAG noted that clinical input it received supports a survival gain of at least 3 months for both dMMR and pMMR. The committee concluded that pembrolizumab with lenvatinib meets the end of life criteria. # Cost-effectiveness estimates ## The most plausible ICER is less than £50,000 per QALY gained The company's updated base-case deterministic and probabilistic ICERs for pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy were less than £50,000 per QALY gained. This was when confidential commercial arrangements for pembrolizumab, lenvatinib and other treatments in the model were included, so the exact ICERs cannot be reported here. However, the company's base case did not incorporate all the committee's preferred assumptions, including: applying waning from years 5 to 7 after starting treatment (3 to 5 years after treatment with pembrolizumab stops; see section 3.9) using progression status to derive utilities (see section 3.10).The committee concluded that the most plausible ICERs using its preferred assumptions were generated from the EAG's scenarios. It was between the EAG's scenario adjusted for treatment switching and the EAG's scenario unadjusted for treatment switching (see section 3.8). The committee noted that these were less than £50,000 per QALY gained. # Innovation ## It is uncertain whether pembrolizumab with lenvatinib meets NICE's criteria for an innovative treatment NICE defines innovation as a 'step-change' in treatment with benefits not accounted for in the modelling. The company stated that there is uncaptured value because there is no standard care and very few treatment options for people with previously treated advanced or recurrent endometrial cancer. It noted that there were no NICE appraisals for endometrial cancer until recently (dostarlimab, TA779). The dostarlimab appraisal only covers a small proportion of people with dMMR disease, as well as only being recommended in the Cancer Drugs Fund. The company noted that prevalence is higher in older people but many people are of working age, and most people with advanced or recurrent disease have expected survival of around 12 months after diagnosis. The company cited the government's Women's Health Strategy that prioritises improving screening and increasing survival rates for gynaecological cancers, including endometrial cancer, for at least 5 years after diagnosis. Clinical experts considered this treatment to be a 'game changer' and a 'huge step change' for people with endometrial cancer who otherwise have limited treatment options. One expert noted that conversations with people with endometrial cancer have changed substantially with this treatment from very difficult discussions to ones of hope. They noted that the response rate with current second-line chemotherapy is only 10% to 15% so the much better response with pembrolizumab and lenvatinib has a real tenable and meaningful difference. The clinical experts also noted that the treatment has shorter treatment duration, less frequent administration, very little monitoring, and no additional testing or unusual concomitant medication. A patient expert explained that they had many activities of daily living back, which make life worth living. At the second committee meeting, patient experts explained that the impact on people faced with chemotherapy or palliative care is not captured in the trials: the chance to live a life and thrive, not just survive. In response to consultation the company reiterated that it considered the combination innovative, noting the synergistic effect of pembrolizumab plus lenvatinib. During the second committee meeting, the company explained that the benefits associated with this technology exceed those directly modelled, noting that there are improvements that are not likely captured in the EQ‑5D questionnaire. A clinical expert noted that the duration of response is more remarkable with this treatment over the comparator. However, the committee noted that these can be directly modelled because duration of response is captured in the model. The committee also felt that the benefits noted by experts would be captured in the domains included on the EQ‑5D questionnaire. The committee concluded that the technology likely reflects a step-change in treatment, but did not identify any benefits not captured by the company's economic modelling. # Equality ## There are no equalities issues Patient experts noted that there are 2 groups disadvantaged by age and sex. Most people with endometrial cancer have been through the menopause and many have obesity, which may be associated with comorbidity and disability. Patient experts noted that, for these people, pembrolizumab with lenvatinib is a kinder treatment than chemotherapy, with a shorter infusion time and fewer side effects affecting quality of life. People who have not been through the menopause are often diagnosed at an advanced stage because healthcare professionals may not recognise symptoms in younger people and because there is no clear guidance about referral for people under 55 years. These people are let down by the health services so deserve access to the best available treatments to allow them to life a longer and more normal day-to-day life. Patient experts also highlighted that the ease of use of pembrolizumab plus lenvatinib compared with chemotherapy could benefit disabled people or people with a lower socioeconomic status. They explained that this is because pembrolizumab plus lenvatinib can be administered in local hospitals, so people would not have to travel to tertiary centres, which may be difficult and expensive. The committee acknowledged these issues, which had also been raised by stakeholders, and agreed that improving outcomes for people with endometrial cancer was important. However, the committee considered that because it was assessing pembrolizumab with lenvatinib for all groups raised its decision would not disadvantage any protected group. # Conclusion ## Pembrolizumab with lenvatinib is recommended The committee concluded that the most plausible ICERs are within the range usually considered a cost-effective use of resources when the end of life criteria are met. So, pembrolizumab with lenvatinib is recommended for treating previously treated advanced or recurrent endometrial cancer.	{'Recommendations': "Pembrolizumab plus lenvatinib is recommended, within its marketing authorisation, for treating advanced or recurrent endometrial cancer in adults:\n\nwhose cancer has progressed on or after platinum-based chemotherapy and\n\nwho cannot have curative surgery or radiotherapy.Pembrolizumab plus lenvatinib is recommended only if the companies provide them according to the commercial arrangements.\n\nWhy the committee made these recommendations\n\nThere is no standard treatment for previously treated advanced or recurrent endometrial cancer. But people would usually have non-platinum-based chemotherapy.\n\nEvidence from a clinical trial suggests that pembrolizumab plus lenvatinib increases the time until the cancer gets worse and how long people live compared with non-platinum-based chemotherapy. But, the results are uncertain because treatments not used in the NHS were used after non-platinum-based chemotherapy in the trial. So, the results may not apply to UK clinical practice.\n\nPembrolizumab plus lenvatinib meets NICE's criteria to be considered a life-extending treatment at the end of life. There is some uncertainty in the economic model about how long the effect of treatment lasts after people stop taking pembrolizumab at 2\xa0years. But the cost-effectiveness estimates are within the range considered acceptable for an end of life treatment. So, pembrolizumab plus lenvatinib is recommended.", 'Information about pembrolizumab with lenvatinib': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, MSD), in combination with lenvatinib (Lenvima, Eisai), is indicated for 'the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab and lenvatinib.\n\n# Price\n\nThe price of pembrolizumab is £2,630 per 100\xa0mg per 4‑ml vial (excluding VAT; BNF online accessed October\xa02022). The price of lenvatinib is £1,437 per 30 4‑mg or 10‑mg capsules (excluding VAT; BNF online accessed October\xa02022). The companies have commercial arrangements. These make pembrolizumab and lenvatinib available to the NHS with discounts. The sizes of the discounts are commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of the discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with advanced or recurrent endometrial cancer would welcome a new treatment option that is well tolerated\n\nEndometrial cancer has a devastating impact on life expectancy and quality of life. Recurrent or advanced endometrial cancer has a reported prognosis of 12\xa0months or less and 5‑year net survival rates of about 20%, compared with 89% for non-recurrent disease. Physical symptoms can be debilitating and include bleeding, pain, discomfort, reduced appetite, nausea and fatigue. There can also be long-term physical effects after treatment affecting quality of life, including ongoing pain, discomfort and incontinence. Patient experts emphasised the devastating impact of the disease on a person's quality of life. The impact is not just limited to physical health, but also mental health and wellbeing. Repeated intimate examinations can psychologically affect sexual function and intimacy, and lead to distance in relationships. People also experience reduced confidence going to social events because of tiredness, access to a toilet and fear of urinary leakage. Limited mobility and pain resulting in being unable to leave home or work (or work less than full-time) can lead to additional concerns and anxiety about finances. Patient experts highlighted the impact of feeling vulnerable while having chemotherapy, such as the fear of neutropenic sepsis. They also noted how it limits normal activities like seeing family and friends, because of the need to be near a hospital in case of a crisis. The lack of available treatment options other than chemotherapy can lead to a lack of hope for the future and fear of relapse. A patient expert described the importance of hope with the availability of a treatment that could offer a longer and fuller life. The committee heard that since taking pembrolizumab their quality of life had improved dramatically with them being able to take part in sports, have an active social life again and focus on their career. The committee concluded that people with advanced or recurrent endometrial cancer would welcome a new treatment option.\n\n# Current clinical management\n\n## There is no standard second-line treatment for advanced or recurrent endometrial cancer\n\nThe marketing authorisation for pembrolizumab with lenvatinib states that it is indicated for use after platinum-based chemotherapy. The committee noted that this could be when a person has advanced or recurrent disease after having neoadjuvant or adjuvant platinum-based chemotherapy, or has had platinum-based chemotherapy as first-line treatment for advanced disease. Clinical experts noted that there are no standard second-line treatment options for endometrial cancer when it has progressed or recurred. Options depend on the time interval from previous chemotherapy, previous response and toxicities to chemotherapy, and patient preference. After neoadjuvant platinum-based treatment, people could then have retreatment with platinum-based doublet chemotherapy. Clinical experts noted that possible options include carboplatin with paclitaxel (as retreatment), but they stated that retreatment with platinum-based chemotherapy is infrequently used in the advanced setting. This is because many people do not want to go through hair loss and risk neutropenic sepsis again and some people would be too frail at this point to have chemotherapy again. Pegylated doxorubicin, and weekly paclitaxel monotherapies, are more commonly used as second-line chemotherapies. The clinical experts noted that the response rate with current second-line chemotherapy is only 10% to 15%. One of the clinical experts stated that weekly paclitaxel may have a slightly higher response rate, but overall the 2 drugs have similar efficacies and are used equally, noting that neither option was good. The EAG highlighted that dostarlimab (see NICE technology appraisal guidance on dostarlimab for previously treated advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency, from now TA779) was recently appraised but could not be considered as a comparator because it was recommended for use in the Cancer Drugs Fund. Hormone therapy, such as high-dose progesterone, may be considered if chemotherapy cannot be tolerated, but it is usually part of palliative care or a 'holding measure' to improve wellbeing for people who are more unwell or less fit. The company noted that best supportive care, which had been included in the scope as a comparator, is used for people not well enough for active treatment so is not a relevant comparator. The EAG noted that people for whom active treatment is suitable may choose best supportive care, but noted that the aims are different so excluding this as a comparator is appropriate. The committee acknowledged that platinum-based chemotherapy retreatment may be the relevant comparator when neoadjuvant platinum-based chemotherapy was used in the previous 12\xa0months. However, it noted the comments from the clinical experts about the minimal use in this setting and noted that the company's scenario has a minor impact on the cost-effectiveness estimates. The committee concluded that there is no standard second-line treatment for advanced or recurrent endometrial cancer after platinum-based chemotherapy. But, for the purposes of this appraisal, doxorubicin or paclitaxel monotherapy are appropriate comparators.\n\n# Clinical evidence\n\n## Key evidence for pembrolizumab with lenvatinib comes from the KEYNOTE-775 trial, which is generalisable to the NHS\n\nThe company presented evidence from the KEYNOTE‑775 trial, an open-label randomised controlled trial in advanced or recurrent endometrial cancer that had progressed after platinum-based chemotherapy in adults who could not have surgery or radiotherapy. The trial compared pembrolizumab plus lenvatinib (n=411) with treatment chosen by physicians (either paclitaxel or doxorubicin monotherapy; n=416). The trial stratified people by mismatch repair status, with about 16% with mismatch repair deficiency (dMMR) or high microsatellite instability, and 84% with proficient mismatch repair (pMMR). The EAG noted, based on clinical input, that people in UK clinical practice are likely to be older and weigh more (and therefore need larger doses of pembrolizumab) than those in the trial. But it noted that both changes had a relatively small impact on the incremental cost-effectiveness ratio (ICER), particularly weight. The company disagreed with the EAG that higher age and weight would be seen in UK practice. It cited 2 real-world evidence studies that reported only a slightly greater age than people in KEYNOTE‑775 from the UK (none of these proportions can be reported here because they are marked as confidential by the company). The first study, ECHO, is a retrospective multicentre chart review of advanced or recurrent endometrial cancer that has progressed after a previous systemic therapy commissioned by the company. The number of people included is marked as confidential by the company. The second is Heffernan (2022; n=999), a retrospective review of the English National Cancer Registration and Analysis Service covering people whose cancer progressed to second-line chemotherapy (meaning those who had previous neoadjuvant platinum-based chemotherapy were not included). The clinical experts explained that people in the trial were a bit younger than in clinical practice, but because the drug combination is suitable for older people and those with a poor performance status, it was unlikely to affect the generalisability of the treatment to clinical practice. They noted that the age reported in the real-world studies was more representative of UK clinical practice. The committee acknowledged that there are often some differences between people selected for trials and those in clinical practice because of stringent selection criteria. The committee concluded that the trial was generalisable to NHS clinical practice for the purposes of this appraisal.\n\n## Pembrolizumab plus lenvatinib improves overall and progression-free survival compared with doxorubicin or paclitaxel monotherapy\n\nThe primary endpoints in the trial were progression-free survival and overall survival. The company presented evidence from an interim data cut (October 2020) from KEYNOTE‑775 in its original submission. At technical engagement the company presented the results from the final data cut (March 2022) but was not able to incorporate the final data cut in the economic model in time for the first committee meeting. In response to consultation on the draft guidance, the company incorporated the final data cut in the model. The final data cut had median 14.7\xa0months follow up. Progression-free survival reached 7.3\xa0months in the pembrolizumab plus lenvatinib arm compared with 3.8\xa0months in the paclitaxel or doxorubicin monotherapy arm. This resulted in a statistically significant improvement in progression-free survival for pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.48 to 0.66). At the final data cut, overall survival was 18.7\xa0months with pembrolizumab plus lenvatinib compared with 11.9\xa0months with paclitaxel or doxorubicin monotherapy. This resulted in a statistically significant improvement in overall survival for pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy (HR 0.65, 95% CI 0.55 to 0.77). The committee concluded that pembrolizumab plus lenvatinib improved both overall and progression-free survival compared with doxorubicin or paclitaxel monotherapy.\n\n## Pembrolizumab plus lenvatinib may be better in dMMR disease than in pMMR disease but there is not enough evidence to conclude this\n\nThe trial had stratified people based on MMR status and reported separate results for pMMR and dMMR disease from the interim data cut. The EAG noted a differential result by MMR status, with the dMMR population having a better response. For the dMMR group, the HR for overall survival was 0.37 (95% CI 0.22 to 0.62) compared with 0.68 (95% CI 0.56 to 0.84) in the pMMR group. Progression-free survival was 0.36 (95% CI 0.23 to 0.57) in the dMMR group compared with 0.60 (95% CI 0.50 to 0.72) in the pMMR group. The EAG acknowledged that the trial was not powered to explore differences and there was limited follow up, so it considered these subgroup analyses exploratory. However, the EAG's clinical expert noted that prognosis and treatment likely differs between these groups. They also noted that there was no separate cost-effectiveness analyses or model functionality to explore a scenario examining these groups separately. While the EAG noted that the impact on the ICER was unknown, pembrolizumab plus lenvatinib may have a lower ICER in dMMR because of the improved overall survival hazard ratio compared with the pMMR group. The company highlighted that it is not clear if the results are clinically or statistically meaningful because the trial was not powered for subgroups; the focus should be on the whole population as per the scope and the marketing authorisation. The company noted that there was a benefit of pembrolizumab plus lenvatinib over doxorubicin or paclitaxel monotherapy in both groups and that there was unmet need in both groups. It also noted that requiring mismatch repair status for treatment may limit access if biopsy or testing is delayed. The clinical experts noted that dMMR cancer may be more likely to relapse after surgery, but that the treatments offered have not differed until the recent guidance on dostarlimab for dMMR disease. They noted that some people with dMMR disease may have dostarlimab (though this is through the Cancer Drugs Fund; see section\xa03.2) so there is currently more unmet need for the pMMR group. The committee noted that, because dostarlimab is not recommended for routine commissioning, dostarlimab and pembrolizumab plus levantinib cannot be compared for this appraisal. The committee concluded that the study was not powered to consider subgroups based on MMR status and that the treatment pathways for routinely commissioned treatments for both subgroups are the same. It further concluded that both subgroups have had benefit from pembrolizumab plus lenvatinib compared with doxorubicin or paclitaxel monotherapy.\n\n# Economic model\n\n## The model structure is suitable for decision making\n\nThe company used a partitioned-survival economic model that included 3 health states: progression-free, progressed disease and death. The time horizon was 40\xa0years with a 1‑week cycle length. There was a 24‑month stopping rule for pembrolizumab, as in KEYNOTE‑775. The EAG considered that the model structure was reasonable. The committee concluded that the model structure was generally appropriate.\n\n## A one-knot spline model for extrapolating progression-free and overall survival is appropriate\n\nThe company originally considered standard parametric and two‑piece parametric curves for the extrapolation of overall and progression-free survival. However, the EAG noted that the hazards were not well tracked with these curves, and that the breakpoint was arbitrary and not determined in an appropriate way. The EAG felt that the company should have considered more sophisticated flexible models (such as cubic splines) because they may better fit the evidence and better track the hazards from the trial. The committee agreed that more sophisticated curves may have a better fit. This was particularly important given the uncertainty and substantial impact on the ICER of the overall survival extrapolation curve and treatment waning assumption. In response to consultation, the company used more flexible spline models and selected the one-knot spline model using an odds scale for the extrapolation of both overall and progression-free survival in both arms over time. The EAG considered the company's new approach to be more defensible and that the results had greater credibility. However, it noted that the justification for the placement of the knot was not clear, which leads to some uncertainty. At the committee meeting, the company advised that it used the default placement for the knot applied by the statistical package used. The EAG noted that the odds scale appears appropriate for the extrapolation of overall survival for the pembrolizumab plus lenvatinib arm, but all extrapolations predicted higher than observed hazards at the end of the observation period. The EAG did an additional scenario using a two‑knot spline for the comparator arm but this had minimal impact on the ICER. The EAG expressed some concerns about the extrapolation of progression-free survival, noting that a comparison of survival estimates was not provided between models for progression-free survival. It also noted that spline models fit the comparator arm better than the pembrolizumab plus lenvatinib arm and odds scale models better fit the pembrolizumab plus lenvatinib arm, but this was less clear for the comparator. The EAG would have liked to test alternative types of models but the company model only allows for the odds scale to be used. The committee concluded that, given the EAG scenarios having minimal impact on the ICER, the one-knot spline model was an appropriate choice for the extrapolation of both overall and progression-free survival in both arms.\n\n## Adjusting for the relative treatment effect to account for people having non-NHS treatments after paclitaxel or doxorubicin monotherapy gives the most optimistic estimate of the benefits of the technology\n\nAt the first committee meeting, the committee noted that the impact of having immunotherapies as subsequent therapy after paclitaxel or doxorubicin monotherapy in KEYNOTE‑775 on the resulting effect estimate had not been explored. In its response to consultation, the company noted that a proportion of people who had paclitaxel or doxorubicin monotherapy had later switched to pembrolizumab plus lenvatinib or other PD1/PD‑L1 or VEGF/VEGFR inhibitor therapies not available in this line in the UK. The proportion cannot be reported here because the company considered it to be confidential. It noted that the trial estimates therefore likely overestimate overall survival for paclitaxel or doxorubicin monotherapy and so underestimate the benefit of pembrolizumab plus lenvatinib compared with the comparator. The company explored different treatment switching methods, noting that all methods improve the benefit of pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy. However, it considered the two-stage estimation (TSE) method to be the least biased and used the adjusted data resulting from using this method in its updated base case. The EAG noted that the committee did not request treatment switching in its preferred base case as the company had done, it just noted that it had not been explored. The EAG noted that the company preferred the TSE method without recensoring, but the reason for excluding recensoring was not stated. However, the EAG acknowledged that differences in the hazard ratios are small and that the more conservative result (with a lower treatment estimate) was chosen. The EAG noted that the TSE method assumes the same treatment effect for all treatments after switching. But, that may not be appropriate because there were a variety of treatments that people switched to after paclitaxel or doxorubicin monotherapy and they may have different effectiveness. The EAG considers that the true effect likely lies between the adjusted and unadjusted values. The committee also noted that the TSE method uses a new baseline at progression, assuming all those who progressed have the same prognostic factors. However, the committee agreed that it is unlikely that all will have the same prognostic factors at the new baseline. It also noted that switching does not necessarily happen immediately after progression. The company had reported the time to progression (the exact value is marked as confidential by the company so cannot be reported here). The committee considered that this could have an impact in the model. The company responded that current treatment has limited impact on overall survival, so people are unlikely to benefit from subsequent therapies if their disease has not responded to current first-line treatments. It also noted that adjusting for specific treatments is more complicated. The committee agreed that a result that was adjusted for treatment switching was likely to be less biased than an unadjusted result but was also likely to be an overly optimistic assumption. So, it concluded that the true result was likely to be between the adjusted and unadjusted values.\n\n## It is appropriate to assume some treatment waning in the model\n\nKEYNOTE‑775 used a 2‑year stopping rule for pembrolizumab while lenvatinib was continued until clinical progression. The company's model assumed a continuing treatment effect after pembrolizumab is stopped at 2\xa0years with no treatment effect waning for the duration of the model's 40‑year time horizon. At the first committee meeting, the committee concluded that it preferred the EAG scenario that included treatment waning from years 3 to 5 after starting treatment, but would prefer to see alternative treatment waning scenarios. In response to consultation, the company maintained its position that treatment waning was not appropriate because there is no evidence to substantiate a treatment effect waning. But it explored several scenarios with waning of different proportions of patients from years 5 to 7 after starting treatment. The company argued that there is no evidence of treatment effect waning in KEYNOTE‑775, noting that both data cuts show a sustained longer-term benefit of pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy. It noted that the biological rationale of no waning is supported by the fact that pembrolizumab and lenvatinib work synergistically. It considered that lenvatinib may continue to benefit people when pembrolizumab stops by helping to shift tumour environment to immune-stimulatory state by inhibiting VEGFR and FGFR. The company's clinical experts confirmed that some people will have a durable response. The company also reported that a small proportion of people in KEYNOTE‑775 were still taking lenvatinib at the last recorded time point of 3\xa0years after starting treatment. The company cited several studies noting that waning was implausible and inappropriate. It noted that multiple pembrolizumab trials in other disease areas (melanoma and non-small cell carcinoma) with 5‑year follow up showed a sustained treatment effect. Hazard plots of pembrolizumab from 2 trials in melanoma showed no structural difference in hazards between the trial that had 2‑year stopping criteria and the trial that had no stopping criteria. The company also noted long-term durability of the treatment effect for CTLA4 agents in advanced melanoma from year\xa03 up to year\xa010 and stated that these work similarly to PD‑1 agents. So, the company considered that a similar plateau would likely occur with pembrolizumab plus lenvatinib in this population. It also noted a plateau for overall survival in KEYNOTE‑146, the longest-term data of the treatment in this population, with 30% survival reported at 5\xa0years. KEYNOTE‑146 was a multicentre, open-label arm phase\xa01b/2 basket trial of people with selected solid tumours who had pembrolizumab plus lenvatinib. It included 108\xa0women with pre-treated endometrial cancer with a median follow-up 34.7\xa0months (95% CI 30.9 to 41.2). The company also noted that in the recent appraisal of the same drug combination in renal cell carcinoma, waning was not included as a preferred assumption. The committee acknowledged that this was because no scenarios incorporating waning had been presented to that committee and its conclusion was not that no waning had been accepted but that treatment waning was plausible but uncertain. The EAG for that topic had acknowledged that there is uncertainty in the long-term treatment effect of pembrolizumab and, because lenvatinib continues after pembrolizumab stops, it is not possible to plausibly separate out any potential waning of treatment effect. The EAG for this topic noted that there is some evidence to support some duration of effect after stopping pembrolizumab, but it is not sufficient to conclude that there is no waning over time. It noted that it is difficult to generalise findings from studies in different disease areas to advanced or recurrent endometrial cancer because previous treatments, patient characteristics and disease severity differed. The EAG noted that the modelled 5‑year overall survival for pembrolizumab plus lenvatinib in KEYNOTE‑775 showed some evidence of a sustained response (the exact value cannot be reported because it is considered confidential). But this was lower than the 30% response reported in KEYNOTE‑146. It also noted that there was uncertainty in the survival rate reported in KEYNOTE‑146 because there was considerable censoring and few patients at risk at 28\xa0months. Clinical experts considered that the treatment effect of pembrolizumab plus lenvatinib was likely durable, but it must be assumed that there would be some treatment waning. NHS England's clinical lead noted that it is not appropriate to apply conclusions made for renal cell carcinoma to this appraisal. This is because tyrosine kinase inhibitors (TKI) are in routine commissioning for that disease but, for this indication, it is the first time a TKI would be seen in an established role. The committee noted that waning scenarios had not been explored in the renal cell carcinoma appraisal and so the conclusion in the renal cell carcinoma appraisal was not applicable to this appraisal. It agreed that this assumption should be explored based on evidence for this specific technology appraisal. The committee concluded that there was unlikely to be a continuing effect with no waning so it preferred some treatment waning in the model.\n\n## There is likely to be a period with a sustained treatment effect before waning starts\n\nThe committee acknowledged that levantinib could continue for some people for a period of time after pembrolizumab had been stopped. But it noted that data presented showed that only a small proportion of people were still on levantinib at 3‑year follow up. It noted that it was unclear how lenvatinib alone (or the synergistic effect of both) could impact a continued benefit from the immunotherapy after it had been stopped. But the committee agreed that it was likely there was a period with a sustained treatment effect before waning was likely to start. So, the committee reconsidered its previously preferred assumption of waning from year 3 to 5 after starting treatment as likely to be pessimistic (this was the EAG's preferred assumption, which was consistent with waning assumptions preferred by NICE in other immunotherapies). However, it was difficult to conclude an appropriate time when waning would start. The committee noted that the company's 3 scenarios examining waning from year\xa05 (the maximum follow up of KEYNOTE‑146) to year\xa07 after starting treatment had been applied to 60%, 70% and 80% of people. The committee acknowledged that there may be some people who have a durable response to treatment. But it agreed that the company's approach was unusual and it was likely that a more appropriate methodology such as a mixture cure model would be needed when taking this approach. The committee therefore agreed to consider all patients in any waning scenario. It concluded that the company's scenario of waning at 5 to 7 years after starting treatment was plausible. But it used the EAG's scenario of all patients waning at 5 to 7 years after starting treatment for decision making because it considered waning of all patients.\n\n## Using progression status to derive utilities is appropriate\n\nThe company used a time to death approach to derive utilities in the model. The EAG preferred an approach of deriving utilities using progression status because it is more consistent with the model structure. It considered that the company's approach 'divorced health-related quality of life from disease status' in the model. The company noted that the time to death approach is becoming more common and allows finer gradations in utility because it distinguishes between multiple health states not just 2. It considered that the limited utility assessments in immunotherapy trials after disease progression means that the time to death approach is more comprehensive because it captures patient utilities across the full spectrum of the disease, including being close to death. The committee noted that the dostarlimab appraisal (TA779) used a time-to-death utility approach but included disease progression as a covariate to predict utility. The committee noted that the company's approach in this appraisal limits the amount of information informing health states. So while the approach may provide more granular information than the progression status approach, the increased uncertainty in the utility estimates obscures differences between each of the time-to-death categories. In response to consultation, the company updated its base case and used an approach similar to that taken for TA779, except it used 6 time to death (TTD) categories (less than 30\xa0days, 30 to 89\xa0days, 90 to 179\xa0days, 180 to 269\xa0days, 270 to 359\xa0days, 360\xa0days and longer) for both the pre- and post-progressed health states rather than the 2 time to death categorise used in TA779 (TTD less than 180\xa0days and TTD 180\xa0days and longer). The EAG noted that the committee concerns about data required and associated uncertainty are still relevant. The EAG conducted a scenario using the approach used in TA779, which made a small to moderate impact on the ICER. The committee appreciated the company trying an alternative method to incorporate progression status. The committee was unclear of the reason for the cut-offs for the 6 TTD categories chosen by the company. The committee and clinical expert looked at the utilities estimated using the company's approach for the health states by the 6 TTD categories. They concluded that it was difficult to know which method was most appropriate given the information that was provided from the company on its scenarios. The committee maintained its conclusion from the first committee meeting that the EAG's approach to deriving utilities using progression status is more appropriate.\n\n## People included in the model should be slightly older than reported in KEYNOTE-775 but younger than used by the EAG\n\nAs discussed in section\xa03.3, clinical experts felt KEYNOTE‑775 was generalisable to UK clinical practice. But, they felt that the average age would be slightly higher than that used by the company and less than that used by the EAG. The experts thought that the most accurate age was likely be around 67, which is between the trial and EAG's estimate and is close to what was reported in the real-world studies. While changing age in the model did not have a very large influence on the results, the committee felt that it was appropriate to include the more applicable average age in the model, as reported in ECHO. Both the company and EAG incorporated a mean age of 67 in their revised base cases. The committee concluded that the age now used in the model is most appropriate.\n\n# End of life\n\n## Pembrolizumab with lenvatinib meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Life expectancy for people with previously treated advanced or recurrent endometrial cancer is typically less than 24\xa0months. The company noted that, at the interim data cut, the paclitaxel or doxorubicin monotherapy arm of KEYNOTE‑775 reported mean survival of 11.4\xa0months at the interim data cut and 11.9\xa0months at the final data cut. It also noted that survival was less than 12\xa0months in both ECHO (the exact value is confidential so cannot be reported) and Heffernan (2022), in which median survival was 10.3\xa0months. This was consistent with the company's model (the exact value is confidential so cannot be reported) as well as the clinical expectations reported to the company of life expectancy being less than 12\xa0months. The EAG noted that survival in the EAG base-case model was around 24\xa0months. But it received clinical input that average life expectancy was plausibly less than 24\xa0months so was satisfied it met this criterion. Pembrolizumab with lenvatinib appears to extend life longer than 3\xa0months. The company noted that, at both the interim and final data cuts, the pembrolizumab with lenvatinib arm extended life by 6.9\xa0months over the paclitaxel or doxorubicin monotherapy arm. This was consistent with the company's modelled mean survival which cannot be reported here because it is marked as confidential. The EAG noted that clinical input it received supports a survival gain of at least 3\xa0months for both dMMR and pMMR. The committee concluded that pembrolizumab with lenvatinib meets the end of life criteria.\n\n# Cost-effectiveness estimates\n\n## The most plausible ICER is less than £50,000 per QALY gained\n\nThe company's updated base-case deterministic and probabilistic ICERs for pembrolizumab plus lenvatinib compared with paclitaxel or doxorubicin monotherapy were less than £50,000 per QALY gained. This was when confidential commercial arrangements for pembrolizumab, lenvatinib and other treatments in the model were included, so the exact ICERs cannot be reported here. However, the company's base case did not incorporate all the committee's preferred assumptions, including:\n\napplying waning from years 5 to 7 after starting treatment (3 to 5 years after treatment with pembrolizumab stops; see section\xa03.9)\n\nusing progression status to derive utilities (see section\xa03.10).The committee concluded that the most plausible ICERs using its preferred assumptions were generated from the EAG's scenarios. It was between the EAG's scenario adjusted for treatment switching and the EAG's scenario unadjusted for treatment switching (see section\xa03.8). The committee noted that these were less than £50,000 per QALY gained.\n\n# Innovation\n\n## It is uncertain whether pembrolizumab with lenvatinib meets NICE's criteria for an innovative treatment\n\nNICE defines innovation as a 'step-change' in treatment with benefits not accounted for in the modelling. The company stated that there is uncaptured value because there is no standard care and very few treatment options for people with previously treated advanced or recurrent endometrial cancer. It noted that there were no NICE appraisals for endometrial cancer until recently (dostarlimab, TA779). The dostarlimab appraisal only covers a small proportion of people with dMMR disease, as well as only being recommended in the Cancer Drugs Fund. The company noted that prevalence is higher in older people but many people are of working age, and most people with advanced or recurrent disease have expected survival of around 12\xa0months after diagnosis. The company cited the government's Women's Health Strategy that prioritises improving screening and increasing survival rates for gynaecological cancers, including endometrial cancer, for at least 5\xa0years after diagnosis. Clinical experts considered this treatment to be a 'game changer' and a 'huge step change' for people with endometrial cancer who otherwise have limited treatment options. One expert noted that conversations with people with endometrial cancer have changed substantially with this treatment from very difficult discussions to ones of hope. They noted that the response rate with current second-line chemotherapy is only 10% to 15% so the much better response with pembrolizumab and lenvatinib has a real tenable and meaningful difference. The clinical experts also noted that the treatment has shorter treatment duration, less frequent administration, very little monitoring, and no additional testing or unusual concomitant medication. A patient expert explained that they had many activities of daily living back, which make life worth living. At the second committee meeting, patient experts explained that the impact on people faced with chemotherapy or palliative care is not captured in the trials: the chance to live a life and thrive, not just survive. In response to consultation the company reiterated that it considered the combination innovative, noting the synergistic effect of pembrolizumab plus lenvatinib. During the second committee meeting, the company explained that the benefits associated with this technology exceed those directly modelled, noting that there are improvements that are not likely captured in the EQ‑5D questionnaire. A clinical expert noted that the duration of response is more remarkable with this treatment over the comparator. However, the committee noted that these can be directly modelled because duration of response is captured in the model. The committee also felt that the benefits noted by experts would be captured in the domains included on the EQ‑5D questionnaire. The committee concluded that the technology likely reflects a step-change in treatment, but did not identify any benefits not captured by the company's economic modelling.\n\n# Equality\n\n## There are no equalities issues\n\nPatient experts noted that there are 2 groups disadvantaged by age and sex. Most people with endometrial cancer have been through the menopause and many have obesity, which may be associated with comorbidity and disability. Patient experts noted that, for these people, pembrolizumab with lenvatinib is a kinder treatment than chemotherapy, with a shorter infusion time and fewer side effects affecting quality of life. People who have not been through the menopause are often diagnosed at an advanced stage because healthcare professionals may not recognise symptoms in younger people and because there is no clear guidance about referral for people under 55\xa0years. These people are let down by the health services so deserve access to the best available treatments to allow them to life a longer and more normal day-to-day life. Patient experts also highlighted that the ease of use of pembrolizumab plus lenvatinib compared with chemotherapy could benefit disabled people or people with a lower socioeconomic status. They explained that this is because pembrolizumab plus lenvatinib can be administered in local hospitals, so people would not have to travel to tertiary centres, which may be difficult and expensive. The committee acknowledged these issues, which had also been raised by stakeholders, and agreed that improving outcomes for people with endometrial cancer was important. However, the committee considered that because it was assessing pembrolizumab with lenvatinib for all groups raised its decision would not disadvantage any protected group.\n\n# Conclusion\n\n## Pembrolizumab with lenvatinib is recommended\n\nThe committee concluded that the most plausible ICERs are within the range usually considered a cost-effective use of resources when the end of life criteria are met. So, pembrolizumab with lenvatinib is recommended for treating previously treated advanced or recurrent endometrial cancer."}	https://www.nice.org.uk/guidance/ta904	Evidence-based recommendations on pembrolizumab (Keytruda) with lenvatinib (Lenvima) for treating advanced or recurrent endometrial cancer in adults.
5f52bb5bf021baa7a9564b9e9d36370170cbcc6e	nice	Upadacitinib for previously treated moderately to severely active Crohn's disease	Upadacitinib for previously treated moderately to severely active Crohn's disease Evidence-based recommendations on upadacitinib (Rinvoq) for previously treated moderately to severely active Crohn’s disease in adults. # Recommendations Upadacitinib is recommended as an option for treating moderately to severely active Crohn's disease in adults, only if: the disease has not responded well enough or lost response to a previous biological treatment or a previous biological treatment was not tolerated or tumour necrosis factor (TNF)-alpha inhibitors are contraindicated.Upadacitinib is only recommended if the company provides it according to the commercial arrangement. If people with the condition and their clinicians consider upadacitinib to be 1 of a range of suitable treatments, after discussing the advantages and disadvantages of all the options, use the least expensive. Take into account the administration costs, dosage, price per dose and commercial arrangements. These recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard treatments for moderately to severely active Crohn's disease when conventional treatments stop working are biological treatments (such as TNF-alpha inhibitors, ustekinumab or vedolizumab). Clinical trial evidence shows that upadacitinib increases the likelihood of disease remission compared with placebo. Indirect comparisons of upadacitinib with ustekinumab and vedolizumab suggest that it is as effective. A cost comparison suggests that upadacitinib has a similar or lower cost than vedolizumab and ustekinumab. So upadacitinib is recommended.# Information about upadacitinib # Marketing authorisation indication Upadacitinib (Rinvoq, AbbVie) is indicated 'for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for upadacitinib. # Price The list price per 28‑tablet pack of upadacitinib is £805.56 for 15‑mg tablets, £1,281.54 for 30‑mg tablets and £2,087.10 for 45-mg tablets (excluding VAT; BNF online, accessed May 2023). The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by AbbVie, a review of this submission by the external assessment group (EAG), and submissions from stakeholders. See the committee papers for full details of the evidence. # The condition ## Living with the condition Crohn's disease is a life-long inflammatory condition of the gastrointestinal tract. It is characterised by recurrent relapses with acute exacerbations and periods of remission. Symptoms include diarrhoea, abdominal pain, fatigue, weight loss and blood or mucus in stools. The patient experts explained that the disease is unpredictable and can have a profound and devastating impact on all aspects of life, including work, education and social life. Treatments for moderately to severely active Crohn's disease include conventional therapy such as glucocorticoids and immunomodulators. This is followed by biological treatments if there is inadequate response, intolerance or contraindication to conventional therapy. The clinical experts explained that there is an unmet need for new treatments for Crohn's disease, particularly for people whose disease is refractory or has lost response to treatment. They also explained that upadacitinib has a different mechanism of action to other treatments. Therefore, it may be effective for a proportion of people whose disease does not respond to these existing treatments. The patient experts explained that having more treatment options available is important, because not all available treatments work for everyone. They also highlighted that upadacitinib is an oral drug, which is a benefit over other treatment options. The committee concluded that more treatment options for severely to moderately active Crohn's disease would be welcomed. # Decision problem ## Comparators The company proposed that upadacitinib should be considered for moderately to severely active Crohn's disease in adults who have had a biological therapy that was not tolerated or did not work well enough, or when a tumour necrosis factor (TNF)‑alpha inhibitor is unsuitable. It would be an alternative to the biological treatments ustekinumab and vedolizumab. This is a narrower population than the marketing authorisation for upadacitinib, which also allows use after conventional therapy only, or if conventional therapy is not tolerated or is contraindicated (see section 2.1). The clinical experts explained that the company's positioning of upadacitinib is appropriate and would reflect its use in clinical practice. The EAG highlighted that, in addition to ustekinumab and vedolizumab, the TNF-alpha inhibitors infliximab and adalimumab may also be relevant comparators, because they are recommended for severe Crohn's disease (NICE's technology appraisal guidance on infliximab and adalimumab for the treatment of Crohn's disease). The clinical experts explained that TNF-alpha inhibitors are usually used as first-line advanced therapy. They explained that if ustekinumab is used as first-line advanced therapy, in line with NICE's technology appraisal guidance on ustekinumab for moderately to severely active Crohn's disease after previous treatment, it is usually because TNF‑alpha inhibitors are unsuitable. In this case, it is inappropriate to use TNF‑alpha inhibitors and so vedolizumab is usually used as second-line biological treatment. The committee concluded that the company's positioning of upadacitinib as an alternative to vedolizumab and ustekinumab was appropriate. ## Comparators for people with risk factors The clinical expert submissions highlighted a safety review of Janus Kinase inhibitors, such as upadacitinib. The safety review led to an update of the special warnings and precautions for use in the summary of product characteristics for upadacitinib. It states that for some people, upadacitinib should only be used if there are no other suitable treatments. It applies to people aged 65 years and older, people with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, and people with malignancy risk factors. The clinical experts explained that clinical judgement is needed to determine the suitability of upadacitinib for each person based on the risks and benefits of treatment. They stated that ustekinumab and vedolizumab remain the relevant comparators for the subgroups highlighted in the special warning. This is because there are no treatment alternatives for these people and retreatment would be offered instead of best supportive care. The committee concluded that ustekinumab and vedolizumab were relevant comparators for the whole population proposed by the company. # Clinical effectiveness ## Data sources Three clinical trials compared upadacitinib with placebo: U‑EXCEL, U‑EXCEED and U‑ENDURE. U‑EXCEL and U‑EXCEED were studies of upadacitinib induction treatment. They both included a randomised-controlled period for 12 weeks (part 1) and an extended treatment period. U‑EXCEL (n=526 for part 1) included people whose disease had had inadequate response or were intolerant to conventional therapy only (conventional care failure) or to biological treatment (biological failure). U‑EXCEED (n=495 for part 1) included only a biological failure population. The committee noted that it was appropriate to consider the biological failure subgroup because this was in line with where the company had positioned upadacitinib in the treatment pathway (see section 3.2). For the biological failure population, both trials showed a statistically significant improvement in the rate of clinical remission and endoscopic response with a 45‑mg induction dose of upadacitinib compared with placebo at 12 weeks. The third study, U‑ENDURE, was a study of upadacitinib maintenance treatment. It was a randomised controlled trial that also included people who had had conventional care failure or biological failure. Cohort 1 of U‑ENDURE (n=502) included people who had had clinical response after 12 weeks of upadacitinib in either U‑EXCEL or U‑EXCEED. For the biological failure population, cohort 1 of U‑ENDURE showed a statistically significant improvement in rates of clinical remission and endoscopic response with a 15‑mg and 30‑mg maintenance dose of upadacitinib compared with placebo at 52 weeks. The data is confidential and cannot be reported here. The committee concluded that upadacitinib was more clinically effective than placebo in the biological failure population for both induction and maintenance treatment. ## Clinical-effectiveness network meta-analyses There were no trials directly comparing upadacitinib with ustekinumab or vedolizumab. So, the company did network meta-analyses to indirectly compare the clinical effectiveness of these treatments. It presented separate network meta-analyses for induction and maintenance treatment for the biological failure and conventional care failure subgroups. The EAG explained that for induction treatment in the biological failure population, the network meta-analysis indicated that upadacitinib is more effective than ustekinumab and vedolizumab for the outcome of clinical remission. For clinical response it has similar efficacy. For maintenance treatment in the biological failure population, the network meta-analysis indicated that upadacitinib has similar efficacy to ustekinumab and vedolizumab for the outcome of clinical remission. The EAG highlighted that only people who had achieved clinical response during induction treatment were enrolled into the trials of maintenance treatment in the network meta-analysis. Therefore, the EAG considered that a limitation of the maintenance treatment network meta-analysis was that it could not provide evidence of effectiveness for people whose disease had not previously responded to upadacitinib. However, the clinical experts explained that only people whose disease has responded to induction treatment would be offered maintenance treatment in practice. The company also explained that all the trials in the maintenance network meta-analysis were designed so that only people whose disease had responded to induction treatment were included in the maintenance treatment trial. Therefore, it believed the studies included in the network meta-analysis were comparable. The EAG accepted that there was no better method that could have been used to demonstrate clinical effectiveness of maintenance treatment given the available evidence for upadacitinib and its comparators. The committee concluded that the network meta-analyses results supported the company's position that upadacitinib has similar clinical effectiveness to ustekinumab and vedolizumab. # Safety analysis ## Adverse events network meta-analyses The company presented network meta-analyses for induction and maintenance treatment to compare the adverse event outcomes of upadacitinib with ustekinumab and vedolizumab. The results showed that for both induction and maintenance treatment, serious adverse events were comparable between arms, with the credible intervals spanning the line of no effect for all comparisons. The EAG highlighted that discontinuation of treatment due to adverse events occurred more often with upadacitinib. However, the credible intervals crossed the line of no effect for all comparisons. The clinical expert explained that discontinuation rates are low for all the drugs and are therefore of limited relevance in clinical practice. The committee concluded that the network meta-analyses indicated that upadacitinib was likely to have a similar adverse event profile to ustekinumab and vedolizumab. # Cost comparison ## Cost-comparison estimates The company presented a base case cost-comparison analysis that modelled the total costs of upadacitinib, ustekinumab and vedolizumab over 1 year. This included the costs for induction and maintenance treatment. It also presented an analysis that showed the total costs of each treatment in the second and subsequent years of treatment. It considered that the clinical evidence available supported the assumption of clinical equivalence between upadacitinib, ustekinumab and vedolizumab. The company and the EAG also ran several scenario analyses that demonstrated the impact on the total costs of each treatment compared with the base case. This included changing the proportion of people having the different available doses of each drug and using different sources for intravenous drug administration costs. Taking into account the confidential prices for upadacitinib, ustekinumab and vedolizumab, the committee concluded that the total costs associated with upadacitinib were similar to or lower than the costs for ustekinumab and vedolizumab. The discounts for all treatments are confidential, so the incremental costs cannot be shared here. # Conclusion ## Recommendation The committee concluded that the criteria for a cost comparison recommendation were met because: upadacitinib provided similar overall health benefits to those of ustekinumab or vedolizumab, and the total costs associated with upadacitinib were similar to or lower than the total costs associated with ustekinumab or vedolizumab.The committee therefore recommended upadacitinib as an option for moderately to severely active Crohn's disease when the disease has not responded well enough or lost response to previous biological treatment or a previous biological treatment was not tolerated, or if a TNF‑alpha inhibitor is contraindicated.	{'Recommendations': "Upadacitinib is recommended as an option for treating moderately to severely active Crohn's disease in adults, only if:\n\nthe disease has not responded well enough or lost response to a previous biological treatment or\n\na previous biological treatment was not tolerated or\n\ntumour necrosis factor (TNF)-alpha inhibitors are contraindicated.Upadacitinib is only recommended if the company provides it according to the commercial arrangement.\n\nIf people with the condition and their clinicians consider upadacitinib to be 1\xa0of a range of suitable treatments, after discussing the advantages and disadvantages of all the options, use the least expensive. Take into account the administration costs, dosage, price per dose and commercial arrangements.\n\nThese recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard treatments for moderately to severely active Crohn's disease when conventional treatments stop working are biological treatments (such as TNF-alpha inhibitors, ustekinumab or vedolizumab).\n\nClinical trial evidence shows that upadacitinib increases the likelihood of disease remission compared with placebo. Indirect comparisons of upadacitinib with ustekinumab and vedolizumab suggest that it is as effective.\n\nA cost comparison suggests that upadacitinib has a similar or lower cost than vedolizumab and ustekinumab. So upadacitinib is recommended.", 'Information about upadacitinib': "# Marketing authorisation indication\n\nUpadacitinib (Rinvoq, AbbVie) is indicated 'for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for upadacitinib.\n\n# Price\n\nThe list price per 28‑tablet pack of upadacitinib is £805.56 for 15‑mg tablets, £1,281.54 for 30‑mg tablets and £2,087.10 for 45-mg tablets (excluding VAT; BNF online, accessed May\xa02023).\n\nThe company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by AbbVie, a review of this submission by the external assessment group (EAG), and submissions from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Living with the condition\n\nCrohn's disease is a life-long inflammatory condition of the gastrointestinal tract. It is characterised by recurrent relapses with acute exacerbations and periods of remission. Symptoms include diarrhoea, abdominal pain, fatigue, weight loss and blood or mucus in stools. The patient experts explained that the disease is unpredictable and can have a profound and devastating impact on all aspects of life, including work, education and social life. Treatments for moderately to severely active Crohn's disease include conventional therapy such as glucocorticoids and immunomodulators. This is followed by biological treatments if there is inadequate response, intolerance or contraindication to conventional therapy. The clinical experts explained that there is an unmet need for new treatments for Crohn's disease, particularly for people whose disease is refractory or has lost response to treatment. They also explained that upadacitinib has a different mechanism of action to other treatments. Therefore, it may be effective for a proportion of people whose disease does not respond to these existing treatments. The patient experts explained that having more treatment options available is important, because not all available treatments work for everyone. They also highlighted that upadacitinib is an oral drug, which is a benefit over other treatment options. The committee concluded that more treatment options for severely to moderately active Crohn's disease would be welcomed.\n\n# Decision problem\n\n## Comparators\n\nThe company proposed that upadacitinib should be considered for moderately to severely active Crohn's disease in adults who have had a biological therapy that was not tolerated or did not work well enough, or when a tumour necrosis factor (TNF)‑alpha inhibitor is unsuitable. It would be an alternative to the biological treatments ustekinumab and vedolizumab. This is a narrower population than the marketing authorisation for upadacitinib, which also allows use after conventional therapy only, or if conventional therapy is not tolerated or is contraindicated (see section\xa02.1). The clinical experts explained that the company's positioning of upadacitinib is appropriate and would reflect its use in clinical practice. The EAG highlighted that, in addition to ustekinumab and vedolizumab, the TNF-alpha inhibitors infliximab and adalimumab may also be relevant comparators, because they are recommended for severe Crohn's disease (NICE's technology appraisal guidance on infliximab and adalimumab for the treatment of Crohn's disease). The clinical experts explained that TNF-alpha inhibitors are usually used as first-line advanced therapy. They explained that if ustekinumab is used as first-line advanced therapy, in line with NICE's technology appraisal guidance on ustekinumab for moderately to severely active Crohn's disease after previous treatment, it is usually because TNF‑alpha inhibitors are unsuitable. In this case, it is inappropriate to use TNF‑alpha inhibitors and so vedolizumab is usually used as second-line biological treatment. The committee concluded that the company's positioning of upadacitinib as an alternative to vedolizumab and ustekinumab was appropriate.\n\n## Comparators for people with risk factors\n\nThe clinical expert submissions highlighted a safety review of Janus Kinase inhibitors, such as upadacitinib. The safety review led to an update of the special warnings and precautions for use in the summary of product characteristics for upadacitinib. It states that for some people, upadacitinib should only be used if there are no other suitable treatments. It applies to people aged 65\xa0years and older, people with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, and people with malignancy risk factors. The clinical experts explained that clinical judgement is needed to determine the suitability of upadacitinib for each person based on the risks and benefits of treatment. They stated that ustekinumab and vedolizumab remain the relevant comparators for the subgroups highlighted in the special warning. This is because there are no treatment alternatives for these people and retreatment would be offered instead of best supportive care. The committee concluded that ustekinumab and vedolizumab were relevant comparators for the whole population proposed by the company.\n\n# Clinical effectiveness\n\n## Data sources\n\nThree clinical trials compared upadacitinib with placebo: U‑EXCEL, U‑EXCEED and U‑ENDURE. U‑EXCEL and U‑EXCEED were studies of upadacitinib induction treatment. They both included a randomised-controlled period for 12\xa0weeks (part\xa01) and an extended treatment period. U‑EXCEL (n=526 for part\xa01) included people whose disease had had inadequate response or were intolerant to conventional therapy only (conventional care failure) or to biological treatment (biological failure). U‑EXCEED (n=495 for part\xa01) included only a biological failure population. The committee noted that it was appropriate to consider the biological failure subgroup because this was in line with where the company had positioned upadacitinib in the treatment pathway (see section\xa03.2). For the biological failure population, both trials showed a statistically significant improvement in the rate of clinical remission and endoscopic response with a 45‑mg induction dose of upadacitinib compared with placebo at 12\xa0weeks. The third study, U‑ENDURE, was a study of upadacitinib maintenance treatment. It was a randomised controlled trial that also included people who had had conventional care failure or biological failure. Cohort\xa01 of U‑ENDURE (n=502) included people who had had clinical response after 12\xa0weeks of upadacitinib in either U‑EXCEL or U‑EXCEED. For the biological failure population, cohort 1 of U‑ENDURE showed a statistically significant improvement in rates of clinical remission and endoscopic response with a 15‑mg and 30‑mg maintenance dose of upadacitinib compared with placebo at 52\xa0weeks. The data is confidential and cannot be reported here. The committee concluded that upadacitinib was more clinically effective than placebo in the biological failure population for both induction and maintenance treatment.\n\n## Clinical-effectiveness network meta-analyses\n\nThere were no trials directly comparing upadacitinib with ustekinumab or vedolizumab. So, the company did network meta-analyses to indirectly compare the clinical effectiveness of these treatments. It presented separate network meta-analyses for induction and maintenance treatment for the biological failure and conventional care failure subgroups. The EAG explained that for induction treatment in the biological failure population, the network meta-analysis indicated that upadacitinib is more effective than ustekinumab and vedolizumab for the outcome of clinical remission. For clinical response it has similar efficacy. For maintenance treatment in the biological failure population, the network meta-analysis indicated that upadacitinib has similar efficacy to ustekinumab and vedolizumab for the outcome of clinical remission. The EAG highlighted that only people who had achieved clinical response during induction treatment were enrolled into the trials of maintenance treatment in the network meta-analysis. Therefore, the EAG considered that a limitation of the maintenance treatment network meta-analysis was that it could not provide evidence of effectiveness for people whose disease had not previously responded to upadacitinib. However, the clinical experts explained that only people whose disease has responded to induction treatment would be offered maintenance treatment in practice. The company also explained that all the trials in the maintenance network meta-analysis were designed so that only people whose disease had responded to induction treatment were included in the maintenance treatment trial. Therefore, it believed the studies included in the network meta-analysis were comparable. The EAG accepted that there was no better method that could have been used to demonstrate clinical effectiveness of maintenance treatment given the available evidence for upadacitinib and its comparators. The committee concluded that the network meta-analyses results supported the company's position that upadacitinib has similar clinical effectiveness to ustekinumab and vedolizumab.\n\n# Safety analysis\n\n## Adverse events network meta-analyses\n\nThe company presented network meta-analyses for induction and maintenance treatment to compare the adverse event outcomes of upadacitinib with ustekinumab and vedolizumab. The results showed that for both induction and maintenance treatment, serious adverse events were comparable between arms, with the credible intervals spanning the line of no effect for all comparisons. The EAG highlighted that discontinuation of treatment due to adverse events occurred more often with upadacitinib. However, the credible intervals crossed the line of no effect for all comparisons. The clinical expert explained that discontinuation rates are low for all the drugs and are therefore of limited relevance in clinical practice. The committee concluded that the network meta-analyses indicated that upadacitinib was likely to have a similar adverse event profile to ustekinumab and vedolizumab.\n\n# Cost comparison\n\n## Cost-comparison estimates\n\nThe company presented a base case cost-comparison analysis that modelled the total costs of upadacitinib, ustekinumab and vedolizumab over 1\xa0year. This included the costs for induction and maintenance treatment. It also presented an analysis that showed the total costs of each treatment in the second and subsequent years of treatment. It considered that the clinical evidence available supported the assumption of clinical equivalence between upadacitinib, ustekinumab and vedolizumab. The company and the EAG also ran several scenario analyses that demonstrated the impact on the total costs of each treatment compared with the base case. This included changing the proportion of people having the different available doses of each drug and using different sources for intravenous drug administration costs. Taking into account the confidential prices for upadacitinib, ustekinumab and vedolizumab, the committee concluded that the total costs associated with upadacitinib were similar to or lower than the costs for ustekinumab and vedolizumab. The discounts for all treatments are confidential, so the incremental costs cannot be shared here.\n\n# Conclusion\n\n## Recommendation\n\nThe committee concluded that the criteria for a cost comparison recommendation were met because:\n\nupadacitinib provided similar overall health benefits to those of ustekinumab or vedolizumab, and\n\nthe total costs associated with upadacitinib were similar to or lower than the total costs associated with ustekinumab or vedolizumab.The committee therefore recommended upadacitinib as an option for moderately to severely active Crohn's disease when the disease has not responded well enough or lost response to previous biological treatment or a previous biological treatment was not tolerated, or if a TNF‑alpha inhibitor is contraindicated."}	https://www.nice.org.uk/guidance/ta905	Evidence-based recommendations on upadacitinib (Rinvoq) for previously treated moderately to severely active Crohn’s disease in adults.
c519dc69bb757edfd94000ed4a1eea5559b99e2c	nice	Caesarean birth	Caesarean birth This guideline covers when to offer and discuss caesarean birth, procedural aspects of the operation, and care after caesarean birth. It aims to improve the consistency and quality of care for women and pregnant people who are thinking about having a caesarean birth or have had a caesarean birth in the past and are now pregnant again. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. This guideline uses specific, inclusive language to describe the population groups it covers (for example, women and pregnant people, or trans and non-binary people) except when: the evidence for the recommendation has not been reviewed, and it is not certain from expert opinion whether it can cover more groups, or the evidence has been reviewed, but the information available for some groups at the time of development was too limited to make specific recommendations, or -nly a very limited number of recommendations have been updated in direct response to new evidence or to reflect a change in practice. Healthcare professionals should use their clinical judgement when implementing gender-specific recommendations, taking into account the individual's circumstances, needs and preferences, and ensuring all people are treated with dignity and respect throughout their care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Planning mode of birth ## Provision of information Offer all pregnant women information and support to enable them to make informed decisions about childbirth. Make sure that: the information is evidence based any information provided is accessible, ideally with a choice of formats to suit different women's needs the language used in any information (written or oral) is respectful and suitable for the woman, taking into account any personal, cultural or religious factors that could form part of the woman's choices the women's preferences and concerns are central to the decision-making process. Discuss mode of birth with all pregnant women early in their pregnancy. Cover information such as: around 25% to 30% of women have a caesarean birth factors that mean women may need a caesarean birth (for example, increased maternal age and BMI) common indications for emergency caesarean birth include slow progression of labour or concern about fetal condition planned place of birth may affect the mode of birth (see choosing planned place of birth in the NICE guideline on intrapartum care) what the caesarean birth procedure involves how a caesarean birth may impact on the postnatal period (for example, need for pain relief) implications for future pregnancies and birth after caesarean birth or vaginal birth (for example, after a caesarean birth the chances of caesarean birth in a future pregnancy may be increased). ## Benefits and risks of caesarean and vaginal birth Discuss the benefits and risks of both caesarean and vaginal birth with women, taking into account their circumstances, concerns, priorities and plans for future pregnancies. Using the information in appendix A, explain to women that: there are benefits and risks associated with both vaginal and caesarean birth, some of which are very small absolute risks and some are greater absolute risks, and they will need to decide which risks are more (or less) acceptable to them there are other risks not included in these tables that might be relevant to their individual circumstances (for example placental adherence problems from multiple caesarean births, fetal lacerations in caesarean birth, term birth injuries with vaginal birth or caesarean birth) these tables give summary estimates only and are intended to help discussions, but precise numerical risk estimates cannot be given for individual women. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on benefits and risks of caesarean and vaginal birth . Full details of the evidence and the committee's discussion are in evidence review A: the benefits and risks of planned caesarean birth. Loading. Please wait. # Planned caesarean birth ## Breech presentation Discuss with women the benefits and risks of planned vaginal birth versus planned caesarean birth for breech presentation, and the option of external cephalic version. Offer women who have an uncomplicated singleton breech pregnancy after 36+0 weeks, external cephalic version, unless: the woman is in established labour there is fetal compromise the woman has ruptured membranes or vaginal bleeding the woman has any other medical conditions (for example, severe hypertension) that would make external cephalic version inadvisable. Before carrying out a caesarean birth for an uncomplicated singleton breech pregnancy, carry out an ultrasound scan to check that the baby is in the breech position. Do this as late as possible before the caesarean birth procedure. ## Multiple pregnancy For recommendations on mode of birth in multiple pregnancy, see mode of birth in the NICE guideline on twin and triplet pregnancy. ## Preterm birth For recommendations on mode of birth in preterm labour and birth, see mode of birth in the NICE guideline on preterm labour and birth. ## Placenta praevia Offer caesarean birth to women with a placenta that partly or completely covers the internal cervical os (minor or major placenta praevia). ## Placenta accreta spectrum For women who have had a previous caesarean birth, offer colour-flow Doppler ultrasound at 32 to 34 weeks as the first diagnostic test for placenta accreta spectrum (PAS) if low-lying placenta is confirmed. If a colour-flow Doppler ultrasound scan result suggests placenta accreta spectrum: discuss with the woman how MRI in addition to ultrasound can help diagnose placenta accreta spectrum and clarify the degree of invasion, particularly with a posterior placenta explain what to expect during an MRI procedure inform the woman that current experience suggests that MRI is safe, but that there is a lack of evidence about any long-term risks to the baby.Offer MRI if this is acceptable to the woman. Discuss birth options (for example, timing of birth, operative interventions including possibility of hysterectomy, need for blood transfusion) with a woman suspected to have placenta accreta spectrum. This discussion should be carried out by a consultant obstetrician, or with a consultant obstetrician present. When performing a caesarean birth for a woman suspected to have placenta accreta spectrum, ensure that: a consultant obstetrician and a consultant anaesthetist are present in the operating theatre a paediatric registrar, consultant, or equivalent, is present a haematology registrar, consultant, or equivalent, is available for advice a critical care bed is available sufficient cross-matched blood and blood products are readily available. Before performing a caesarean birth for women suspected to have placenta accreta spectrum, the multidisciplinary team should agree which other healthcare professionals need to be consulted or present, and the responsibilities of each team member. All hospitals should have a locally agreed protocol for managing placenta accreta spectrum that sets out how these elements of care should be provided. ## Predicting caesarean birth for cephalopelvic disproportion in labour Do not use pelvimetry for decision making about mode of birth. Do not use the following for decision making about mode of birth, as they do not accurately predict cephalopelvic disproportion: maternal shoe size maternal height estimations of fetal size (ultrasound or clinical examination). ## Mother-to-child transmission of maternal infections Provide women with HIV information about the benefits and risks for them and their baby of the HIV treatment options and mode of birth as early as possible in their pregnancy, so that they can make an informed decision. Obtain specialist advice about HIV in pregnancy from a sexual health specialist if necessary. Do not offer pregnant women with hepatitis B a planned caesarean birth for this reason alone, as mother-to-baby transmission of hepatitis B can be reduced if the baby receives immunoglobulin and vaccination. Do not offer women who are infected with hepatitis C a planned caesarean birth for this reason alone. Offer pregnant women who are co-infected with hepatitis C virus and HIV a planned caesarean birth to reduce mother-to-baby transmission of hepatitis C virus and HIV. Offer women with primary genital herpes simplex virus (HSV) infection occurring in the third trimester of pregnancy a planned caesarean birth to decrease the risk of neonatal HSV infection. Do not routinely offer pregnant women with recurrent HSV infection a planned caesarean birth outside of the context of research. ## Body mass index Do not use a body mass index (BMI) of over 50 kg/m2 alone as an indication for planned caesarean birth. ## Shared decision making Ask for consent for caesarean birth only after providing pregnant women with evidence-based information. Ensure the woman's dignity, privacy, views and culture are respected, while taking the woman's clinical situation into account. Advise women that they are entitled to decline the offer of treatment such as caesarean birth, even when it would benefit their or their baby's health. When a woman decides on or declines a caesarean birth, document the factors that that are important to the woman when making her decision. ## Maternal choice for caesarean birth When a woman or pregnant person with no medical indication for a caesarean birth requests a caesarean birth: -ffer to discuss and explore the reasons for the request ensure they have balanced and accurate information -ffer to discuss alternative birth options (for example, place of birth, continuity of midwifery care where available, pain relief options), which may help address concerns they have about the birth -ffer discussions with a consultant midwife or senior midwife, ideally in a birth options clinic or at a birth options appointment -ffer discussions with a consultant or senior obstetrician and other members of the team (for example an anaesthetist) if necessary or requested by the woman or pregnant person record the discussions and decisions. If a woman or pregnant person requests a caesarean birth, discuss the overall benefits and risks of caesarean birth compared with vaginal birth (see the section on planning mode of birth) and record that this discussion has taken place. If a woman or pregnant person requests a caesarean birth because they have tokophobia or other severe anxiety about childbirth (for example, following abuse or a previous traumatic event), offer referral to a healthcare professional with expertise in providing perinatal mental health support to help with their anxiety. See the NICE guideline on antenatal and postnatal mental health for more detailed advice on providing mental health services during pregnancy. Ensure healthcare professionals providing perinatal mental health support for women or pregnant people with tokophobia or other severe anxiety about childbirth are able to access the planned place of birth with the woman or pregnant person during the antenatal period, as part of the support offered to help them overcome fears and concerns about the labour and birth. If, after an informed discussion about the options for birth (including the offer of perinatal mental health support if appropriate; see recommendation 1.2.27), the woman or pregnant person requests a caesarean birth, support their choice. If a woman or pregnant person requests a caesarean birth this should be offered within their obstetric unit. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on maternal choice for caesarean birth . Loading. Please wait. # Factors affecting the likelihood of emergency caesarean birth during intrapartum care ## Factors reducing the likelihood of caesarean birth Inform women that continuous support during labour from women, with or without prior training, reduces the likelihood of caesarean birth. Use a partogram with a 4‑hour action line to monitor progress of women in spontaneous labour with an uncomplicated singleton pregnancy at term to reduce the likelihood of caesarean birth. Involve a consultant obstetrician in decision-making for caesarean birth. ## No influence on the likelihood of caesarean birth Inform women that the following interventions during intrapartum care have not been shown to influence the likelihood of caesarean birth, although they can affect other outcomes: walking in labour non-supine position during the second stage of labour immersion in water during labour epidural analgesia during labour the use of raspberry leaves. Inform women that the effects on the likelihood of caesarean birth of complementary therapies used during labour (such as acupuncture, aromatherapy, hypnosis, herbal products, nutritional supplements, homeopathic medicines, and Chinese medicines) are uncertain. ## Slow progression in labour and caesarean birth Do not offer the following as they do not influence the likelihood of caesarean birth for slow progression in labour, although they can affect other outcomes: active management of labour (comprising a strict definition of established labour, early routine amniotomy, routine 2-hourly vaginal examination, oxytocin if labour becomes slow) early amniotomy. ## Eating during labour Inform women that eating a low-residue diet during labour (toast, crackers, low-fat cheese) results in larger gastric volumes, but the effect on the risk of aspiration if anaesthesia is needed is uncertain. Inform women that having isotonic drinks during labour prevents ketosis without a concomitant increase in gastric volume. # Procedural aspects of caesarean birth ## Timing of planned caesarean birth Do not routinely carry out planned caesarean birth before 39 weeks, as this can increase the risk of respiratory morbidity in babies. ## Classification of urgency for caesarean birth Use the following standardised scheme to document the urgency of caesarean birth and aid clear communication between healthcare professionals: Category 1. Immediate threat to the life of the woman or fetus (for example, suspected uterine rupture, major placental abruption, cord prolapse, fetal hypoxia or persistent fetal bradycardia). Category 2. Maternal or fetal compromise which is not immediately life-threatening. Category 3. No maternal or fetal compromise but needs early birth. Category 4. Birth timed to suit woman or healthcare provider. ## Decision-to-birth interval for unplanned and emergency caesarean birth Category 1 caesarean birth is when there is immediate threat to the life of the woman or fetus, and category 2 caesarean birth is when there is maternal or fetal compromise which is not immediately life-threatening. Perform category 1 caesarean birth as soon as possible, and in most situations within 30 minutes of making the decision. Perform category 2 caesarean birth as soon as possible, and in most situations within 75 minutes of making the decision. Take into account the condition of the woman and the unborn baby when making decisions about rapid birth. Be aware that rapid birth can be harmful in certain circumstances. ## Preoperative testing and preparation for caesarean birth Before caesarean birth, carry out a full blood count to identify anaemia, antibody screening, and blood grouping with saving of serum. Do not routinely carry out the following tests before caesarean birth: cross-matching of blood a clotting screen preoperative ultrasound for localisation of the placenta. Carry out caesarean birth for pregnant women with antepartum haemorrhage, abruption or placenta praevia at a maternity unit with on-site blood transfusion services, as they are at increased risk of blood loss of more than 1,000 ml. Give women having caesarean birth with regional anaesthesia an indwelling urinary catheter to prevent over-distension of the bladder. ## Anaesthesia for caesarean birth Provide pregnant women having a caesarean birth with information on the different types of post‑caesarean birth analgesia, so that they can make an informed choice (see recommendation 1.6.9). Offer women who are having a caesarean birth regional anaesthesia in preference to general anaesthesia, including women who have a diagnosis of placenta praevia. Carry out induction of anaesthesia, including regional anaesthesia, for caesarean birth in theatre. Apply a left lateral tilt of up to 15 degrees or appropriate uterine displacement once the woman is in a supine position on the operating table to reduce maternal hypotension. Offer women who are having a caesarean birth under spinal anaesthesia a prophylactic intravenous infusion of phenylephrine, started immediately after the spinal injection. Adjust the rate of infusion to keep maternal blood pressure at 90% or more of baseline value and avoid decreases to less than 80% of baseline. When using phenylephrine infusion, give intravenous ephedrine boluses to manage hypotension during caesarean birth, for example if the heart rate is low and blood pressure is less than 90% of baseline. Use intravenous crystalloid co-loading in addition to vasopressors to reduce the risk of hypotension occurring during caesarean birth. Ensure each maternity unit has a set of procedures for failed intubation during obstetric anaesthesia. Offer women antacids and drugs (such as H2‑receptor antagonists or proton pump inhibitors) to reduce gastric volumes and acidity before caesarean birth.In March 2021, this was an off-label use of proton pump inhibitors. See NICE's information on prescribing medicines. Offer women having a caesarean birth anti-emetics (either pharmacological or acupressure) to reduce nausea and vomiting during caesarean birth. Include pre-oxygenation, cricoid pressure and rapid sequence induction in general anaesthesia for caesarean birth to reduce the risk of aspiration. ## Prevention and management of hypothermia and shivering Warm IV fluids (500 ml or more) and blood products used during caesarean birth to 37 degrees Celsius using a fluid warming device. Warm all irrigation fluids used during caesarean birth to 38 to 40 degrees Celsius in a thermostatically controlled cabinet. Consider forced air warming for women who shiver, feel cold, or have a temperature of less than 36 degrees Celsius during caesarean birth. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prevention and management of hypothermia and shivering . Full details of the evidence and the committee's discussion are in evidence review C: prevention and management of hypothermia and shivering. Loading. Please wait. ## Surgical techniques for caesarean birth Use alcohol-based chlorhexidine skin preparation before caesarean birth to reduce the risk of wound infections. If alcohol-based chlorhexidine skin preparation is not available, alcohol-based iodine skin preparation can be used. See the NICE guideline on surgical site infections. Use aqueous iodine vaginal preparation before caesarean birth in women with ruptured membranes to reduce the risk of endometritis. If aqueous iodine vaginal preparation is not available or is contraindicated, aqueous chlorhexidine vaginal preparation can be used. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on methods to reduce infectious morbidity and wound care after caesarean birth . Full details of the evidence and the committee's discussion are in evidence review B: methods to reduce infectious morbidity at caesarean birth. Loading. Please wait. Wear double gloves when performing or assisting a caesarean birth for women who have tested positive for HIV, to reduce the risk of HIV infection of staff. Follow general recommendations for safe surgical practice during caesarean birth to reduce the risk of HIV infection of staff. Perform caesarean birth using a transverse abdominal incision to: make postoperative pain less likely give an improved cosmetic effect compared with a midline incision. Perform caesarean birth using a transverse incision (a straight skin incision, 3 cm above the symphysis pubis; subsequent tissue layers are opened bluntly and, if necessary, extended with scissors and not a knife). This allows for shorter operating times and reduces postoperative febrile morbidity. Do not use separate surgical knives to incise the skin and the deeper tissues in caesarean birth, as it does not decrease wound infection. When there is a well formed lower uterine segment, use blunt rather than sharp extension of the uterine incision to reduce blood loss, incidences of postpartum haemorrhage and the need for transfusion during caesarean birth. Inform women who are having a caesarean birth that the risk of fetal lacerations is about 2%. Only use forceps in caesarean birth if there is difficulty delivering the baby's head. The effect on neonatal morbidity of the routine use of forceps at caesarean birth remains uncertain. Use oxytocin 5 IU by slow intravenous injection in caesarean birth to encourage contraction of the uterus and decrease blood loss. Remove the placenta in caesarean birth using controlled cord traction and not manual removal to reduce the risk of endometritis. Perform intraperitoneal repair of the uterus for caesarean birth. Routine exteriorisation of the uterus is not recommended because it is associated with more pain and does not improve operative outcomes such as haemorrhage and infection. Use single layer or double layer uterine closure in caesarean birth, depending on the clinical circumstances. Note that single layer closure does not increase the risk of postoperative bleeding or uterine rupture in a subsequent pregnancy. For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on closure of the uterus . Full details of the evidence and the committee's discussion are in evidence review D: techniques to close the uterus at caesarean birth. Loading. Please wait. Do not suture the visceral or the parietal peritoneum in caesarean birth to reduce operating time and the need for postoperative analgesia, and improve maternal satisfaction. If a midline abdominal incision is used in caesarean birth, use mass closure with slowly absorbable continuous sutures as this results in fewer incisional hernias and less dehiscence than layered closure. Do not routinely close the subcutaneous tissue space in caesarean birth unless the woman has more than 2 cm subcutaneous fat, as it does not reduce the incidence of wound infection. Do not routinely use superficial wound drains in caesarean birth as they do not decrease the incidence of wound infection or wound haematoma. See recommendation 1.7.2 on the use of negative pressure wound therapy. Consider using sutures rather than staples to close the skin after caesarean birth to reduce the risk of superficial wound dehiscence. See closure methods in the NICE guideline on surgical site infections. Perform paired umbilical artery and vein measurements of cord blood gases after caesarean birth for suspected fetal compromise, to allow for assessment of fetal wellbeing and guide ongoing care of the baby. Offer women prophylactic antibiotics before skin incision for caesarean birth, choosing antibiotics that are effective against endometritis, urinary tract and wound infections. Inform women that: endometritis, urinary tract and wound infections occur in about 8% of women who have had a caesarean birth using prophylactic antibiotics before skin incision reduces the risk of maternal infection more than prophylactic antibiotics given after skin incision, and that there is no known effect on the baby. Do not use co-amoxiclav when giving prophylactic antibiotics before skin incision for caesarean birth. Offer thromboprophylaxis to women having a caesarean birth. Take into account the risk of thromboembolic disease when choosing the method of prophylaxis (for example, graduated stockings, hydration, early mobilisation, low molecular weight heparin). Accommodate a woman's preferences for her caesarean birth whenever possible, such as, music playing in theatre, lowering the screen to see the baby born, or silence so that the mother's voice is the first the baby hears. # Care of the baby born by caesarean birth ## Presence of paediatrician at caesarean birth Ensure an appropriately trained practitioner skilled in the resuscitation of newborn babies is present for caesarean birth performed under general anaesthesia, or if there is evidence of fetal compromise. ## Thermal care for babies born by caesarean birth As babies born by caesarean birth are more likely to have a lower temperature, ensure thermal care is in accordance with good practice for thermal care of newborn babies. ## Maternal contact (skin-to-skin) Offer and facilitate early skin-to-skin contact between the woman and her baby. ## Breastfeeding Offer women who have had a caesarean birth and who wish to breastfeed support to help them to start breastfeeding as soon as possible after the birth of their baby. # Care of the woman after caesarean birth ## High-dependency unit/intensive therapy unit admission Be aware that, although it is rare for women to need intensive care after childbirth, this may occur after caesarean birth. ## Monitoring after caesarean birth After caesarean birth under a general anaesthetic, a healthcare professional with airway skills should carry out continuous, one-to-one observation of the woman until: she has regained airway control, and is haemodynamically stable, and is able to communicate. When a woman has regained airway control, is haemodynamically stable, and is able to communicate after caesarean birth under a general anaesthetic: continue observations (oxygen saturation, respiratory rate, heart rate, blood pressure, temperature, pain and sedation) every half hour for 2 hours after 2 hours, if these observations are stable, carry out routine observations in accordance with local protocols if these observations are not stable, or the woman has other risk factors or complications (for example, severe hypertension, or signs of infection or sepsis), carry out a medical review and increase the duration and frequency of observations. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. After caesarean birth under a spinal or epidural anaesthetic, a healthcare professional should carry out continuous one-to-one observation of the woman until she is haemodynamically stable (for example when pulse and blood pressure have returned to baseline values). Provide a woman who has had spinal or epidural diamorphine for caesarean birth, and who is at an increased risk of respiratory depression (for example, a significantly raised BMI, or diagnosed obstructive sleep apnoea syndrome), with: continuous pulse oximetry monitoring, and hourly monitoring of respiratory rate heart rate blood pressure temperature pain sedation.Monitor the woman for at least 12 hours, continue until they are stable enough to be discharged from anaesthetic care, and then carry out routine observations in accordance with local protocols. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. For a woman who has had spinal or epidural diamorphine for caesarean birth, but is not at an increased risk of respiratory depression, carry out routine observations in accordance with local protocols. When deciding on the location and frequency of monitoring for respiratory depression in women who have had spinal or epidural diamorphine for caesarean birth, take into account other factors that could affect monitoring needs (for example, a complicated birth, or unstable observations in first 2 hours after birth). Ensure women who have patient-controlled analgesia with opioids after caesarean birth have routine hourly monitoring of respiratory rate, sedation and pain scores throughout treatment, and for at least 2 hours after discontinuation of treatment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring after caesarean birth . Full details of the evidence and the committee's discussion are in evidence review E: monitoring after intrathecal or epidural opioids for caesarean birth. Loading. Please wait. ## Pain management after caesarean birth Offer women diamorphine (0.3 to 0.4 mg intrathecally) for analgesia to reduce the need for supplemental analgesia after a caesarean birth. Epidural diamorphine (2.5 to 5 mg) is a suitable alternative where intrathecal diamorphine has not been given.In March 2021, this was an off-label use of diamorphine (both intrathecal and epidural). See NICE's information on prescribing medicines. Discuss options with women for pain relief after caesarean birth and explain that: pain after caesarean birth can be controlled using oral or injectable medicines their choice of pain relief medicines after caesarean birth will depend on: the severity of pain whether they had spinal or epidural anaesthesia, or general anaesthesia if they wish to breastfeed, they will usually be able to do this and care for their baby while taking pain relief medicines. Offer oral morphine sulfate to women who have received spinal or epidural anaesthesia for caesarean birth. If the woman cannot take oral medication (for example, because of nausea or vomiting), offer intravenous, intramuscular or subcutaneous morphine. Consider intravenous patient-controlled analgesia (PCA) using morphine for women who have had a general anaesthetic for caesarean birth. If intravenous PCA is not acceptable to the woman, or the pain is less severe, consider oral morphine sulfate. Use paracetamol and, unless contraindicated, a non-steroidal anti-inflammatory drug (for example, ibuprofen) in combination after caesarean birth, to reduce the need for opioids, and to allow them to be stepped down and stopped as early as possible. If paracetamol does not provide sufficient pain relief after caesarean birth, or non-steroidal anti‑inflammatory drugs cannot be taken, consider adding dihydrocodeine to paracetamol, or changing to co-dydramol (combination preparation of paracetamol and dihydrocodeine) as an alternative to paracetamol. Do not offer codeine or co‑codamol (combination preparation of paracetamol and codeine) to women who are currently breastfeeding, because this can lead to serious neonatal sedation and respiratory depression. Follow the MHRA safety advice on Codeine for analgesia: restricted use in children because of reports of morphine toxicity. When using paracetamol, dihyrocodeine, co-dydramol or a non-steroidal anti-inflammatory drug after caesarean birth, prescribe them to be taken regularly and not just when needed for pain relief. For women with severe pain after caesarean birth, when other pain relief is not sufficient: perform a full assessment to exclude other causes for the pain (for example, sepsis, haemorrhage, urinary retention) discuss with the woman that stronger pain relief medicines are available make sure the woman is aware that, if taken while breastfeeding, these medicines could increase the risk of neonatal sedation and respiratory depression.If the women chooses to take stronger medicines, consider a short course of tramadol or oxycodone at the lowest effective dose. In breastfeeding women, use opioid analgesics (for example, morphine, dihyrocodeine, tramadol or oxycodone) at the lowest effective dose and for the shortest duration, and not for more than 3 days without close supervision. If, after a caesarean birth, a woman is discharged home on opioids, advise the woman to contact their healthcare provider if they are concerned about their baby (for example drowsiness, breathing difficulties, constipation or difficulty feeding). Consider laxatives for women taking opioids, for the prevention of constipation. Consider anti-emetics for women taking opioids, if needed for nausea and vomiting. Advise women that some over-the-counter medicines contain codeine, and should not be taken while breastfeeding because this can lead to serious neonatal sedation and respiratory depression. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain management after caesarean birth . Full details of the evidence and the committee's discussion are in evidence review F: opioids for pain relief after caesarean birth. Loading. Please wait. ## Early eating and drinking after caesarean birth If women are recovering well after caesarean birth and do not have complications, they can eat and drink as normal. ## Urinary catheter removal after caesarean birth Offer removal of the urinary bladder catheter once a woman is mobile after a regional anaesthetic for caesarean birth, but no sooner than 12 hours after the last 'top-up' dose. ## Respiratory physiotherapy after caesarean birth Do not offer routine respiratory physiotherapy to women after a caesarean birth under general anaesthesia as it does not improve respiratory outcomes (for example, coughing, phlegm, body temperature, chest palpation or auscultatory changes). ## Length of hospital stay and readmission to hospital Inform women that length of hospital stay is likely to be longer after caesarean birth than after a vaginal birth. Offer women who are recovering well, are apyrexial and do not have complications after caesarean birth, discharge from hospital after 24 hours and follow up at home, as this is not associated with more readmissions for babies or mothers. # Recovery after caesarean birth In addition to general postnatal care, provide women who have had a caesarean birth with: specific care related to recovery after caesarean birth care related to management of other complications during pregnancy or childbirth. ## Wound care Consider negative pressure wound therapy after caesarean birth for women with a BMI of 35 kg/m2 or more to reduce the risk of wound infections. When using standard (not negative pressure) wound dressings after caesarean birth take into account that: no type of wound dressing has been shown to be better than another at reducing the risk of wound infections there is no difference in the risk of wound infection when dressings are removed 6 hours postoperatively, compared with 24 hours postoperatively. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on methods to reduce infectious morbidity and wound care after caesarean birth . Full details of the evidence and the committee's discussion are in evidence review B: methods to reduce infectious morbidity at caesarean birth. Loading. Please wait. Ensure caesarean birth wound care includes: removing standard dressings 6 to 24 hours after the caesarean birth specific monitoring for fever assessing the wound for signs of infection (such as increasing pain, redness or discharge), separation or dehiscence encouraging the woman to wear loose, comfortable clothes and cotton underwear gently cleaning and drying the wound daily if needed, planning the removal of sutures or clips.Follow the recommendations in the NICE guideline on surgical site infections. ## Management of symptoms When caring for women who have had a caesarean birth who have urinary symptoms, consider possible diagnoses of: urinary tract infection stress incontinence (occurs in about 4% of women after caesarean birth) urinary tract injury (occurs in about 1 per 1,000 caesarean births) urinary retention. When caring for women who have had a caesarean birth who have heavy and/or irregular vaginal bleeding, consider whether this is more likely to be because of endometritis than retained products of conception, and manage accordingly. Pay particular attention to women who have respiratory symptoms (such as cough or shortness of breath) or leg symptoms (such as painful swollen calf), as women who have had a caesarean birth may be at increased risk of thromboembolic disease (both deep vein thrombosis and pulmonary embolism). ## Resuming activities and discharge home Inform women who have had a caesarean birth that they can resume activities such as driving a vehicle, carrying heavy items, formal exercise and sexual intercourse when they feel they have fully recovered from the caesarean birth (including any physical restrictions or pain). When caring for women who have had a caesarean birth, discuss that after a caesarean birth they are not at increased risk of depression, post-traumatic stress symptoms, pain on sexual intercourse, faecal incontinence or difficulties with breastfeeding. While women are in hospital after having an emergency or unplanned caesarean birth, give them the opportunity to discuss with healthcare professionals the reasons for the caesarean birth, and provide both verbal and printed information about birth options for any future pregnancies. If the woman prefers, provide this at a later date. Inform the woman's GP if follow-up investigations are needed after discharge from hospital (for example, a repeat full blood count if there has been a large amount of blood loss), and include details of the plan or course of action if the results are abnormal. # Pregnancy and childbirth after caesarean birth When advising about the mode of birth after a previous caesarean birth, consider: maternal preferences and priorities the risks and benefits of repeat planned caesarean birth the risks and benefits of planned vaginal birth after caesarean birth, including the risk of unplanned caesarean birth. Inform women who have had up to and including 4 caesarean births that the risk of fever, bladder injuries and surgical injuries does not vary with planned mode of birth, but that the risk of uterine rupture is higher for planned vaginal birth. Offer women planning a vaginal birth who have had a previous caesarean birth: electronic fetal monitoring during labour care during labour in a unit where there is immediate access to caesarean birth and on-site blood transfusion services. During induction of labour, women who have had a previous caesarean birth should be monitored closely, with access to electronic fetal monitoring and with immediate access to caesarean birth, as they are at increased risk of uterine rupture. For further information see the NICE guideline on inducing labour. Pregnant women with both previous caesarean birth and a previous vaginal birth should be informed that they have an increased likelihood of having a vaginal birth than women who have had a previous caesarean birth but no previous vaginal birth. # Recommendations for research The guideline committee has made the following key recommendations for research. As part of the 2021 update, the guideline committee removed the research recommendation on 'What are the medium- to long-term risks and benefits to women and their babies of planned caesarean birth compared with planned vaginal birth?' and replaced it with a research recommendation on the short-term and long-term risks and benefits of planned caesarean birth compared with planned vaginal birth. # Short-term and long-term benefits and risks of planned caesarean birth compared to planned vaginal birth What are the benefits and risks (short term and long term) of planned caesarean birth compared with planned vaginal birth at term for women and babies/infants/children? ## Why this is important Information provided to women with low-risk pregnancies in relation to the short- and long-term benefits and risks of planned caesarean birth compared with planned vaginal birth should reflect the relevant risks during the antenatal period when a woman is planning mode of birth. Studies used to inform these discussions with women should be from 'intention to treat' type analyses. However this type of evidence is sparse for outcomes relevant to the early neonatal period and minimal for long-term outcomes and further research is needed. For a short explanation of why the committee made the recommendation for research, see the rationale on benefits and risks of caesarean and vaginal birth . Full details of the evidence and the committee's discussion are in evidence review A: the benefits and risks of planned caesarean birth. Loading. Please wait. # Decision-to-birth interval (category 1 urgency) What factors influence the decision-to-birth interval when there is a category 1 level of urgency for caesarean birth? ## Why this is important 'Crash' caesarean birth is a psychologically traumatic event for women and their partners, and is also stressful for clinical staff. Staff and resources might have to be obtained from other areas of clinical care. This should be done as efficiently and effectively as possible, minimising anxiety and ensuring the safety of the mother and her baby. For category 1 caesarean birth there is a recognised urgency to deliver as quickly as is reasonably possible. Most research in this area is quantitative and looks at the impact of the decision-to-birth interval on various aspects of fetal and maternal outcomes rather than the interplay of factors that can affect this time period itself. Much of this evidence is retrospective. Although some work has been done in the UK to examine where the systematic delays are and how to avoid them, more work is needed to determine how to optimise the decision-to-birth interval. This work should use qualitative as well as quantitative research methods to assess which factors influence the decision-to-birth interval for a category 1 caesarean birth. Evaluation of these factors could be used to inform future NICE guidance, for example, specific guidance for management of category 1 caesarean birth. Such information could also be used by hospitals for maternity services planning, and at a team level would assist with audit and ongoing evaluation and training of the multidisciplinary team. A large amount of NHS and other state funding is used to provide continuing care for babies who are disabled as a result of birth asphyxia and in providing lifelong support for the child and their family. In addition, large sums of public money are spent on litigation and compensation in some of these cases through the Clinical Negligence Scheme for Trusts (CNST). If research helped to reduce the incidence of birth asphyxia this would reduce the costs of continuing care to the state and the burden to the child, their family and the wider community. More realistic and more relevant expectations for the decision-to-delivery interval based on evidence would inform debate in the legal system and could help to reduce the cost to the state of related litigation. # Decision-to-birth interval (category 2 urgency) A prospective study to determine whether the decision-to-birth interval has an impact on maternal and neonatal outcomes when there is a category 2 level of urgency for caesarean birth. ## Why this is important This research is important to inform the ongoing debate about the management of category 2 caesarean birth. The 'continuum of risk' in this setting has been recognised. However, most of the work in this area, looking at maternal and fetal outcomes, generally considers unplanned caesarean birth as a whole group without making any distinction between degrees of urgency. Furthermore, much of this work is retrospective. Most women who undergo intrapartum caesarean birth fall into the category 2 level of urgency and therefore specific information for this group could affect and benefit many women and contribute to the delivery of equity of care. Delay in birth with a compromised fetus could result in major and long-term harm including cerebral palsy and other major long-term disability. The immediate and long-term effect on a family of the birth of a baby requiring lifelong specialised care and support is enormous. If such harm could be avoided by appropriate haste this would be an important improvement in outcome. However, if such haste is of no benefit then any related risk of adverse maternal outcome needs to be minimised. A large amount of NHS and other state funding is used to provide continuing care for babies who are disabled as a result of delay in birth and in providing lifelong support for the child and their family. In addition, large sums of public money are spent on litigation and compensation in some of these cases through the CNST. If research helped to reduce the incidence of delay in birth this would reduce the costs of continuing care to the state and the burden to the child, their family and the wider community. More realistic and more relevant expectations for the decision-to-birth interval based on evidence would inform debate within the legal system and could help to reduce the cost to the state of related litigation. # Maternal request for caesarean birth What support or psychological interventions would be appropriate for women who have a fear of vaginal childbirth and request a caesarean birth? ## Why this is important Fear of vaginal childbirth can stem from: fear of damage to the maternal pelvic floor damage to the baby during childbirth self-doubt on the ability to physically have a vaginal birth previous childbirth experience unresolved issues related to the genital area. Currently there is a wide variation in practice and limited resources lead to limited availability of effective interventions. Interventions that might be appropriate include: antenatal clinics dedicated to providing care for women with no obstetric indications who request a caesarean birth referral to a psychologist or a mental health professional referral to an obstetric anaesthetist intensive midwifery support. Continuity of healthcare professional support from the antenatal to the intrapartum periods and 'one-to-one' midwifery care during labour are also often lacking and could make a difference to women who are anxious or afraid. All of these interventions have different resource implications and there is no clear evidence to suggest that any are of benefit. The proposed research would compare in a randomised controlled trial 2 or more of these interventions in women requesting a caesarean birth. In the absence of any evidence, there is a case for comparing these interventions with routine antenatal care (that is, no special intervention). This research is relevant because it would help to guide the optimal use of these limited resources and future guideline recommendations.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion. # Benefits and risks of caesarean and vaginal birth Recommendations 1.1.3 and 1.1.4 ## Why the committee made the recommendations There was some evidence for a selected number of outcomes on the short- and long-term effects of caesarean birth compared with vaginal birth, although there were some limitations with the quality of the evidence, and not all evidence was from a comparison of planned mode of birth. The committee used this evidence, along with their clinical expertise, to update the advice comparing the relative benefits and risks of these 2 modes of birth. For some outcomes there was conflicting or limited evidence, and there were also a number of outcomes for which no evidence was identified for inclusion, so the committee highlighted these uncertainties. As the evidence was limited for this review the committee made a research recommendation. There were also 3 outcomes included in the 2011 guideline which had not been included in this current review (vaginal tears, length of stay and pain) but the committee agreed that the advice was still appropriate and should be carried forward into the updated guideline. ## How the recommendations might affect practice The committee considered that their recommendations would reinforce best practice. It is already current practice to discuss the risks and benefits of alternative modes of birth during the antenatal period and this review has simply led to an update of the information that should be discussed with women. Return to recommendations # Maternal choice for caesarean birth Recommendations 1.2.25 to 1.2.30 ## Why the committee made the recommendations The committee discussed the fact that some women or pregnant people may request a caesarean birth because they have concerns about aspects of the birth and believe that a caesarean birth would be the best way to alleviate these concerns. However, there may be cases where the concerns can be addressed in other ways, such as choosing an alternative place of birth, opting for a birth which will provide greater continuity of midwifery care, or by planning adequate pain relief. The committee therefore expanded the advice to include these aspects in the discussion. The committee were aware that this discussion would be best held in a clinic where there was time to explore the different options and preferences, and so suggested this should be in a birth options clinic. The committee were aware that consultant midwives were often involved in such discussions and so included them in the list of healthcare professionals who should be involved. The committee revised the wording of the recommendation on perinatal mental health support to clarify that the access to the planned place of birth was needed during the antenatal period, and not that all antenatal support had to be provided at the planned place of birth. The committee revised the wording of the recommendation on offering caesarean birth to be more person-centred, and to ensure the woman or pregnant person's choice to have a caesarean birth was supported. The committee agreed that women and pregnant people should not have to move to a different obstetric unit for a caesarean birth, and so recommended that caesarean birth should be offered within their obstetric unit. The committee discussed the potential rare situations where there was a clinical reason behind a reluctance to perform a maternal request caesarean birth, but agreed that in this situation a full multidisciplinary team discussion would be needed during the pregnancy to agree a plan for the woman or pregnant person. ## How the recommendations might affect practice This change to add more factors into the discussions around requests for caesarean birth may mean more women and pregnant people can be supported to have their preferred mode of birth. The change may also increase the number of women or pregnant people being seen by a consultant midwife or senior midwife for a longer 'birth options' appointment, but is unlikely to have a resource impact as these conversations would previously have been held across multiple midwife appointments. This change to recommend that caesarean birth should be offered within the woman or pregnant person's obstetric unit will reduce the number of people who have to move to a different obstetric unit in order to have a caesarean birth. This will benefit the following groups in particular: women or pregnant people with disabilities who find it difficult to travel or feel anxious about change women or pregnant people from lower socioeconomic groups where the increased travel costs are a concern younger women or pregnant people who may not feel confident enough to transfer to another unit women or pregnant people from certain racial groups who may experience bias surrounding decisions relating to mode of birth and who may have less favourable maternity outcomes women or pregnant people who do not speak English as a first language, or those from groups such as migrants or refugees who may not be familiar with navigating the healthcare system and who therefore may have more difficulty changing their provider or travelling to another unit. Return to recommendations # Prevention and management of hypothermia and shivering Recommendations 1.4.21 to 1.4.23 ## Why the committee made the recommendations There was evidence for the effectiveness of active warming measures (for example, forced air warming, under body pads, warmed IV fluids) to prevent shivering and hypothermia in women having a caesarean birth, and there was some evidence for improved thermal comfort and maternal temperature. The committee recommended the use of warmed IV fluids and irrigation fluids for all women having caesarean birth, but because of the low incidence of hypothermia and shivering during caesarean birth, the physiological differences between women having caesarean birth and the general surgical population, the lack of beneficial effect on wound infections, and the fact that warming methods are likely to be as effective at managing hypothermia and shivering as they are at preventing it, the committee recommended that other warming measures should only be used in women who were shivering, said they felt cold or were hypothermic, and not in all women for prevention. The committee recommended forced air warming as the method of choice as this was already widely available, easier to use and could be easily moved with the woman. There was evidence that pethidine was also effective at reducing shivering, but the committee did not recommend this because of the possible adverse effects on breastfeeding. ## How the recommendations might affect practice The recommendation to use forced air warming will standardise practice across the NHS. There could be resource implications for units to purchase the disposable 'blankets' used, but this could be offset by earlier discharge of women from recovery to the postnatal ward. The use of warmed intravenous fluids, blood and irrigation fluids is already standard practice, so this recommendation will not change this. Return to recommendations # Methods to reduce infectious morbidity and wound care after caesarean birth Recommendations 1.4.24 and 1.4.25 and recommendations 1.7.2 and 1.7.3 ## Why the committee made the recommendations There was evidence that alcohol-based chlorhexidine solution skin preparations reduce the risk of surgical site infections, compared with alcohol-based iodine solutions. There was also evidence that aqueous iodine vaginal preparations reduce the risk of endometritis in women with ruptured membranes. Although there was some evidence on chlorhexidine vaginal preparations, overall the evidence indicated that that iodine vaginal preparations might be more effective. There was some evidence that negative pressure wound therapy (NPWT) reduces the risk of wound or surgical site infections for women with a BMI of 30 kg/m2 or more but economic evidence indicated that this would not be cost effective in those with a BMI of less than 35 kg/m2 and only borderline cost effective in the group with a BMI of 35 kg/m2 or more. The evidence showed no difference in wound infection or readmissions into hospital when the dressing was removed either 6 hours or 24 hours after surgery. There was very limited evidence on the use of 2 different types of dressing, but the committee agreed it was not enough to recommend a specific type. There was no evidence on the use of incise drapes, diathermy or body hair removal, so the committee did not make recommendations about these, but noted that the NICE guideline on surgical site infections (which covers general surgery rather than caesarean birth) has recommendations on some of these interventions. ## How the recommendations might affect practice The recommendations on skin preparation are broadly in line with current best clinical practice. The committee agreed that the recommendation to use aqueous iodine vaginal preparation will be a change in clinical practice, because the use of vaginal preparation is not routine across England. The committee identified that considering the use of NPWT for women with a BMI of 35 kg/m2 will be a change of practice for many units (some units do not use it at all, or only at higher BMI thresholds), and could have resource implications, particularly in areas where a higher proportion of pregnant women will meet the criteria. Return to the recommendations # Closure of the uterus Recommendation 1.4.37 ## Why the committee made the recommendation There was evidence showing that there was no difference in any outcomes when comparing single and double layer closure of the uterus. There was some evidence of the reduced need for blood transfusions with single layer compared with double layer closure, as part of a comparison of different caesarean birth techniques, but this could have been confounded by other differences in the techniques. ## How the recommendation might affect practice Current practice is to use a double layer uterine closure technique, except in occasional circumstances when there is a specific reason for using single layer closure. This recommendation will allow surgeons to choose single or double layer closure, depending on the individual clinical circumstances at the time of the surgery. Return to recommendation # Monitoring after caesarean birth Recommendations 1.6.2 to 1.6.7 ## Why the committee made the recommendations There was no evidence found on the best monitoring schedule for women, but the committee used their knowledge and expertise of current best practice to develop recommendations on the monitoring schedule, including identifying women who would be at higher risk and so would need more intensive monitoring. ## How the recommendations might affect practice The recommendations should lead to a reduction in the frequency and duration of monitoring of most women who have received intrathecal or epidural opioids at the time of caesarean birth, but will mean women need to be assessed for risk factors to determine if they need a more intensive monitoring schedule. However, as only women identified as high risk will need intensive monitoring, it is anticipated that the overall monitoring workload will decrease. Return to recommendations # Pain management after caesarean birth Recommendations 1.6.10 to 1.6.12 and 1.6.14 to 1.6.22 ## Why the committee made the recommendations The committee developed separate recommendations for women receiving regional or general anaesthesia, based on their knowledge of the likely differences in analgesia requirements. For all women, the committee agreed that any postoperative analgesia should be suitable for use while breastfeeding, but that women should be made aware of any potential adverse effects on their baby. The committee agreed to retain the previous NICE recommendation to offer diamorphine (delivered intrathecally or by epidural) for women who have regional anaesthesia. Giving spinal or epidural diamorphine in this way reduces the need for additional opioids and other rescue medications during surgery, and it remains effective for up to 12 hours (when pain is likely to be most severe). The committee agreed that women receiving regional anaesthesia should be offered oral morphine sulfate, as the evidence showed it to be effective. The evidence on pain relief for women after general anaesthesia was sparse, but the committee agreed that intravenous patient-controlled analgesia (PCA) using morphine should be offered as these women will likely have a higher level of pain. If PCA morphine is not acceptable to the woman, then oral morphine should be considered as a less invasive alternative. From their knowledge and experience, the committee agreed that paracetamol and a non-steroidal anti-inflammatory drug (NSAID) such as ibuprofen should be offered in combination to all women to limit the amount of opioids needed, and to allow opioids to be stopped. Based on the evidence on the benefits of fixed interval pain management timing, the committee recommended these be prescribed to be taken regularly to maintain good pain control, in preference to on-request administration, which had lower rates of satisfaction reported by the women. Some women will have contraindications to NSAIDs (for example, inflammatory bowel disease, gastric ulcer or pre-eclampsia), and will not get sufficient pain relief from paracetamol alone. Based on their experience, the committee suggested an alternative of dihydocodeine in addition to paracetamol, or co-dydramol, as these are also suitable for use while breastfeeding. There was evidence for the effectiveness of oxycodone, and some evidence for tramadol, but the committee were aware both of these drugs can cause neonatal sedation and respiratory depression if used when breastfeeding. However, in women with severe pain the committee agreed that a short course of tramadol or oxycodone could be considered as long as the woman was informed of the risks and chose to use them. The length of the course was not defined as there was no evidence for a specific period or dosage. The committee were aware that there were general recommendations in the BNF on the use of opioids in breastfeeding women and so included these as part of their recommendations. The committee were also aware of an MHRA warning on the risk of serious neonatal respiratory depression and sedation with codeine in some women. Because of this, they recommended that codeine, or medications that include codeine (such as co‑codamol) should not be used, and that women should be advised not to use codeine‑containing medicines while breastfeeding. Based on their knowledge and experience, the committee recommended that anti-emetics could be prescribed if needed for nausea and vomiting, and that laxatives should be considered for the prevention of constipation. ## How the recommendations might affect practice The committee agreed that these recommendations would reinforce current practice. However, there may be a reduction in the use of intravenous PCA opioids for pain management after caesarean birth, and an increase in the use of oral morphine. The committee agreed that the recommendations relating to dihydrocodeine and codeine‑containing medicines would provide greater clarity and increase safety. Return to recommendations# Context This guideline has been developed to help ensure consistent quality care for women who have had a caesarean birth (caesarean section) in the past and are now pregnant again, who have a clinical indication for a caesarean birth, or are considering a caesarean birth when planning their birth, and there is no medical indication. It provides some evidence-based information for healthcare professionals and women about the risks and benefits of caesarean birth compared with vaginal birth, and this has now been updated to include the short- and long-term risks and benefits for both women and babies/children. It also provides guidance on specific indications for caesarean birth, effective management strategies to avoid unplanned caesarean birth and the organisational and environmental factors that affect caesarean birth rates. For women who undergo a caesarean birth, guidance is provided on the anaesthetic and surgical aspects of care, including interventions to reduce morbidity from caesarean birth. The recommendations on monitoring after caesarean birth, pain relief after caesarean birth and on uterine closure have been updated. This update also contains new recommendations on techniques to reduce infectious morbidity and techniques to prevent and manage hypothermia and shivering.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nThis guideline uses specific, inclusive language to describe the population groups it covers (for example, women and pregnant people, or trans and non-binary people) except when:\n\nthe evidence for the recommendation has not been reviewed, and it is not certain from expert opinion whether it can cover more groups, or\n\nthe evidence has been reviewed, but the information available for some groups at the time of development was too limited to make specific recommendations, or\n\nonly a very limited number of recommendations have been updated in direct response to new evidence or to reflect a change in practice.\n\nHealthcare professionals should use their clinical judgement when implementing gender-specific recommendations, taking into account the individual's circumstances, needs and preferences, and ensuring all people are treated with dignity and respect throughout their care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Planning mode of birth\n\n## Provision of information\n\nOffer all pregnant women information and support to enable them to make informed decisions about childbirth. Make sure that:\n\nthe information is evidence based\n\nany information provided is accessible, ideally with a choice of formats to suit different women's needs\n\nthe language used in any information (written or oral) is respectful and suitable for the woman, taking into account any personal, cultural or religious factors that could form part of the woman's choices\n\nthe women's preferences and concerns are central to the decision-making process. [2004, amended 2021]\n\nDiscuss mode of birth with all pregnant women early in their pregnancy. Cover information such as:\n\naround 25% to 30% of women have a caesarean birth\n\nfactors that mean women may need a caesarean birth (for example, increased maternal age and BMI)\n\ncommon indications for emergency caesarean birth include slow progression of labour or concern about fetal condition\n\nplanned place of birth may affect the mode of birth (see choosing planned place of birth in the NICE guideline on intrapartum care)\n\nwhat the caesarean birth procedure involves\n\nhow a caesarean birth may impact on the postnatal period (for example, need for pain relief)\n\nimplications for future pregnancies and birth after caesarean birth or vaginal birth (for example, after a caesarean birth the chances of caesarean birth in a future pregnancy may be increased). [2011, amended 2021]\n\n## Benefits and risks of caesarean and vaginal birth\n\nDiscuss the benefits and risks of both caesarean and vaginal birth with women, taking into account their circumstances, concerns, priorities and plans for future pregnancies. \n\nUsing the information in appendix A, explain to women that:\n\nthere are benefits and risks associated with both vaginal and caesarean birth, some of which are very small absolute risks and some are greater absolute risks, and they will need to decide which risks are more (or less) acceptable to them\n\nthere are other risks not included in these tables that might be relevant to their individual circumstances (for example placental adherence problems from multiple caesarean births, fetal lacerations in caesarean birth, term birth injuries with vaginal birth or caesarean birth)\n\nthese tables give summary estimates only and are intended to help discussions, but precise numerical risk estimates cannot be given for individual women. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on benefits and risks of caesarean and vaginal birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: the benefits and risks of planned caesarean birth.\n\nLoading. Please wait.\n\n# Planned caesarean birth\n\n## Breech presentation\n\nDiscuss with women the benefits and risks of planned vaginal birth versus planned caesarean birth for breech presentation, and the option of external cephalic version. [2004, amended 2021]\n\nOffer women who have an uncomplicated singleton breech pregnancy after 36+0\xa0weeks, external cephalic version, unless:\n\nthe woman is in established labour\n\nthere is fetal compromise\n\nthe woman has ruptured membranes or vaginal bleeding\n\nthe woman has any other medical conditions (for example, severe hypertension) that would make external cephalic version inadvisable. [2004, amended 2021]\n\nBefore carrying out a caesarean birth for an uncomplicated singleton breech pregnancy, carry out an ultrasound scan to check that the baby is in the breech position. Do this as late as possible before the caesarean birth procedure. \n\n## Multiple pregnancy\n\nFor recommendations on mode of birth in multiple pregnancy, see mode of birth in the NICE guideline on twin and triplet pregnancy. \n\n## Preterm birth\n\nFor recommendations on mode of birth in preterm labour and birth, see mode of birth in the NICE guideline on preterm labour and birth. \n\n## Placenta praevia\n\nOffer caesarean birth to women with a placenta that partly or completely covers the internal cervical os (minor or major placenta praevia). [2004, amended 2011]\n\n## Placenta accreta spectrum\n\nFor women who have had a previous caesarean birth, offer colour-flow Doppler ultrasound at 32 to 34\xa0weeks as the first diagnostic test for placenta accreta spectrum (PAS) if low-lying placenta is confirmed. [2011, amended 2021]\n\nIf a colour-flow Doppler ultrasound scan result suggests placenta accreta spectrum:\n\ndiscuss with the woman how MRI in addition to ultrasound can help diagnose placenta accreta spectrum and clarify the degree of invasion, particularly with a posterior placenta\n\nexplain what to expect during an MRI procedure\n\ninform the woman that current experience suggests that MRI is safe, but that there is a lack of evidence about any long-term risks to the baby.Offer MRI if this is acceptable to the woman. [2011, amended 2021]\n\nDiscuss birth options (for example, timing of birth, operative interventions including possibility of hysterectomy, need for blood transfusion) with a woman suspected to have placenta accreta spectrum. This discussion should be carried out by a consultant obstetrician, or with a consultant obstetrician present. [2011, amended 2021]\n\nWhen performing a caesarean birth for a woman suspected to have placenta accreta spectrum, ensure that:\n\na consultant obstetrician and a consultant anaesthetist are present in the operating theatre\n\na paediatric registrar, consultant, or equivalent, is present\n\na haematology registrar, consultant, or equivalent, is available for advice\n\na critical care bed is available\n\nsufficient cross-matched blood and blood products are readily available. [2011, amended 2021]\n\nBefore performing a caesarean birth for women suspected to have placenta accreta spectrum, the multidisciplinary team should agree which other healthcare professionals need to be consulted or present, and the responsibilities of each team member. [2011, amended 2021]\n\nAll hospitals should have a locally agreed protocol for managing placenta accreta spectrum that sets out how these elements of care should be provided. \n\n## Predicting caesarean birth for cephalopelvic disproportion in labour\n\nDo not use pelvimetry for decision making about mode of birth. [2004, amended 2021]\n\nDo not use the following for decision making about mode of birth, as they do not accurately predict cephalopelvic disproportion:\n\nmaternal shoe size\n\nmaternal height\n\nestimations of fetal size (ultrasound or clinical examination). [2004, amended 2021]\n\n## Mother-to-child transmission of maternal infections\n\nProvide women with HIV information about the benefits and risks for them and their baby of the HIV treatment options and mode of birth as early as possible in their pregnancy, so that they can make an informed decision. Obtain specialist advice about HIV in pregnancy from a sexual health specialist if necessary. [2011, amended 2021]\n\nDo not offer pregnant women with hepatitis B a planned caesarean birth for this reason alone, as mother-to-baby transmission of hepatitis B can be reduced if the baby receives immunoglobulin and vaccination. [2004, amended 2021]\n\nDo not offer women who are infected with hepatitis C a planned caesarean birth for this reason alone. [2004, amended 2021]\n\nOffer pregnant women who are co-infected with hepatitis C virus and HIV a planned caesarean birth to reduce mother-to-baby transmission of hepatitis C virus and HIV. [2004, amended 2021]\n\nOffer women with primary genital herpes simplex virus (HSV) infection occurring in the third trimester of pregnancy a planned caesarean birth to decrease the risk of neonatal HSV infection. \n\nDo not routinely offer pregnant women with recurrent HSV infection a planned caesarean birth outside of the context of research. [2004, amended 2021]\n\n## Body mass index\n\nDo not use a body mass index (BMI) of over 50\xa0kg/m2 alone as an indication for planned caesarean birth. \n\n## Shared decision making\n\nAsk for consent for caesarean birth only after providing pregnant women with evidence-based information. Ensure the woman's dignity, privacy, views and culture are respected, while taking the woman's clinical situation into account. [2004, amended 2021]\n\nAdvise women that they are entitled to decline the offer of treatment such as caesarean birth, even when it would benefit their or their baby's health. [2004, amended 2021]\n\nWhen a woman decides on or declines a caesarean birth, document the factors that that are important to the woman when making her decision. [2004, amended 2021]\n\n## Maternal choice for caesarean birth\n\nWhen a woman or pregnant person with no medical indication for a caesarean birth requests a caesarean birth:\n\noffer to discuss and explore the reasons for the request\n\nensure they have balanced and accurate information\n\noffer to discuss alternative birth options (for example, place of birth, continuity of midwifery care where available, pain relief options), which may help address concerns they have about the birth\n\noffer discussions with a consultant midwife or senior midwife, ideally in a birth options clinic or at a birth options appointment\n\noffer discussions with a consultant or senior obstetrician and other members of the team (for example an anaesthetist) if necessary or requested by the woman or pregnant person\n\nrecord the discussions and decisions. [2011, amended 2023]\n\nIf a woman or pregnant person requests a caesarean birth, discuss the overall benefits and risks of caesarean birth compared with vaginal birth (see the section on planning mode of birth) and record that this discussion has taken place. \n\nIf a woman or pregnant person requests a caesarean birth because they have tokophobia or other severe anxiety about childbirth (for example, following abuse or a previous traumatic event), offer referral to a healthcare professional with expertise in providing perinatal mental health support to help with their anxiety. See the NICE guideline on antenatal and postnatal mental health for more detailed advice on providing mental health services during pregnancy. [2011, amended 2021]\n\nEnsure healthcare professionals providing perinatal mental health support for women or pregnant people with tokophobia or other severe anxiety about childbirth are able to access the planned place of birth with the woman or pregnant person during the antenatal period, as part of the support offered to help them overcome fears and concerns about the labour and birth. [2011, amended 2023]\n\nIf, after an informed discussion about the options for birth (including the offer of perinatal mental health support if appropriate; see recommendation 1.2.27), the woman or pregnant person requests a caesarean birth, support their choice. [2011, amended 2023]\n\nIf a woman or pregnant person requests a caesarean birth this should be offered within their obstetric unit. [2011, amended 2023]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on maternal choice for caesarean birth\xa0.\n\nLoading. Please wait.\n\n# Factors affecting the likelihood of emergency caesarean birth during intrapartum care\n\n## Factors reducing the likelihood of caesarean birth\n\nInform women that continuous support during labour from women, with or without prior training, reduces the likelihood of caesarean birth. \n\nUse a partogram with a 4‑hour action line to monitor progress of women in spontaneous labour with an uncomplicated singleton pregnancy at term to reduce the likelihood of caesarean birth. \n\nInvolve a consultant obstetrician in decision-making for caesarean birth. [2004, amended 2021]\n\n## No influence on the likelihood of caesarean birth\n\nInform women that the following interventions during intrapartum care have not been shown to influence the likelihood of caesarean birth, although they can affect other outcomes:\n\nwalking in labour\n\nnon-supine position during the second stage of labour\n\nimmersion in water during labour\n\nepidural analgesia during labour\n\nthe use of raspberry leaves. [2004, amended 2021]\n\nInform women that the effects on the likelihood of caesarean birth of complementary therapies used during labour (such as acupuncture, aromatherapy, hypnosis, herbal products, nutritional supplements, homeopathic medicines, and Chinese medicines) are uncertain. [2004, amended 2021]\n\n## Slow progression in labour and caesarean birth\n\nDo not offer the following as they do not influence the likelihood of caesarean birth for slow progression in labour, although they can affect other outcomes:\n\nactive management of labour (comprising a strict definition of established labour, early routine amniotomy, routine 2-hourly vaginal examination, oxytocin if labour becomes slow)\n\nearly amniotomy. [2004, amended 2021]\n\n## Eating during labour\n\nInform women that eating a low-residue diet during labour (toast, crackers, low-fat cheese) results in larger gastric volumes, but the effect on the risk of aspiration if anaesthesia is needed is uncertain. \n\nInform women that having isotonic drinks during labour prevents ketosis without a concomitant increase in gastric volume. \n\n# Procedural aspects of caesarean birth\n\n## Timing of planned caesarean birth\n\nDo not routinely carry out planned caesarean birth before 39\xa0weeks, as this can increase the risk of respiratory morbidity in babies. \n\n## Classification of urgency for caesarean birth\n\nUse the following standardised scheme to document the urgency of caesarean birth and aid clear communication between healthcare professionals:\n\nCategory\xa01. Immediate threat to the life of the woman or fetus (for example, suspected uterine rupture, major placental abruption, cord prolapse, fetal hypoxia or persistent fetal bradycardia).\n\nCategory\xa02. Maternal or fetal compromise which is not immediately life-threatening.\n\nCategory\xa03. No maternal or fetal compromise but needs early birth.\n\nCategory\xa04. Birth timed to suit woman or healthcare provider. [2004, amended 2021]\n\n## Decision-to-birth interval for unplanned and emergency caesarean birth\n\nCategory\xa01 caesarean birth is when there is immediate threat to the life of the woman or fetus, and category 2\xa0caesarean birth is when there is maternal or fetal compromise which is not immediately life-threatening.\n\nPerform category\xa01 caesarean birth as soon as possible, and in most situations within 30\xa0minutes of making the decision. [2011, amended 2021]\n\nPerform category\xa02 caesarean birth as soon as possible, and in most situations within 75\xa0minutes of making the decision. [2011, amended 2021]\n\nTake into account the condition of the woman and the unborn baby when making decisions about rapid birth. Be aware that rapid birth can be harmful in certain circumstances. \n\n## Preoperative testing and preparation for caesarean birth\n\nBefore caesarean birth, carry out a full blood count to identify anaemia, antibody screening, and blood grouping with saving of serum. [2004, amended 2021]\n\nDo not routinely carry out the following tests before caesarean birth:\n\ncross-matching of blood\n\na clotting screen\n\npreoperative ultrasound for localisation of the placenta. [2004, amended 2021]\n\nCarry out caesarean birth for pregnant women with antepartum haemorrhage, abruption or placenta praevia at a maternity unit with on-site blood transfusion services, as they are at increased risk of blood loss of more than 1,000\xa0ml. [2004, amended 2021]\n\nGive women having caesarean birth with regional anaesthesia an indwelling urinary catheter to prevent over-distension of the bladder. [2004, amended 2021]\n\n## Anaesthesia for caesarean birth\n\nProvide pregnant women having a caesarean birth with information on the different types of post‑caesarean birth analgesia, so that they can make an informed choice (see recommendation\xa01.6.9). \n\nOffer women who are having a caesarean birth regional anaesthesia in preference to general anaesthesia, including women who have a diagnosis of placenta praevia. [2004, amended 2021]\n\nCarry out induction of anaesthesia, including regional anaesthesia, for caesarean birth in theatre. [2004, amended 2021]\n\nApply a left lateral tilt of up to 15 degrees or appropriate uterine displacement once the woman is in a supine position on the operating table to reduce maternal hypotension. [2004, amended 2021]\n\nOffer women who are having a caesarean birth under spinal anaesthesia a prophylactic intravenous infusion of phenylephrine, started immediately after the spinal injection. Adjust the rate of infusion to keep maternal blood pressure at 90% or more of baseline value and avoid decreases to less than 80% of baseline. [2004, amended 2021]\n\nWhen using phenylephrine infusion, give intravenous ephedrine boluses to manage hypotension during caesarean birth, for example if the heart rate is low and blood pressure is less than 90% of baseline. [2004, amended 2021]\n\nUse intravenous crystalloid co-loading in addition to vasopressors to reduce the risk of hypotension occurring during caesarean birth. [2004, amended 2021]\n\nEnsure each maternity unit has a set of procedures for failed intubation during obstetric anaesthesia. \n\nOffer women antacids and drugs (such as H2‑receptor antagonists or proton pump inhibitors) to reduce gastric volumes and acidity before caesarean birth.In March 2021, this was an off-label use of proton pump inhibitors. See NICE's information on prescribing medicines. [2004, amended 2021]\n\nOffer women having a caesarean birth anti-emetics (either pharmacological or acupressure) to reduce nausea and vomiting during caesarean birth. \n\nInclude pre-oxygenation, cricoid pressure and rapid sequence induction in general anaesthesia for caesarean birth to reduce the risk of aspiration. [2004, amended 2011]\n\n## Prevention and management of hypothermia and shivering\n\nWarm IV fluids (500\xa0ml or more) and blood products used during caesarean birth to 37\xa0degrees Celsius using a fluid warming device. \n\nWarm all irrigation fluids used during caesarean birth to 38 to 40\xa0degrees Celsius in a thermostatically controlled cabinet. \n\nConsider forced air warming for women who shiver, feel cold, or have a temperature of less than 36\xa0degrees Celsius during caesarean birth. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prevention and management of hypothermia and shivering\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: prevention and management of hypothermia and shivering.\n\nLoading. Please wait.\n\n## Surgical techniques for caesarean birth\n\nUse alcohol-based chlorhexidine skin preparation before caesarean birth to reduce the risk of wound infections. If alcohol-based chlorhexidine skin preparation is not available, alcohol-based iodine skin preparation can be used. See the NICE guideline on surgical site infections. \n\nUse aqueous iodine vaginal preparation before caesarean birth in women with ruptured membranes to reduce the risk of endometritis. If aqueous iodine vaginal preparation is not available or is contraindicated, aqueous chlorhexidine vaginal preparation can be used. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on methods to reduce infectious morbidity and wound care after caesarean birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: methods to reduce infectious morbidity at caesarean birth.\n\nLoading. Please wait.\n\nWear double gloves when performing or assisting a caesarean birth for women who have tested positive for HIV, to reduce the risk of HIV infection of staff. \n\nFollow general recommendations for safe surgical practice during caesarean birth to reduce the risk of HIV infection of staff. \n\nPerform caesarean birth using a transverse abdominal incision to:\n\nmake postoperative pain less likely\n\ngive an improved cosmetic effect compared with a midline incision. \n\nPerform caesarean birth using a transverse incision (a straight skin incision, 3\xa0cm above the symphysis pubis; subsequent tissue layers are opened bluntly and, if necessary, extended with scissors and not a knife). This allows for shorter operating times and reduces postoperative febrile morbidity. \n\nDo not use separate surgical knives to incise the skin and the deeper tissues in caesarean birth, as it does not decrease wound infection. \n\nWhen there is a well formed lower uterine segment, use blunt rather than sharp extension of the uterine incision to reduce blood loss, incidences of postpartum haemorrhage and the need for transfusion during caesarean birth. \n\nInform women who are having a caesarean birth that the risk of fetal lacerations is about 2%. \n\nOnly use forceps in caesarean birth if there is difficulty delivering the baby's head. The effect on neonatal morbidity of the routine use of forceps at caesarean birth remains uncertain. \n\nUse oxytocin 5\xa0IU by slow intravenous injection in caesarean birth to encourage contraction of the uterus and decrease blood loss. \n\nRemove the placenta in caesarean birth using controlled cord traction and not manual removal to reduce the risk of endometritis. \n\nPerform intraperitoneal repair of the uterus for caesarean birth. Routine exteriorisation of the uterus is not recommended because it is associated with more pain and does not improve operative outcomes such as haemorrhage and infection. [2004, amended 2021]\n\nUse single layer or double layer uterine closure in caesarean birth, depending on the clinical circumstances. Note that single layer closure does not increase the risk of postoperative bleeding or uterine rupture in a subsequent pregnancy. \n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on closure of the uterus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: techniques to close the uterus at caesarean birth.\n\nLoading. Please wait.\n\nDo not suture the visceral or the parietal peritoneum in caesarean birth to reduce operating time and the need for postoperative analgesia, and improve maternal satisfaction. \n\nIf a midline abdominal incision is used in caesarean birth, use mass closure with slowly absorbable continuous sutures as this results in fewer incisional hernias and less dehiscence than layered closure. \n\nDo not routinely close the subcutaneous tissue space in caesarean birth unless the woman has more than 2\xa0cm subcutaneous fat, as it does not reduce the incidence of wound infection. \n\nDo not routinely use superficial wound drains in caesarean birth as they do not decrease the incidence of wound infection or wound haematoma. See recommendation\xa01.7.2 on the use of negative pressure wound therapy. [2004, amended 2021]\n\nConsider using sutures rather than staples to close the skin after caesarean birth to reduce the risk of superficial wound dehiscence. See closure methods in the NICE guideline on surgical site infections. \n\nPerform paired umbilical artery and vein measurements of cord blood gases after caesarean birth for suspected fetal compromise, to allow for assessment of fetal wellbeing and guide ongoing care of the baby. [2004, amended 2021]\n\nOffer women prophylactic antibiotics before skin incision for caesarean birth, choosing antibiotics that are effective against endometritis, urinary tract and wound infections. [2011, amended 2021]\n\nInform women that:\n\nendometritis, urinary tract and wound infections occur in about 8% of women who have had a caesarean birth\n\nusing prophylactic antibiotics before skin incision reduces the risk of maternal infection more than prophylactic antibiotics given after skin incision, and that there is no known effect on the baby. [2011, amended 2021]\n\nDo not use co-amoxiclav when giving prophylactic antibiotics before skin incision for caesarean birth. \n\nOffer thromboprophylaxis to women having a caesarean birth. Take into account the risk of thromboembolic disease when choosing the method of prophylaxis (for example, graduated stockings, hydration, early mobilisation, low molecular weight heparin). \n\nAccommodate a woman's preferences for her caesarean birth whenever possible, such as, music playing in theatre, lowering the screen to see the baby born, or silence so that the mother's voice is the first the baby hears. \n\n# Care of the baby born by caesarean birth\n\n## Presence of paediatrician at caesarean birth\n\nEnsure an appropriately trained practitioner skilled in the resuscitation of newborn babies is present for caesarean birth performed under general anaesthesia, or if there is evidence of fetal compromise. \n\n## Thermal care for babies born by caesarean birth\n\nAs babies born by caesarean birth are more likely to have a lower temperature, ensure thermal care is in accordance with good practice for thermal care of newborn babies. \n\n## Maternal contact (skin-to-skin)\n\nOffer and facilitate early skin-to-skin contact between the woman and her baby. [2004, amended 2021]\n\n## Breastfeeding\n\nOffer women who have had a caesarean birth and who wish to breastfeed support to help them to start breastfeeding as soon as possible after the birth of their baby. [2004, amended 2021]\n\n# Care of the woman after caesarean birth\n\n## High-dependency unit/intensive therapy unit admission\n\nBe aware that, although it is rare for women to need intensive care after childbirth, this may occur after caesarean birth. [2004, amended 2021]\n\n## Monitoring after caesarean birth\n\nAfter caesarean birth under a general anaesthetic, a healthcare professional with airway skills should carry out continuous, one-to-one observation of the woman until:\n\nshe has regained airway control, and\n\nis haemodynamically stable, and\n\nis able to communicate. \n\nWhen a woman has regained airway control, is haemodynamically stable, and is able to communicate after caesarean birth under a general anaesthetic:\n\ncontinue observations (oxygen saturation, respiratory rate, heart rate, blood pressure, temperature, pain and sedation) every half hour for 2\xa0hours\n\nafter 2\xa0hours, if these observations are stable, carry out routine observations in accordance with local protocols\n\nif these observations are not stable, or the woman has other risk factors or complications (for example, severe hypertension, or signs of infection or sepsis), carry out a medical review and increase the duration and frequency of observations. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nAfter caesarean birth under a spinal or epidural anaesthetic, a healthcare professional should carry out continuous one-to-one observation of the woman until she is haemodynamically stable (for example when pulse and blood pressure have returned to baseline values). \n\nProvide a woman who has had spinal or epidural diamorphine for caesarean birth, and who is at an increased risk of respiratory depression (for example, a significantly raised BMI, or diagnosed obstructive sleep apnoea syndrome), with:\n\ncontinuous pulse oximetry monitoring, and\n\nhourly monitoring of\n\n\n\nrespiratory rate\n\nheart rate\n\nblood pressure\n\ntemperature\n\npain\n\nsedation.Monitor the woman for at least 12\xa0hours, continue until they are stable enough to be discharged from anaesthetic care, and then carry out routine observations in accordance with local protocols. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\n\n\nFor a woman who has had spinal or epidural diamorphine for caesarean birth, but is not at an increased risk of respiratory depression, carry out routine observations in accordance with local protocols. \n\nWhen deciding on the location and frequency of monitoring for respiratory depression in women who have had spinal or epidural diamorphine for caesarean birth, take into account other factors that could affect monitoring needs (for example, a complicated birth, or unstable observations in first 2\xa0hours after birth). \n\nEnsure women who have patient-controlled analgesia with opioids after caesarean birth have routine hourly monitoring of respiratory rate, sedation and pain scores throughout treatment, and for at least 2\xa0hours after discontinuation of treatment. [2004, amended 2021]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring after caesarean birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: monitoring after intrathecal or epidural opioids for caesarean birth.\n\nLoading. Please wait.\n\n## Pain management after caesarean birth\n\nOffer women diamorphine (0.3 to 0.4\xa0mg intrathecally) for analgesia to reduce the need for supplemental analgesia after a caesarean birth. Epidural diamorphine (2.5 to 5\xa0mg) is a suitable alternative where intrathecal diamorphine has not been given.In March 2021, this was an off-label use of diamorphine (both intrathecal and epidural). See NICE's information on prescribing medicines. [2004, amended 2021]\n\nDiscuss options with women for pain relief after caesarean birth and explain that:\n\npain after caesarean birth can be controlled using oral or injectable medicines\n\ntheir choice of pain relief medicines after caesarean birth will depend on:\n\n\n\nthe severity of pain\n\nwhether they had spinal or epidural anaesthesia, or general anaesthesia\n\n\n\nif they wish to breastfeed, they will usually be able to do this and care for their baby while taking pain relief medicines. \n\nOffer oral morphine sulfate to women who have received spinal or epidural anaesthesia for caesarean birth. If the woman cannot take oral medication (for example, because of nausea or vomiting), offer intravenous, intramuscular or subcutaneous morphine. \n\nConsider intravenous patient-controlled analgesia (PCA) using morphine for women who have had a general anaesthetic for caesarean birth. If intravenous PCA is not acceptable to the woman, or the pain is less severe, consider oral morphine sulfate. \n\nUse paracetamol and, unless contraindicated, a non-steroidal anti-inflammatory drug (for example, ibuprofen) in combination after caesarean birth, to reduce the need for opioids, and to allow them to be stepped down and stopped as early as possible. [2004, amended 2021]\n\nIf paracetamol does not provide sufficient pain relief after caesarean birth, or non-steroidal anti‑inflammatory drugs cannot be taken, consider adding dihydrocodeine to paracetamol, or changing to co-dydramol (combination preparation of paracetamol and dihydrocodeine) as an alternative to paracetamol. \n\nDo not offer codeine or co‑codamol (combination preparation of paracetamol and codeine) to women who are currently breastfeeding, because this can lead to serious neonatal sedation and respiratory depression. Follow the MHRA safety advice on Codeine for analgesia: restricted use in children because of reports of morphine toxicity. \n\nWhen using paracetamol, dihyrocodeine, co-dydramol or a non-steroidal anti-inflammatory drug after caesarean birth, prescribe them to be taken regularly and not just when needed for pain relief. \n\nFor women with severe pain after caesarean birth, when other pain relief is not sufficient:\n\nperform a full assessment to exclude other causes for the pain (for example, sepsis, haemorrhage, urinary retention)\n\ndiscuss with the woman that stronger pain relief medicines are available\n\nmake sure the woman is aware that, if taken while breastfeeding, these medicines could increase the risk of neonatal sedation and respiratory depression.If the women chooses to take stronger medicines, consider a short course of tramadol or oxycodone at the lowest effective dose. \n\nIn breastfeeding women, use opioid analgesics (for example, morphine, dihyrocodeine, tramadol or oxycodone) at the lowest effective dose and for the shortest duration, and not for more than 3\xa0days without close supervision. \n\nIf, after a caesarean birth, a woman is discharged home on opioids, advise the woman to contact their healthcare provider if they are concerned about their baby (for example drowsiness, breathing difficulties, constipation or difficulty feeding). \n\nConsider laxatives for women taking opioids, for the prevention of constipation. \n\nConsider anti-emetics for women taking opioids, if needed for nausea and vomiting. \n\nAdvise women that some over-the-counter medicines contain codeine, and should not be taken while breastfeeding because this can lead to serious neonatal sedation and respiratory depression. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain management after caesarean birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: opioids for pain relief after caesarean birth.\n\nLoading. Please wait.\n\n## Early eating and drinking after caesarean birth\n\nIf women are recovering well after caesarean birth and do not have complications, they can eat and drink as normal. \n\n## Urinary catheter removal after caesarean birth\n\nOffer removal of the urinary bladder catheter once a woman is mobile after a regional anaesthetic for caesarean birth, but no sooner than 12\xa0hours after the last 'top-up' dose. [2004, amended 2021]\n\n## Respiratory physiotherapy after caesarean birth\n\nDo not offer routine respiratory physiotherapy to women after a caesarean birth under general anaesthesia as it does not improve respiratory outcomes (for example, coughing, phlegm, body temperature, chest palpation or auscultatory changes). \n\n## Length of hospital stay and readmission to hospital\n\nInform women that length of hospital stay is likely to be longer after caesarean birth than after a vaginal birth. [2004, amended 2021]\n\nOffer women who are recovering well, are apyrexial and do not have complications after caesarean birth, discharge from hospital after 24\xa0hours and follow up at home, as this is not associated with more readmissions for babies or mothers. [2004, amended 2021]\n\n# Recovery after caesarean birth\n\nIn addition to general postnatal care, provide women who have had a caesarean birth with:\n\nspecific care related to recovery after caesarean birth\n\ncare related to management of other complications during pregnancy or childbirth. \n\n## Wound care\n\nConsider negative pressure wound therapy after caesarean birth for women with a BMI of 35\xa0kg/m2 or more to reduce the risk of wound infections. \n\nWhen using standard (not negative pressure) wound dressings after caesarean birth take into account that:\n\nno type of wound dressing has been shown to be better than another at reducing the risk of wound infections\n\nthere is no difference in the risk of wound infection when dressings are removed 6\xa0hours postoperatively, compared with 24\xa0hours postoperatively. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on methods to reduce infectious morbidity and wound care after caesarean birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: methods to reduce infectious morbidity at caesarean birth.\n\nLoading. Please wait.\n\nEnsure caesarean birth wound care includes:\n\nremoving standard dressings 6 to 24\xa0hours after the caesarean birth\n\nspecific monitoring for fever\n\nassessing the wound for signs of infection (such as increasing pain, redness or discharge), separation or dehiscence\n\nencouraging the woman to wear loose, comfortable clothes and cotton underwear\n\ngently cleaning and drying the wound daily\n\nif needed, planning the removal of sutures or clips.Follow the recommendations in the NICE guideline on surgical site infections. [2004, amended 2021]\n\n## Management of symptoms\n\nWhen caring for women who have had a caesarean birth who have urinary symptoms, consider possible diagnoses of:\n\nurinary tract infection\n\nstress incontinence (occurs in about 4% of women after caesarean birth)\n\nurinary tract injury (occurs in about 1 per 1,000 caesarean births)\n\nurinary retention. [2004, amended 2021]\n\nWhen caring for women who have had a caesarean birth who have heavy and/or irregular vaginal bleeding, consider whether this is more likely to be because of endometritis than retained products of conception, and manage accordingly. [2004, amended 2021]\n\nPay particular attention to women who have respiratory symptoms (such as cough or shortness of breath) or leg symptoms (such as painful swollen calf), as women who have had a caesarean birth may be at increased risk of thromboembolic disease (both deep vein thrombosis and pulmonary embolism). [2004, amended 2021]\n\n## Resuming activities and discharge home\n\nInform women who have had a caesarean birth that they can resume activities such as driving a vehicle, carrying heavy items, formal exercise and sexual intercourse when they feel they have fully recovered from the caesarean birth (including any physical restrictions or pain). [2004, amended 2021]\n\nWhen caring for women who have had a caesarean birth, discuss that after a caesarean birth they are not at increased risk of depression, post-traumatic stress symptoms, pain on sexual intercourse, faecal incontinence or difficulties with breastfeeding. [2004, amended 2021]\n\nWhile women are in hospital after having an emergency or unplanned caesarean birth, give them the opportunity to discuss with healthcare professionals the reasons for the caesarean birth, and provide both verbal and printed information about birth options for any future pregnancies. If the woman prefers, provide this at a later date. [2011, amended 2021]\n\nInform the woman's GP if follow-up investigations are needed after discharge from hospital (for example, a repeat full blood count if there has been a large amount of blood loss), and include details of the plan or course of action if the results are abnormal. \n\n# Pregnancy and childbirth after caesarean birth\n\nWhen advising about the mode of birth after a previous caesarean birth, consider:\n\nmaternal preferences and priorities\n\nthe risks and benefits of repeat planned caesarean birth\n\nthe risks and benefits of planned vaginal birth after caesarean birth, including the risk of unplanned caesarean birth. \n\nInform women who have had up to and including 4\xa0caesarean births that the risk of fever, bladder injuries and surgical injuries does not vary with planned mode of birth, but that the risk of uterine rupture is higher for planned vaginal birth. \n\nOffer women planning a vaginal birth who have had a previous caesarean birth:\n\nelectronic fetal monitoring during labour\n\ncare during labour in a unit where there is immediate access to caesarean birth and on-site blood transfusion services. \n\nDuring induction of labour, women who have had a previous caesarean birth should be monitored closely, with access to electronic fetal monitoring and with immediate access to caesarean birth, as they are at increased risk of uterine rupture. For further information see the NICE guideline on inducing labour. \n\nPregnant women with both previous caesarean birth and a previous vaginal birth should be informed that they have an increased likelihood of having a vaginal birth than women who have had a previous caesarean birth but no previous vaginal birth. ", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\nAs part of the 2021 update, the guideline committee removed the research recommendation on 'What are the medium- to long-term risks and benefits to women and their babies of planned caesarean birth compared with planned vaginal birth?' and replaced it with a research recommendation on the short-term and long-term risks and benefits of planned caesarean birth compared with planned vaginal birth.\n\n# Short-term and long-term benefits and risks of planned caesarean birth compared to planned vaginal birth\n\nWhat are the benefits and risks (short term and long term) of planned caesarean birth compared with planned vaginal birth at term for women and babies/infants/children? \n\n## Why this is important\n\nInformation provided to women with low-risk pregnancies in relation to the short- and long-term benefits and risks of planned caesarean birth compared with planned vaginal birth should reflect the relevant risks during the antenatal period when a woman is planning mode of birth. Studies used to inform these discussions with women should be from 'intention to treat' type analyses. However this type of evidence is sparse for outcomes relevant to the early neonatal period and minimal for long-term outcomes and further research is needed.\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on benefits and risks of caesarean and vaginal birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: the benefits and risks of planned caesarean birth.\n\nLoading. Please wait.\n\n# Decision-to-birth interval (category\xa01 urgency)\n\nWhat factors influence the decision-to-birth interval when there is a category\xa01 level of urgency for caesarean birth? \n\n## Why this is important\n\n'Crash' caesarean birth is a psychologically traumatic event for women and their partners, and is also stressful for clinical staff. Staff and resources might have to be obtained from other areas of clinical care. This should be done as efficiently and effectively as possible, minimising anxiety and ensuring the safety of the mother and her baby.\n\nFor category\xa01 caesarean birth there is a recognised urgency to deliver as quickly as is reasonably possible. Most research in this area is quantitative and looks at the impact of the decision-to-birth interval on various aspects of fetal and maternal outcomes rather than the interplay of factors that can affect this time period itself. Much of this evidence is retrospective. Although some work has been done in the UK to examine where the systematic delays are and how to avoid them, more work is needed to determine how to optimise the decision-to-birth interval. This work should use qualitative as well as quantitative research methods to assess which factors influence the decision-to-birth interval for a category\xa01 caesarean birth. Evaluation of these factors could be used to inform future NICE guidance, for example, specific guidance for management of category\xa01 caesarean birth. Such information could also be used by hospitals for maternity services planning, and at a team level would assist with audit and ongoing evaluation and training of the multidisciplinary team.\n\nA large amount of NHS and other state funding is used to provide continuing care for babies who are disabled as a result of birth asphyxia and in providing lifelong support for the child and their family. In addition, large sums of public money are spent on litigation and compensation in some of these cases through the Clinical Negligence Scheme for Trusts (CNST). If research helped to reduce the incidence of birth asphyxia this would reduce the costs of continuing care to the state and the burden to the child, their family and the wider community.\n\nMore realistic and more relevant expectations for the decision-to-delivery interval based on evidence would inform debate in the legal system and could help to reduce the cost to the state of related litigation.\n\n# Decision-to-birth interval (category\xa02 urgency)\n\nA prospective study to determine whether the decision-to-birth interval has an impact on maternal and neonatal outcomes when there is a category\xa02 level of urgency for caesarean birth. \n\n## Why this is important\n\nThis research is important to inform the ongoing debate about the management of category\xa02 caesarean birth. The 'continuum of risk' in this setting has been recognised. However, most of the work in this area, looking at maternal and fetal outcomes, generally considers unplanned caesarean birth as a whole group without making any distinction between degrees of urgency. Furthermore, much of this work is retrospective. Most women who undergo intrapartum caesarean birth fall into the category\xa02 level of urgency and therefore specific information for this group could affect and benefit many women and contribute to the delivery of equity of care.\n\nDelay in birth with a compromised fetus could result in major and long-term harm including cerebral palsy and other major long-term disability. The immediate and long-term effect on a family of the birth of a baby requiring lifelong specialised care and support is enormous. If such harm could be avoided by appropriate haste this would be an important improvement in outcome. However, if such haste is of no benefit then any related risk of adverse maternal outcome needs to be minimised.\n\nA large amount of NHS and other state funding is used to provide continuing care for babies who are disabled as a result of delay in birth and in providing lifelong support for the child and their family. In addition, large sums of public money are spent on litigation and compensation in some of these cases through the CNST. If research helped to reduce the incidence of delay in birth this would reduce the costs of continuing care to the state and the burden to the child, their family and the wider community.\n\nMore realistic and more relevant expectations for the decision-to-birth interval based on evidence would inform debate within the legal system and could help to reduce the cost to the state of related litigation.\n\n# Maternal request for caesarean birth\n\nWhat support or psychological interventions would be appropriate for women who have a fear of vaginal childbirth and request a caesarean birth? \n\n## Why this is important\n\nFear of vaginal childbirth can stem from:\n\nfear of damage to the maternal pelvic floor\n\ndamage to the baby during childbirth\n\nself-doubt on the ability to physically have a vaginal birth\n\nprevious childbirth experience\n\nunresolved issues related to the genital area.\n\nCurrently there is a wide variation in practice and limited resources lead to limited availability of effective interventions. Interventions that might be appropriate include:\n\nantenatal clinics dedicated to providing care for women with no obstetric indications who request a caesarean birth\n\nreferral to a psychologist or a mental health professional\n\nreferral to an obstetric anaesthetist\n\nintensive midwifery support.\n\nContinuity of healthcare professional support from the antenatal to the intrapartum periods and 'one-to-one' midwifery care during labour are also often lacking and could make a difference to women who are anxious or afraid.\n\nAll of these interventions have different resource implications and there is no clear evidence to suggest that any are of benefit. The proposed research would compare in a randomised controlled trial 2\xa0or more of these interventions in women requesting a caesarean birth. In the absence of any evidence, there is a case for comparing these interventions with routine antenatal care (that is, no special intervention).\n\nThis research is relevant because it would help to guide the optimal use of these limited resources and future guideline recommendations.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Benefits and risks of caesarean and vaginal birth\n\nRecommendations 1.1.3 and 1.1.4\n\n## Why the committee made the recommendations\n\nThere was some evidence for a selected number of outcomes on the short- and long-term effects of caesarean birth compared with vaginal birth, although there were some limitations with the quality of the evidence, and not all evidence was from a comparison of planned mode of birth. The committee used this evidence, along with their clinical expertise, to update the advice comparing the relative benefits and risks of these 2\xa0modes of birth.\n\nFor some outcomes there was conflicting or limited evidence, and there were also a number of outcomes for which no evidence was identified for inclusion, so the committee highlighted these uncertainties.\n\nAs the evidence was limited for this review the committee made a research recommendation.\n\nThere were also 3\xa0outcomes included in the 2011 guideline which had not been included in this current review (vaginal tears, length of stay and pain) but the committee agreed that the advice was still appropriate and should be carried forward into the updated guideline.\n\n## How the recommendations might affect practice\n\nThe committee considered that their recommendations would reinforce best practice. It is already current practice to discuss the risks and benefits of alternative modes of birth during the antenatal period and this review has simply led to an update of the information that should be discussed with women.\n\nReturn to recommendations\n\n# Maternal choice for caesarean birth\n\nRecommendations 1.2.25 to 1.2.30\n\n## Why the committee made the recommendations\n\nThe committee discussed the fact that some women or pregnant people may request a caesarean birth because they have concerns about aspects of the birth and believe that a caesarean birth would be the best way to alleviate these concerns. However, there may be cases where the concerns can be addressed in other ways, such as choosing an alternative place of birth, opting for a birth which will provide greater continuity of midwifery care, or by planning adequate pain relief. The committee therefore expanded the advice to include these aspects in the discussion.\n\nThe committee were aware that this discussion would be best held in a clinic where there was time to explore the different options and preferences, and so suggested this should be in a birth options clinic. The committee were aware that consultant midwives were often involved in such discussions and so included them in the list of healthcare professionals who should be involved.\n\nThe committee revised the wording of the recommendation on perinatal mental health support to clarify that the access to the planned place of birth was needed during the antenatal period, and not that all antenatal support had to be provided at the planned place of birth.\n\nThe committee revised the wording of the recommendation on offering caesarean birth to be more person-centred, and to ensure the woman or pregnant person's choice to have a caesarean birth was supported.\n\nThe committee agreed that women and pregnant people should not have to move to a different obstetric unit for a caesarean birth, and so recommended that caesarean birth should be offered within their obstetric unit. The committee discussed the potential rare situations where there was a clinical reason behind a reluctance to perform a maternal request caesarean birth, but agreed that in this situation a full multidisciplinary team discussion would be needed during the pregnancy to agree a plan for the woman or pregnant person.\n\n## How the recommendations might affect practice\n\nThis change to add more factors into the discussions around requests for caesarean birth may mean more women and pregnant people can be supported to have their preferred mode of birth. The change may also increase the number of women or pregnant people being seen by a consultant midwife or senior midwife for a longer 'birth options' appointment, but is unlikely to have a resource impact as these conversations would previously have been held across multiple midwife appointments.\n\nThis change to recommend that caesarean birth should be offered within the woman or pregnant person's obstetric unit will reduce the number of people who have to move to a different obstetric unit in order to have a caesarean birth. This will benefit the following groups in particular:\n\nwomen or pregnant people with disabilities who find it difficult to travel or feel anxious about change\n\nwomen or pregnant people from lower socioeconomic groups where the increased travel costs are a concern\n\nyounger women or pregnant people who may not feel confident enough to transfer to another unit\n\nwomen or pregnant people from certain racial groups who may experience bias surrounding decisions relating to mode of birth and who may have less favourable maternity outcomes\n\nwomen or pregnant people who do not speak English as a first language, or those from groups such as migrants or refugees who may not be familiar with navigating the healthcare system and who therefore may have more difficulty changing their provider or travelling to another unit.\n\nReturn to recommendations\n\n# Prevention and management of hypothermia and shivering\n\nRecommendations 1.4.21 to 1.4.23\n\n## Why the committee made the recommendations\n\nThere was evidence for the effectiveness of active warming measures (for example, forced air warming, under body pads, warmed IV fluids) to prevent shivering and hypothermia in women having a caesarean birth, and there was some evidence for improved thermal comfort and maternal temperature. The committee recommended the use of warmed IV fluids and irrigation fluids for all women having caesarean birth, but because of the low incidence of hypothermia and shivering during caesarean birth, the physiological differences between women having caesarean birth and the general surgical population, the lack of beneficial effect on wound infections, and the fact that warming methods are likely to be as effective at managing hypothermia and shivering as they are at preventing it, the committee recommended that other warming measures should only be used in women who were shivering, said they felt cold or were hypothermic, and not in all women for prevention. The committee recommended forced air warming as the method of choice as this was already widely available, easier to use and could be easily moved with the woman.\n\nThere was evidence that pethidine was also effective at reducing shivering, but the committee did not recommend this because of the possible adverse effects on breastfeeding.\n\n## How the recommendations might affect practice\n\nThe recommendation to use forced air warming will standardise practice across the NHS. There could be resource implications for units to purchase the disposable 'blankets' used, but this could be offset by earlier discharge of women from recovery to the postnatal ward.\n\nThe use of warmed intravenous fluids, blood and irrigation fluids is already standard practice, so this recommendation will not change this.\n\nReturn to recommendations\n\n# Methods to reduce infectious morbidity and wound care after caesarean birth\n\nRecommendations\xa01.4.24 and 1.4.25 and recommendations\xa01.7.2 and 1.7.3\n\n## Why the committee made the recommendations\n\nThere was evidence that alcohol-based chlorhexidine solution skin preparations reduce the risk of surgical site infections, compared with alcohol-based iodine solutions.\n\nThere was also evidence that aqueous iodine vaginal preparations reduce the risk of endometritis in women with ruptured membranes. Although there was some evidence on chlorhexidine vaginal preparations, overall the evidence indicated that that iodine vaginal preparations might be more effective.\n\nThere was some evidence that negative pressure wound therapy (NPWT) reduces the risk of wound or surgical site infections for women with a BMI of 30\xa0kg/m2 or more but economic evidence indicated that this would not be cost effective in those with a BMI of less than 35\xa0kg/m2 and only borderline cost effective in the group with a BMI of 35\xa0kg/m2 or more.\n\nThe evidence showed no difference in wound infection or readmissions into hospital when the dressing was removed either 6\xa0hours or 24\xa0hours after surgery.\n\nThere was very limited evidence on the use of 2 different types of dressing, but the committee agreed it was not enough to recommend a specific type.\n\nThere was no evidence on the use of incise drapes, diathermy or body hair removal, so the committee did not make recommendations about these, but noted that the NICE guideline on surgical site infections (which covers general surgery rather than caesarean birth) has recommendations on some of these interventions.\n\n## How the recommendations might affect practice\n\nThe recommendations on skin preparation are broadly in line with current best clinical practice. The committee agreed that the recommendation to use aqueous iodine vaginal preparation will be a change in clinical practice, because the use of vaginal preparation is not routine across England.\n\nThe committee identified that considering the use of NPWT for women with a BMI of 35\xa0kg/m2 will be a change of practice for many units (some units do not use it at all, or only at higher BMI thresholds), and could have resource implications, particularly in areas where a higher proportion of pregnant women will meet the criteria.\n\nReturn to the recommendations\n\n# Closure of the uterus\n\nRecommendation\xa01.4.37\n\n## Why the committee made the recommendation\n\nThere was evidence showing that there was no difference in any outcomes when comparing single and double layer closure of the uterus. There was some evidence of the reduced need for blood transfusions with single layer compared with double layer closure, as part of a comparison of different caesarean birth techniques, but this could have been confounded by other differences in the techniques.\n\n## How the recommendation might affect practice\n\nCurrent practice is to use a double layer uterine closure technique, except in occasional circumstances when there is a specific reason for using single layer closure. This recommendation will allow surgeons to choose single or double layer closure, depending on the individual clinical circumstances at the time of the surgery.\n\nReturn to recommendation\n\n# Monitoring after caesarean birth\n\nRecommendations\xa01.6.2 to 1.6.7\n\n## Why the committee made the recommendations\n\nThere was no evidence found on the best monitoring schedule for women, but the committee used their knowledge and expertise of current best practice to develop recommendations on the monitoring schedule, including identifying women who would be at higher risk and so would need more intensive monitoring.\n\n## How the recommendations might affect practice\n\nThe recommendations should lead to a reduction in the frequency and duration of monitoring of most women who have received intrathecal or epidural opioids at the time of caesarean birth, but will mean women need to be assessed for risk factors to determine if they need a more intensive monitoring schedule. However, as only women identified as high risk will need intensive monitoring, it is anticipated that the overall monitoring workload will decrease.\n\nReturn to recommendations\n\n# Pain management after caesarean birth\n\nRecommendations\xa01.6.10 to 1.6.12 and 1.6.14 to 1.6.22\n\n## Why the committee made the recommendations\n\nThe committee developed separate recommendations for women receiving regional or general anaesthesia, based on their knowledge of the likely differences in analgesia requirements. For all women, the committee agreed that any postoperative analgesia should be suitable for use while breastfeeding, but that women should be made aware of any potential adverse effects on their baby.\n\nThe committee agreed to retain the previous NICE recommendation to offer diamorphine (delivered intrathecally or by epidural) for women who have regional anaesthesia. Giving spinal or epidural diamorphine in this way reduces the need for additional opioids and other rescue medications during surgery, and it remains effective for up to 12\xa0hours (when pain is likely to be most severe).\n\nThe committee agreed that women receiving regional anaesthesia should be offered oral morphine sulfate, as the evidence showed it to be effective.\n\nThe evidence on pain relief for women after general anaesthesia was sparse, but the committee agreed that intravenous patient-controlled analgesia (PCA) using morphine should be offered as these women will likely have a higher level of pain. If PCA morphine is not acceptable to the woman, then oral morphine should be considered as a less invasive alternative.\n\nFrom their knowledge and experience, the committee agreed that paracetamol and a non-steroidal anti-inflammatory drug (NSAID) such as ibuprofen should be offered in combination to all women to limit the amount of opioids needed, and to allow opioids to be stopped. Based on the evidence on the benefits of fixed interval pain management timing, the committee recommended these be prescribed to be taken regularly to maintain good pain control, in preference to on-request administration, which had lower rates of satisfaction reported by the women.\n\nSome women will have contraindications to NSAIDs (for example, inflammatory bowel disease, gastric ulcer or pre-eclampsia), and will not get sufficient pain relief from paracetamol alone. Based on their experience, the committee suggested an alternative of dihydocodeine in addition to paracetamol, or co-dydramol, as these are also suitable for use while breastfeeding.\n\nThere was evidence for the effectiveness of oxycodone, and some evidence for tramadol, but the committee were aware both of these drugs can cause neonatal sedation and respiratory depression if used when breastfeeding. However, in women with severe pain the committee agreed that a short course of tramadol or oxycodone could be considered as long as the woman was informed of the risks and chose to use them. The length of the course was not defined as there was no evidence for a specific period or dosage.\n\nThe committee were aware that there were general recommendations in the BNF on the use of opioids in breastfeeding women and so included these as part of their recommendations. The committee were also aware of an MHRA warning on the risk of serious neonatal respiratory depression and sedation with codeine in some women. Because of this, they recommended that codeine, or medications that include codeine (such as co‑codamol) should not be used, and that women should be advised not to use codeine‑containing medicines while breastfeeding.\n\nBased on their knowledge and experience, the committee recommended that anti-emetics could be prescribed if needed for nausea and vomiting, and that laxatives should be considered for the prevention of constipation.\n\n## How the recommendations might affect practice\n\nThe committee agreed that these recommendations would reinforce current practice. However, there may be a reduction in the use of intravenous PCA opioids for pain management after caesarean birth, and an increase in the use of oral morphine. The committee agreed that the recommendations relating to dihydrocodeine and codeine‑containing medicines would provide greater clarity and increase safety.\n\nReturn to recommendations", 'Context': 'This guideline has been developed to help ensure consistent quality care for women who have had a caesarean birth (caesarean section) in the past and are now pregnant again, who have a clinical indication for a caesarean birth, or are considering a caesarean birth when planning their birth, and there is no medical indication.\n\nIt provides some evidence-based information for healthcare professionals and women about the risks and benefits of caesarean birth compared with vaginal birth, and this has now been updated to include the short- and long-term risks and benefits for both women and babies/children. It also provides guidance on specific indications for caesarean birth, effective management strategies to avoid unplanned caesarean birth and the organisational and environmental factors that affect caesarean birth rates.\n\nFor women who undergo a caesarean birth, guidance is provided on the anaesthetic and surgical aspects of care, including interventions to reduce morbidity from caesarean birth. The recommendations on monitoring after caesarean birth, pain relief after caesarean birth and on uterine closure have been updated.\n\nThis update also contains new recommendations on techniques to reduce infectious morbidity and techniques to prevent and manage hypothermia and shivering.'}	https://www.nice.org.uk/guidance/ng192	This guideline covers when to offer and discuss caesarean birth, procedural aspects of the operation, and care after caesarean birth. It aims to improve the consistency and quality of care for women and pregnant people who are thinking about having a caesarean birth or have had a caesarean birth in the past and are now pregnant again.
331e1c5fca2afcafcc701be281ebc9453d3916c3	nice	Early and locally advanced breast cancer: diagnosis and management	Early and locally advanced breast cancer: diagnosis and management This guideline covers diagnosing and managing early and locally advanced breast cancer. It aims to help healthcare professionals offer the right treatments to people, taking into account the person's individual preferences. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. This guideline uses specific, inclusive language to describe the population groups it covers (for example, women and pregnant people, or trans and non-binary people) except when: the evidence for the recommendation has not been reviewed and it is not certain from expert opinion whether it can cover more groups, or the evidence has been reviewed, but the information available for some groups at the time of development was too limited to make specific recommendations, or -nly a very limited number of recommendations have been updated in direct response to new evidence or to reflect a change in practice. Healthcare professionals should use their clinical judgement when implementing gender-specific recommendations, taking into account the individual's circumstances, needs and preferences, and ensuring all people are treated with dignity and respect throughout their care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Preoperative assessment For people having investigations for early and locally advanced invasive breast cancer: perform pretreatment ultrasound evaluation of the axilla, and if abnormal lymph nodes are identified, perform ultrasound-guided needle sampling. Do not routinely use MRI of the breast as part of the preoperative assessment of people with biopsy-proven invasive breast cancer or ductal carcinoma in situ (DCIS). Offer MRI of the breast as part of preoperative assessment to people with invasive breast cancer: if the extent of disease is not clear from clinical examination, mammography and ultrasound assessment for planning treatment if accurate mammographic assessment is difficult because of breast density to assess the tumour size if breast-conserving surgery is being considered for invasive lobular cancer. ## Genetic testing Offer genetic testing for BRCA1 and BRCA2 mutations to women under 50 years with triple-negative breast cancer, including those with no family history of breast or ovarian cancer (also see the recommendations on genetic testing in the NICE guideline on familial breast cancer). # Providing information and psychological support Ensure all people with breast cancer have a named clinical nurse specialist, or other specialist key worker with equivalent skills, to support them throughout diagnosis, treatment and follow-up. Offer all people with breast cancer prompt access to specialist psychological support and, where appropriate, psychiatric services. Discuss opportunities for people with breast cancer to be involved in research, and encourage entry into clinical trials and other studies. For guidance on fertility preservation, see the recommendations on people with cancer who wish to preserve fertility in the NICE guideline on fertility problems. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on providing information and psychological support . Loading. Please wait. # Surgery to the breast Offer further surgery (re-excision or mastectomy, as appropriate) after breast-conserving surgery where invasive cancer or DCIS is present at the radial margins ('tumour on ink'; 0 mm). For women who have had breast-conserving surgery where invasive cancer or DCIS is present within 2 mm of, but not at, the radial margins (greater than 0 mm and less than 2 mm): discuss the benefits and risks of further surgery (re-excision or mastectomy) to minimise the risk of local recurrence take into account the woman's preferences, comorbidities, tumour characteristics and the potential use of radiotherapy (also see radiotherapy after breast-conserving surgery). For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on surgery to the breast . Full details of the evidence and the committee's discussion are in evidence review A: surgery to the breast. Loading. Please wait. All breast units should audit their recurrence rates after treatment. ## Paget's disease Offer breast-conserving surgery with removal of the nipple–areolar complex as an alternative to mastectomy for people with Paget's disease of the nipple that has been assessed as localised. Offer oncoplastic repair techniques to maximise cosmesis. # Surgery to the axilla ## Invasive breast cancer Perform surgery using sentinel lymph node biopsy (SLNB) rather than axillary lymph node clearance to stage the axilla for people with invasive breast cancer if they have: no evidence of lymph node involvement on ultrasound, or a negative ultrasound-guided needle biopsy. Perform SLNB using the dual technique with isotope and blue dye. Breast units should audit their axillary recurrence rates. ## Ductal carcinoma in situ Do not routinely perform SLNB for women with a preoperative diagnosis of DCIS who are having breast-conserving surgery, unless they are considered to be at high risk of invasive disease. People at high risk of invasive disease include those with a palpable mass or extensive microcalcifications. Offer SLNB to all people who are having a mastectomy for DCIS. ## Evaluation and management of a positive axillary lymph node identified by a preoperative ultrasound-guided needle biopsy Offer axillary node clearance to people with invasive breast cancer who have a preoperative ultrasound-guided needle biopsy with pathologically proven lymph node metastases. ## Evaluation and management of a positive axillary lymph node identified by a sentinel lymph node biopsy (in people with a normal preoperative ultrasound-guided needle biopsy) Offer further axillary treatment (axillary node clearance or radiotherapy) after SLNB to people who have 1 or more sentinel lymph node macrometastasis. Discuss the benefits and risks of not having further axillary treatment after primary breast-conserving surgery (within clinical trials where available) with women who: have 1 or 2 sentinel lymph node macrometastases and have been advised to have whole-breast radiotherapy with systemic therapy (which may be endocrine therapy). Do not offer further axillary treatment to people who only have micrometastases in their sentinel lymph nodes after primary surgery for invasive breast cancer. Do not offer further axillary treatment to people who have isolated tumour cells in their sentinel lymph nodes after primary surgery for invasive breast cancer. Classify this as lymph node-negative breast cancer. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on evaluation and management of a positive axillary lymph node . Full details of the evidence and the committee's discussion are in evidence review B: management of the positive axilla. Loading. Please wait. # Breast reconstruction Offer breast reconstruction to people after they have had mastectomy for breast cancer. Be aware that some people may prefer not to have breast reconstruction surgery. Offer both breast reconstruction options to women (immediate reconstruction and delayed reconstruction), whether or not they are available locally. Offer immediate breast reconstruction to women who have been advised to have a mastectomy, including those who may need radiotherapy, unless they have comorbidities that rule out reconstructive surgery. Discuss the benefits and risks of immediate breast reconstruction and delayed breast reconstruction with women. Topics to discuss include those in table 1 and: the timing of breast reconstruction surgery (at the same time as mastectomy or later) different breast reconstruction surgery options and what they involve how the timing of breast reconstruction surgery affects the options available the uncertainty over long-term outcomes in women having radiotherapy. Category Immediate breast reconstruction Delayed breast reconstruction Definition Reconstruction is started in the same operation as the mastectomy After a mastectomy, reconstruction is done in a separate operation Number and timing of operations More than 1 operation is usually needed to complete the reconstruction The total number of operations will vary. It may be affected by factors such as: type of reconstruction (for example, some are planned in stages; a prosthesis may be worn until reconstruction is complete) personal preferences (such as whether a nipple reconstruction is requested) Fewer operations may be needed More than 1 operation is usually needed to complete the reconstruction The total number of operations will vary. It may be affected by factors such as: type of reconstruction (for example, some are planned in stages; a prosthesis may be worn until reconstruction is complete) personal preferences (such as whether a nipple reconstruction is requested) More operations may be needed Breast reconstruction options available These will vary depending on personal preferences (such as breast size desired), current body shape, other health conditions, previous operations and lifestyle factors (such as hobbies) Not all hospitals or surgeons can offer all procedures. Travel to a different hospital may be needed for a specific option Options may be available that spare or preserve the breast skin (which may mean less scarring and a more natural look) Limited time to make a decision about options (which may include not having a reconstruction) before surgery These will vary depending on personal preferences (such as breast size desired), current body shape, other health conditions, previous operations and lifestyle factors (such as hobbies) Not all hospitals or surgeons can offer all procedures. Travel to a different hospital may be needed for a specific option Certain options that spare or preserve the breast skin may not be available More time to make a decision (which may include not having a reconstruction) and to plan reconstruction Benefits Breast shape remains, which may help maintain body image and have subsequent psychological benefits Lifestyle changes (such as losing weight and taking regular exercise) may be possible, which increase the options and lower the risks of reconstruction surgery Procedures (and associated recovery) can be planned around other commitments Risks Surgical complications can occur after any breast reconstruction and will vary by type of procedure and personal risk factors May be lower rates of: tissue breakdown surgery for flap removal if it cannot be used because of a complication (which may lead to delayed reconstruction and flat appearance for a period of time) procedures to improve symmetry Complications from the mastectomy or axillary surgery can occur during the recovery period Surgical complications can occur after any breast reconstruction and will vary by type of procedure and personal risk factors May be lower rates of: mastectomy site complications flap or implant failure (which may lead to delayed reconstruction and flat appearance for a period of time) capsular contracture (a scar layer around the implant that may lead to pain if severe) May need to interrupt hormone therapies (tamoxifen) for further surgery Satisfaction No clear differences in satisfaction with completed reconstructions No clear differences in satisfaction with completed reconstructions Reconstruction and adjuvant therapy (including radiotherapy and chemotherapy) Radiotherapy or chemotherapy can be given but may be delayed if there are complications from the mastectomy or reconstruction Immediate reconstructions using implants may be more affected by radiotherapy than immediate flap reconstructions May need adaptions to scans if a tissue expander is used. For example, may not be able to have MRI scans and may need modified radiotherapy planning Complications can also occur after mastectomy alone, which may delay chemotherapy or radiotherapy For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on breast reconstruction . Full details of the evidence and the committee's discussion are in evidence review I: postmastectomy radiotherapy. Loading. Please wait. # Diagnostic assessment and adjuvant therapy planning ## Predictive factors Assess the oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status of all invasive breast cancers simultaneously at the time of initial histopathological diagnosis. Assess the ER status of all invasive breast cancers using standardised and quality-assured immunohistochemical techniques, and report the results quantitatively. Assess the PR status of all invasive breast cancers using standardised and quality-assured immunohistochemical techniques, and report the results quantitatively. Assess the HER2 status of all invasive breast cancers using standardised and quality-assured techniques, and report the results quantitatively. Ensure that the ER, PR and HER2 statuses are available and recorded at the preoperative and postoperative multidisciplinary team meetings when systemic treatment is discussed. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on predictive factors . Full details of the evidence and the committee's discussion are in evidence review C: adjuvant systemic therapy planning. Loading. Please wait. ## Adjuvant therapy planning Consider adjuvant therapy after surgery for people with invasive breast cancer, and ensure that recommendations are documented at the multidisciplinary team meeting. Base recommendations about adjuvant therapy on multidisciplinary team assessment of the prognostic and predictive factors, and the possible risks and benefits of the treatment. Make decisions with the person after discussing these factors. Use the PREDICT tool to estimate prognosis and the absolute benefits of adjuvant therapy for women with invasive breast cancer. When using the PREDICT tool, be aware that: it is less accurate for: women under 30 with ER-positive breast cancer women aged 70 and over women with tumours larger than 50 mm it has not been validated in men, and the validation may have under-represented some ethnic groups.Take into account that the potential limitations in versions of PREDICT after 2.0 may differ from those listed here (also see the PREDICT tool frequently asked questions). For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on adjuvant therapy planning . Full details of the evidence and the committee's discussion are in evidence review C: adjuvant systemic therapy planning. Loading. Please wait. ## Tumour profiling tests to guide adjuvant chemotherapy decisions The NICE diagnostics guidance on tumour profiling tests provides evidence-based recommendations on tumour profiling tests to guide adjuvant chemotherapy decisions. # Endocrine therapy Treat all people with invasive breast cancer with surgery and appropriate systemic therapy, rather than endocrine therapy alone, unless a significant comorbidity means surgery is not suitable for them. ## Adjuvant endocrine therapy for invasive breast cancer Offer tamoxifen as the initial adjuvant endocrine therapy for men and premenopausal women with ER-positive invasive breast cancer. Offer an aromatase inhibitor as the initial adjuvant endocrine therapy for postmenopausal women with ER-positive invasive breast cancer who are at medium or high risk of disease recurrence. Offer tamoxifen to women who are at low risk of disease recurrence, or if aromatase inhibitors are not tolerated or are contraindicated. ## Ovarian function suppression Consider ovarian function suppression in addition to endocrine therapy for premenopausal women with ER-positive invasive breast cancer. Discuss the benefits and risks of ovarian function suppression in addition to endocrine therapy with premenopausal women with ER-positive invasive breast cancer. Explain to women that ovarian function suppression may be most beneficial for those women who are at sufficient risk of disease recurrence to have been offered chemotherapy. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on ovarian function suppression . Full details of the evidence and the committee's discussion are in evidence review D: endocrine therapy for invasive disease. Loading. Please wait. ## Extended endocrine (hormone) therapy In June 2023, the use of aromatase inhibitors in recommendations 1.7.6 and 1.7.7 was off-label. See NICE's information on prescribing medicines. Discuss the benefits and risks of extended endocrine therapy with people who this treatment may be suitable for (see table 2). Offer extended endocrine therapy (past the 5‑year point) with an aromatase inhibitor for postmenopausal women with ER-positive invasive breast cancer who are at medium or high risk of disease recurrence and who have been taking tamoxifen for 2 to 5 years. Medium or high risk may include people who have lymph node-positive breast cancer, with tumours that are T2 or greater and higher grade. Consider extended endocrine therapy (past the 5‑year point) with an aromatase inhibitor for postmenopausal women with ER-positive invasive breast cancer who are at low risk of disease recurrence and who have been taking tamoxifen for 2 to 5 years. Low risk may include people with lymph node-negative breast cancer, with smaller or lower-grade tumours. Consider extending the duration of tamoxifen therapy for longer than 5 years for people with ER-positive invasive breast cancer. Category Extended tamoxifen therapy (after an initial 5 years of tamoxifen therapy) Extended endocrine therapy with an aromatase inhibitor (after 5 years of tamoxifen therapy) Definition Continuing to take tamoxifen after 5 years of tamoxifen therapy Switching to an aromatase inhibitor after 5 years of tamoxifen therapy Who can take this therapy People with ER-positive invasive breast cancer Postmenopausal women with ER-positive invasive breast cancer Effect on breast cancer recurrence: The benefit for an individual person will depend on the risk of their cancer returning. For people with a low risk of recurrence, the benefits may not outweigh the risks or side effects Medium or high risk may include people who have lymph node-positive breast cancer, with tumours that are T2 or greater and higher grade. Low risk may include people with lymph node-negative breast cancer, with smaller or lower-grade tumours Evidence shows lower rates of breast cancer recurrence compared with 5 years of tamoxifen therapy in women Lower rates of breast cancer recurrence compared with 5 years of tamoxifen therapy In postmenopausal women, switching to an aromatase inhibitor may be more effective at reducing recurrence than continuing with tamoxifen Side effects: These are common side effects experienced during additional years taking endocrine therapy. Most effects are reversible when tablets are stopped Side effects of endocrine therapy will continue for additional years (for example, menopausal symptoms such as hot flushes) Side effects may differ in men With extended use of tamoxifen: increased risk of thrombosis and endometrial cancer, and possibly bone density loss in premenopausal women Side effects of endocrine therapy will continue for additional years (for example, menopausal symptoms such as hot flushes) With extended use of aromatase inhibitors: bone density loss, and joint and muscle pain Fertility and family planning For women, effects on fertility and family planning will continue for additional years as they should not become pregnant while taking tamoxifen, or within 2 months of stopping, because it may have adverse effects on the baby Not applicable as postmenopausal women only For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on extended endocrine therapy . Full details of the evidence and the committee's discussion are in evidence review D: endocrine therapy for invasive disease. Loading. Please wait. ## Endocrine therapy for ductal carcinoma in situ Discuss the benefits and risks (see table 3) of endocrine therapy after breast-conserving surgery for women with ER-positive DCIS. Offer endocrine therapy after breast-conserving surgery for women with ER-positive DCIS if radiotherapy is recommended but not received. Consider endocrine therapy after breast-conserving surgery for women with ER-positive DCIS if radiotherapy is not recommended. Category Endocrine therapy after breast-conserving surgery for women with ER-positive DCIS Definition Tamoxifen or an aromatase inhibitor for 5 years, taken as a once-daily tablet Effect on survival and disease recurrence: The benefit for an individual person will depend on the risk of their cancer returning. For people with low risk of recurrence, the benefits may not outweigh the risks or side effects Risk can be estimated using a range of standardised tools and clinical expertise No effect on survival at 5 or 10 years after diagnosis Lower rate of recurrence of DCIS and lower rate of invasive breast cancer, compared with women who did not receive endocrine therapy or radiotherapy after surgery Side effects All endocrine therapies: menopausal symptoms, such as hot flushes For tamoxifen: increased risk of thrombosis, endometrial cancer and possibly bone density loss in premenopausal women For aromatase inhibitors: joint and muscle pain, urogenital symptoms and bone density loss Fertility and family planning Effects on fertility and family planning as women should not become pregnant while taking tamoxifen, or within 2 months of stopping, because it may have adverse effects on the baby For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on endocrine therapy for DCIS . Full details of the evidence and the committee's discussion are in evidence review D: endocrine therapy for invasive disease. Loading. Please wait. # Adjuvant chemotherapy for invasive breast cancer For people with breast cancer where chemotherapy is indicated, offer a regimen that contains both a taxane and an anthracycline. Refer to the summaries of product characteristics for individual taxanes and anthracyclines to check for differences in licensed indications. Discuss with people the benefits and risks of adding a taxane to anthracycline-containing regimens. Topics to discuss include those in table 4 and: the benefits of reduced cardiac toxicity and reduced nausea the risks of additional side effects, including neuropathy, neutropenia and hypersensitivity the different side effects and dosing frequencies of different docetaxel and paclitaxel regimens, and the additional clinic visits that may be needed that absolute benefit is proportional to absolute risk of recurrenceRefer to the summaries of product characteristics for individual taxanes and anthracyclines to check for differences in licensed indications. Effect of adding a taxane to an anthracycline-containing regimen ‑weekly docetaxel Weekly or fortnightly paclitaxel Effect on survival: The benefit for an individual person will depend on the risk of their cancer returning. For people with low risk of recurrence, the benefits may not outweigh the risks or side effects Some evidence for improved outcomes, including reducing the risk of breast cancer returning and increasing the chance of surviving Some evidence for improved outcomes, including reducing the risk of breast cancer returning and increasing the chance of surviving Benefits Smaller doses of anthracyclines can be used, which can reduce the risk of side effects such as nausea and vomiting Smaller cumulative doses of individual drugs may reduce long-term side effects, for example, cardiac toxicity and risk of second malignancies Smaller doses of anthracyclines can be used, which can reduce the risk of side effects such as nausea and vomiting Smaller cumulative doses of individual drugs may reduce long-term side effects, for example, cardiac toxicity and risk of second malignancies Side effects Additional side effects may include joint and muscle pain, nerve damage, higher rates of febrile neutropenia and hypersensitivity reactions Some people have long-term hair loss (alopecia) after treatment with taxanes Additional side effects may include nerve damage and hypersensitivity reactions, but febrile neutropenia is less likely than with 3‑weekly docetaxel Some people have long-term hair loss (alopecia) after treatment with taxanes Weekly paclitaxel is tolerated best, but even fortnightly is better tolerated than 3‑weekly docetaxel Administration Visits to hospital every 3 weeks Visits to hospital every week or every 2 weeks Length of course to 12 weeks (3 to 4 cycles) to 12 weeks Ensure weekly and fortnightly paclitaxel is available locally, as it is better tolerated than 3‑weekly docetaxel, particularly in people with comorbidities. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on adjuvant chemotherapy for invasive breast cancer . Full details of the evidence and the committee's discussion are in evidence review E: adjuvant chemotherapy. Loading. Please wait. ## Biological therapy Offer adjuvant trastuzumab for people with T1c and above HER2-positive invasive breast cancer. Give this at 3‑week intervals for 1 year in combination with surgery, chemotherapy, endocrine therapy and radiotherapy, as appropriate. Consider adjuvant trastuzumab for people with T1a/T1b HER2-positive invasive breast cancer, taking into account any comorbidities, prognostic features, possible toxicity of chemotherapy and the person's preferences. For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on biological therapy . Full details of the evidence and the committee's discussion are in evidence review F: adjuvant biological therapy. Loading. Please wait. Use trastuzumab with caution in people with HER2-positive invasive breast cancer if they have any of the following: a baseline left ventricular ejection fraction (LVEF) of 55% or less a history of, or current, congestive heart failure a history of myocardial infarction angina pectoris needing medication cardiomyopathy cardiac arrhythmias needing medical treatment clinically significant valvular heart disease haemodynamic-effective pericardial effusion poorly controlled hypertension. # Bisphosphonate therapy ## Adjuvant bisphosphonate therapy In June 2023, the use of bisphosphonates (zoledronic acid or sodium clodronate) in recommendations 1.9.1 and 1.9.2 was off-label. See NICE's information on prescribing medicines. Offer bisphosphonates (zoledronic acid or sodium clodronate) as adjuvant therapy to postmenopausal women with node-positive invasive breast cancer. Consider bisphosphonates (zoledronic acid or sodium clodronate) as adjuvant therapy for postmenopausal women with node-negative invasive breast cancer and a high risk of recurrence. Discuss the benefits and risks of bisphosphonate treatment with women, particularly the risk of osteonecrosis of the jaw, atypical femoral fractures and osteonecrosis of the external auditory canal. Follow the Medicines and Healthcare products Regulatory Agency/Commission on Human Medicines (MHRA/CHM) advice on bisphosphonates. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on adjuvant bisphosphonate therapy . Full details of the evidence and the committee's discussion are in evidence review G: adjuvant bisphosphonates. Loading. Please wait. ## Bone health Offer a baseline dual-energy X-ray absorptiometry (DEXA) scan to assess bone mineral density in women with invasive breast cancer who are not receiving bisphosphonates as adjuvant therapy and who: are starting adjuvant aromatase inhibitor treatment, or have treatment-induced menopause, or are starting ovarian ablation/suppression therapy. Do not offer a DEXA scan to people with invasive breast cancer who are receiving tamoxifen alone. Offer bisphosphonates to women identified by algorithms 1 and 2 in the guidance for the management of breast cancer treatment‑induced bone loss: a consensus position statement from a UK expert group (2008; this guidance is not NICE accredited). # Radiotherapy Use a radiotherapy technique that minimises the dose to the lung and heart. Use a deep inspiratory breath-hold radiotherapy technique for people with left-sided breast cancer to reduce the dose to the heart. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on radiotherapy techniques . Full details of the evidence and the committee's discussion are in evidence review H: breast radiotherapy. Loading. Please wait. ## Radiotherapy after breast-conserving surgery Offer whole-breast radiotherapy to women with invasive breast cancer who have had breast-conserving surgery with clear margins. Consider partial-breast radiotherapy as an alternative to whole-breast radiotherapy for women who have had breast-conserving surgery for invasive cancer (excluding lobular type) with clear margins and who: have a low absolute risk of local recurrence (defined as women aged 50 and over with tumours that are 3 cm or less, N0, ER‑positive, HER2‑negative and grade 1 to 2), and have been advised to have adjuvant endocrine therapy for a minimum of 5 years. If partial-breast radiotherapy (see recommendation 1.10.4) may be suitable for a woman, discuss the benefits and risks with them and reach a shared decision on its use. Topics to cover include that: local recurrence with partial-breast radiotherapy at 5 years is equivalent to that with whole-breast radiotherapy the risk of local recurrence beyond 5 years is not yet known there is a potential reduction in late adverse effects. When giving partial-breast radiotherapy, use external beam radiotherapy. Consider not using radiotherapy for women who: have had breast-conserving surgery for invasive breast cancer with clear margins and have a very low absolute risk of local recurrence (defined as women aged 65 and over with tumours that are T1N0, ER-positive, HER2-negative and grade 1 to 2) and are willing to take adjuvant endocrine therapy for a minimum of 5 years. When considering not using radiotherapy (see recommendation 1.10.7), discuss the benefits and risks with the woman (see table 5) and explain that: without radiotherapy, local recurrence occurs in about 50 women per 1,000 at 5 years, and with radiotherapy, occurs in about 10 women per 1,000 at 5 years -verall survival at 10 years is the same with or without radiotherapy there is no increase in serious late effects if radiotherapy is given (for example, congestive cardiac failure, myocardial infarction or secondary cancer). Category Radiotherapy No radiotherapy Effect on local recurrence On average, in 1,000 women, over 5 years local recurrence occurs in about 10 women, and does not occur in about 990 women On average, in 1,000 women, over 5 years local recurrence occurs in about 50 women, and does not occur in about 950 women Effect on survival No difference in overall survival at 10 years No difference in overall survival at 10 years Risks Possibility of short- and long-term adverse effects on the breast, and resulting cosmetic changes (such as skin soreness, changes to colour of skin, radiation fibrosis or stiffening of the breast tissue) No short- or long-term adverse effects on the breast, or cosmetic changes Side effects In this group of women at low risk, there is no increase in serious late side effects of radiotherapy (such as congestive cardiac failure, myocardial infarction or secondary cancer) No side effects of radiotherapy will occur Administration Given at the treatment centre 5 days a week for 3 weeks after surgery No need to attend the treatment centre for radiotherapy sessions Consider adjuvant radiotherapy for women with DCIS following breast-conserving surgery with clear margins. Discuss the possible benefits and risks of radiotherapy (also see the section on surgery to the breast) and make a shared decision about its use. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on radiotherapy after breast‑conserving surgery . Full details of the evidence and the committee's discussion are in evidence review H: breast radiotherapy. Loading. Please wait. ## Radiotherapy after mastectomy Offer adjuvant postmastectomy radiotherapy to people with node-positive (macrometastases) invasive breast cancer or involved resection margins. Consider adjuvant postmastectomy radiotherapy for people with node-negative T3 or T4 invasive breast cancer. Do not offer radiotherapy following mastectomy to people with invasive breast cancer who are at low risk of local recurrence (for example, most people who have lymph node-negative breast cancer). For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on radiotherapy after mastectomy . Full details of the evidence and the committee's discussion are in evidence review I: postmastectomy radiotherapy. Loading. Please wait. ## Dose fractionation for external beam radiotherapy Offer 26 Gy in 5 fractions over 1 week for people with invasive breast cancer having partial-breast, whole-breast or chest-wall radiotherapy, without regional lymph node irradiation, after breast-conserving surgery or mastectomy. Consider 40 Gy in 15 fractions over 3 weeks for people with invasive breast cancer having partial-breast, whole-breast or chest-wall radiotherapy, without regional lymph node irradiation, after breast-conserving surgery or mastectomy when they: have a diagnosis that increases sensitivity to radiotherapy, or have had implant-based reconstruction, or have any other factor that could mean having radiotherapy over 3 weeks is more acceptable (such as high BMI or fibromyalgia). When discussing the benefits and risks of the 2 regimens, follow the recommendations on: enabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services, and communicating risks, benefits and consequences in the NICE guideline on shared decision making. Offer 40 Gy in 15 fractions over 3 weeks for people with invasive breast cancer having regional lymph node irradiation, with or without whole-breast or chest-wall radiotherapy, after breast-conserving treatment or mastectomy. For a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on dose fractionation of external beam radiotherapy . Full details of the evidence and the committee's discussion are in evidence review M: effectiveness of different external beam hypofractionation radiotherapy regimens in people with early-stage or locally advanced invasive breast cancer. Loading. Please wait. ## Breast boost following breast-conserving surgery Offer an external beam boost to the tumour bed for women with invasive breast cancer and a high risk of local recurrence, following whole-breast radiotherapy. Inform women of the risk of side effects associated with an external beam boost to the tumour bed following whole-breast radiotherapy. ## Radiotherapy to nodal areas Do not offer adjuvant radiotherapy to regional lymph nodes to people with invasive breast cancer who have histologically lymph node-negative breast cancer. Do not offer people with invasive breast cancer adjuvant radiotherapy to the axilla after axillary clearance. Offer adjuvant radiotherapy to the supraclavicular fossa to people with invasive breast cancer and 4 or more involved axillary lymph nodes. Offer adjuvant radiotherapy to the supraclavicular fossa to people with invasive breast cancer and 1 to 3 positive lymph nodes if they have other poor prognostic factors (for example, T3 and/or histological grade 3 tumours) and good performance status. Consider including the internal mammary chain within the nodal radiotherapy target for people with node-positive (macrometastases) invasive breast cancer. For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on radiotherapy to nodal areas . Full details of the evidence and the committee's discussion are in evidence review H: breast radiotherapy. Loading. Please wait. ## Intraoperative radiotherapy For guidance on intraoperative radiotherapy, see the NICE technology appraisal guidance on the intrabeam radiotherapy system for adjuvant treatment of early breast cancer. # Primary systemic therapy ## Neoadjuvant chemotherapy Offer neoadjuvant chemotherapy to people with ER-negative invasive breast cancer as an option to reduce tumour size. Offer neoadjuvant chemotherapy to people with HER2-positive invasive breast cancer in line with the NICE technology appraisal guidance on pertuzumab for the neoadjuvant treatment of HER2‑positive breast cancer. Consider neoadjuvant chemotherapy for people with ER-positive invasive breast cancer as an option to reduce tumour size if chemotherapy is indicated. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on neoadjuvant chemotherapy . Full details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer. Loading. Please wait. ## Neoadjuvant chemotherapy regimens In June 2023, the use of platinums in recommendations 1.11.4 and 1.11.5 was off-label. See NICE's information on prescribing medicines. For people with ER/PR/HER2-negative (triple-negative) invasive breast cancer, consider a neoadjuvant chemotherapy regimen that contains both a platinum and an anthracycline. Discuss the benefits and risks of adding a platinum to an anthracycline-containing neoadjuvant chemotherapy regimen (see table 6), and in particular the risk of increased toxicity. Category Effect of adding a platinum to anthracycline-containing (with or without taxane) neoadjuvant chemotherapy Effect on breast conservation rate Adding a platinum improves response rates compared with anthracycline-based (with or without taxane) chemotherapy. This may mean that some women who would otherwise need a mastectomy can be offered breast-conserving surgery Effect on pathological complete response rate (no residual cancer found at surgery) Adding a platinum improves the chances of all signs of cancer disappearing in both the breast and lymph nodes in the axilla, compared with anthracycline-based (with or without taxane) neoadjuvant chemotherapy Effect on survival No increase in overall survival with platinum-based chemotherapy Side effects: Platinum-based therapy is only suitable for fit patients with no significant comorbidities Adding a platinum may mean that side effects are more severe. Anaemia, thrombocytopenia, neutropenia and febrile neutropenia are seen more frequently with platinum-based chemotherapy On average, if 1,000 women with triple-negative breast cancer receive platinum-containing neoadjuvant chemotherapy, about 70 additional women would experience severe or life-threatening side effects compared with non-platinum neoadjuvant chemotherapy Bone marrow suppression and renal problems are likely in older people For a short explanation why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on neoadjuvant chemotherapy regimens . Full details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer. Loading. Please wait. ## Neoadjuvant endocrine therapy Consider neoadjuvant endocrine therapy for postmenopausal women with ER-positive invasive breast cancer as an option to reduce tumour size if there is no definite indication for chemotherapy. Advise premenopausal women that neoadjuvant chemotherapy may be more likely to produce a clinical response than neoadjuvant endocrine therapy, but that some tumours do respond to neoadjuvant endocrine therapy. Discuss with women the benefits and risks of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy (see table 7). Category Neoadjuvant endocrine therapy Neoadjuvant chemotherapy Definition Tamoxifen or an aromatase inhibitor started before surgery Only an option for women with ER-positive breast cancer Chemotherapy given before surgery Only an option for people who would be recommended adjuvant (after surgery) chemotherapy Administration Tablet taken once a day at home Intravenous administration in hospital, as an outpatient Effectiveness For postmenopausal women: may be as effective as neoadjuvant chemotherapy in terms of breast conservation rates and shrinking the tumour For premenopausal women: less effective than neoadjuvant chemotherapy at shrinking the tumour (but some tumours may respond so may be effective in some women) For postmenopausal women: effective at improving breast conservation rates and shrinking the tumour For premenopausal women: more effective than endocrine therapy at shrinking the tumour Potential disadvantages If neoadjuvant endocrine therapy is not effective, then women may proceed to surgery earlier or may still need to have chemotherapy, either before or after surgery Side effects All endocrine therapies: menopausal symptoms such as hot flushes For tamoxifen: increased risk of thrombosis and endometrial cancer For aromatase inhibitors: joint and muscle pain, urogenital symptoms, bone density loss (may also occur with tamoxifen in premenopausal women) Side effects are usually reversible May allow women to avoid the additional side effects of chemotherapy (although women may still need adjuvant chemotherapy after surgery) Side effects may include nausea and vomiting, risk of infections that may be life threatening, fatigue, neuropathy, cardiac toxicity, diarrhoea, constipation, sore mouth, skin and nail changes, risk of blood clots, risk of second malignancies, fluid retention, allergic reactions and hair loss Side effects may persist long term Fertility and family planning Women should not become pregnant while taking tamoxifen, or within 2 months of stopping, because it may have adverse effects on the baby Often causes temporary infertility May cause permanent infertility Length of course May take longer than chemotherapy to shrink the tumour enough for breast-conserving surgery The duration of neoadjuvant chemotherapy is shorter than neoadjuvant endocrine therapy For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on neoadjuvant endocrine therapy . Full details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer. Loading. Please wait. ## Radiotherapy after neoadjuvant chemotherapy Offer local treatment with mastectomy (or, in exceptional cases, breast-conserving surgery) followed by radiotherapy to people with locally advanced or inflammatory breast cancer that has been treated with neoadjuvant chemotherapy. Offer postmastectomy radiotherapy after neoadjuvant chemotherapy if post-treatment histology shows node-positive (macrometastases) breast cancer or involved resection margins. Offer postmastectomy radiotherapy after neoadjuvant chemotherapy if pretreatment investigations show node-positive (macrometastases) breast cancer. Consider postmastectomy radiotherapy after neoadjuvant chemotherapy if post-treatment histology shows node-negative T3 breast cancer. Consider postmastectomy radiotherapy after neoadjuvant chemotherapy if pretreatment investigations show node-negative T3 breast cancer. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on radiotherapy after neoadjuvant chemotherapy . Full details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer. Loading. Please wait. # Complications of local treatment and menopausal symptoms ## Lymphoedema Inform people with breast cancer about lymphoedema and their risk of developing it after treatment with surgery and radiotherapy (see recommendation 1.12.2). Give them relevant written information before treatment to take away and refer back to. When informing people with breast cancer about the risk of developing lymphoedema, advise them that: lymphoedema can occur in the arm, breast or chest wall they do not need to restrict their physical activity there is no consistent evidence of increased risk of lymphoedema associated with air travel, travel to hot countries, manicures, hot-tub use or sports injuries there is no consistent evidence of increased risk of lymphoedema associated with medical procedures (for example, blood tests, injections, intravenous medicines and blood pressure measurement) on the treated side, and the decision to perform medical procedures using the arm on the treated side should depend on clinical need and the possibility of alternatives. Give people who have had treatment for breast cancer advice on how to reduce the risk of infection that may cause or exacerbate lymphoedema. Ensure that people with breast cancer who develop lymphoedema have prompt access to a specialist lymphoedema service. For a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on lymphoedema . Full details of the evidence and the committee's discussion are in evidence review B: management of the positive axilla. Loading. Please wait. ## Arm and shoulder mobility Ensure breast care units have documented local guidelines in place for postoperative physiotherapy that have been agreed with the physiotherapy department. Guidelines should cover: details of the upper limb exercises to be carried out after surgical or radiotherapy interventions situations where the exercises should be tailored for individual circumstances and needs who should give information and instructions, and at what points in the person's care this should happen how healthcare staff can best deliver information about the exercises. Give people who are going to have surgery or radiotherapy for breast cancer instructions and information on upper limb exercises before their treatment begins: explain the benefits of doing the exercises explain when the exercises should be started ensure the information is in a format suitable for the person to take away to refer to later answer any questions the person may have on the exercises, or how to perform them give details about who to contact if more information is needed.Also see the section on communication in the NICE guideline on patient experience in adult NHS services. Preoperatively identify people who are having surgery for breast cancer as being at high risk of developing shoulder problems if they have any of the following factors: any pre-existing shoulder conditions, such as: history of shoulder surgery shoulder trauma injury (fracture or shoulder dislocation) frozen shoulder -steoarthritis or rheumatoid arthritis affecting the shoulder non-specific shoulder pain stiffness decreased function their BMI is over 30 kg/m2 they have axillary node clearance planned they have radiotherapy to the axilla or supraclavicular nodes planned. After surgery, if a person with breast cancer needs previously unplanned axillary node clearance or radiotherapy to the axilla or supraclavicular nodes, identify them as being at high risk. Offer supervised support when performing upper limb exercises to people who have been identified as being at high risk of developing shoulder problems after surgery for breast cancer (see recommendation 1.12.7 for assessment). Consider supervised support when performing upper limb exercises for people who: are having surgery and have not been identified as being at high risk of developing shoulder problems (as defined by the criteria in recommendation 1.12.7), but who may still benefit from supervised support or are having radiotherapy without surgery. Ensure supervised support for upper limb exercises: is available as either individual, group or virtual support, depending on the person's circumstances, needs and preferences is tailored to the person's needs (for example, modifying exercises for people with more complex needs) includes checking that the person is performing the activity correctly is delivered by physiotherapy staff members or other appropriately trained allied health professionals. Refer people to the physiotherapy department for individual assessment and treatment if they report a persistent reduction in arm and shoulder mobility after breast cancer surgery or radiotherapy. For a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on arm and shoulder mobility . Full details of the evidence and the committee's discussion are in evidence review L: strategies for reducing arm and shoulder problems after breast cancer surgery or radiotherapy. Loading. Please wait. ## Menopausal symptoms Offer women information and counselling about the possibility of early menopause and menopausal symptoms associated with breast cancer treatment. Stop systemic hormone replacement therapy (HRT) in women who are diagnosed with breast cancer. Do not routinely offer HRT (including oestrogen/progestogen combination) to women with menopausal symptoms and a history of breast cancer. In June 2023, this was an off-label use of HRT, and HRT is contraindicated in women with a history of breast cancer. See NICE's information on prescribing medicines. In exceptional circumstances, offer HRT to women with severe menopausal symptoms and a history of breast cancer after a discussion of the associated risks. In June 2023, this was an off-label use of HRT, and HRT is contraindicated in women with a history of breast cancer. See NICE's information on prescribing medicines. Consider selective serotonin reuptake inhibitor (SSRI) antidepressants for women with breast cancer for relieving menopausal symptoms, particularly hot flushes, but not for those taking tamoxifen. For guidance on safe prescribing of antidepressants (such as SSRIs) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. In June 2023, this was an off-label use of SSRIs. See NICE's information on prescribing medicines. Do not offer soy (isoflavone), red clover, black cohosh, vitamin E or magnetic devices to treat vasomotor symptoms in women with breast cancer. # Follow-up ## Follow-up imaging Offer annual mammography for 5 years to all people who have had or are being treated for breast cancer, including DCIS. For women, continue annual mammography past 5 years until they enter the NHS Breast Screening Programme (NHSBSP) in England or the Breast Test Wales Screening Programme (BTWSP) in Wales. Do not perform mammography of the ipsilateral soft tissues after mastectomy. Do not routinely use ultrasound or MRI for post-treatment surveillance in people who have had treatment for invasive breast cancer or DCIS. ## Clinical follow-up Ensure all people who have had treatment for breast cancer have an agreed, written care plan, recorded in their notes by a named healthcare professional (or professionals) from the multidisciplinary team. Give a copy to the person and to their GP. The plan should include: designated named healthcare professionals dates for review of any adjuvant therapy details of surveillance mammography signs and symptoms to look out for and seek advice on contact details for immediate referral to specialist care contact details for support services, for example, support for people with lymphoedema. # Lifestyle Advise people who have had or are being treated for breast cancer that a healthy lifestyle is associated with a lower risk of recurrence, and that this should include: achieving and maintaining a healthy weight (see the NICE guidelines on preventing excess weight gain and obesity) limiting alcohol intake to below 5 units per week regular physical activity (see the NICE guideline on physical activity for adults). For guidance on smoking cessation, see the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. For a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on lifestyle . Full details of the evidence and the committee's discussion are in evidence review K: lifestyle. Loading. Please wait. # Terms used in this guideline ## Upper limb exercises Upper limb exercises predominantly focus on gentle shoulder range-of-movement exercises and stretches aimed at regaining full and pain-free range of movement of the shoulder following breast cancer surgery and/or radiotherapy. The term can also refer to exercises that progress onto strengthening the shoulder and arm.# Recommendations for research The guideline committee has made the following key recommendations for research. # Surgery to the breast What is the optimum tumour-free margin width after breast-conserving surgery for women with ductal carcinoma in situ (DCIS) and invasive breast cancer? For a short explanation of why the committee made the recommendation for research, see the rationale section on surgery to the breast . Full details of the evidence and the committee's discussion are in evidence review A: surgery to the breast. Loading. Please wait. # Adjuvant bisphosphonate therapy Which groups of people with early and locally advanced breast cancer would benefit from the use of adjuvant bisphosphonates? For a short explanation of why the committee made the recommendation for research, see the rationale section on adjuvant bisphosphonate therapy . Full details of the evidence and the committee's discussion are in evidence review G: adjuvant bisphosphonates. Loading. Please wait. # Breast reconstruction What are the long-term outcomes for breast reconstruction in women having radiotherapy to the chest wall? For a short explanation of why the committee made the recommendation for research, see the rationale section on breast reconstruction . Full details of the evidence and the committee's discussion are in evidence review I: postmastectomy radiotherapy. Loading. Please wait. # Neoadjuvant endocrine therapy in premenopausal women Is neoadjuvant endocrine therapy safe in premenopausal women with early breast cancer? For a short explanation of why the committee made the recommendation for research, see the rationale section on neoadjuvant endocrine therapy . Full details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer. Loading. Please wait. # Neoadjuvant endocrine therapy in postmenopausal women Is there a benefit for neoadjuvant endocrine therapy in postmenopausal women with early breast cancer? For a short explanation of why the committee made the recommendation for research, see the rationale section on neoadjuvant endocrine therapy . Full details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer. Loading. Please wait. # Neoadjuvant treatment What are the indications for postmastectomy radiotherapy after neoadjuvant chemotherapy? For a short explanation of why the committee made the recommendation for research, see the rationale section on radiotherapy after neoadjuvant chemotherapy. Full details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer. Loading. Please wait. # Strategies to reduce arm and shoulder problems What is the most effective and cost-effective way of delivering the intervention (for example, type of physiotherapy or exercise, mode of delivery, number of sessions) to reduce arm and shoulder problems after breast cancer surgery or radiotherapy, and what is the acceptability of the intervention for different groups, such as: women, men, trans people and non-binary people people from minority ethnic family backgrounds people with learning disabilities or cognitive impairment, or physical disabilities, or both neurodiverse people? For a short explanation of why the committee made the recommendation for research, see the rationale section on arm and shoulder mobility . Full details of the evidence and the committee's discussion are in evidence review L: strategies for reducing arm and shoulder problems after breast cancer surgery or radiotherapy. Loading. Please wait. # Adherence and satisfaction for interventions to reduce arm and shoulder problems What is the adherence to, and satisfaction with, different intervention formats (for example, individual, group, virtual, and face to face) to reduce arm and shoulder problems after breast cancer surgery or radiotherapy, and what is the impact of greater adherence on effectiveness for different groups, such as: women, men, trans people and non-binary people people from minority ethnic family backgrounds people with learning disabilities or cognitive impairment, or physical disabilities, or both neurodiverse people? For a short explanation of why the committee made the recommendation for research, see the rationale section on arm and shoulder mobility . Full details of the evidence and the committee's discussion are in evidence review L: strategies for reducing arm and shoulder problems after breast cancer surgery or radiotherapy. Loading. Please wait. # Effectiveness of 26 Gy in 5 fractions over 1 week regimen in people receiving breast reconstruction What is the effectiveness of radiotherapy given in 26 Gy in 5 fractions over 1 week compared with 40 Gy in 15 fractions over 3 weeks in people with early or locally advanced invasive breast cancer who are offered breast reconstruction? For a short explanation of why the committee made the recommendation for research, see the rationale section on dose fractionation of external beam radiotherapy . Full details of the evidence and the committee's discussion are in evidence review M: effectiveness of different external beam hypofractionation radiotherapy regimens in people with early-stage or locally advanced invasive breast cancer. Loading. Please wait. # Effectiveness of 26 Gy in 5 fractions over 1 week regimen in people receiving nodal irradiation What is the effectiveness of radiotherapy given in 26 Gy in 5 fractions over 1 week compared with 40 Gy in 15 fractions over 3 weeks in people with early or locally advanced invasive breast cancer who are also offered nodal irradiation? For a short explanation of why the committee made the recommendation for research, see the rationale section on dose fractionation of external beam radiotherapy . Full details of the evidence and the committee's discussion are in evidence review M: effectiveness of different external beam hypofractionation radiotherapy regimens in people with early-stage or locally advanced invasive breast cancer. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion. # Providing information and psychological support Recommendations 1.2.3 and 1.2.4 ## Why the committee made the recommendations The committee agreed, based on their clinical expertise, that continued improvement in breast cancer survival as well as post-diagnosis quality of life needs ongoing research into new or refined treatment options to allow further optimisation of care. People having treatment for breast cancer should be advised about options for preserving their fertility, so the existing NICE guideline on this topic was cross-referred to. ## How the recommendations might affect practice Recruitment into clinical trials wherever possible is already standard practice, so the recommendation is unlikely to result in a change in practice. Discussion of fertility options is already standard practice, so the recommendation is unlikely to result in a change in practice. Return to recommendations # Surgery to the breast Recommendations 1.3.1 and 1.3.2 ## Why the committee made the recommendations There was some evidence that there was a reduced risk of ductal carcinoma in situ (DCIS) local recurrence if tissue margins were greater than 0 mm, so the committee recommended further surgery (re-excision or mastectomy) to extend the margins if needed. Although there was no consistent evidence about tissue margins for invasive breast cancer, the committee agreed that further surgery should be offered. The committee agreed that complete excision of the tumour with clear margins was essential for the high-quality care of people with DCIS or invasive breast cancer. Although there was evidence that aiming for wider margins reduced local recurrence, this did not improve overall survival. In addition, aiming for wider margins could lead to some people having unnecessary extra surgery. Given this uncertainty, the committee agreed the importance of personalised care and discussion to decide whether further surgery is needed. There was not enough evidence to clearly define an optimum margin width between 0 mm and 2 mm to minimise local recurrence rates and minimise further surgery. So, the committee agreed that this was an important topic for further research and made a recommendation for research on the optimum tumour‑free margin width after surgery to the breast. ## How the recommendations might affect practice The rates of further surgery currently vary across the country. Although the committee noted that the recommendations will reinforce current best practice, there may be some centres that will need to amend their practice in order to follow these recommendations. Return to recommendations # Evaluation and management of a positive axillary lymph node Recommendations 1.4.7 to 1.4.10 ## Why the committee made the recommendations There was no new evidence that led the committee to change from the existing recommended practice (as recommended in the previous NICE guideline CG80) of: -ffering axillary clearance to people with preoperatively pathologically proven involvement of the axillary lymph nodes not offering axillary treatment after primary surgery to people with isolated tumour cells in their sentinel lymph nodes. The committee agreed that current evidence shows that further axillary treatment after primary surgery does not improve survival for people with micrometastases and there are risks such as lymphoedema, so further treatment should not be offered to this population. There were unclear benefits and risks of further axillary treatment after primary surgery in people with only 1 or 2 sentinel lymph node macrometastases who have had breast-conserving surgery and have been advised to have whole-breast radiotherapy and systemic therapy, so the committee agreed that the risks and benefits of further treatment should be discussed with this group. Studies of neoadjuvant therapy were excluded from the evidence review. ## How the recommendations might affect practice The committee agreed that the recommendations will result in a minor change in practice because some centres currently use mainly surgery and may not use radiotherapy. In addition, more time may need to be factored in to plan and deliver radiotherapy treatment. Return to recommendations # Breast reconstruction Recommendations 1.5.2 to 1.5.5 ## Why the committee made the recommendations There was not much good evidence, but the committee agreed that the main benefits of immediate breast reconstruction compared with delayed reconstruction are improved aesthetic satisfaction, improved symmetry, improved health-related quality of life, lower overall rates of complications and a reduced need for further surgery. The committee agreed that in some circumstances, there are advantages to delayed reconstruction compared with immediate reconstruction (for example, reduced mastectomy flap loss and capsular contracture). Therefore, delayed reconstruction should also be an option for women who wish to have a reconstruction after mastectomy. The committee also agreed that the option of no reconstruction should also be discussed, because this may be the preferred option for some women. In addition, although radiotherapy can impact on outcomes after breast reconstruction, there was no consistent evidence for worse outcomes between radiotherapy delivered after immediate reconstructions compared with radiotherapy before delayed reconstructions. Therefore, the committee agreed that immediate reconstruction should be offered regardless of plans for chest-wall radiotherapy. There is little evidence regarding longer-term outcomes and different types of reconstruction. Because of this, the committee agreed that more research is needed to understand whether immediate breast reconstruction or delayed breast reconstruction is better in women who may need postmastectomy radiotherapy. So, they made a recommendation for research on long‑term outcomes for breast reconstruction in women having radiotherapy to the chest wall. ## How the recommendations might affect practice The recommendations may result in a substantial change in practice because many centres do not routinely offer immediate breast reconstruction to all women (especially those who have been advised to have radiotherapy). The impact will depend on how many immediate reconstructions are already carried out. In addition, the uptake of immediate breast reconstruction will also depend on women's preferences. There may be cost savings associated with immediate reconstructions because fewer surgical procedures are needed (reconstruction is done at the same time as mastectomy and there are lower rates of additional symmetrisation surgery). Return to recommendations # Predictive factors Recommendations 1.6.1, 1.6.3 and 1.6.5 ## Why the committee made the recommendations There was not enough good evidence, so the committee agreed, using a formal consensus scoring system and their knowledge and experience, that progesterone receptor (PR) status should be assessed for all invasive breast cancers because: it will help when tailoring adjuvant therapy it will reduce delays in starting treatment if people are already having testing at this stage, their PR status can be assessed without them having to wait for additional test results. The committee also agreed that oestrogen receptor (ER), PR and human epidermal growth factor receptor 2 (HER2) status assessments should be requested simultaneously at the time of initial diagnosis to ensure that results are available at the initial preoperative multidisciplinary team meeting (as well as the postoperative meeting). This will avoid delays and the need for additional discussions. ## How the recommendations might affect practice Most people with invasive breast cancer have PR testing in current practice, although it is not always performed at diagnosis. The recommendations should reduce variation in practice and delays in starting treatment, and the need for pathology results to be discussed at more than 1 multidisciplinary meeting, so may lead to a small cost saving. Return to recommendations # Adjuvant therapy planning Recommendations 1.6.8 and 1.6.9 ## Why the committee made the recommendations Good evidence showed that the prognostic tool PREDICT is an accurate tool to estimate prognosis and the benefits of treatment in most people. ## How the recommendations might affect practice The committee agreed that most healthcare professionals already use the PREDICT tool, so this recommendation will not mean a big change in practice. Return to recommendations # Ovarian function suppression Recommendations 1.7.4 and 1.7.5 ## Why the committee made the recommendations There was evidence that ovarian function suppression increased overall survival when combined with tamoxifen, and that women who have had chemotherapy benefited more. However, ovarian function suppression did not improve disease-free survival. In addition, it induces a temporary menopause and can worsen the menopausal symptoms seen with tamoxifen. Given the limited evidence of benefits and the side effects of the treatment, the committee agreed that healthcare professionals should discuss the potential benefits and risks with women. This will help women decide which treatment is right for them. ## How the recommendations might affect practice There is variation among centres in the use of ovarian function suppression, so the recommendations should lead to greater consistency and improve access to the treatment, even though not all women will wish to have it. There will be an increase in required resources for centres that do not currently provide ovarian function suppression because additional appointments will be needed to administer the medication and monitor side effects. However, this was not anticipated to be a substantial cost increase because of the number of centres already offering ovarian function suppression. Further, increased costs will be at least partially offset by improvements in survival outcomes. Return to recommendations # Extended endocrine therapy Recommendations 1.7.6 to 1.7.9 ## Why the committee made the recommendations Good evidence showed that switching to an aromatase inhibitor after 5 years of tamoxifen improved disease-free survival compared with postmenopausal women who had only received tamoxifen for 5 years, with the benefits being greater in those women who had a greater risk of disease recurrence. The evidence showed no benefit in terms of disease-free survival or overall survival from continuing tamoxifen beyond 5 years. However, some of the studies on tamoxifen were conducted in the 1980s and may not be relevant to current practice. In the committee's experience, continuing tamoxifen can be beneficial for some women. However, evidence showed that being on endocrine therapy for more than 5 years can increase the risk of problems such as endometrial cancer, osteoporosis, toxicity and phlebitis. The committee agreed that people will often prioritise survival even if this means they will have a reduced quality of life, but that people need to be informed about the possible benefits and risks so they can make a choice. Because of the risk of problems with taking endocrine therapy for more than 5 years, the committee agreed that healthcare professionals should discuss the potential benefits and risks with women to help them make an informed choice about treatment, based on their own risk factors. ## How the recommendations might affect practice Some centres already review treatment at 5 years and continue endocrine therapy with tamoxifen or an aromatase inhibitor when it could benefit women. Because a large number of women will be affected by these recommendations, the resource impact will be large for centres that are not currently providing treatment after 5 years. Return to recommendations # Endocrine therapy for ductal carcinoma in situ Recommendations 1.7.10 to 1.7.12 ## Why the committee made the recommendations There was good evidence that tamoxifen after breast-conserving surgery for ER-positive DCIS improved disease-free survival and reduced rates of local recurrence in women who did not have radiotherapy. Because of their concerns about over-treatment, the committee agreed that women who were at higher risk (those who should have had radiotherapy, but who did not receive it) would benefit more. There was no evidence available for aromatase inhibitors; however, the committee agreed they would likely produce similar improvements in disease-free survival and reductions in local recurrence as tamoxifen. Therefore, the committee recommended endocrine therapy, rather than specifically tamoxifen. The committee agreed that the benefits and risks of endocrine therapy should be discussed with the woman because of the potential treatment-related complications, such as menopausal symptoms, and the impact on family planning. ## How the recommendations might affect practice Offering endocrine therapy after initial treatment of DCIS will be a change of practice because it is not currently routinely offered to these women. However, because of the small number of people with DCIS who will not receive radiotherapy, and the low cost of the medicines, the committee agreed that the impact will not be significant. Return to recommendations # Adjuvant chemotherapy for invasive breast cancer Recommendations 1.8.1 to 1.8.3 ## Why the committee made the recommendations There was good evidence of improved survival when taxanes are added to anthracycline-based chemotherapy in people with node-positive and node-negative breast cancer. In both groups, the benefits and risks of treatment should be discussed because of the potential side effects associated with taxanes. Three-weekly docetaxel was identified as a regimen with potentially more toxicity than weekly or fortnightly paclitaxel. ## How the recommendations might affect practice These recommendations may result in a substantial change in practice because of increased taxane use, particularly for people with node-negative breast cancer and comorbidities. In addition, there will be an increase in weekly and fortnightly chemotherapy regimens being offered (for people who cannot tolerate 3‑weekly regimens). These regimens have a higher cost because they are more resource intensive, and may affect capacity in chemotherapy services. Return to recommendations # Biological therapy Recommendation 1.8.5 ## Why the committee made the recommendation There was evidence that adjuvant trastuzumab can improve disease-free survival and overall survival in some people with T1a and T1b HER2-positive invasive breast cancer who were treated with adjuvant trastuzumab and chemotherapy. However, only a small number of people will benefit from this treatment and, because trastuzumab can cause heart problems, it is important to avoid offering it to people who do not need it. Because of this, the committee agreed that adjuvant trastuzumab should be an option for women with T1a and T1b tumours rather than a standard treatment. Combined chemotherapy and trastuzumab was not found to be cost effective when compared with chemotherapy alone. However, the committee agreed that it was more appropriate to compare combined chemotherapy and trastuzumab with no treatment because these are the strategies that are likely to be used in clinical practice. Because it is the HER2 positivity that increases risk of recurrence for people with small (T1a and T1b) tumours, it does not make sense from a clinical perspective to not treat the component that is increasing risk (that is, trastuzumab treatment for HER2 positivity). Further, the effect of chemotherapy alone in the economic model may be overestimated because the data may not fully reflect the population under consideration. ## How the recommendation might affect practice Currently, T1 tumours are not routinely treated with adjuvant trastuzumab, so this recommendation will lead to a change in practice. However, the committee agreed that the number of additional people having treatment would be small, so the impact on current practice would be minor and unlikely to require a substantial increase in resources. Return to recommendation # Adjuvant bisphosphonate therapy Recommendations 1.9.1 to 1.9.3 ## Why the committee made the recommendations There was good evidence that treatment with sodium clodronate and zoledronic acid improved disease-free and overall survival in postmenopausal women with node-positive invasive breast cancer. There was little evidence of benefit for other bisphosphonates. The committee recommended considering zoledronic acid or sodium clodronate treatment for other high-risk populations (such as postmenopausal women with node-negative invasive breast cancer and a high risk of recurrence), based on the evidence that sodium clodronate has overall survival benefits in mixed populations. Although there is evidence that intravenous (IV) bisphosphonates have a higher risk of osteonecrosis of the jaw, oral bisphosphonates have a higher risk of gastrointestinal problems. There is also a risk of atypical femoral fractures and osteonecrosis of the external auditory canal with bisphosphonates. Because each drug and regimen has different risks, the potential benefits and risks should be discussed with women to help them make an informed choice. There was little evidence on survival, particularly for premenopausal women on ovarian suppression, those with node-positive or node-negative disease, and those with positive or negative oestrogen or progestogen statuses. There was not enough evidence to make a recommendation relating to the use of adjuvant bisphosphonates in premenopausal women. The committee agreed that further research is needed to determine the long-term survival benefits and the groups of people most likely to benefit from adjuvant bisphosphonates. So, they made a recommendation for research on groups of people who would benefit from the use of adjuvant bisphosphonates. The committee did not look at the evidence relating to the use of bisphosphonates for bone health or for the use of baseline dual-energy X-ray absorptiometry (DEXA) scanning, so did not make any new recommendations. ## How the recommendations might affect practice Bisphosphonates are not consistently offered as adjuvant treatment, so this recommendation may lead to an increase in prescribing. GPs may need to monitor people taking oral bisphosphonates, but this is likely to be an annual review so would not have a large workload impact. However, people may make more GP visits if they have side effects from bisphosphonate treatment. The committee agreed that IV bisphosphonates would usually be administered at the same time as chemotherapy drugs for the first 6 months of treatment, so this would not result in extra hospital visits for this period. After that, extra visits for administration and monitoring may be needed. Return to recommendations # Radiotherapy techniques Recommendations 1.10.1 and 1.10.2 ## Why the committee made the recommendations There was good evidence that radiotherapy to the internal mammary nodes reduced locoregional recurrence and improved survival. However, the committee took into account the potential for lung and heart toxicity, so recommended using a radiotherapy technique that minimises this risk. There was evidence that deep inspiratory breath-hold radiotherapy techniques reduce the mean radiotherapy heart dose for adults with left-sided invasive breast cancer receiving whole-breast radiotherapy. The committee did not identify any harms. There was also evidence that deep inspiration breath-hold radiotherapy techniques did not reduce the target coverage of whole-breast radiotherapy. There was no evidence about the use of deep inspiration breath-hold radiotherapy techniques for people with right-sided breast cancer, so the committee did not make separate recommendations for this subgroup. ## How the recommendations might affect practice Using a radiotherapy technique that minimises the dose to the lung and heart is likely to need a change in practice for many centres. There will be some impact on resources in order to implement this recommendation because additional training will be needed, and local protocols will need developing. However, the long-term impact on resources will be minimal: some additional planning time will be needed but there is no impact on the length or number of radiotherapy sessions. Currently, deep inspiratory breath-hold radiotherapy techniques are not routinely offered to people with invasive breast cancer having whole-breast radiotherapy. However, the committee noted that the Royal College of Radiologists has produced consensus statements that advise using this technique, and that many centres already offer it. The recommendation will ensure consistent practice and ensure that people can access the best care. Return to recommendations # Radiotherapy after breast-conserving surgery Recommendations 1.10.3 to 1.10.8 ## Why the committee made the recommendations There is evidence that whole-breast radiotherapy after breast-conserving surgery reduces the risk of recurrence and increases overall survival. It also decreases rates of depression and anxiety. However, because the risk of breast cancer recurring at 5 years is very low and there are harms associated with radiotherapy, the benefits of radiotherapy for women with a very low risk of recurrence are less certain. For these women, the committee agreed that healthcare professionals should fully discuss the benefits and risks with women before a decision is made. Good evidence showed that partial-breast radiotherapy led to similar results to whole-breast radiotherapy after breast-conserving surgery in women with a low risk of local recurrence. In addition, it may have fewer treatment-related adverse effects. There was evidence for multicatheter interstitial brachytherapy, but this was not recommended because it is not currently available in England. ## How the recommendations might affect practice Most women are already offered radiotherapy after breast-conserving surgery so this reflects current practice, but more time may be needed to discuss the balance of benefits and risks with women. The committee was aware that current practice for external beam partial-breast radiotherapy after breast-conserving surgery is based on the Royal College of Radiologists' 2016 consensus statement, so there would be no change to recommended practice. Return to recommendations # Radiotherapy after mastectomy Recommendations 1.10.10 to 1.10.12 ## Why the committee made the recommendations The committee agreed that adjuvant postmastectomy radiotherapy should be offered to people who have macroscopically node-positive invasive breast cancer or have involved resection margins. This is because the evidence showed a beneficial effect on survival and local recurrence. Although the evidence was limited and the committee acknowledged that radiotherapy is associated with lung and cardiac morbidity, they concluded that for this group of women, the benefits of radiotherapy outweigh the harms. There was evidence of a beneficial effect of postmastectomy radiotherapy on local recurrence and overall survival for people with node-negative invasive breast cancer. However, the committee agreed that there was a risk of over-treatment if all people with node-negative invasive breast cancer received postmastectomy radiotherapy. Therefore, the committee recommended that adjuvant postmastectomy radiotherapy should be considered for people with node-negative T3 or T4 invasive breast cancer. There was no evidence for this specific subgroup, but they would be considered at increased risk of recurrence and mortality relative to smaller, node-negative invasive breast cancers because of the size of the tumour. The committee agreed that radiotherapy after mastectomy should not be offered to women with early invasive breast cancer who are at low risk of local recurrence (for example, most women who are lymph node-negative) because the evidence showed limited benefit in survival and local recurrence. ## How the recommendations might affect practice The committee agreed that the recommendations will reinforce current practice, so there would be little change in practice. Return to recommendations # Dose fractionation of external beam radiotherapy Recommendations 1.10.13 to 1.10.16 ## Why the committee made the recommendations The committee noted that most centres use regimens of either 40 Gy in 15 fractions or 26 Gy in 5 fractions. However, there was variation between centres in which external beam hypofractionation regimen they used. The evidence compared a number of different external beam hypofractionation regimens, but the committee focused on the evidence from 2 randomised controlled trials (RCTs) that compared clinical effectiveness and safety, and a cost-effectiveness analysis, of the 2 hypofractionation regimens that are established in current practice (40 Gy in 15 fractions over 3 weeks and 26 Gy in 5 fractions over 1 week). High-quality to very low-quality evidence showed that the effects of both external beam hypofractionation regimens were comparable, with no clinically important differences between treatment arms for all-cause mortality, breast cancer-related mortality or disease recurrence. Economic evidence showed the 26 Gy in 5 fractions as an effective use of NHS resources compared with 40 Gy in 15 fractions and supported its use in current practice. In addition, the committee noted that in their experience, most people preferred to attend radiotherapy appointments over the course of 1 week rather than over 3 weeks for practical reasons related to fewer trips to the hospital (for example, reduced travelling time and costs, less time off work or from caring responsibilities). The committee recognised how the COVID-19 pandemic had also impacted current practice and had accelerated the change to implement the shorter 26 Gy in 5 fractions regimen. The evidence showed that there was a higher incidence of outcomes related to clinician-assessed adverse events at 5 years and quality-of-life measurements (related to harder or firmer breasts) for people who were given 26 Gy in 5 fractions compared with 40 Gy in 15 fractions. However, with the exception of a quality-of-life outcome related to swollen breasts, the differences in effect between the 2 regimens were not clinically significant. The committee agreed that in their experience, 26 Gy in 5 fractions is widely accepted by people, despite the small risk of increased adverse events. After taking into account the benefits of a shorter regimen and the impact of the adverse events, the committee recommended the use of 26 Gy in 5 fractions for people having partial-breast, whole-breast or chest-wall radiotherapy, without nodal irradiation, after breast-conserving surgery or mastectomy. The committee noted that the evidence presented was from populations who were receiving whole-breast radiotherapy. There was no evidence for people who are at lower risk of disease recurrence than those included in the evidence base and who are offered partial-breast radiotherapy because of their reduced risk. However, the committee agreed that, considering the already lower risk for this population, the findings of 26 Gy in 5 fractions in the higher-risk population could be extrapolated to also cover the lower-risk population. The committee also noted that the decision over whether someone has partial-breast or whole-breast radiotherapy can change based on clinical judgement and assessment of the treatment area. As such, the committee agreed that if partial-breast radiotherapy were excluded, the recommendations would not be in line with current practice and may disadvantage a large group of people. The committee recognised that there may be circumstances when 40 Gy in 15 fractions would be more suitable than 26 Gy in 5 fractions. For example, the committee noted that, in their clinical experience, some groups of people, such as those with a high BMI or fibromyalgia, may experience a greater number of acute adverse events from the 5-fraction regimen (for example, skin reactions, breast oedema or pain). Therefore, some people may prefer the 15-fraction regimen. The committee also noted that the number of people in the studies who had undergone breast reconstruction surgery was small, and it was difficult to determine the most effective hypofractionation regimen for this group. The 15-fraction regimen may also be used for those whose dosimetry is outside that used in the FAST-Forward trial. The committee highlighted the importance of shared decision making for these groups and ensuring that people are aware of the benefits and risks of each treatment option. As such, the committee made a recommendation that 40 Gy in 15 fractions over 3 weeks should be considered for some groups of people, and that its use should be agreed between the person and their care team. The committee discussed the eligibility criteria for some of the trials in the evidence and noted that people who received nodal radiotherapy were excluded from the main study populations. They highlighted that there are particular concerns around adverse effects such as lymphoedema for people who received regional lymph node irradiation. The committee acknowledged that future trials and the FAST-Forward nodal sub-study results may address some of these concerns, but until further evidence is available the 40 Gy in 15 fractions regimen should continue to be used for this group. There was limited evidence comparing the 2 hypofractionation regimens in people having breast reconstruction or having regional lymph node irradiation. As such, the committee developed recommendations for research on people having breast reconstruction (including autologous breast reconstruction, but particularly implant-based reconstruction) and people having regional lymph node irradiation. These should provide clinicians with an increased understanding of how effective the 26 Gy in 5 fractions regimen is for these groups in future. ## How the recommendations might affect practice The recommendations may reduce variation in practice, with most people being offered 26 Gy in 5 fractions rather than 40 Gy in 15 fractions. This is already current practice in many centres and will not have a major impact for those centres. In those centres where 26 Gy in 5 fractions is not yet current practice, there will be significant cost savings and capacity will be released for more appointments. For places where 40 Gy in 15 fractions is used more routinely, these recommendations may increase the number of people who are offered 26 Gy over 5 fractions. This will reduce the treatment duration and the costs associated with treatment. Return to recommendations # Radiotherapy to nodal areas Recommendation 1.10.23 ## Why the committee made the recommendation There was good evidence that radiotherapy to the internal mammary nodes reduced locoregional recurrence and improved survival. However, the committee took into account the potential for lung and heart toxicity, and agreed the importance of using a radiotherapy technique that minimises this risk. ## How the recommendation might affect practice This recommendation is likely to need a change in practice for many centres. There will be some impact on resources in order to implement this recommendation because additional training will be needed, and local protocols will need developing. However, the long-term impact on resources will be minimal: some additional planning time will be needed but there is no impact on the length or number of radiotherapy sessions. Return to recommendation # Neoadjuvant chemotherapy Recommendations 1.11.1 to 1.11.3 ## Why the committee made the recommendations There was good evidence to say that having chemotherapy before surgery (neoadjuvant chemotherapy) enables some women to have breast-conserving surgery who would otherwise have had total removal of their breast. The committee agreed that the response to neoadjuvant therapy could help guide the choice of subsequent adjuvant therapy. ## How the recommendations might affect practice The committee agreed that the recommendations would not result in a major change in practice because neoadjuvant chemotherapy is already offered in many centres. These recommendations will help improve consistency in practice. Return to recommendations # Neoadjuvant chemotherapy regimens Recommendations 1.11.4 and 1.11.5 ## Why the committee made the recommendations There was evidence that platinum-containing neoadjuvant chemotherapy regimens can improve pathological complete response rate and breast conservation rate in people with triple-negative invasive breast cancer. However, the committee took into account that platinum-containing regimens can cause anaemia, thrombocytopenia, neutropenia and febrile neutropenia, as well as bone marrow problems and renal problems in older people. The committee agreed that healthcare professionals should have a full discussion with people about the benefits and risks of these regimens. There was no evidence on people with the BRCA germline mutation, so the committee did not make separate recommendations for this subgroup. ## How the recommendations might affect practice Currently, platinum-containing neoadjuvant chemotherapy is not routinely offered to people with triple-negative early and locally advanced breast cancer, although the committee was aware that some centres may offer it. The recommendations will therefore bring a change in practice and will make practice more consistent across the NHS. The committee estimated that approximately 30% to 40% of people receiving neoadjuvant chemotherapy may be affected by the recommendations. Return to recommendations # Neoadjuvant endocrine therapy Recommendations 1.11.6 to 1.11.8 ## Why the committee made the recommendations For postmenopausal women, there was some evidence that breast conservation rates, changes in tumour size and overall survival are the same with neoadjuvant endocrine therapy and neoadjuvant chemotherapy. Endocrine therapy is safer and has fewer side effects than chemotherapy, but there was not enough evidence to recommend endocrine therapy over chemotherapy for every woman. The committee agreed that healthcare professionals should discuss the potential benefits and risks with women to help them decide which treatment is right for them and that more research is needed to say whether neoadjuvant endocrine therapy is as effective as neoadjuvant chemotherapy. The evidence for premenopausal women showed that neoadjuvant chemotherapy was more effective than endocrine therapy, but that endocrine therapy may be effective in some women. However, some women may prefer endocrine therapy because it is safer and has fewer side effects. Because of this, the committee agreed that healthcare professionals should discuss the potential benefits and risks with women to help them decide which treatment is right for them. The committee agreed that more research is needed on the long-term safety of neoadjuvant endocrine therapy, and to identify which premenopausal women will benefit from it. So, they made recommendations for research on the safety of neoadjuvant endocrine therapy in premenopausal women and postmenopausal women with early breast cancer. ## How the recommendations might affect practice Neoadjuvant endocrine therapy is already being used, although there may be an increase in the number of people being offered it. Return to recommendations # Radiotherapy after neoadjuvant chemotherapy Recommendations 1.11.10 to 1.11.13 ## Why the committee made the recommendations There was not enough evidence to recommend subgroups of women in whom postmastectomy radiotherapy could be safely omitted after neoadjuvant chemotherapy. Therefore, the committee agreed that the recommendations for postmastectomy radiotherapy among people who have not received neoadjuvant chemotherapy applied to this population. People with node-negative T4 cancer were not included in this review because they are covered by the recommendation from the previous guideline which has been retained. Women who respond well to neoadjuvant chemotherapy may derive less benefit from radiotherapy, but the committee agreed that further research was required to determine if the risks of radiotherapy outweighed the benefits in some women. So, they made a recommendation for research on the indications for postmastectomy radiotherapy after neoadjuvant chemotherapy. ## How the recommendations might affect practice The committee noted that decisions about postmastectomy radiotherapy after neoadjuvant chemotherapy are currently based on pretreatment investigations, so there will be no change to practice. Return to recommendations # Lymphoedema Recommendation 1.12.2 ## Why the committee made the recommendation Good evidence showed that there is no increased risk of lymphoedema associated with maintaining exercise levels after axillary intervention, so the committee agreed that people should not restrict or avoid physical activity. Although the evidence was limited and mixed, the committee concluded that there is no consistent evidence of increased risk of lymphoedema associated with air travel, travel to hot countries, manicures, hot-tub use, sports injuries, or medical procedures on the treated side. ## How the recommendation might affect practice Advice about preventing lymphoedema is already being provided as part of routine care, so there is unlikely to be much change in practice. However, the recommendation will lead to greater consistency in the advice offered. It should also reduce inequality and improve the quality of standard care if people who have had axillary treatment need immunisations or elective procedures. Return to recommendation # Arm and shoulder mobility Recommendations 1.12.5 to 1.12.12 ## Why the committee made the recommendations The committee noted there was very little high-quality evidence for any of the outcomes, and most of the evidence was low to very low quality. The committee agreed that they did not feel confident in making recommendations based on low-quality evidence from mainly single studies. Therefore, they used their clinical knowledge and experience alongside high-quality evidence from 1 UK-based RCT to support their decision making. This evidence showed improved outcomes with a physiotherapy-led structured supervised exercise programme in addition to usual care for reduction of pain, quality-of-life improvement and adherence to arm and shoulder exercises in people with a higher risk of developing shoulder problems. The trial provided all participants with information leaflets about exercises to help with arm and shoulder mobility after breast cancer surgery. This reflects standard practice in the UK, and the committee agreed it was important to reflect this advice in the recommendations. The recommendations also highlight that instructions on upper limb exercises and information should be discussed, explained and clarified with the person before radiotherapy begins, as the exercises should have been well established before starting treatment. The committee recommended that this should also happen before surgery. The committee were aware that instructions on upper limb exercises are not always given out by someone who is a specialist in physiotherapy (for example, breast care nurses), so they also recommended that breast care units have documented local guidelines in place that include details about who and how to deliver this information effectively. They thought it was important that the information included details on when the exercises should be started. For most people, this will be the day after surgery, but it may be later for others, such as those who have certain surgical procedures (for example, free flap reconstruction or implant reconstruction) where exercising the day after surgery could interfere with their recovery. Exercises should be tailored to each person based on their needs (for example, comorbidities and side effects of cancer treatment), but for the majority of patients, a standard programme of upper limb exercises will be suitable. The committee also agreed it was important that instructions on upper limb exercises should be available in other formats to be accessible to people with different needs (for example, video or large print and various languages). There are already recommendations on communication in the NICE guideline on patient experience in adult NHS services, so a link to this was included as part of the recommendation. Based on the effectiveness of the intervention in the UK-based trial, the committee agreed that people who met the same criteria as those included in the trial should be identified as being at higher risk of developing shoulder problems. These people should then be offered supervised support to apply the exercises. The baseline shoulder identification of someone as high risk of developing shoulder problems could be done by a member of the clinical team (for example, a clinical nurse specialist) and could be done by looking at a person's medical history and asking the person if they have experienced any of the issues listed in the recommendation (for example, asking if they have stiffness of their shoulder or if the function of their shoulder is reduced). The evidence did not specify that these risk factors were only relevant to the affected side and the committee noted that people should be considered at high risk if they have any of the pre-existing shoulder conditions in the contralateral side. It was also highlighted that for most people radiotherapy to the axilla or supraclavicular nodes is decided before surgery. However, for some people this may be decided after postoperative pathology review. For this reason, they recommended that people who are identified as needing radiotherapy to the axilla or supraclavicular nodes after surgery should also be considered as being at higher risk of developing shoulder problems. This ensures that people would not miss out from supervised support if the need for radiotherapy was not identified before surgery. The committee also agreed that, in their experience, other people having surgery for breast cancer who did not meet the high-risk criteria in the recommendations could benefit from supervised support. This includes, for example, people with learning or sensory disabilities, which could adversely affect their ability to carry out exercises without supervision and make them more likely to develop shoulder problems as a result. It also includes people having breast cancer surgery who have side effects from additional cancer treatments or who have other commonly performed adjunct surgeries in addition to breast cancer surgery, as well as people who are having radiotherapy without surgery. Based on their experience, the committee recommended that supervised support should be delivered by a physiotherapy staff member or other appropriately trained allied health professional (for example, an occupational therapist). This should include checking the performance of the exercises and correcting them as needed. The committee agreed that people may not feel confident in translating written exercise instructions into physical movement, so would benefit from having advice on whether they are doing them correctly. This support also allows people who might be experiencing difficulties with both the exercises and with shoulder function to be identified early after radiotherapy or surgery. It will also ensure that people are able to receive the full benefit from the exercises, and may increase adherence if someone is confident they are doing the exercises correctly. The committee also agreed supervised exercises and physiotherapy support should be available in different formats (for example, virtual or group sessions), and be tailored to individual circumstances and needs (for example, mental health and learning needs) to help with adherence. There was no evidence about interventions delivered virtually, but the committee agreed to recommend this option as it may help to reduce health inequalities and address access options for people where other interventions are not locally available. The committee were aware that some people may not be able to access virtual services for a range of reasons, such as a lack of access to suitable devices, living in areas of poor connectivity and difficulties with using the technology. However, including virtual services in the recommendations should not provide barriers to these people accessing support, as they can be given the option of face-to-face sessions. The committee also highlighted that face-to-face physiotherapy may be more beneficial for people with complex needs or those at higher risk (for example, people from minority ethnic family backgrounds, people with disabilities, neurodiverse people, those who experience physical difficulties with recovery or rehabilitation) because they might need specific instructions and feedback. The committee were mindful that, while their experience shows that virtual interventions are beneficial, there is a lack of evidence for this and that there was no evidence on whether the format of the intervention (individual, group, virtual, and face to face) impacted adherence or satisfaction. Therefore, the committee took this into account when making recommendations for research to cover this gap in the evidence. There was limited, low-quality evidence on long-term outcomes and no evidence on outcomes for different population subgroups, such as people from minority ethnic family backgrounds, disabled people and neurodiverse people. The committee also noted that lower-quality evidence comparing interventions was not conclusive. The committee discussed the importance of understanding the most effective and cost-effective way of delivering the intervention (for example, type of physiotherapy or exercise, mode of delivery, number of sessions) and the acceptability of such intervention for different populations, and made a recommendation for research on the most effective and cost-effective way of delivering the intervention to address this gap in the evidence. The committee also recommended that people should be referred to the physiotherapy department if they report a persistent reduction in arm and shoulder mobility after breast cancer treatment. This allows people to continue to seek support if it is needed. The committee noted that the recommendation for research into adherence to, and satisfaction with, different intervention formats will gather evidence about the long-term effects of strategies to reduce arm and shoulder problems, and this may reduce the number of people who have to be referred to the physiotherapy department in future. ## How the recommendations might affect practice There may be an increase in the number of people having supervised exercise or physiotherapy support after breast cancer surgery or before radiotherapy. However, if this could be delivered virtually (individual or group), it is likely to have a lower impact on NHS resources than in‑person 1‑to‑1 sessions and could free up resources for face-to-face interventions for those for whom virtual services are not appropriate or if there are barriers to them accessing virtual services. Return to recommendations # Lifestyle Recommendations 1.14.1 and 1.14.2 ## Why the committee made the recommendations There was evidence that both dietary changes (reducing fat intake and maintaining a healthy weight) and physical activity increase survival in people with invasive breast cancer. There was some evidence that cancer recurrence is more likely in people who drink more than 3 or 4 alcoholic drinks per week or 6 g of alcohol per day. This equates to approximately 5 units of alcohol per week. There was no evidence that smoking cessation reduces recurrence of breast cancer, although the view of the committee was that smoking cessation should always be recommended to people with breast cancer. ## How the recommendations might affect practice The committee discussed that many NHS services would already be advising people with breast cancer about the importance of a healthy lifestyle, and how they can make lifestyle changes to reduce the risk of recurrence. The committee agreed that these recommendations will help to direct conversations towards effective lifestyle changes. There will be no impact on resources because these discussions were already happening, and most of the lifestyle changes will be 'self-care' and implemented by patients themselves. Return to recommendations# Context This guideline updates and replaces the NICE guideline on early and locally advanced breast cancer (CG80). This is because new evidence was identified in surveillance that could affect recommendations, and has already changed clinical practice in some locations. People with symptoms that could be caused by breast cancer are referred by their GP to designated breast clinics in local hospitals (see NICE's guideline on suspected cancer: recognition and referral). In addition, eligible women are invited for screening through the NHS Breast Screening Programme (NHSBSP) in England or the Breast Test Wales Screening Programme (BTWSP) in Wales. For most people, whether they are referred following breast screening or after presentation to a GP, diagnosis in the breast clinic is made by triple assessment (clinical assessment, mammography and/or ultrasound imaging, and core biopsy and/or fine-needle aspiration cytology). It is best practice to carry out these assessments at the same visit (see NICE's cancer service guideline on improving outcomes in breast cancer). Breast cancer is the most common cancer in the UK, with approximately 54,000 new cases of invasive disease and around 7,000 new cases of pre-invasive (in situ) disease diagnosed annually. Most of the breast cancers occur in women, but just over 300 men in the UK are also diagnosed with invasive breast cancer every year. Most breast cancers are diagnosed at an early stage and are therefore potentially curable with modern treatments. Survival rates have improved over recent decades with almost 90% of women diagnosed with breast cancer surviving their disease for 5 or more years after diagnosis. Survival is, however, linked to the stage of the disease at diagnosis; only 15% of women diagnosed with stage IV disease are alive at 5 years. Breast cancer remains the leading cause of death in women aged 35 to 49 years and is second only to lung cancer as the leading cause of cancer death in all women. The main risk factor for breast cancer is being female; the disease is 100 times less common in men. It is also a disease of ageing, with the risk of breast cancer increasing with increasing age. Some breast cancers are linked to lifestyle factors that include obesity, alcohol intake and use of hormone replacement therapy, whereas other lifestyle factors, including physical activity and breastfeeding, protect against breast cancer. About 5% of breast cancers are because of inherited mutations in high-risk genes such as BRCA1/2 and p53. Adults (18 and over) with: newly diagnosed invasive adenocarcinoma of the breast of any size (T1 to T4), with or without spread to locoregional lymph nodes (N0 to N3) and with no distant metastases (M0) newly diagnosed ductal carcinoma in situ (DCIS) Paget's disease of the breast. Adults (18 and over) with: invasive adenocarcinoma of the breast and distant metastases (clinical or pathological M1) rare breast tumours (for example, angiosarcoma or lymphoma) benign breast tumours (for example, fibroadenoma) phyllodes tumour locally recurrent breast cancer or DCIS lobular carcinoma in situ (LCIS) no personal history of breast cancer and an increased risk of breast cancer due to family history.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nThis guideline uses specific, inclusive language to describe the population groups it covers (for example, women and pregnant people, or trans and non-binary people) except when:\n\nthe evidence for the recommendation has not been reviewed and it is not certain from expert opinion whether it can cover more groups, or\n\nthe evidence has been reviewed, but the information available for some groups at the time of development was too limited to make specific recommendations, or\n\nonly a very limited number of recommendations have been updated in direct response to new evidence or to reflect a change in practice.\n\nHealthcare professionals should use their clinical judgement when implementing gender-specific recommendations, taking into account the individual's circumstances, needs and preferences, and ensuring all people are treated with dignity and respect throughout their care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Preoperative assessment\n\nFor people having investigations for early and locally advanced invasive breast cancer:\n\nperform pretreatment ultrasound evaluation of the axilla, and\n\nif abnormal lymph nodes are identified, perform ultrasound-guided needle sampling. \n\nDo not routinely use MRI of the breast as part of the preoperative assessment of people with biopsy-proven invasive breast cancer or ductal carcinoma in situ (DCIS). \n\nOffer MRI of the breast as part of preoperative assessment to people with invasive breast cancer:\n\nif the extent of disease is not clear from clinical examination, mammography and ultrasound assessment for planning treatment\n\nif accurate mammographic assessment is difficult because of breast density\n\nto assess the tumour size if breast-conserving surgery is being considered for invasive lobular cancer. \n\n## Genetic testing\n\nOffer genetic testing for BRCA1 and BRCA2 mutations to women under 50 years with triple-negative breast cancer, including those with no family history of breast or ovarian cancer (also see the recommendations on genetic testing in the NICE guideline on familial breast cancer). \n\n# Providing information and psychological support\n\nEnsure all people with breast cancer have a named clinical nurse specialist, or other specialist key worker with equivalent skills, to support them throughout diagnosis, treatment and follow-up. [2009, amended 2018]\n\nOffer all people with breast cancer prompt access to specialist psychological support and, where appropriate, psychiatric services. \n\nDiscuss opportunities for people with breast cancer to be involved in research, and encourage entry into clinical trials and other studies. \n\nFor guidance on fertility preservation, see the recommendations on people with cancer who wish to preserve fertility in the NICE guideline on fertility problems. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on providing information and psychological support\xa0.\n\nLoading. Please wait.\n\n# Surgery to the breast\n\nOffer further surgery (re-excision or mastectomy, as appropriate) after breast-conserving surgery where invasive cancer or DCIS is present at the radial margins ('tumour on ink'; 0\xa0mm). \n\nFor women who have had breast-conserving surgery where invasive cancer or DCIS is present within 2\xa0mm of, but not at, the radial margins (greater than 0\xa0mm and less than 2\xa0mm):\n\ndiscuss the benefits and risks of further surgery (re-excision or mastectomy) to minimise the risk of local recurrence\n\ntake into account the woman's preferences, comorbidities, tumour characteristics and the potential use of radiotherapy (also see radiotherapy after breast-conserving surgery). \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on surgery to the breast\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: surgery to the breast.\n\nLoading. Please wait.\n\nAll breast units should audit their recurrence rates after treatment. [2009, amended 2018]\n\n## Paget's disease\n\nOffer breast-conserving surgery with removal of the nipple–areolar complex as an alternative to mastectomy for people with Paget's disease of the nipple that has been assessed as localised. Offer oncoplastic repair techniques to maximise cosmesis. \n\n# Surgery to the axilla\n\n## Invasive breast cancer\n\nPerform surgery using sentinel lymph node biopsy (SLNB) rather than axillary lymph node clearance to stage the axilla for people with invasive breast cancer if they have:\n\nno evidence of lymph node involvement on ultrasound, or\n\na negative ultrasound-guided needle biopsy. [2009, amended 2023]\n\nPerform SLNB using the dual technique with isotope and blue dye. \n\nBreast units should audit their axillary recurrence rates. \n\n## Ductal carcinoma in situ\n\nDo not routinely perform SLNB for women with a preoperative diagnosis of DCIS who are having breast-conserving surgery, unless they are considered to be at high risk of invasive disease. People at high risk of invasive disease include those with a palpable mass or extensive microcalcifications. \n\nOffer SLNB to all people who are having a mastectomy for DCIS. \n\n## Evaluation and management of a positive axillary lymph node identified by a preoperative ultrasound-guided needle biopsy\n\nOffer axillary node clearance to people with invasive breast cancer who have a preoperative ultrasound-guided needle biopsy with pathologically proven lymph node metastases. [2009, amended 2018]\n\n## Evaluation and management of a positive axillary lymph node identified by a sentinel lymph node biopsy (in people with a normal preoperative ultrasound-guided needle biopsy)\n\nOffer further axillary treatment (axillary node clearance or radiotherapy) after SLNB to people who have 1\xa0or more sentinel lymph node macrometastasis. \n\nDiscuss the benefits and risks of not having further axillary treatment after primary breast-conserving surgery (within clinical trials where available) with women who:\n\nhave 1\xa0or 2\xa0sentinel lymph node macrometastases and\n\nhave been advised to have whole-breast radiotherapy with systemic therapy (which may be endocrine therapy). \n\nDo not offer further axillary treatment to people who only have micrometastases in their sentinel lymph nodes after primary surgery for invasive breast cancer. \n\nDo not offer further axillary treatment to people who have isolated tumour cells in their sentinel lymph nodes after primary surgery for invasive breast cancer. Classify this as lymph node-negative breast cancer. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on evaluation and management of a positive axillary lymph node\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: management of the positive axilla.\n\nLoading. Please wait.\n\n# Breast reconstruction\n\nOffer breast reconstruction to people after they have had mastectomy for breast cancer. \n\nBe aware that some people may prefer not to have breast reconstruction surgery. \n\nOffer both breast reconstruction options to women (immediate reconstruction and delayed reconstruction), whether or not they are available locally. \n\nOffer immediate breast reconstruction to women who have been advised to have a mastectomy, including those who may need radiotherapy, unless they have comorbidities that rule out reconstructive surgery. [2018, amended 2023]\n\nDiscuss the benefits and risks of immediate breast reconstruction and delayed breast reconstruction with women. Topics to discuss include those in table\xa01 and:\n\nthe timing of breast reconstruction surgery (at the same time as mastectomy or later)\n\ndifferent breast reconstruction surgery options and what they involve\n\nhow the timing of breast reconstruction surgery affects the options available\n\nthe uncertainty over long-term outcomes in women having radiotherapy. \n\nCategory\n\nImmediate breast reconstruction\n\nDelayed breast reconstruction\n\nDefinition\n\nReconstruction is started in the same operation as the mastectomy\n\nAfter a mastectomy, reconstruction is done in a separate operation\n\nNumber and timing of operations\n\nMore than 1 operation is usually needed to complete the reconstruction\n\nThe total number of operations will vary. It may be affected by factors such as:\n\ntype of reconstruction (for example, some are planned in stages; a prosthesis may be worn until reconstruction is complete)\n\npersonal preferences (such as whether a nipple reconstruction is requested)\n\nFewer operations may be needed\n\nMore than 1 operation is usually needed to complete the reconstruction\n\nThe total number of operations will vary. It may be affected by factors such as:\n\ntype of reconstruction (for example, some are planned in stages; a prosthesis may be worn until reconstruction is complete)\n\npersonal preferences (such as whether a nipple reconstruction is requested)\n\nMore operations may be needed\n\nBreast reconstruction options available\n\nThese will vary depending on personal preferences (such as breast size desired), current body shape, other health conditions, previous operations and lifestyle factors (such as hobbies)\n\nNot all hospitals or surgeons can offer all procedures. Travel to a different hospital may be needed for a specific option\n\nOptions may be available that spare or preserve the breast skin (which may mean less scarring and a more natural look)\n\nLimited time to make a decision about options (which may include not having a reconstruction) before surgery\n\nThese will vary depending on personal preferences (such as breast size desired), current body shape, other health conditions, previous operations and lifestyle factors (such as hobbies)\n\nNot all hospitals or surgeons can offer all procedures. Travel to a different hospital may be needed for a specific option\n\nCertain options that spare or preserve the breast skin may not be available\n\nMore time to make a decision (which may include not having a reconstruction) and to plan reconstruction\n\nBenefits\n\nBreast shape remains, which may help maintain body image and have subsequent psychological benefits\n\nLifestyle changes (such as losing weight and taking regular exercise) may be possible, which increase the options and lower the risks of reconstruction surgery\n\nProcedures (and associated recovery) can be planned around other commitments\n\nRisks\n\nSurgical complications can occur after any breast reconstruction and will vary by type of procedure and personal risk factors\n\nMay be lower rates of:\n\ntissue breakdown\n\nsurgery for flap removal if it cannot be used because of a complication (which may lead to delayed reconstruction and flat appearance for a period of time)\n\nprocedures to improve symmetry\n\nComplications from the mastectomy or axillary surgery can occur during the recovery period\n\nSurgical complications can occur after any breast reconstruction and will vary by type of procedure and personal risk factors\n\nMay be lower rates of:\n\nmastectomy site complications\n\nflap or implant failure (which may lead to delayed reconstruction and flat appearance for a period of time)\n\ncapsular contracture (a scar layer around the implant that may lead to pain if severe)\n\nMay need to interrupt hormone therapies (tamoxifen) for further surgery\n\nSatisfaction\n\nNo clear differences in satisfaction with completed reconstructions\n\nNo clear differences in satisfaction with completed reconstructions\n\nReconstruction and adjuvant therapy (including radiotherapy and chemotherapy)\n\nRadiotherapy or chemotherapy can be given but may be delayed if there are complications from the mastectomy or reconstruction\n\nImmediate reconstructions using implants may be more affected by radiotherapy than immediate flap reconstructions\n\nMay need adaptions to scans if a tissue expander is used. For example, may not be able to have MRI scans and may need modified radiotherapy planning\n\nComplications can also occur after mastectomy alone, which may delay chemotherapy or radiotherapy\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on breast reconstruction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: postmastectomy radiotherapy.\n\nLoading. Please wait.\n\n# Diagnostic assessment and adjuvant therapy planning\n\n## Predictive factors\n\nAssess the oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor\xa02 (HER2) status of all invasive breast cancers simultaneously at the time of initial histopathological diagnosis. \n\nAssess the ER status of all invasive breast cancers using standardised and quality-assured immunohistochemical techniques, and report the results quantitatively. \n\nAssess the PR status of all invasive breast cancers using standardised and quality-assured immunohistochemical techniques, and report the results quantitatively. \n\nAssess the HER2 status of all invasive breast cancers using standardised and quality-assured techniques, and report the results quantitatively. \n\nEnsure that the ER, PR and HER2 statuses are available and recorded at the preoperative and postoperative multidisciplinary team meetings when systemic treatment is discussed. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on predictive factors\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: adjuvant systemic therapy planning.\n\nLoading. Please wait.\n\n## Adjuvant therapy planning\n\nConsider adjuvant therapy after surgery for people with invasive breast cancer, and ensure that recommendations are documented at the multidisciplinary team meeting. \n\nBase recommendations about adjuvant therapy on multidisciplinary team assessment of the prognostic and predictive factors, and the possible risks and benefits of the treatment. Make decisions with the person after discussing these factors. [2009, amended 2018]\n\nUse the PREDICT tool to estimate prognosis and the absolute benefits of adjuvant therapy for women with invasive breast cancer. \n\nWhen using the PREDICT tool, be aware that:\n\nit is less accurate for:\n\n\n\nwomen under\xa030 with ER-positive breast cancer\n\nwomen aged 70\xa0and over\n\nwomen with tumours larger than 50\xa0mm\n\n\n\nit has not been validated in men, and\n\nthe validation may have under-represented some ethnic groups.Take into account that the potential limitations in versions of PREDICT after 2.0 may differ from those listed here (also see the PREDICT tool frequently asked questions). [2018, amended 2023]\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on adjuvant therapy planning\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: adjuvant systemic therapy planning.\n\nLoading. Please wait.\n\n## Tumour profiling tests to guide adjuvant chemotherapy decisions\n\nThe NICE diagnostics guidance on tumour profiling tests provides evidence-based recommendations on tumour profiling tests to guide adjuvant chemotherapy decisions.\n\n# Endocrine therapy\n\nTreat all people with invasive breast cancer with surgery and appropriate systemic therapy, rather than endocrine therapy alone, unless a significant comorbidity means surgery is not suitable for them. \n\n## Adjuvant endocrine therapy for invasive breast cancer\n\nOffer tamoxifen as the initial adjuvant endocrine therapy for men and premenopausal women with ER-positive invasive breast cancer. [2009, amended 2018]\n\nOffer an aromatase inhibitor as the initial adjuvant endocrine therapy for postmenopausal women with ER-positive invasive breast cancer who are at medium or high risk of disease recurrence. Offer tamoxifen to women who are at low risk of disease recurrence, or if aromatase inhibitors are not tolerated or are contraindicated. [2009, amended 2018]\n\n## Ovarian function suppression\n\nConsider ovarian function suppression in addition to endocrine therapy for premenopausal women with ER-positive invasive breast cancer. \n\nDiscuss the benefits and risks of ovarian function suppression in addition to endocrine therapy with premenopausal women with ER-positive invasive breast cancer. Explain to women that ovarian function suppression may be most beneficial for those women who are at sufficient risk of disease recurrence to have been offered chemotherapy. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on ovarian function suppression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: endocrine therapy for invasive disease.\n\nLoading. Please wait.\n\n## Extended endocrine (hormone) therapy\n\nIn June 2023, the use of aromatase inhibitors in recommendations 1.7.6 and 1.7.7 was off-label. See NICE's information on prescribing medicines.\n\nDiscuss the benefits and risks of extended endocrine therapy with people who this treatment may be suitable for (see table\xa02). [2018, amended 2023]\n\nOffer extended endocrine therapy (past the 5‑year point) with an aromatase inhibitor for postmenopausal women with ER-positive invasive breast cancer who are at medium or high risk of disease recurrence and who have been taking tamoxifen for 2\xa0to 5\xa0years. Medium or high risk may include people who have lymph node-positive breast cancer, with tumours that are T2 or greater and higher grade. \n\nConsider extended endocrine therapy (past the 5‑year point) with an aromatase inhibitor for postmenopausal women with ER-positive invasive breast cancer who are at low risk of disease recurrence and who have been taking tamoxifen for 2\xa0to 5\xa0years. Low risk may include people with lymph node-negative breast cancer, with smaller or lower-grade tumours. \n\nConsider extending the duration of tamoxifen therapy for longer than 5\xa0years for people with ER-positive invasive breast cancer. \n\nCategory\n\nExtended tamoxifen therapy (after an initial 5\xa0years of tamoxifen therapy)\n\nExtended endocrine therapy with an aromatase inhibitor (after 5\xa0years of tamoxifen therapy)\n\nDefinition\n\nContinuing to take tamoxifen after 5\xa0years of tamoxifen therapy\n\nSwitching to an aromatase inhibitor after 5\xa0years of tamoxifen therapy\n\nWho can take this therapy\n\nPeople with ER-positive invasive breast cancer\n\nPostmenopausal women with ER-positive invasive breast cancer\n\nEffect on breast cancer recurrence:\n\nThe benefit for an individual person will depend on the risk of their cancer returning. For people with a low risk of recurrence, the benefits may not outweigh the risks or side effects\n\nMedium or high risk may include people who have lymph node-positive breast cancer, with tumours that are T2 or greater and higher grade. Low risk may include people with lymph node-negative breast cancer, with smaller or lower-grade tumours\n\nEvidence shows lower rates of breast cancer recurrence compared with 5\xa0years of tamoxifen therapy in women\n\nLower rates of breast cancer recurrence compared with 5\xa0years of tamoxifen therapy\n\nIn postmenopausal women, switching to an aromatase inhibitor may be more effective at reducing recurrence than continuing with tamoxifen\n\n\n\nSide effects:\n\nThese are common side effects experienced during additional years taking endocrine therapy. Most effects are reversible when tablets are stopped\n\nSide effects of endocrine therapy will continue for additional years (for example, menopausal symptoms such as hot flushes)\n\nSide effects may differ in men\n\nWith extended use of tamoxifen: increased risk of thrombosis and endometrial cancer, and possibly bone density loss in premenopausal women\n\nSide effects of endocrine therapy will continue for additional years (for example, menopausal symptoms such as hot flushes)\n\nWith extended use of aromatase inhibitors: bone density loss, and joint and muscle pain\n\nFertility and family planning\n\nFor women, effects on fertility and family planning will continue for additional years as they should not become pregnant while taking tamoxifen, or within 2\xa0months of stopping, because it may have adverse effects on the baby\n\nNot applicable as postmenopausal women only\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on extended endocrine therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: endocrine therapy for invasive disease.\n\nLoading. Please wait.\n\n## Endocrine therapy for ductal carcinoma in situ\n\nDiscuss the benefits and risks (see table\xa03) of endocrine therapy after breast-conserving surgery for women with ER-positive DCIS. \n\nOffer endocrine therapy after breast-conserving surgery for women with ER-positive DCIS if radiotherapy is recommended but not received. \n\nConsider endocrine therapy after breast-conserving surgery for women with ER-positive DCIS if radiotherapy is not recommended. \n\nCategory\n\nEndocrine therapy after breast-conserving surgery for women with ER-positive DCIS\n\nDefinition\n\nTamoxifen or an aromatase inhibitor for 5\xa0years, taken as a once-daily tablet\n\nEffect on survival and disease recurrence:\n\nThe benefit for an individual person will depend on the risk of their cancer returning. For people with low risk of recurrence, the benefits may not outweigh the risks or side effects\n\nRisk can be estimated using a range of standardised tools and clinical expertise\n\nNo effect on survival at 5 or 10\xa0years after diagnosis\n\nLower rate of recurrence of DCIS and lower rate of invasive breast cancer, compared with women who did not receive endocrine therapy or radiotherapy after surgery\n\nSide effects\n\nAll endocrine therapies: menopausal symptoms, such as hot flushes\n\nFor tamoxifen: increased risk of thrombosis, endometrial cancer and possibly bone density loss in premenopausal women\n\nFor aromatase inhibitors: joint and muscle pain, urogenital symptoms and bone density loss\n\nFertility and family planning\n\nEffects on fertility and family planning as women should not become pregnant while taking tamoxifen, or within 2\xa0months of stopping, because it may have adverse effects on the baby\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on endocrine therapy for DCIS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: endocrine therapy for invasive disease.\n\nLoading. Please wait.\n\n# Adjuvant chemotherapy for invasive breast cancer\n\nFor people with breast cancer where chemotherapy is indicated, offer a regimen that contains both a taxane and an anthracycline. Refer to the summaries of product characteristics for individual taxanes and anthracyclines to check for differences in licensed indications. [2018, amended 2023]\n\nDiscuss with people the benefits and risks of adding a taxane to anthracycline-containing regimens. Topics to discuss include those in table\xa04 and:\n\nthe benefits of reduced cardiac toxicity and reduced nausea\n\nthe risks of additional side effects, including neuropathy, neutropenia and hypersensitivity\n\nthe different side effects and dosing frequencies of different docetaxel and paclitaxel regimens, and the additional clinic visits that may be needed\n\nthat absolute benefit is proportional to absolute risk of recurrenceRefer to the summaries of product characteristics for individual taxanes and anthracyclines to check for differences in licensed indications. \n\nEffect of adding a taxane to an anthracycline-containing regimen\n\n‑weekly docetaxel\n\nWeekly or fortnightly paclitaxel\n\nEffect on survival:\n\nThe benefit for an individual person will depend on the risk of their cancer returning. For people with low risk of recurrence, the benefits may not outweigh the risks or side effects\n\n\n\nSome evidence for improved outcomes, including reducing the risk of breast cancer returning and increasing the chance of surviving\n\nSome evidence for improved outcomes, including reducing the risk of breast cancer returning and increasing the chance of surviving\n\nBenefits\n\nSmaller doses of anthracyclines can be used, which can reduce the risk of side effects such as nausea and vomiting\n\nSmaller cumulative doses of individual drugs may reduce long-term side effects, for example, cardiac toxicity and risk of second malignancies\n\nSmaller doses of anthracyclines can be used, which can reduce the risk of side effects such as nausea and vomiting\n\nSmaller cumulative doses of individual drugs may reduce long-term side effects, for example, cardiac toxicity and risk of second malignancies\n\nSide effects\n\nAdditional side effects may include joint and muscle pain, nerve damage, higher rates of febrile neutropenia and hypersensitivity reactions\n\nSome people have long-term hair loss (alopecia) after treatment with taxanes\n\n\n\nAdditional side effects may include nerve damage and hypersensitivity reactions, but febrile neutropenia is less likely than with 3‑weekly docetaxel\n\nSome people have long-term hair loss (alopecia) after treatment with taxanes\n\nWeekly paclitaxel is tolerated best, but even fortnightly is better tolerated than 3‑weekly docetaxel\n\nAdministration\n\nVisits to hospital every 3\xa0weeks\n\nVisits to hospital every week or every 2\xa0weeks\n\nLength of course\n\nto 12\xa0weeks (3 to 4\xa0cycles)\n\nto 12\xa0weeks\n\nEnsure weekly and fortnightly paclitaxel is available locally, as it is better tolerated than 3‑weekly docetaxel, particularly in people with comorbidities. [2018, amended 2023]\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on adjuvant chemotherapy for invasive breast cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: adjuvant chemotherapy.\n\nLoading. Please wait.\n\n## Biological therapy\n\nOffer adjuvant trastuzumab for people with T1c and above HER2-positive invasive breast cancer. Give this at 3‑week intervals for 1\xa0year in combination with surgery, chemotherapy, endocrine therapy and radiotherapy, as appropriate. [2009, amended 2023]\n\nConsider adjuvant trastuzumab for people with T1a/T1b HER2-positive invasive breast cancer, taking into account any comorbidities, prognostic features, possible toxicity of chemotherapy and the person's preferences. \n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on biological therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: adjuvant biological therapy.\n\nLoading. Please wait.\n\nUse trastuzumab with caution in people with HER2-positive invasive breast cancer if they have any of the following:\n\na baseline left ventricular ejection fraction (LVEF) of 55% or less\n\na history of, or current, congestive heart failure\n\na history of myocardial infarction\n\nangina pectoris needing medication\n\ncardiomyopathy\n\ncardiac arrhythmias needing medical treatment\n\nclinically significant valvular heart disease\n\nhaemodynamic-effective pericardial effusion\n\npoorly controlled hypertension. [2009, amended 2018]\n\n# Bisphosphonate therapy\n\n## Adjuvant bisphosphonate therapy\n\nIn June 2023, the use of bisphosphonates (zoledronic acid or sodium clodronate) in recommendations\xa01.9.1 and 1.9.2 was off-label. See NICE's information on prescribing medicines.\n\nOffer bisphosphonates (zoledronic acid or sodium clodronate) as adjuvant therapy to postmenopausal women with node-positive invasive breast cancer. \n\nConsider bisphosphonates (zoledronic acid or sodium clodronate) as adjuvant therapy for postmenopausal women with node-negative invasive breast cancer and a high risk of recurrence. \n\nDiscuss the benefits and risks of bisphosphonate treatment with women, particularly the risk of osteonecrosis of the jaw, atypical femoral fractures and osteonecrosis of the external auditory canal. Follow the Medicines and Healthcare products Regulatory Agency/Commission on Human Medicines (MHRA/CHM) advice on bisphosphonates. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on adjuvant bisphosphonate therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: adjuvant bisphosphonates.\n\nLoading. Please wait.\n\n## Bone health\n\nOffer a baseline dual-energy X-ray absorptiometry (DEXA) scan to assess bone mineral density in women with invasive breast cancer who are not receiving bisphosphonates as adjuvant therapy and who:\n\nare starting adjuvant aromatase inhibitor treatment, or\n\nhave treatment-induced menopause, or\n\nare starting ovarian ablation/suppression therapy. [2009, amended 2018]\n\nDo not offer a DEXA scan to people with invasive breast cancer who are receiving tamoxifen alone. [2009, amended 2023]\n\nOffer bisphosphonates to women identified by algorithms\xa01 and 2 in the guidance for the management of breast cancer treatment‑induced bone loss: a consensus position statement from a UK expert group (2008; this guidance is not NICE accredited). \n\n# Radiotherapy\n\nUse a radiotherapy technique that minimises the dose to the lung and heart. \n\nUse a deep inspiratory breath-hold radiotherapy technique for people with left-sided breast cancer to reduce the dose to the heart. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on radiotherapy techniques\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: breast radiotherapy.\n\nLoading. Please wait.\n\n## Radiotherapy after breast-conserving surgery\n\nOffer whole-breast radiotherapy to women with invasive breast cancer who have had breast-conserving surgery with clear margins. \n\nConsider partial-breast radiotherapy as an alternative to whole-breast radiotherapy for women who have had breast-conserving surgery for invasive cancer (excluding lobular type) with clear margins and who:\n\nhave a low absolute risk of local recurrence (defined as women aged 50\xa0and over with tumours that are 3\xa0cm or less, N0, ER‑positive, HER2‑negative and grade\xa01 to 2), and\n\nhave been advised to have adjuvant endocrine therapy for a minimum of 5\xa0years. \n\nIf partial-breast radiotherapy (see recommendation\xa01.10.4) may be suitable for a woman, discuss the benefits and risks with them and reach a shared decision on its use. Topics to cover include that:\n\nlocal recurrence with partial-breast radiotherapy at 5\xa0years is equivalent to that with whole-breast radiotherapy\n\nthe risk of local recurrence beyond 5\xa0years is not yet known\n\nthere is a potential reduction in late adverse effects. [2018, amended 2023]\n\nWhen giving partial-breast radiotherapy, use external beam radiotherapy. \n\nConsider not using radiotherapy for women who:\n\nhave had breast-conserving surgery for invasive breast cancer with clear margins and\n\nhave a very low absolute risk of local recurrence (defined as women aged 65\xa0and over with tumours that are T1N0, ER-positive, HER2-negative and grade\xa01 to 2) and\n\nare willing to take adjuvant endocrine therapy for a minimum of 5\xa0years. \n\nWhen considering not using radiotherapy (see recommendation\xa01.10.7), discuss the benefits and risks with the woman (see table\xa05) and explain that:\n\nwithout radiotherapy, local recurrence occurs in about 50 women per 1,000 at 5\xa0years, and with radiotherapy, occurs in about 10 women per 1,000 at 5\xa0years\n\noverall survival at 10\xa0years is the same with or without radiotherapy\n\nthere is no increase in serious late effects if radiotherapy is given (for example, congestive cardiac failure, myocardial infarction or secondary cancer). \n\nCategory\n\nRadiotherapy\n\nNo radiotherapy\n\nEffect on local recurrence\n\nOn average, in 1,000\xa0women, over 5\xa0years local recurrence occurs in about 10 women, and does not occur in about 990 women\n\nOn average, in 1,000 women, over 5\xa0years local recurrence occurs in about 50 women, and does not occur in about 950 women\n\nEffect on survival\n\nNo difference in overall survival at 10\xa0years\n\nNo difference in overall survival at 10\xa0years\n\nRisks\n\nPossibility of short- and long-term adverse effects on the breast, and resulting cosmetic changes (such as skin soreness, changes to colour of skin, radiation fibrosis or stiffening of the breast tissue)\n\nNo short- or long-term adverse effects on the breast, or cosmetic changes\n\nSide effects\n\nIn this group of women at low risk, there is no increase in serious late side effects of radiotherapy (such as congestive cardiac failure, myocardial infarction or secondary cancer)\n\nNo side effects of radiotherapy will occur\n\nAdministration\n\nGiven at the treatment centre 5\xa0days a week for 3\xa0weeks after surgery\n\nNo need to attend the treatment centre for radiotherapy sessions\n\nConsider adjuvant radiotherapy for women with DCIS following breast-conserving surgery with clear margins. Discuss the possible benefits and risks of radiotherapy (also see the section on surgery to the breast) and make a shared decision about its use. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on radiotherapy after breast‑conserving surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: breast radiotherapy.\n\nLoading. Please wait.\n\n## Radiotherapy after mastectomy\n\nOffer adjuvant postmastectomy radiotherapy to people with node-positive (macrometastases) invasive breast cancer or involved resection margins. \n\nConsider adjuvant postmastectomy radiotherapy for people with node-negative T3 or T4 invasive breast cancer. \n\nDo not offer radiotherapy following mastectomy to people with invasive breast cancer who are at low risk of local recurrence (for example, most people who have lymph node-negative breast cancer). [2018, amended 2023]\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on radiotherapy after mastectomy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: postmastectomy radiotherapy.\n\nLoading. Please wait.\n\n## Dose fractionation for external beam radiotherapy\n\nOffer 26\xa0Gy in 5 fractions over 1\xa0week for people with invasive breast cancer having partial-breast, whole-breast or chest-wall radiotherapy, without regional lymph node irradiation, after breast-conserving surgery or mastectomy. \n\nConsider 40\xa0Gy in 15 fractions over 3\xa0weeks for people with invasive breast cancer having partial-breast, whole-breast or chest-wall radiotherapy, without regional lymph node irradiation, after breast-conserving surgery or mastectomy when they:\n\nhave a diagnosis that increases sensitivity to radiotherapy, or\n\nhave had implant-based reconstruction, or\n\nhave any other factor that could mean having radiotherapy over 3\xa0weeks is more acceptable (such as high BMI or fibromyalgia). \n\nWhen discussing the benefits and risks of the 2 regimens, follow the recommendations on:\n\nenabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services, and\n\ncommunicating risks, benefits and consequences in the NICE guideline on shared decision making. \n\nOffer 40\xa0Gy in 15 fractions over 3\xa0weeks for people with invasive breast cancer having regional lymph node irradiation, with or without whole-breast or chest-wall radiotherapy, after breast-conserving treatment or mastectomy. \n\nFor a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on dose fractionation of external beam radiotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: effectiveness of different external beam hypofractionation radiotherapy regimens in people with early-stage or locally advanced invasive breast cancer.\n\nLoading. Please wait.\n\n## Breast boost following breast-conserving surgery\n\nOffer an external beam boost to the tumour bed for women with invasive breast cancer and a high risk of local recurrence, following whole-breast radiotherapy. [2009, amended 2018]\n\nInform women of the risk of side effects associated with an external beam boost to the tumour bed following whole-breast radiotherapy. [2009, amended 2018]\n\n## Radiotherapy to nodal areas\n\nDo not offer adjuvant radiotherapy to regional lymph nodes to people with invasive breast cancer who have histologically lymph node-negative breast cancer. [2009, amended 2018]\n\nDo not offer people with invasive breast cancer adjuvant radiotherapy to the axilla after axillary clearance. [2009, amended 2023]\n\nOffer adjuvant radiotherapy to the supraclavicular fossa to people with invasive breast cancer and 4\xa0or more involved axillary lymph nodes. \n\nOffer adjuvant radiotherapy to the supraclavicular fossa to people with invasive breast cancer and 1 to 3 positive lymph nodes if they have other poor prognostic factors (for example, T3 and/or histological grade\xa03 tumours) and good performance status. \n\nConsider including the internal mammary chain within the nodal radiotherapy target for people with node-positive (macrometastases) invasive breast cancer. \n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on radiotherapy to nodal areas\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: breast radiotherapy.\n\nLoading. Please wait.\n\n## Intraoperative radiotherapy\n\nFor guidance on intraoperative radiotherapy, see the NICE technology appraisal guidance on the intrabeam radiotherapy system for adjuvant treatment of early breast cancer. \n\n# Primary systemic therapy\n\n## Neoadjuvant chemotherapy\n\nOffer neoadjuvant chemotherapy to people with ER-negative invasive breast cancer as an option to reduce tumour size. \n\nOffer neoadjuvant chemotherapy to people with HER2-positive invasive breast cancer in line with the NICE technology appraisal guidance on pertuzumab for the neoadjuvant treatment of HER2‑positive breast cancer. \n\nConsider neoadjuvant chemotherapy for people with ER-positive invasive breast cancer as an option to reduce tumour size if chemotherapy is indicated. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on neoadjuvant chemotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer.\n\nLoading. Please wait.\n\n## Neoadjuvant chemotherapy regimens\n\nIn June 2023, the use of platinums in recommendations\xa01.11.4 and 1.11.5 was off-label. See NICE's information on prescribing medicines.\n\nFor people with ER/PR/HER2-negative (triple-negative) invasive breast cancer, consider a neoadjuvant chemotherapy regimen that contains both a platinum and an anthracycline. \n\nDiscuss the benefits and risks of adding a platinum to an anthracycline-containing neoadjuvant chemotherapy regimen (see table\xa06), and in particular the risk of increased toxicity. \n\nCategory\n\nEffect of adding a platinum to anthracycline-containing (with or without taxane) neoadjuvant chemotherapy\n\nEffect on breast conservation rate\n\nAdding a platinum improves response rates compared with anthracycline-based (with or without taxane) chemotherapy. This may mean that some women who would otherwise need a mastectomy can be offered breast-conserving surgery\n\nEffect on pathological complete response rate (no residual cancer found at surgery)\n\nAdding a platinum improves the chances of all signs of cancer disappearing in both the breast and lymph nodes in the axilla, compared with anthracycline-based (with or without taxane) neoadjuvant chemotherapy\n\nEffect on survival\n\nNo increase in overall survival with platinum-based chemotherapy\n\nSide effects:\n\nPlatinum-based therapy is only suitable for fit patients with no significant comorbidities\n\nAdding a platinum may mean that side effects are more severe. Anaemia, thrombocytopenia, neutropenia and febrile neutropenia are seen more frequently with platinum-based chemotherapy\n\nOn average, if 1,000 women with triple-negative breast cancer receive platinum-containing neoadjuvant chemotherapy, about 70 additional women would experience severe or life-threatening side effects compared with non-platinum neoadjuvant chemotherapy\n\nBone marrow suppression and renal problems are likely in older people\n\nFor a short explanation why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on neoadjuvant chemotherapy regimens\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer.\n\nLoading. Please wait.\n\n## Neoadjuvant endocrine therapy\n\nConsider neoadjuvant endocrine therapy for postmenopausal women with ER-positive invasive breast cancer as an option to reduce tumour size if there is no definite indication for chemotherapy. \n\nAdvise premenopausal women that neoadjuvant chemotherapy may be more likely to produce a clinical response than neoadjuvant endocrine therapy, but that some tumours do respond to neoadjuvant endocrine therapy. \n\nDiscuss with women the benefits and risks of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy (see table\xa07). \n\nCategory\n\nNeoadjuvant endocrine therapy\n\nNeoadjuvant chemotherapy\n\nDefinition\n\nTamoxifen or an aromatase inhibitor started before surgery\n\nOnly an option for women with ER-positive breast cancer\n\nChemotherapy given before surgery\n\nOnly an option for people who would be recommended adjuvant (after surgery) chemotherapy\n\nAdministration\n\nTablet taken once a day at home\n\nIntravenous administration in hospital, as an outpatient\n\nEffectiveness\n\nFor postmenopausal women: may be as effective as neoadjuvant chemotherapy in terms of breast conservation rates and shrinking the tumour\n\nFor premenopausal women: less effective than neoadjuvant chemotherapy at shrinking the tumour (but some tumours may respond so may be effective in some women)\n\nFor postmenopausal women: effective at improving breast conservation rates and shrinking the tumour\n\nFor premenopausal women: more effective than endocrine therapy at shrinking the tumour\n\n\n\nPotential disadvantages\n\nIf neoadjuvant endocrine therapy is not effective, then women may proceed to surgery earlier or may still need to have chemotherapy, either before or after surgery\n\n–\n\nSide effects\n\nAll endocrine therapies: menopausal symptoms such as hot flushes\n\nFor tamoxifen: increased risk of thrombosis and endometrial cancer\n\nFor aromatase inhibitors: joint and muscle pain, urogenital symptoms, bone density loss (may also occur with tamoxifen in premenopausal women)\n\nSide effects are usually reversible\n\nMay allow women to avoid the additional side effects of chemotherapy (although women may still need adjuvant chemotherapy after surgery)\n\nSide effects may include nausea and vomiting, risk of infections that may be life threatening, fatigue, neuropathy, cardiac toxicity, diarrhoea, constipation, sore mouth, skin and nail changes, risk of blood clots, risk of second malignancies, fluid retention, allergic reactions and hair loss\n\nSide effects may persist long term\n\nFertility and family planning\n\nWomen should not become pregnant while taking tamoxifen, or within 2\xa0months of stopping, because it may have adverse effects on the baby\n\nOften causes temporary infertility\n\nMay cause permanent infertility\n\nLength of course\n\nMay take longer than chemotherapy to shrink the tumour enough for breast-conserving surgery\n\nThe duration of neoadjuvant chemotherapy is shorter than neoadjuvant endocrine therapy\n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on neoadjuvant endocrine therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer.\n\nLoading. Please wait.\n\n## Radiotherapy after neoadjuvant chemotherapy\n\nOffer local treatment with mastectomy (or, in exceptional cases, breast-conserving surgery) followed by radiotherapy to people with locally advanced or inflammatory breast cancer that has been treated with neoadjuvant chemotherapy. \n\nOffer postmastectomy radiotherapy after neoadjuvant chemotherapy if post-treatment histology shows node-positive (macrometastases) breast cancer or involved resection margins. \n\nOffer postmastectomy radiotherapy after neoadjuvant chemotherapy if pretreatment investigations show node-positive (macrometastases) breast cancer. \n\nConsider postmastectomy radiotherapy after neoadjuvant chemotherapy if post-treatment histology shows node-negative T3 breast cancer. \n\nConsider postmastectomy radiotherapy after neoadjuvant chemotherapy if pretreatment investigations show node-negative T3 breast cancer. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on radiotherapy after neoadjuvant chemotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer.\n\nLoading. Please wait.\n\n# Complications of local treatment and menopausal symptoms\n\n## Lymphoedema\n\nInform people with breast cancer about lymphoedema and their risk of developing it after treatment with surgery and radiotherapy (see recommendation\xa01.12.2). Give them relevant written information before treatment to take away and refer back to. \n\nWhen informing people with breast cancer about the risk of developing lymphoedema, advise them that:\n\nlymphoedema can occur in the arm, breast or chest wall\n\nthey do not need to restrict their physical activity\n\nthere is no consistent evidence of increased risk of lymphoedema associated with air travel, travel to hot countries, manicures, hot-tub use or sports injuries\n\nthere is no consistent evidence of increased risk of lymphoedema associated with medical procedures (for example, blood tests, injections, intravenous medicines and blood pressure measurement) on the treated side, and the decision to perform medical procedures using the arm on the treated side should depend on clinical need and the possibility of alternatives. [2018, amended 2023]\n\nGive people who have had treatment for breast cancer advice on how to reduce the risk of infection that may cause or exacerbate lymphoedema. \n\nEnsure that people with breast cancer who develop lymphoedema have prompt access to a specialist lymphoedema service. \n\nFor a short explanation of why the committee made the 2018 recommendation and how it might affect practice, see the rationale and impact section on lymphoedema\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: management of the positive axilla.\n\nLoading. Please wait.\n\n## Arm and shoulder mobility\n\nEnsure breast care units have documented local guidelines in place for postoperative physiotherapy that have been agreed with the physiotherapy department. Guidelines should cover:\n\ndetails of the upper limb exercises to be carried out after surgical or radiotherapy interventions\n\nsituations where the exercises should be tailored for individual circumstances and needs\n\nwho should give information and instructions, and at what points in the person's care this should happen\n\nhow healthcare staff can best deliver information about the exercises. \n\nGive people who are going to have surgery or radiotherapy for breast cancer instructions and information on upper limb exercises before their treatment begins:\n\nexplain the benefits of doing the exercises\n\nexplain when the exercises should be started\n\nensure the information is in a format suitable for the person to take away to refer to later\n\nanswer any questions the person may have on the exercises, or how to perform them\n\ngive details about who to contact if more information is needed.Also see the section on communication in the NICE guideline on patient experience in adult NHS services. \n\nPreoperatively identify people who are having surgery for breast cancer as being at high risk of developing shoulder problems if they have any of the following factors:\n\nany pre-existing shoulder conditions, such as:\n\n\n\nhistory of shoulder surgery\n\nshoulder trauma injury (fracture or shoulder dislocation)\n\nfrozen shoulder\n\nosteoarthritis or rheumatoid arthritis affecting the shoulder\n\nnon-specific shoulder pain\n\nstiffness\n\ndecreased function\n\n\n\ntheir BMI is over 30\xa0kg/m2\n\nthey have axillary node clearance planned\n\nthey have radiotherapy to the axilla or supraclavicular nodes planned. \n\nAfter surgery, if a person with breast cancer needs previously unplanned axillary node clearance or radiotherapy to the axilla or supraclavicular nodes, identify them as being at high risk. \n\nOffer supervised support when performing upper limb exercises to people who have been identified as being at high risk of developing shoulder problems after surgery for breast cancer (see recommendation\xa01.12.7 for assessment). \n\nConsider supervised support when performing upper limb exercises for people who:\n\nare having surgery and have not been identified as being at high risk of developing shoulder problems (as defined by the criteria in recommendation\xa01.12.7), but who may still benefit from supervised support or\n\nare having radiotherapy without surgery. \n\nEnsure supervised support for upper limb exercises:\n\nis available as either individual, group or virtual support, depending on the person's circumstances, needs and preferences\n\nis tailored to the person's needs (for example, modifying exercises for people with more complex needs)\n\nincludes checking that the person is performing the activity correctly\n\nis delivered by physiotherapy staff members or other appropriately trained allied health professionals. \n\nRefer people to the physiotherapy department for individual assessment and treatment if they report a persistent reduction in arm and shoulder mobility after breast cancer surgery or radiotherapy. \n\nFor a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on arm and shoulder mobility\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: strategies for reducing arm and shoulder problems after breast cancer surgery or radiotherapy.\n\nLoading. Please wait.\n\n## Menopausal symptoms\n\nOffer women information and counselling about the possibility of early menopause and menopausal symptoms associated with breast cancer treatment. \n\nStop systemic hormone replacement therapy (HRT) in women who are diagnosed with breast cancer. \n\nDo not routinely offer HRT (including oestrogen/progestogen combination) to women with menopausal symptoms and a history of breast cancer. [2009, amended 2023]In June 2023, this was an off-label use of HRT, and HRT is contraindicated in women with a history of breast cancer. See NICE's information on prescribing medicines.\n\nIn exceptional circumstances, offer HRT to women with severe menopausal symptoms and a history of breast cancer after a discussion of the associated risks. [2009, amended 2023]In June 2023, this was an off-label use of HRT, and HRT is contraindicated in women with a history of breast cancer. See NICE's information on prescribing medicines.\n\nConsider selective serotonin reuptake inhibitor (SSRI) antidepressants for women with breast cancer for relieving menopausal symptoms, particularly hot flushes, but not for those taking tamoxifen. For guidance on safe prescribing of antidepressants (such as SSRIs) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. [2009, amended 2018]In June 2023, this was an off-label use of SSRIs. See NICE's information on prescribing medicines.\n\nDo not offer soy (isoflavone), red clover, black cohosh, vitamin\xa0E or magnetic devices to treat vasomotor symptoms in women with breast cancer. [2009, amended 2023]\n\n# Follow-up\n\n## Follow-up imaging\n\nOffer annual mammography for 5\xa0years to all people who have had or are being treated for breast cancer, including DCIS. For women, continue annual mammography past 5\xa0years until they enter the NHS Breast Screening Programme (NHSBSP) in England or the Breast Test Wales Screening Programme (BTWSP) in Wales. [2009, amended 2023]\n\nDo not perform mammography of the ipsilateral soft tissues after mastectomy. \n\nDo not routinely use ultrasound or MRI for post-treatment surveillance in people who have had treatment for invasive breast cancer or DCIS. [2009, amended 2023]\n\n## Clinical follow-up\n\nEnsure all people who have had treatment for breast cancer have an agreed, written care plan, recorded in their notes by a named healthcare professional (or professionals) from the multidisciplinary team. Give a copy to the person and to their GP. The plan should include:\n\ndesignated named healthcare professionals\n\ndates for review of any adjuvant therapy\n\ndetails of surveillance mammography\n\nsigns and symptoms to look out for and seek advice on\n\ncontact details for immediate referral to specialist care\n\ncontact details for support services, for example, support for people with lymphoedema. [2009, amended 2023]\n\n# Lifestyle\n\nAdvise people who have had or are being treated for breast cancer that a healthy lifestyle is associated with a lower risk of recurrence, and that this should include:\n\nachieving and maintaining a healthy weight (see the NICE guidelines on preventing excess weight gain and obesity)\n\nlimiting alcohol intake to below 5\xa0units per week\n\nregular physical activity (see the NICE guideline on physical activity for adults). \n\nFor guidance on smoking cessation, see the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. \n\nFor a short explanation of why the committee made the 2018 recommendations and how they might affect practice, see the rationale and impact section on lifestyle\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: lifestyle.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Upper limb exercises\n\nUpper limb exercises predominantly focus on gentle shoulder range-of-movement exercises and stretches aimed at regaining full and pain-free range of movement of the shoulder following breast cancer surgery and/or radiotherapy. The term can also refer to exercises that progress onto strengthening the shoulder and arm.", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\n# Surgery to the breast\n\nWhat is the optimum tumour-free margin width after breast-conserving surgery for women with ductal carcinoma in situ (DCIS) and invasive breast cancer? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on surgery to the breast\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: surgery to the breast.\n\nLoading. Please wait.\n\n# Adjuvant bisphosphonate therapy\n\nWhich groups of people with early and locally advanced breast cancer would benefit from the use of adjuvant bisphosphonates? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on adjuvant bisphosphonate therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: adjuvant bisphosphonates.\n\nLoading. Please wait.\n\n# Breast reconstruction\n\nWhat are the long-term outcomes for breast reconstruction in women having radiotherapy to the chest wall? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on breast reconstruction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: postmastectomy radiotherapy.\n\nLoading. Please wait.\n\n# Neoadjuvant endocrine therapy in premenopausal women\n\nIs neoadjuvant endocrine therapy safe in premenopausal women with early breast cancer? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on neoadjuvant endocrine therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer.\n\nLoading. Please wait.\n\n# Neoadjuvant endocrine therapy in postmenopausal women\n\nIs there a benefit for neoadjuvant endocrine therapy in postmenopausal women with early breast cancer? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on neoadjuvant endocrine therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer.\n\nLoading. Please wait.\n\n# Neoadjuvant treatment\n\nWhat are the indications for postmastectomy radiotherapy after neoadjuvant chemotherapy? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on radiotherapy after neoadjuvant chemotherapy.\n\nFull details of the evidence and the committee's discussion are in evidence review J: neoadjuvant treatment of early and locally advanced breast cancer.\n\nLoading. Please wait.\n\n# Strategies to reduce arm and shoulder problems\n\nWhat is the most effective and cost-effective way of delivering the intervention (for example, type of physiotherapy or exercise, mode of delivery, number of sessions) to reduce arm and shoulder problems after breast cancer surgery or radiotherapy, and what is the acceptability of the intervention for different groups, such as:\n\nwomen, men, trans people and non-binary people\n\npeople from minority ethnic family backgrounds\n\npeople with learning disabilities or cognitive impairment, or physical disabilities, or both\n\nneurodiverse people? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on arm and shoulder mobility\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: strategies for reducing arm and shoulder problems after breast cancer surgery or radiotherapy.\n\nLoading. Please wait.\n\n# Adherence and satisfaction for interventions to reduce arm and shoulder problems\n\nWhat is the adherence to, and satisfaction with, different intervention formats (for example, individual, group, virtual, and face to face) to reduce arm and shoulder problems after breast cancer surgery or radiotherapy, and what is the impact of greater adherence on effectiveness for different groups, such as:\n\nwomen, men, trans people and non-binary people\n\npeople from minority ethnic family backgrounds\n\npeople with learning disabilities or cognitive impairment, or physical disabilities, or both\n\nneurodiverse people? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on arm and shoulder mobility\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: strategies for reducing arm and shoulder problems after breast cancer surgery or radiotherapy.\n\nLoading. Please wait.\n\n# Effectiveness of 26\xa0Gy in 5 fractions over 1\xa0week regimen in people receiving breast reconstruction\n\nWhat is the effectiveness of radiotherapy given in 26\xa0Gy in 5 fractions over 1\xa0week compared with 40\xa0Gy in 15 fractions over 3\xa0weeks in people with early or locally advanced invasive breast cancer who are offered breast reconstruction? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on dose fractionation of external beam radiotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: effectiveness of different external beam hypofractionation radiotherapy regimens in people with early-stage or locally advanced invasive breast cancer.\n\nLoading. Please wait.\n\n# Effectiveness of 26\xa0Gy in 5 fractions over 1\xa0week regimen in people receiving nodal irradiation\n\nWhat is the effectiveness of radiotherapy given in 26\xa0Gy in 5 fractions over 1\xa0week compared with 40\xa0Gy in 15 fractions over 3\xa0weeks in people with early or locally advanced invasive breast cancer who are also offered nodal irradiation? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on dose fractionation of external beam radiotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: effectiveness of different external beam hypofractionation radiotherapy regimens in people with early-stage or locally advanced invasive breast cancer.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Providing information and psychological support\n\nRecommendations\xa01.2.3 and 1.2.4\n\n## Why the committee made the recommendations\n\nThe committee agreed, based on their clinical expertise, that continued improvement in breast cancer survival as well as post-diagnosis quality of life needs ongoing research into new or refined treatment options to allow further optimisation of care.\n\nPeople having treatment for breast cancer should be advised about options for preserving their fertility, so the existing NICE guideline on this topic was cross-referred to.\n\n## How the recommendations might affect practice\n\nRecruitment into clinical trials wherever possible is already standard practice, so the recommendation is unlikely to result in a change in practice.\n\nDiscussion of fertility options is already standard practice, so the recommendation is unlikely to result in a change in practice.\n\nReturn to recommendations\n\n# Surgery to the breast\n\nRecommendations\xa01.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nThere was some evidence that there was a reduced risk of ductal carcinoma in situ (DCIS) local recurrence if tissue margins were greater than 0\xa0mm, so the committee recommended further surgery (re-excision or mastectomy) to extend the margins if needed. Although there was no consistent evidence about tissue margins for invasive breast cancer, the committee agreed that further surgery should be offered.\n\nThe committee agreed that complete excision of the tumour with clear margins was essential for the high-quality care of people with DCIS or invasive breast cancer.\n\nAlthough there was evidence that aiming for wider margins reduced local recurrence, this did not improve overall survival. In addition, aiming for wider margins could lead to some people having unnecessary extra surgery. Given this uncertainty, the committee agreed the importance of personalised care and discussion to decide whether further surgery is needed.\n\nThere was not enough evidence to clearly define an optimum margin width between 0\xa0mm and 2\xa0mm to minimise local recurrence rates and minimise further surgery. So, the committee agreed that this was an important topic for further research and made a recommendation for research on the optimum tumour‑free margin width after surgery to the breast.\n\n## How the recommendations might affect practice\n\nThe rates of further surgery currently vary across the country. Although the committee noted that the recommendations will reinforce current best practice, there may be some centres that will need to amend their practice in order to follow these recommendations.\n\nReturn to recommendations\n\n# Evaluation and management of a positive axillary lymph node\n\nRecommendations\xa01.4.7 to 1.4.10\n\n## Why the committee made the recommendations\n\nThere was no new evidence that led the committee to change from the existing recommended practice (as recommended in the previous NICE guideline CG80) of:\n\noffering axillary clearance to people with preoperatively pathologically proven involvement of the axillary lymph nodes\n\nnot offering axillary treatment after primary surgery to people with isolated tumour cells in their sentinel lymph nodes.\n\nThe committee agreed that current evidence shows that further axillary treatment after primary surgery does not improve survival for people with micrometastases and there are risks such as lymphoedema, so further treatment should not be offered to this population. There were unclear benefits and risks of further axillary treatment after primary surgery in people with only 1 or 2 sentinel lymph node macrometastases who have had breast-conserving surgery and have been advised to have whole-breast radiotherapy and systemic therapy, so the committee agreed that the risks and benefits of further treatment should be discussed with this group.\n\nStudies of neoadjuvant therapy were excluded from the evidence review.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations will result in a minor change in practice because some centres currently use mainly surgery and may not use radiotherapy. In addition, more time may need to be factored in to plan and deliver radiotherapy treatment.\n\nReturn to recommendations\n\n# Breast reconstruction\n\nRecommendations\xa01.5.2 to 1.5.5\n\n## Why the committee made the recommendations\n\nThere was not much good evidence, but the committee agreed that the main benefits of immediate breast reconstruction compared with delayed reconstruction are improved aesthetic satisfaction, improved symmetry, improved health-related quality of life, lower overall rates of complications and a reduced need for further surgery. The committee agreed that in some circumstances, there are advantages to delayed reconstruction compared with immediate reconstruction (for example, reduced mastectomy flap loss and capsular contracture). Therefore, delayed reconstruction should also be an option for women who wish to have a reconstruction after mastectomy. The committee also agreed that the option of no reconstruction should also be discussed, because this may be the preferred option for some women.\n\nIn addition, although radiotherapy can impact on outcomes after breast reconstruction, there was no consistent evidence for worse outcomes between radiotherapy delivered after immediate reconstructions compared with radiotherapy before delayed reconstructions. Therefore, the committee agreed that immediate reconstruction should be offered regardless of plans for chest-wall radiotherapy.\n\nThere is little evidence regarding longer-term outcomes and different types of reconstruction. Because of this, the committee agreed that more research is needed to understand whether immediate breast reconstruction or delayed breast reconstruction is better in women who may need postmastectomy radiotherapy. So, they made a recommendation for research on long‑term outcomes for breast reconstruction in women having radiotherapy to the chest wall.\n\n## How the recommendations might affect practice\n\nThe recommendations may result in a substantial change in practice because many centres do not routinely offer immediate breast reconstruction to all women (especially those who have been advised to have radiotherapy). The impact will depend on how many immediate reconstructions are already carried out. In addition, the uptake of immediate breast reconstruction will also depend on women's preferences. There may be cost savings associated with immediate reconstructions because fewer surgical procedures are needed (reconstruction is done at the same time as mastectomy and there are lower rates of additional symmetrisation surgery).\n\nReturn to recommendations\n\n# Predictive factors\n\nRecommendations\xa01.6.1, 1.6.3 and 1.6.5\n\n## Why the committee made the recommendations\n\nThere was not enough good evidence, so the committee agreed, using a formal consensus scoring system and their knowledge and experience, that progesterone receptor (PR) status should be assessed for all invasive breast cancers because:\n\nit will help when tailoring adjuvant therapy\n\nit will reduce delays in starting treatment\n\nif people are already having testing at this stage, their PR status can be assessed without them having to wait for additional test results.\n\nThe committee also agreed that oestrogen receptor (ER), PR and human epidermal growth factor receptor 2 (HER2) status assessments should be requested simultaneously at the time of initial diagnosis to ensure that results are available at the initial preoperative multidisciplinary team meeting (as well as the postoperative meeting). This will avoid delays and the need for additional discussions.\n\n## How the recommendations might affect practice\n\nMost people with invasive breast cancer have PR testing in current practice, although it is not always performed at diagnosis. The recommendations should reduce variation in practice and delays in starting treatment, and the need for pathology results to be discussed at more than 1 multidisciplinary meeting, so may lead to a small cost saving.\n\nReturn to recommendations\n\n# Adjuvant therapy planning\n\nRecommendations\xa01.6.8 and 1.6.9\n\n## Why the committee made the recommendations\n\nGood evidence showed that the prognostic tool PREDICT is an accurate tool to estimate prognosis and the benefits of treatment in most people.\n\n## How the recommendations might affect practice\n\nThe committee agreed that most healthcare professionals already use the PREDICT tool, so this recommendation will not mean a big change in practice.\n\nReturn to recommendations\n\n# Ovarian function suppression\n\nRecommendations\xa01.7.4 and 1.7.5\n\n## Why the committee made the recommendations\n\nThere was evidence that ovarian function suppression increased overall survival when combined with tamoxifen, and that women who have had chemotherapy benefited more. However, ovarian function suppression did not improve disease-free survival. In addition, it induces a temporary menopause and can worsen the menopausal symptoms seen with tamoxifen.\n\nGiven the limited evidence of benefits and the side effects of the treatment, the committee agreed that healthcare professionals should discuss the potential benefits and risks with women. This will help women decide which treatment is right for them.\n\n## How the recommendations might affect practice\n\nThere is variation among centres in the use of ovarian function suppression, so the recommendations should lead to greater consistency and improve access to the treatment, even though not all women will wish to have it. There will be an increase in required resources for centres that do not currently provide ovarian function suppression because additional appointments will be needed to administer the medication and monitor side effects. However, this was not anticipated to be a substantial cost increase because of the number of centres already offering ovarian function suppression. Further, increased costs will be at least partially offset by improvements in survival outcomes.\n\nReturn to recommendations\n\n# Extended endocrine therapy\n\nRecommendations\xa01.7.6 to 1.7.9\n\n## Why the committee made the recommendations\n\nGood evidence showed that switching to an aromatase inhibitor after 5\xa0years of tamoxifen improved disease-free survival compared with postmenopausal women who had only received tamoxifen for 5\xa0years, with the benefits being greater in those women who had a greater risk of disease recurrence.\n\nThe evidence showed no benefit in terms of disease-free survival or overall survival from continuing tamoxifen beyond 5\xa0years. However, some of the studies on tamoxifen were conducted in the 1980s and may not be relevant to current practice. In the committee's experience, continuing tamoxifen can be beneficial for some women.\n\nHowever, evidence showed that being on endocrine therapy for more than 5\xa0years can increase the risk of problems such as endometrial cancer, osteoporosis, toxicity and phlebitis. The committee agreed that people will often prioritise survival even if this means they will have a reduced quality of life, but that people need to be informed about the possible benefits and risks so they can make a choice.\n\nBecause of the risk of problems with taking endocrine therapy for more than 5\xa0years, the committee agreed that healthcare professionals should discuss the potential benefits and risks with women to help them make an informed choice about treatment, based on their own risk factors.\n\n## How the recommendations might affect practice\n\nSome centres already review treatment at 5\xa0years and continue endocrine therapy with tamoxifen or an aromatase inhibitor when it could benefit women. Because a large number of women will be affected by these recommendations, the resource impact will be large for centres that are not currently providing treatment after 5\xa0years.\n\nReturn to recommendations\n\n# Endocrine therapy for ductal carcinoma in situ\n\nRecommendations\xa01.7.10 to 1.7.12\n\n## Why the committee made the recommendations\n\nThere was good evidence that tamoxifen after breast-conserving surgery for ER-positive DCIS improved disease-free survival and reduced rates of local recurrence in women who did not have radiotherapy. Because of their concerns about over-treatment, the committee agreed that women who were at higher risk (those who should have had radiotherapy, but who did not receive it) would benefit more. There was no evidence available for aromatase inhibitors; however, the committee agreed they would likely produce similar improvements in disease-free survival and reductions in local recurrence as tamoxifen. Therefore, the committee recommended endocrine therapy, rather than specifically tamoxifen.\n\nThe committee agreed that the benefits and risks of endocrine therapy should be discussed with the woman because of the potential treatment-related complications, such as menopausal symptoms, and the impact on family planning.\n\n## How the recommendations might affect practice\n\nOffering endocrine therapy after initial treatment of DCIS will be a change of practice because it is not currently routinely offered to these women. However, because of the small number of people with DCIS who will not receive radiotherapy, and the low cost of the medicines, the committee agreed that the impact will not be significant.\n\nReturn to recommendations\n\n# Adjuvant chemotherapy for invasive breast cancer\n\nRecommendations\xa01.8.1 to 1.8.3\n\n## Why the committee made the recommendations\n\nThere was good evidence of improved survival when taxanes are added to anthracycline-based chemotherapy in people with node-positive and node-negative breast cancer. In both groups, the benefits and risks of treatment should be discussed because of the potential side effects associated with taxanes. Three-weekly docetaxel was identified as a regimen with potentially more toxicity than weekly or fortnightly paclitaxel.\n\n## How the recommendations might affect practice\n\nThese recommendations may result in a substantial change in practice because of increased taxane use, particularly for people with node-negative breast cancer and comorbidities.\n\nIn addition, there will be an increase in weekly and fortnightly chemotherapy regimens being offered (for people who cannot tolerate 3‑weekly regimens). These regimens have a higher cost because they are more resource intensive, and may affect capacity in chemotherapy services.\n\nReturn to recommendations\n\n# Biological therapy\n\nRecommendation\xa01.8.5\n\n## Why the committee made the recommendation\n\nThere was evidence that adjuvant trastuzumab can improve disease-free survival and overall survival in some people with T1a and T1b HER2-positive invasive breast cancer who were treated with adjuvant trastuzumab and chemotherapy. However, only a small number of people will benefit from this treatment and, because trastuzumab can cause heart problems, it is important to avoid offering it to people who do not need it. Because of this, the committee agreed that adjuvant trastuzumab should be an option for women with T1a and T1b tumours rather than a standard treatment.\n\nCombined chemotherapy and trastuzumab was not found to be cost effective when compared with chemotherapy alone. However, the committee agreed that it was more appropriate to compare combined chemotherapy and trastuzumab with no treatment because these are the strategies that are likely to be used in clinical practice. Because it is the HER2 positivity that increases risk of recurrence for people with small (T1a and T1b) tumours, it does not make sense from a clinical perspective to not treat the component that is increasing risk (that is, trastuzumab treatment for HER2 positivity). Further, the effect of chemotherapy alone in the economic model may be overestimated because the data may not fully reflect the population under consideration.\n\n## How the recommendation might affect practice\n\nCurrently, T1 tumours are not routinely treated with adjuvant trastuzumab, so this recommendation will lead to a change in practice. However, the committee agreed that the number of additional people having treatment would be small, so the impact on current practice would be minor and unlikely to require a substantial increase in resources.\n\nReturn to recommendation\n\n# Adjuvant bisphosphonate therapy\n\nRecommendations\xa01.9.1 to 1.9.3\n\n## Why the committee made the recommendations\n\nThere was good evidence that treatment with sodium clodronate and zoledronic acid improved disease-free and overall survival in postmenopausal women with node-positive invasive breast cancer.\n\nThere was little evidence of benefit for other bisphosphonates. The committee recommended considering zoledronic acid or sodium clodronate treatment for other high-risk populations (such as postmenopausal women with node-negative invasive breast cancer and a high risk of recurrence), based on the evidence that sodium clodronate has overall survival benefits in mixed populations.\n\nAlthough there is evidence that intravenous (IV) bisphosphonates have a higher risk of osteonecrosis of the jaw, oral bisphosphonates have a higher risk of gastrointestinal problems. There is also a risk of atypical femoral fractures and osteonecrosis of the external auditory canal with bisphosphonates. Because each drug and regimen has different risks, the potential benefits and risks should be discussed with women to help them make an informed choice.\n\nThere was little evidence on survival, particularly for premenopausal women on ovarian suppression, those with node-positive or node-negative disease, and those with positive or negative oestrogen or progestogen statuses. There was not enough evidence to make a recommendation relating to the use of adjuvant bisphosphonates in premenopausal women. The committee agreed that further research is needed to determine the long-term survival benefits and the groups of people most likely to benefit from adjuvant bisphosphonates. So, they made a recommendation for research on groups of people who would benefit from the use of adjuvant bisphosphonates.\n\nThe committee did not look at the evidence relating to the use of bisphosphonates for bone health or for the use of baseline dual-energy X-ray absorptiometry (DEXA) scanning, so did not make any new recommendations.\n\n## How the recommendations might affect practice\n\nBisphosphonates are not consistently offered as adjuvant treatment, so this recommendation may lead to an increase in prescribing.\n\nGPs may need to monitor people taking oral bisphosphonates, but this is likely to be an annual review so would not have a large workload impact. However, people may make more GP visits if they have side effects from bisphosphonate treatment.\n\nThe committee agreed that IV bisphosphonates would usually be administered at the same time as chemotherapy drugs for the first 6\xa0months of treatment, so this would not result in extra hospital visits for this period. After that, extra visits for administration and monitoring may be needed.\n\nReturn to recommendations\n\n# Radiotherapy techniques\n\nRecommendations\xa01.10.1 and 1.10.2\n\n## Why the committee made the recommendations\n\nThere was good evidence that radiotherapy to the internal mammary nodes reduced locoregional recurrence and improved survival. However, the committee took into account the potential for lung and heart toxicity, so recommended using a radiotherapy technique that minimises this risk.\n\nThere was evidence that deep inspiratory breath-hold radiotherapy techniques reduce the mean radiotherapy heart dose for adults with left-sided invasive breast cancer receiving whole-breast radiotherapy. The committee did not identify any harms. There was also evidence that deep inspiration breath-hold radiotherapy techniques did not reduce the target coverage of whole-breast radiotherapy.\n\nThere was no evidence about the use of deep inspiration breath-hold radiotherapy techniques for people with right-sided breast cancer, so the committee did not make separate recommendations for this subgroup.\n\n## How the recommendations might affect practice\n\nUsing a radiotherapy technique that minimises the dose to the lung and heart is likely to need a change in practice for many centres. There will be some impact on resources in order to implement this recommendation because additional training will be needed, and local protocols will need developing. However, the long-term impact on resources will be minimal: some additional planning time will be needed but there is no impact on the length or number of radiotherapy sessions.\n\nCurrently, deep inspiratory breath-hold radiotherapy techniques are not routinely offered to people with invasive breast cancer having whole-breast radiotherapy. However, the committee noted that the Royal College of Radiologists has produced consensus statements that advise using this technique, and that many centres already offer it. The recommendation will ensure consistent practice and ensure that people can access the best care.\n\nReturn to recommendations\n\n# Radiotherapy after breast-conserving surgery\n\nRecommendations\xa01.10.3 to 1.10.8\n\n## Why the committee made the recommendations\n\nThere is evidence that whole-breast radiotherapy after breast-conserving surgery reduces the risk of recurrence and increases overall survival. It also decreases rates of depression and anxiety.\n\nHowever, because the risk of breast cancer recurring at 5\xa0years is very low and there are harms associated with radiotherapy, the benefits of radiotherapy for women with a very low risk of recurrence are less certain. For these women, the committee agreed that healthcare professionals should fully discuss the benefits and risks with women before a decision is made.\n\nGood evidence showed that partial-breast radiotherapy led to similar results to whole-breast radiotherapy after breast-conserving surgery in women with a low risk of local recurrence. In addition, it may have fewer treatment-related adverse effects. There was evidence for multicatheter interstitial brachytherapy, but this was not recommended because it is not currently available in England.\n\n## How the recommendations might affect practice\n\nMost women are already offered radiotherapy after breast-conserving surgery so this reflects current practice, but more time may be needed to discuss the balance of benefits and risks with women.\n\nThe committee was aware that current practice for external beam partial-breast radiotherapy after breast-conserving surgery is based on the Royal College of Radiologists' 2016 consensus statement, so there would be no change to recommended practice.\n\nReturn to recommendations\n\n# Radiotherapy after mastectomy\n\nRecommendations\xa01.10.10 to 1.10.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that adjuvant postmastectomy radiotherapy should be offered to people who have macroscopically node-positive invasive breast cancer or have involved resection margins. This is because the evidence showed a beneficial effect on survival and local recurrence. Although the evidence was limited and the committee acknowledged that radiotherapy is associated with lung and cardiac morbidity, they concluded that for this group of women, the benefits of radiotherapy outweigh the harms.\n\nThere was evidence of a beneficial effect of postmastectomy radiotherapy on local recurrence and overall survival for people with node-negative invasive breast cancer. However, the committee agreed that there was a risk of over-treatment if all people with node-negative invasive breast cancer received postmastectomy radiotherapy. Therefore, the committee recommended that adjuvant postmastectomy radiotherapy should be considered for people with node-negative T3 or T4 invasive breast cancer. There was no evidence for this specific subgroup, but they would be considered at increased risk of recurrence and mortality relative to smaller, node-negative invasive breast cancers because of the size of the tumour.\n\nThe committee agreed that radiotherapy after mastectomy should not be offered to women with early invasive breast cancer who are at low risk of local recurrence (for example, most women who are lymph node-negative) because the evidence showed limited benefit in survival and local recurrence.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations will reinforce current practice, so there would be little change in practice.\n\nReturn to recommendations\n\n# Dose fractionation of external beam radiotherapy\n\nRecommendations\xa01.10.13 to 1.10.16\n\n## Why the committee made the recommendations\n\nThe committee noted that most centres use regimens of either 40\xa0Gy in 15 fractions or 26\xa0Gy in 5 fractions. However, there was variation between centres in which external beam hypofractionation regimen they used.\n\nThe evidence compared a number of different external beam hypofractionation regimens, but the committee focused on the evidence from 2 randomised controlled trials (RCTs) that compared clinical effectiveness and safety, and a cost-effectiveness analysis, of the 2 hypofractionation regimens that are established in current practice (40\xa0Gy in 15 fractions over 3\xa0weeks and 26\xa0Gy in 5 fractions over 1\xa0week). High-quality to very low-quality evidence showed that the effects of both external beam hypofractionation regimens were comparable, with no clinically important differences between treatment arms for all-cause mortality, breast cancer-related mortality or disease recurrence. Economic evidence showed the 26\xa0Gy in 5 fractions as an effective use of NHS resources compared with 40\xa0Gy in 15 fractions and supported its use in current practice. In addition, the committee noted that in their experience, most people preferred to attend radiotherapy appointments over the course of 1\xa0week rather than over 3\xa0weeks for practical reasons related to fewer trips to the hospital (for example, reduced travelling time and costs, less time off work or from caring responsibilities). The committee recognised how the COVID-19 pandemic had also impacted current practice and had accelerated the change to implement the shorter 26\xa0Gy in 5 fractions regimen.\n\nThe evidence showed that there was a higher incidence of outcomes related to clinician-assessed adverse events at 5\xa0years and quality-of-life measurements (related to harder or firmer breasts) for people who were given 26\xa0Gy in 5 fractions compared with 40\xa0Gy in 15 fractions. However, with the exception of a quality-of-life outcome related to swollen breasts, the differences in effect between the 2 regimens were not clinically significant. The committee agreed that in their experience, 26\xa0Gy in 5 fractions is widely accepted by people, despite the small risk of increased adverse events. After taking into account the benefits of a shorter regimen and the impact of the adverse events, the committee recommended the use of 26\xa0Gy in 5 fractions for people having partial-breast, whole-breast or chest-wall radiotherapy, without nodal irradiation, after breast-conserving surgery or mastectomy.\n\nThe committee noted that the evidence presented was from populations who were receiving whole-breast radiotherapy. There was no evidence for people who are at lower risk of disease recurrence than those included in the evidence base and who are offered partial-breast radiotherapy because of their reduced risk. However, the committee agreed that, considering the already lower risk for this population, the findings of 26\xa0Gy in 5 fractions in the higher-risk population could be extrapolated to also cover the lower-risk population. The committee also noted that the decision over whether someone has partial-breast or whole-breast radiotherapy can change based on clinical judgement and assessment of the treatment area. As such, the committee agreed that if partial-breast radiotherapy were excluded, the recommendations would not be in line with current practice and may disadvantage a large group of people.\n\nThe committee recognised that there may be circumstances when 40\xa0Gy in 15 fractions would be more suitable than 26\xa0Gy in 5 fractions. For example, the committee noted that, in their clinical experience, some groups of people, such as those with a high BMI or fibromyalgia, may experience a greater number of acute adverse events from the 5-fraction regimen (for example, skin reactions, breast oedema or pain). Therefore, some people may prefer the 15-fraction regimen. The committee also noted that the number of people in the studies who had undergone breast reconstruction surgery was small, and it was difficult to determine the most effective hypofractionation regimen for this group. The 15-fraction regimen may also be used for those whose dosimetry is outside that used in the FAST-Forward trial. The committee highlighted the importance of shared decision making for these groups and ensuring that people are aware of the benefits and risks of each treatment option. As such, the committee made a recommendation that 40\xa0Gy in 15 fractions over 3\xa0weeks should be considered for some groups of people, and that its use should be agreed between the person and their care team.\n\nThe committee discussed the eligibility criteria for some of the trials in the evidence and noted that people who received nodal radiotherapy were excluded from the main study populations. They highlighted that there are particular concerns around adverse effects such as lymphoedema for people who received regional lymph node irradiation. The committee acknowledged that future trials and the FAST-Forward nodal sub-study results may address some of these concerns, but until further evidence is available the 40\xa0Gy in 15 fractions regimen should continue to be used for this group.\n\nThere was limited evidence comparing the 2 hypofractionation regimens in people having breast reconstruction or having regional lymph node irradiation. As such, the committee developed recommendations for research on people having breast reconstruction (including autologous breast reconstruction, but particularly implant-based reconstruction) and people having regional lymph node irradiation. These should provide clinicians with an increased understanding of how effective the 26\xa0Gy in 5 fractions regimen is for these groups in future.\n\n## How the recommendations might affect practice\n\nThe recommendations may reduce variation in practice, with most people being offered 26\xa0Gy in 5 fractions rather than 40\xa0Gy in 15 fractions. This is already current practice in many centres and will not have a major impact for those centres. In those centres where 26\xa0Gy in 5 fractions is not yet current practice, there will be significant cost savings and capacity will be released for more appointments. For places where 40\xa0Gy in 15 fractions is used more routinely, these recommendations may increase the number of people who are offered 26\xa0Gy over 5 fractions. This will reduce the treatment duration and the costs associated with treatment.\n\nReturn to recommendations\n\n# Radiotherapy to nodal areas\n\nRecommendation\xa01.10.23\n\n## Why the committee made the recommendation\n\nThere was good evidence that radiotherapy to the internal mammary nodes reduced locoregional recurrence and improved survival. However, the committee took into account the potential for lung and heart toxicity, and agreed the importance of using a radiotherapy technique that minimises this risk.\n\n## How the recommendation might affect practice\n\nThis recommendation is likely to need a change in practice for many centres. There will be some impact on resources in order to implement this recommendation because additional training will be needed, and local protocols will need developing. However, the long-term impact on resources will be minimal: some additional planning time will be needed but there is no impact on the length or number of radiotherapy sessions.\n\nReturn to recommendation\n\n# Neoadjuvant chemotherapy\n\nRecommendations\xa01.11.1 to 1.11.3\n\n## Why the committee made the recommendations\n\nThere was good evidence to say that having chemotherapy before surgery (neoadjuvant chemotherapy) enables some women to have breast-conserving surgery who would otherwise have had total removal of their breast. The committee agreed that the response to neoadjuvant therapy could help guide the choice of subsequent adjuvant therapy.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations would not result in a major change in practice because neoadjuvant chemotherapy is already offered in many centres. These recommendations will help improve consistency in practice.\n\nReturn to recommendations\n\n# Neoadjuvant chemotherapy regimens\n\nRecommendations\xa01.11.4 and 1.11.5\n\n## Why the committee made the recommendations\n\nThere was evidence that platinum-containing neoadjuvant chemotherapy regimens can improve pathological complete response rate and breast conservation rate in people with triple-negative invasive breast cancer. However, the committee took into account that platinum-containing regimens can cause anaemia, thrombocytopenia, neutropenia and febrile neutropenia, as well as bone marrow problems and renal problems in older people. The committee agreed that healthcare professionals should have a full discussion with people about the benefits and risks of these regimens.\n\nThere was no evidence on people with the BRCA germline mutation, so the committee did not make separate recommendations for this subgroup.\n\n## How the recommendations might affect practice\n\nCurrently, platinum-containing neoadjuvant chemotherapy is not routinely offered to people with triple-negative early and locally advanced breast cancer, although the committee was aware that some centres may offer it. The recommendations will therefore bring a change in practice and will make practice more consistent across the NHS. The committee estimated that approximately 30% to 40% of people receiving neoadjuvant chemotherapy may be affected by the recommendations.\n\nReturn to recommendations\n\n# Neoadjuvant endocrine therapy\n\nRecommendations\xa01.11.6 to 1.11.8\n\n## Why the committee made the recommendations\n\nFor postmenopausal women, there was some evidence that breast conservation rates, changes in tumour size and overall survival are the same with neoadjuvant endocrine therapy and neoadjuvant chemotherapy. Endocrine therapy is safer and has fewer side effects than chemotherapy, but there was not enough evidence to recommend endocrine therapy over chemotherapy for every woman. The committee agreed that healthcare professionals should discuss the potential benefits and risks with women to help them decide which treatment is right for them and that more research is needed to say whether neoadjuvant endocrine therapy is as effective as neoadjuvant chemotherapy.\n\nThe evidence for premenopausal women showed that neoadjuvant chemotherapy was more effective than endocrine therapy, but that endocrine therapy may be effective in some women. However, some women may prefer endocrine therapy because it is safer and has fewer side effects. Because of this, the committee agreed that healthcare professionals should discuss the potential benefits and risks with women to help them decide which treatment is right for them. The committee agreed that more research is needed on the long-term safety of neoadjuvant endocrine therapy, and to identify which premenopausal women will benefit from it. So, they made recommendations for research on the safety of neoadjuvant endocrine therapy in premenopausal women and postmenopausal women with early breast cancer.\n\n## How the recommendations might affect practice\n\nNeoadjuvant endocrine therapy is already being used, although there may be an increase in the number of people being offered it.\n\nReturn to recommendations\n\n# Radiotherapy after neoadjuvant chemotherapy\n\nRecommendations\xa01.11.10 to 1.11.13\n\n## Why the committee made the recommendations\n\nThere was not enough evidence to recommend subgroups of women in whom postmastectomy radiotherapy could be safely omitted after neoadjuvant chemotherapy. Therefore, the committee agreed that the recommendations for postmastectomy radiotherapy among people who have not received neoadjuvant chemotherapy applied to this population.\n\nPeople with node-negative T4 cancer were not included in this review because they are covered by the recommendation from the previous guideline which has been retained.\n\nWomen who respond well to neoadjuvant chemotherapy may derive less benefit from radiotherapy, but the committee agreed that further research was required to determine if the risks of radiotherapy outweighed the benefits in some women. So, they made a recommendation for research on the indications for postmastectomy radiotherapy after neoadjuvant chemotherapy.\n\n## How the recommendations might affect practice\n\nThe committee noted that decisions about postmastectomy radiotherapy after neoadjuvant chemotherapy are currently based on pretreatment investigations, so there will be no change to practice.\n\nReturn to recommendations\n\n# Lymphoedema\n\nRecommendation\xa01.12.2\n\n## Why the committee made the recommendation\n\nGood evidence showed that there is no increased risk of lymphoedema associated with maintaining exercise levels after axillary intervention, so the committee agreed that people should not restrict or avoid physical activity.\n\nAlthough the evidence was limited and mixed, the committee concluded that there is no consistent evidence of increased risk of lymphoedema associated with air travel, travel to hot countries, manicures, hot-tub use, sports injuries, or medical procedures on the treated side.\n\n## How the recommendation might affect practice\n\nAdvice about preventing lymphoedema is already being provided as part of routine care, so there is unlikely to be much change in practice. However, the recommendation will lead to greater consistency in the advice offered. It should also reduce inequality and improve the quality of standard care if people who have had axillary treatment need immunisations or elective procedures.\n\nReturn to recommendation\n\n# Arm and shoulder mobility\n\nRecommendations\xa01.12.5 to 1.12.12\n\n## Why the committee made the recommendations\n\nThe committee noted there was very little high-quality evidence for any of the outcomes, and most of the evidence was low to very low quality. The committee agreed that they did not feel confident in making recommendations based on low-quality evidence from mainly single studies. Therefore, they used their clinical knowledge and experience alongside high-quality evidence from 1 UK-based RCT to support their decision making. This evidence showed improved outcomes with a physiotherapy-led structured supervised exercise programme in addition to usual care for reduction of pain, quality-of-life improvement and adherence to arm and shoulder exercises in people with a higher risk of developing shoulder problems. The trial provided all participants with information leaflets about exercises to help with arm and shoulder mobility after breast cancer surgery. This reflects standard practice in the UK, and the committee agreed it was important to reflect this advice in the recommendations. The recommendations also highlight that instructions on upper limb exercises and information should be discussed, explained and clarified with the person before radiotherapy begins, as the exercises should have been well established before starting treatment. The committee recommended that this should also happen before surgery.\n\nThe committee were aware that instructions on upper limb exercises are not always given out by someone who is a specialist in physiotherapy (for example, breast care nurses), so they also recommended that breast care units have documented local guidelines in place that include details about who and how to deliver this information effectively. They thought it was important that the information included details on when the exercises should be started. For most people, this will be the day after surgery, but it may be later for others, such as those who have certain surgical procedures (for example, free flap reconstruction or implant reconstruction) where exercising the day after surgery could interfere with their recovery. Exercises should be tailored to each person based on their needs (for example, comorbidities and side effects of cancer treatment), but for the majority of patients, a standard programme of upper limb exercises will be suitable. The committee also agreed it was important that instructions on upper limb exercises should be available in other formats to be accessible to people with different needs (for example, video or large print and various languages). There are already recommendations on communication in the NICE guideline on patient experience in adult NHS services, so a link to this was included as part of the recommendation.\n\nBased on the effectiveness of the intervention in the UK-based trial, the committee agreed that people who met the same criteria as those included in the trial should be identified as being at higher risk of developing shoulder problems. These people should then be offered supervised support to apply the exercises. The baseline shoulder identification of someone as high risk of developing shoulder problems could be done by a member of the clinical team (for example, a clinical nurse specialist) and could be done by looking at a person's medical history and asking the person if they have experienced any of the issues listed in the recommendation (for example, asking if they have stiffness of their shoulder or if the function of their shoulder is reduced). The evidence did not specify that these risk factors were only relevant to the affected side and the committee noted that people should be considered at high risk if they have any of the pre-existing shoulder conditions in the contralateral side. It was also highlighted that for most people radiotherapy to the axilla or supraclavicular nodes is decided before surgery. However, for some people this may be decided after postoperative pathology review. For this reason, they recommended that people who are identified as needing radiotherapy to the axilla or supraclavicular nodes after surgery should also be considered as being at higher risk of developing shoulder problems. This ensures that people would not miss out from supervised support if the need for radiotherapy was not identified before surgery.\n\nThe committee also agreed that, in their experience, other people having surgery for breast cancer who did not meet the high-risk criteria in the recommendations could benefit from supervised support. This includes, for example, people with learning or sensory disabilities, which could adversely affect their ability to carry out exercises without supervision and make them more likely to develop shoulder problems as a result. It also includes people having breast cancer surgery who have side effects from additional cancer treatments or who have other commonly performed adjunct surgeries in addition to breast cancer surgery, as well as people who are having radiotherapy without surgery.\n\nBased on their experience, the committee recommended that supervised support should be delivered by a physiotherapy staff member or other appropriately trained allied health professional (for example, an occupational therapist). This should include checking the performance of the exercises and correcting them as needed. The committee agreed that people may not feel confident in translating written exercise instructions into physical movement, so would benefit from having advice on whether they are doing them correctly. This support also allows people who might be experiencing difficulties with both the exercises and with shoulder function to be identified early after radiotherapy or surgery. It will also ensure that people are able to receive the full benefit from the exercises, and may increase adherence if someone is confident they are doing the exercises correctly.\n\nThe committee also agreed supervised exercises and physiotherapy support should be available in different formats (for example, virtual or group sessions), and be tailored to individual circumstances and needs (for example, mental health and learning needs) to help with adherence. There was no evidence about interventions delivered virtually, but the committee agreed to recommend this option as it may help to reduce health inequalities and address access options for people where other interventions are not locally available. The committee were aware that some people may not be able to access virtual services for a range of reasons, such as a lack of access to suitable devices, living in areas of poor connectivity and difficulties with using the technology. However, including virtual services in the recommendations should not provide barriers to these people accessing support, as they can be given the option of face-to-face sessions. The committee also highlighted that face-to-face physiotherapy may be more beneficial for people with complex needs or those at higher risk (for example, people from minority ethnic family backgrounds, people with disabilities, neurodiverse people, those who experience physical difficulties with recovery or rehabilitation) because they might need specific instructions and feedback.\n\nThe committee were mindful that, while their experience shows that virtual interventions are beneficial, there is a lack of evidence for this and that there was no evidence on whether the format of the intervention (individual, group, virtual, and face to face) impacted adherence or satisfaction. Therefore, the committee took this into account when making recommendations for research to cover this gap in the evidence.\n\nThere was limited, low-quality evidence on long-term outcomes and no evidence on outcomes for different population subgroups, such as people from minority ethnic family backgrounds, disabled people and neurodiverse people. The committee also noted that lower-quality evidence comparing interventions was not conclusive. The committee discussed the importance of understanding the most effective and cost-effective way of delivering the intervention (for example, type of physiotherapy or exercise, mode of delivery, number of sessions) and the acceptability of such intervention for different populations, and made a recommendation for research on the most effective and cost-effective way of delivering the intervention to address this gap in the evidence.\n\nThe committee also recommended that people should be referred to the physiotherapy department if they report a persistent reduction in arm and shoulder mobility after breast cancer treatment. This allows people to continue to seek support if it is needed. The committee noted that the recommendation for research into adherence to, and satisfaction with, different intervention formats will gather evidence about the long-term effects of strategies to reduce arm and shoulder problems, and this may reduce the number of people who have to be referred to the physiotherapy department in future.\n\n## How the recommendations might affect practice\n\nThere may be an increase in the number of people having supervised exercise or physiotherapy support after breast cancer surgery or before radiotherapy. However, if this could be delivered virtually (individual or group), it is likely to have a lower impact on NHS resources than in‑person 1‑to‑1 sessions and could free up resources for face-to-face interventions for those for whom virtual services are not appropriate or if there are barriers to them accessing virtual services.\n\nReturn to recommendations\n\n# Lifestyle\n\nRecommendations\xa01.14.1 and 1.14.2\n\n## Why the committee made the recommendations\n\nThere was evidence that both dietary changes (reducing fat intake and maintaining a healthy weight) and physical activity increase survival in people with invasive breast cancer.\n\nThere was some evidence that cancer recurrence is more likely in people who drink more than 3 or 4 alcoholic drinks per week or 6\xa0g of alcohol per day. This equates to approximately 5\xa0units of alcohol per week.\n\nThere was no evidence that smoking cessation reduces recurrence of breast cancer, although the view of the committee was that smoking cessation should always be recommended to people with breast cancer.\n\n## How the recommendations might affect practice\n\nThe committee discussed that many NHS services would already be advising people with breast cancer about the importance of a healthy lifestyle, and how they can make lifestyle changes to reduce the risk of recurrence. The committee agreed that these recommendations will help to direct conversations towards effective lifestyle changes. There will be no impact on resources because these discussions were already happening, and most of the lifestyle changes will be 'self-care' and implemented by patients themselves.\n\nReturn to recommendations", 'Context': "This guideline updates and replaces the NICE guideline on early and locally advanced breast cancer (CG80). This is because new evidence was identified in surveillance that could affect recommendations, and has already changed clinical practice in some locations.\n\nPeople with symptoms that could be caused by breast cancer are referred by their GP to designated breast clinics in local hospitals (see NICE's guideline on suspected cancer: recognition and referral). In addition, eligible women are invited for screening through the NHS Breast Screening Programme (NHSBSP) in England or the Breast Test Wales Screening Programme (BTWSP) in Wales. For most people, whether they are referred following breast screening or after presentation to a GP, diagnosis in the breast clinic is made by triple assessment (clinical assessment, mammography and/or ultrasound imaging, and core biopsy and/or fine-needle aspiration cytology). It is best practice to carry out these assessments at the same visit (see NICE's cancer service guideline on improving outcomes in breast cancer).\n\nBreast cancer is the most common cancer in the UK, with approximately 54,000 new cases of invasive disease and around 7,000 new cases of pre-invasive (in situ) disease diagnosed annually. Most of the breast cancers occur in women, but just over 300 men in the UK are also diagnosed with invasive breast cancer every year.\n\nMost breast cancers are diagnosed at an early stage and are therefore potentially curable with modern treatments. Survival rates have improved over recent decades with almost 90% of women diagnosed with breast cancer surviving their disease for 5\xa0or more years after diagnosis. Survival is, however, linked to the stage of the disease at diagnosis; only 15% of women diagnosed with stage\xa0IV disease are alive at 5\xa0years. Breast cancer remains the leading cause of death in women aged 35 to 49\xa0years and is second only to lung cancer as the leading cause of cancer death in all women.\n\nThe main risk factor for breast cancer is being female; the disease is 100 times less common in men. It is also a disease of ageing, with the risk of breast cancer increasing with increasing age. Some breast cancers are linked to lifestyle factors that include obesity, alcohol intake and use of hormone replacement therapy, whereas other lifestyle factors, including physical activity and breastfeeding, protect against breast cancer. About 5% of breast cancers are because of inherited mutations in high-risk genes such as BRCA1/2 and\xa0p53.\n\nAdults (18 and over) with:\n\nnewly diagnosed invasive adenocarcinoma of the breast of any size (T1 to T4), with or without spread to locoregional lymph nodes (N0 to N3) and with no distant metastases (M0)\n\nnewly diagnosed ductal carcinoma in situ (DCIS)\n\nPaget's disease of the breast.\n\nAdults (18 and over) with:\n\ninvasive adenocarcinoma of the breast and distant metastases (clinical or pathological M1)\n\nrare breast tumours (for example, angiosarcoma or lymphoma)\n\nbenign breast tumours (for example, fibroadenoma)\n\nphyllodes tumour\n\nlocally recurrent breast cancer or DCIS\n\nlobular carcinoma in situ (LCIS)\n\nno personal history of breast cancer and an increased risk of breast cancer due to family history."}	https://www.nice.org.uk/guidance/ng101	This guideline covers diagnosing and managing early and locally advanced breast cancer. It aims to help healthcare professionals offer the right treatments to people, taking into account the person's individual preferences.
8b167ca2fb46a9479651ef28d8a8c5fc358d1053	nice	Dabrafenib plus trametinib for treating BRAF V600 mutation-positive advanced non-small-cell lung cancer	Dabrafenib plus trametinib for treating BRAF V600 mutation-positive advanced non-small-cell lung cancer Evidence-based recommendations on dabrafenib (Tafinlar) plus trametinib (Mekinist) for BRAF V600 mutation-positive advanced non-small-cell lung cancer in adults. # Recommendations Dabrafenib plus trametinib is recommended as an option for treating BRAF V600 mutation-positive advanced non-small-cell lung cancer (NSCLC) in adults, only if: it is used as first-line treatment of advanced stage cancer, and the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with dabrafenib plus trametinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard treatment options for BRAF V600 mutation-positive advanced NSCLC include pembrolizumab plus platinum chemotherapy. During the COVID‑19 pandemic, dabrafenib plus trametinib has also been available in the NHS as an interim treatment. The results of a clinical trial of dabrafenib plus trametinib suggest that it shrinks tumours and increases how long people live and how long they live before their condition gets worse. But the results are uncertain because the number of people in the trial was small. Because dabrafenib plus trametinib was not directly compared with any other treatment, several potential sources of evidence for the comparator, pembrolizumab plus chemotherapy, were assessed. But the clinical-effectiveness results from all these sources are uncertain. Because the clinical-effectiveness results are uncertain, the cost-effectiveness estimates are also uncertain. Also, there was no cost-effectiveness evidence provided for dabrafenib plus trametinib used after other treatments have not worked in people with advanced NSCLC. After taking into account the available evidence and impact of the uncertainty, the cost-effectiveness estimates are likely to be within the range that NICE considers an acceptable use of NHS resources in people with untreated advanced NSCLC. So, dabrafenib plus trametinib is recommended for this group.# Information about dabrafenib plus trametinib # Marketing authorisation indication Dabrafenib (Tafinlar, Novartis) in combination with trametinib (Mekinist, Novartis) is indicated for 'the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for dabrafenib. # Price Dabrafenib costs £1,400 per 28‑pack of 75 mg capsules and trametinib costs £4,800 per 30‑pack of 2 mg tablets (excluding VAT; BNF online accessed February 2023). The company has a commercial arrangement. This makes dabrafenib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Novartis, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical management ## Clinical need People with advanced non-small-cell lung cancer (NSCLC) generally have a poor prognosis. The symptoms can be hard to treat and distressing for the person with the condition and their family members. There are targeted treatments for NSCLC that have other specific driver mutations. But there is currently no NICE-recommended option specifically for NSCLC that is positive for a BRAF V600 mutation. A BRAF mutation is present in around 1% to 3% of lung cancers. Around half of all BRAF mutations are V600 mutations, and most BRAF V600 mutations are V600E mutations. BRAF V600 mutations are commonly found in older people and in people with a history of smoking. The clinical expert submission explained that chemotherapy and immunotherapy may not be tolerated in this group of people. The clinical expert said that existing treatment options (see section 3.2) are associated with substantial healthcare resource use, and many chemotherapy day units have long waiting times. The committee considered that BRAF V600 mutation-positive advanced NSCLC has a substantial effect on quality of life, and that there is an unmet need for a new treatment option. ## Treatment options There are several NICE-recommended first-line treatments for advanced NSCLC. These include immunotherapy or chemotherapy alone, and immunotherapy plus platinum chemotherapy. Some treatment options depend on the PD‑L1 status of the cancer. Dabrafenib plus trametinib has been available in the NHS since 2020 as a COVID‑19 interim treatment, and the NHS England Cancer Drugs Fund clinical lead (from here, the Cancer Drugs Fund lead) explained that it was being used first line and second line. It was made available because having an oral therapy reduces the need to travel to chemotherapy day centres, and because existing chemotherapy regimens carried a risk of immunosuppression. People with BRAF V600 mutation-positive advanced NSCLC would generally have it first line (see section 3.15). Second-line treatment options for advanced disease include chemotherapy or immunotherapy alone. What is used depends on previous treatment, as well as tumour PD‑L1 status. If people have not had dabrafenib plus trametinib first line, they can have it second line. The committee noted the various treatment options available. ## Comparators The company selected pembrolizumab plus platinum chemotherapy as the only comparator at first line. It said that this is the most common treatment used when dabrafenib plus trametinib is not available or cannot be used because of delays in BRAF V600 mutation testing results. This was confirmed by the clinical expert. They also noted that pembrolizumab or atezolizumab alone may be used first line when the cancer has a high PD‑L1 status, or when chemotherapy is not suitable. The Cancer Drugs Fund lead agreed and said that only a relatively small proportion of people would have pembrolizumab or atezolizumab alone. The committee noted that the company had submitted clinical efficacy evidence for dabrafenib plus trametinib second line. But it had not provided a comparison of cost effectiveness of dabrafenib plus trametinib with standard care second line. The committee concluded that pembrolizumab plus platinum chemotherapy was the most appropriate comparator for dabrafenib plus trametinib first line. # Clinical effectiveness ## BRF113928 clinical trial The clinical-effectiveness evidence for dabrafenib plus trametinib came from BRF113928. This was a single-arm trial with 6 years of follow up. It included people with stage 4 NSCLC with a BRAF V600E mutation. Trial outcomes included overall response rate, progression-free survival and overall survival. The trial was done across a range of sites in 11 countries, including 5 sites in England. There were 3 cohorts, with cohorts B and C having dabrafenib plus trametinib. Cohort C included 36 people who had had no anticancer therapies for metastatic disease. In cohort C, the overall response rate was 64%, comprising a complete response rate (cancer not detectable) of 6%, and a partial response rate (cancer had shrunk by 30% and not spread) of 58%. The median progression-free survival in cohort C was 11 months (95% confidence interval 7 to 15 months) and the median overall survival was 17 months (95% CI 12 to 40 months). The clinical-effectiveness evidence from cohort C was used to inform the cost-effectiveness evidence for dabrafenib plus trametinib as first-line treatment (see section 3.5 and sections 3.7 and 3.8). Cohort B included 57 people whose cancer had relapsed after at least 1 previous line of platinum-based chemotherapy. The company did not submit any cost-effectiveness evidence for using dabrafenib plus trametinib at second line, so the clinical-effectiveness evidence for cohort B was not discussed in detail at the committee meeting (see section 3.15). The EAG noted that the median progression-free survival and overall survival was similar in cohorts B and C of the trial. The committee acknowledged the evidence on the clinical effectiveness of dabrafenib plus trametinib but noted that it was from a single-arm trial with few people. ## FLATIRON database There were no studies directly comparing dabrafenib plus trametinib with pembrolizumab plus platinum chemotherapy in BRAF V600 mutation-positive advanced NSCLC. So, the company explored various sources of clinical-effectiveness evidence for pembrolizumab plus platinum chemotherapy in this population. FLATIRON is a large cancer database in the US that collects survival data on a range of cancers and their mutations. The company's initial analysis compared cohort C of BRF113928 (see section 3.4) with a subpopulation from FLATIRON who had BRAF V600E mutation-positive advanced NSCLC and had had first-line pembrolizumab plus platinum chemotherapy. The number of people in this population is considered to be academic in confidence by the company and cannot be reported here. The FLATIRON population was adjusted using the inverse probability of treatment weighting method to better match the cohort C population. The EAG noted that the FLATIRON data was from a BRAF V600 mutation-positive population, which is the target population for this appraisal. But it also noted that the estimates of comparative efficacy from this analysis were uncertain, and the committee considered that it was not possible to draw robust conclusions from the comparison. This was because the populations in both FLATIRON and cohort C of BRF113928 were small, and FLATIRON had limited follow up. The committee considered that the comparison of cohort C from BRF113928 with the BRAF V600E population from FLATIRON was one of a range of plausible evidence sources to inform clinical efficacy in the model. But, after considering other sources (see sections 3.7 to 3.9) it concluded that FLATIRON was not its preferred evidence source for decision making. ## Assumption of clinical equivalence The company also presented an analysis in which it assumed clinical equivalence between dabrafenib plus trametinib and pembrolizumab plus platinum chemotherapy. It said that, in the absence of trial evidence, this was a conservative assumption. The EAG considered that this assumption was not supported by any evidence. It also noted that it would ignore the effects of subsequent treatments, which would differ between the 2 treatments. The committee concluded that assuming clinical equivalence between dabrafenib plus trametinib and pembrolizumab plus chemotherapy was one of a range of plausible assumptions to inform clinical efficacy in the model. But without evidence to support it, this was not its preferred assumption for decision making. ## KEYNOTE-189 The company also presented data from KEYNOTE‑189. This was a phase 3 double-blind randomised controlled trial comparing pembrolizumab plus pemetrexed plus platinum chemotherapy with pemetrexed plus platinum chemotherapy. It included 616 people with advanced or metastatic NSCLC not specific to any driver mutation. Also, KEYNOTE‑189 did not collect data on BRAF mutation status. The EAG suggested that KEYNOTE‑189 could be used to inform the efficacy of the pembrolizumab plus platinum chemotherapy comparator in the model. The company presented analyses using BRF113928 to inform efficacy of dabrafenib plus trametinib, and KEYNOTE‑189 to inform efficacy of pembrolizumab plus platinum chemotherapy. The committee questioned whether the KEYNOTE‑189 data was generalisable to this appraisal because most people in the trial would not have had a BRAF V600 mutation. It asked if there was any prognostic value of BRAF V600 mutations. The clinical expert explained that BRAF V600 mutations can be associated with poorer prognosis after surgery or chemotherapy, but it is less certain if this is the case after immunotherapy. The Cancer Drugs Fund lead considered that BRAF mutations were unlikely to be a strong prognostic factor. Both they and the clinical expert agreed that people in BRF113928 would have been eligible for inclusion in KEYNOTE‑189. Also, they considered that KEYNOTE‑189 was an appropriate data source to inform comparator efficacy in the model. The committee considered that there was mixed evidence on the prognostic value of BRAF mutation status. But it agreed that it had not seen any strong evidence to suggest that it was a strong prognostic factor for progression-free or overall survival. It considered that it would have preferred to see evidence taken from a BRAF V600-specific population for both arms. It noted that KEYNOTE‑189 was one of a range of plausible evidence sources to inform clinical efficacy in the model. The committee concluded that KEYNOTE‑189 was an acceptable source of comparator clinical efficacy evidence and was its preferred evidence source for decision making. ## Matching-adjusted indirect comparison with KEYNOTE-189 The company did a matching-adjusted indirect comparison (MAIC) to compare the clinical effectiveness of dabrafenib plus trametinib, using data from cohort C of BRF113928, with pembrolizumab plus platinum chemotherapy, using data from KEYNOTE‑189. In the MAIC, the BRF113928 population was statistically adjusted to better resemble the KEYNOTE‑189 population. This was to predict the treatment effect if dabrafenib plus trametinib had been evaluated in the KEYNOTE‑189 population. The results of the MAIC are considered to be confidential by the company and cannot be reported here. The EAG noted that the MAIC reduced the effect of cross-trial differences. But it noted that it also reduced the effective sample size of BRF113928 and so increased the uncertainty around the effect estimates. It also observed that the relative effects generated by the MAIC applied to the KEYNOTE‑189 population rather than to the BRF113928 population, which was not representative of the target population for this appraisal. So, the results from the MAIC may not be generalisable to the target population. Finally, the EAG noted that the MAIC was unanchored (which means that the trials had no common comparator). So, the results assumed that all effect modifiers and prognostic factors had been identified. Because the company presented no evidence on potential unidentified covariates, the EAG considered that the results of the MAIC were uncertain. For these reasons, the EAG presented 2 base cases, 1 informed by the MAIC and 1 informed by a naive (no adjustments made) unanchored comparison between BRF113928 and KEYNOTE‑189. The committee understood that a naive comparison would include a larger sample size. But it acknowledged that any estimates of comparative efficacy would still be uncertain because of cross-trial differences and possible confounding. It also recalled that it had seen no strong evidence that BRAF mutation status had prognostic value (see section 3.7). The committee considered that the results of the MAIC were uncertain, and noted that there were other plausible sources of clinical evidence (see sections 3.5 and 3.6). But it concluded that, despite the limitations of the MAIC, it was an acceptable source of comparator clinical efficacy evidence and was the committee's preferred source for decision making. ## Covariates included in the MAIC The company did a sensitivity analysis to explore the impact of adjusting for different covariates on the results of the MAIC. The base-case analysis adjusted for covariates that were found to be statistically significantly associated with either progression-free or overall survival. It also included covariates that were used in MAICs in NICE's technology appraisal guidance on tepotinib, osimertinib, lorlatinib and ceritinib. The company also did a sensitivity analysis that only adjusted for the covariates found to be statistically significantly associated with progression-free or overall survival, and that did not adjust for the covariates identified in the previous appraisals. Both the company and the EAG selected the base-case MAIC for their base-case analyses. The committee understood that the sensitivity MAIC had a larger effective sample size and less uncertain effect estimates than the base-case MAIC. It noted that the sample size of the BRF113928 trial was already small. So, it concluded that it was preferable to use the sensitivity MAIC of BRF113928 with KEYNOTE‑189 to inform the clinical efficacy of dabrafenib plus trametinib and pembrolizumab plus platinum chemotherapy. # Economic model ## Company's modelling approach The company used a partitioned survival model with 3 health states: progression free, progressed disease and death, to model the cost effectiveness of dabrafenib plus trametinib and pembrolizumab plus platinum chemotherapy. The efficacy of the intervention and comparator was informed by the base-case MAIC (see sections 3.8 and 3.9). In the model, health state utilities were taken from NICE's technology appraisal guidance on pralsetinib and adverse event disutilities from NICE's technology appraisal guidance on tepotinib. The committee considered that this approach was in line with other similar appraisals in the same disease area, but noted that there was uncertainty around the modelling of an intravenous infusion disutility (see section 3.13). The committee concluded that the model was acceptable for decision making. # Costs ## Costs of BRAF V600 mutation testing The company did not include the costs of genomic testing of tumours for a BRAF V600 mutation in its base case because it said this test is already done in routine practice. The EAG questioned whether BRAF V600 mutation testing was routine practice, given that its continued use would depend on NICE recommending dabrafenib plus trametinib. The Cancer Drugs Fund lead explained that dabrafenib plus trametinib has been widely used in practice to treat advanced NSCLC since 2020 (see section 3.2) and that the BRAF V600 test is in NHS England's National Genomic Test Directory and is considered part of routine testing. But the Cancer Drugs Fund lead and the clinical expert noted that there is some variation in access to the testing, and delays in some areas (see section 3.3). The committee concluded that BRAF V600 mutation testing is routine practice and that, in line with NICE methodology, it was not appropriate to include the costs of these tests in the cost-effectiveness analysis. ## Discounting The company chose to model discounting of future costs discretely from the beginning of the second year of the model. The EAG adopted a different approach, choosing to discount costs continuously from the outset of the model. The committee questioned why the company and the EAG had taken different approaches. The EAG explained that, in its approach, the discount rate was updated every cycle. In the company's approach the discount rate was updated annually and no discounting was applied until a full year had elapsed. This placed a greater weight on short-term costs and benefits. The EAG noted that both methods were valid. The company agreed that both methods were appropriate. The committee understood that the choice of discounting method only had a small effect on the cost-effectiveness estimates. It also noted that the EAG's method had been used more frequently in previous NICE technology appraisal models. The committee concluded that it was preferable to model discounting of future costs continuously from the outset of the model. # Utility values ## Modelling intravenous disutility The company modelled a disutility decrement for intravenous infusion of 0.023 per cycle for people having pembrolizumab plus platinum chemotherapy. This value came from a study that assessed the negative effect of having an intravenous infusion on quality of life. The EAG noted that this value was double that which had been applied in the model for a person being hospitalised with pneumonia. It also explained that the study used a method of obtaining a utility estimate that was not in line with NICE's reference case, which specifies that the EQ‑5D should be used. The EAG also noted that it was done in the UK general population, not a NSCLC-specific population. It considered that this decrement was too high and should either be removed completely or reduced. The company modified the decrement so that it was only incurred in every model cycle in which people had had an intravenous infusion, instead of in every model cycle. The EAG did not include a disutility decrement in its base case. The clinical expert considered that it is plausible that intravenous infusions can have a negative effect on health-related quality of life, especially considering the additional appointments that people would need. Also, capacity issues in NHS chemotherapy centres mean that some people may have to wait before having a scheduled intravenous infusion of pembrolizumab plus chemotherapy. This wait could also have a negative effect on health-related quality of life. The Cancer Drugs Fund lead noted that people having an oral treatment would usually still need to travel to the hospital pharmacy to collect the treatment. The patient organisation submission noted that intravenous infusions have a negative impact on quality of life. But it noted that the perceived effect on quality of life was reduced by the anticancer effects of the treatments. The patient organisation submission explained that most people would prefer an oral treatment but also noted that some people may prefer to have an intravenous infusion because this allows them to have a month's treatment in 1 day. The committee considered that most people would be more likely to prefer an oral treatment, but that there would be a smaller number who would choose intravenous treatment options. It noted that in previous appraisals in NSCLC that compared an oral drug with an intravenous-administered comparator, disutility associated with intravenous infusion was rarely modelled explicitly. The committee understood that previous committees had sometimes considered such effects qualitatively when coming to conclusions on cost-effectiveness thresholds. It considered that, while it was plausible that there was a disutility associated with intravenous infusion, the size of the effect was difficult to quantify. It also noted that some people may prefer to have an intravenous infusion. So, the committee concluded that it preferred not to include an explicit modelling of disutility in the base case, but noted that it would consider this as a potentially uncaptured health benefit in its decision making. ## Adherence to oral therapies The EAG noted that there are possible drawbacks to oral therapies when compared with intravenous infusions, such as non-adherence. It noted that these could have a negative and unmodelled effect on efficacy. The company considered that any effect of non-adherence would be included in the model through its effect on progression-free and overall survival in the trial. It considered that it would also be included in the cost calculations, which take into account relative dose intensity. It noted that most instances of non-adherence in the trial were because of dose escalation, or interruption or reduction in response to adverse events. The clinical expert commented that there were minimal drawbacks to oral therapies compared with intravenous infusion, and they expected adherence to be high in practice. The committee concluded that any non-adherence to an oral therapy was adequately accounted for in the cost-effectiveness modelling. # Cost-effectiveness estimates ## Using dabrafenib plus trametinib second line The committee noted that the company had not submitted any cost-effectiveness modelling for using dabrafenib plus trametinib second line. The company said that most people with advanced NSCLC with a BRAF V600 mutation would have dabrafenib plus trametinib first line. It explained that the main reason for people with a BRAF V600 mutation not having dabrafenib plus trametinib at first line is a delay in getting their genomic screening results (see section 3.3). It said that only a few people with a BRAF V600 mutation have delayed screening results and start a treatment other than dabrafenib plus trametinib first line. The company said that delays in testing are being resolved, so it expects that the number of people affected will decrease. The committee noted that the NHS England Blueteq data showed there are some people who are eligible for dabrafenib plus trametinib but who have other therapies for untreated NSCLC. The exact numbers are considered confidential and cannot be reported here. The clinical expert agreed with the company that many of these people would have had other therapies because of genomic testing delays, and that these delays are likely to fall substantially in the coming years. So, they agreed that the second-line population would fall over time. The clinical expert also noted that, for untreated NSCLC, some clinicians may prefer to use immunotherapy and some people may not be able to have dabrafenib plus trametinib because of technical errors. The Cancer Drugs Fund lead confirmed that, at the time of writing, most eligible people have dabrafenib plus trametinib first line. They also noted that dabrafenib plus trametinib appeared to be as effective when used second line as when used first line. The company presented hazard ratios and Kaplan–Meier graphs that compared cohort B (previously treated cancer) of BRF113928 with a subgroup of the FLATIRON database that had a BRAF V600E mutation (see section 3.5) and had chemotherapy second line. The EAG said that the results from cohort B of BRF113928 were broadly similar to those of cohort C. So, it considered that it was feasible that dabrafenib plus trametinib had similar effectiveness when used first or second line. But it noted that the sample numbers included in this analysis were very small and that cohort B had previous treatment with chemotherapy, not immunochemotherapy. So, it considered that the second-line effectiveness of dabrafenib plus trametinib was uncertain. The committee considered that the size of the population having previous treatment was likely to fall substantially. It also noted that it was plausible that dabrafenib plus trametinib was similarly effective when used first and second line. But it had not seen any cost-effectiveness evidence to support using dabrafenib plus trametinib in previously treated NSCLC, so was unable to consider this population further. ## Acceptable ICER NICE's health technology evaluations manual states that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of the technology as an effective use of NHS resources will consider the degree of uncertainty around the ICER and any benefits of the technology that were not captured in the QALY calculations. The committee will be more cautious about recommending a technology if it is less certain about the evidence presented. The committee recalled that the results of the MAIC that informed the cost-effectiveness estimates were very uncertain (see section 3.8). It also recalled that clinicians and people with NSCLC may prefer oral therapies and that there were potential disadvantages associated with an intravenous therapy when compared with an oral therapy, which were not captured in the QALY calculations (see section 3.13). After taking these into account, the committee considered that the maximum acceptable ICER would be at the lower end of the £20,000 to £30,000 range normally considered a cost-effective use of NHS resources. ## Committee's preferred assumptions The committee considered a range of plausible evidence sources to inform clinical efficacy in the model and all of these were associated with substantial uncertainty (see sections 3.5 to 3.9). It concluded that its preferred assumptions for the cost-effectiveness modelling of dabrafenib plus trametinib compared with pembrolizumab plus platinum chemotherapy were to: use KEYNOTE‑189 to inform the efficacy of pembrolizumab plus chemotherapy (see section 3.7) use the sensitivity MAIC with KEYNOTE‑189 to inform the efficacy of dabrafenib plus trametinib and pembrolizumab plus platinum chemotherapy (see section 3.9) model discounting continuously from the model outset (see section 3.12) not include the cost of BRAF V600 mutation testing in the model (see section 3.11) not explicitly model a disutility decrement for intravenous infusion (see section 3.13). ## Cost-effectiveness estimates The committee considered the cost-effectiveness estimates generated by its preferred assumptions. Because there are confidential commercial arrangements for the treatments and comparators, the exact ICERs cannot be reported here. But the committee noted that, after considering the uncertainty in the cost-effectiveness analysis, the most plausible ICER is within the range that NICE usually considers a cost-effective use of NHS resources. # Conclusion ## Recommendation The committee concluded that there was substantial uncertainty in the cost-effectiveness estimates, so considered that the maximum acceptable ICER would be at the lower end of the £20,000 to £30,000 range normally considered a cost-effective use of NHS resources. It considered that when its preferred assumptions are incorporated, the cost-effectiveness estimates for dabrafenib plus trametinib are within what NICE considers a cost-effective use of NHS resources. So, dabrafenib plus trametinib is recommended as an option for treating BRAF V600 mutation-positive advanced NSCLC that has not been treated at the advanced stage.	{'Recommendations': 'Dabrafenib plus trametinib is recommended as an option for treating BRAF\xa0V600 mutation-positive advanced non-small-cell lung cancer (NSCLC) in adults, only if:\n\nit is used as first-line treatment of advanced stage cancer, and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with dabrafenib plus trametinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard treatment options for BRAF\xa0V600 mutation-positive advanced NSCLC include pembrolizumab plus platinum chemotherapy. During the COVID‑19 pandemic, dabrafenib plus trametinib has also been available in the NHS as an interim treatment.\n\nThe results of a clinical trial of dabrafenib plus trametinib suggest that it shrinks tumours and increases how long people live and how long they live before their condition gets worse. But the results are uncertain because the number of people in the trial was small. Because dabrafenib plus trametinib was not directly compared with any other treatment, several potential sources of evidence for the comparator, pembrolizumab plus chemotherapy, were assessed. But the clinical-effectiveness results from all these sources are uncertain.\n\nBecause the clinical-effectiveness results are uncertain, the cost-effectiveness estimates are also uncertain. Also, there was no cost-effectiveness evidence provided for dabrafenib plus trametinib used after other treatments have not worked in people with advanced NSCLC.\n\nAfter taking into account the available evidence and impact of the uncertainty, the cost-effectiveness estimates are likely to be within the range that NICE considers an acceptable use of NHS resources in people with untreated advanced NSCLC. So, dabrafenib plus trametinib is recommended for this group.', 'Information about dabrafenib plus trametinib': "# Marketing authorisation indication\n\nDabrafenib (Tafinlar, Novartis) in combination with trametinib (Mekinist, Novartis) is indicated for 'the treatment of adult patients with advanced non-small cell lung cancer with a BRAF\xa0V600 mutation'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for dabrafenib.\n\n# Price\n\nDabrafenib costs £1,400 per 28‑pack of 75\xa0mg capsules and trametinib costs £4,800 per 30‑pack of 2\xa0mg tablets (excluding VAT; BNF online accessed February\xa02023).\n\nThe company has a commercial arrangement. This makes dabrafenib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Novartis, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## Clinical need\n\nPeople with advanced non-small-cell lung cancer (NSCLC) generally have a poor prognosis. The symptoms can be hard to treat and distressing for the person with the condition and their family members. There are targeted treatments for NSCLC that have other specific driver mutations. But there is currently no NICE-recommended option specifically for NSCLC that is positive for a BRAF\xa0V600 mutation. A BRAF mutation is present in around 1% to 3% of lung cancers. Around half of all BRAF mutations are V600 mutations, and most BRAF\xa0V600 mutations are V600E mutations. BRAF\xa0V600 mutations are commonly found in older people and in people with a history of smoking. The clinical expert submission explained that chemotherapy and immunotherapy may not be tolerated in this group of people. The clinical expert said that existing treatment options (see section\xa03.2) are associated with substantial healthcare resource use, and many chemotherapy day units have long waiting times. The committee considered that BRAF\xa0V600 mutation-positive advanced NSCLC has a substantial effect on quality of life, and that there is an unmet need for a new treatment option.\n\n## Treatment options\n\nThere are several NICE-recommended first-line treatments for advanced NSCLC. These include immunotherapy or chemotherapy alone, and immunotherapy plus platinum chemotherapy. Some treatment options depend on the PD‑L1 status of the cancer. Dabrafenib plus trametinib has been available in the NHS since 2020 as a COVID‑19 interim treatment, and the NHS England Cancer Drugs Fund clinical lead (from here, the Cancer Drugs Fund lead) explained that it was being used first line and second line. It was made available because having an oral therapy reduces the need to travel to chemotherapy day centres, and because existing chemotherapy regimens carried a risk of immunosuppression. People with BRAF\xa0V600 mutation-positive advanced NSCLC would generally have it first line (see section\xa03.15). Second-line treatment options for advanced disease include chemotherapy or immunotherapy alone. What is used depends on previous treatment, as well as tumour PD‑L1 status. If people have not had dabrafenib plus trametinib first line, they can have it second line. The committee noted the various treatment options available.\n\n## Comparators\n\nThe company selected pembrolizumab plus platinum chemotherapy as the only comparator at first line. It said that this is the most common treatment used when dabrafenib plus trametinib is not available or cannot be used because of delays in BRAF\xa0V600 mutation testing results. This was confirmed by the clinical expert. They also noted that pembrolizumab or atezolizumab alone may be used first line when the cancer has a high PD‑L1 status, or when chemotherapy is not suitable. The Cancer Drugs Fund lead agreed and said that only a relatively small proportion of people would have pembrolizumab or atezolizumab alone. The committee noted that the company had submitted clinical efficacy evidence for dabrafenib plus trametinib second line. But it had not provided a comparison of cost effectiveness of dabrafenib plus trametinib with standard care second line. The committee concluded that pembrolizumab plus platinum chemotherapy was the most appropriate comparator for dabrafenib plus trametinib first line.\n\n# Clinical effectiveness\n\n## BRF113928 clinical trial\n\nThe clinical-effectiveness evidence for dabrafenib plus trametinib came from BRF113928. This was a single-arm trial with 6\xa0years of follow up. It included people with stage\xa04 NSCLC with a BRAF V600E mutation. Trial outcomes included overall response rate, progression-free survival and overall survival. The trial was done across a range of sites in 11\xa0countries, including 5\xa0sites in England. There were 3\xa0cohorts, with cohorts\xa0B and\xa0C having dabrafenib plus trametinib. Cohort\xa0C included 36\xa0people who had had no anticancer therapies for metastatic disease. In cohort\xa0C, the overall response rate was 64%, comprising a complete response rate (cancer not detectable) of 6%, and a partial response rate (cancer had shrunk by 30% and not spread) of 58%. The median progression-free survival in cohort\xa0C was 11\xa0months (95% confidence interval [CI] 7\xa0to 15\xa0months) and the median overall survival was 17\xa0months (95%\xa0CI 12\xa0to 40\xa0months). The clinical-effectiveness evidence from cohort\xa0C was used to inform the cost-effectiveness evidence for dabrafenib plus trametinib as first-line treatment (see section 3.5 and sections 3.7 and 3.8). Cohort\xa0B included 57\xa0people whose cancer had relapsed after at least 1\xa0previous line of platinum-based chemotherapy. The company did not submit any cost-effectiveness evidence for using dabrafenib plus trametinib at second line, so the clinical-effectiveness evidence for cohort\xa0B was not discussed in detail at the committee meeting (see section\xa03.15). The EAG noted that the median progression-free survival and overall survival was similar in cohorts\xa0B and C of the trial. The committee acknowledged the evidence on the clinical effectiveness of dabrafenib plus trametinib but noted that it was from a single-arm trial with few people.\n\n## FLATIRON database\n\nThere were no studies directly comparing dabrafenib plus trametinib with pembrolizumab plus platinum chemotherapy in BRAF\xa0V600 mutation-positive advanced NSCLC. So, the company explored various sources of clinical-effectiveness evidence for pembrolizumab plus platinum chemotherapy in this population. FLATIRON is a large cancer database in the US that collects survival data on a range of cancers and their mutations. The company's initial analysis compared cohort\xa0C of BRF113928 (see section\xa03.4) with a subpopulation from FLATIRON who had BRAF\xa0V600E mutation-positive advanced NSCLC and had had first-line pembrolizumab plus platinum chemotherapy. The number of people in this population is considered to be academic in confidence by the company and cannot be reported here. The FLATIRON population was adjusted using the inverse probability of treatment weighting method to better match the cohort\xa0C population. The EAG noted that the FLATIRON data was from a BRAF V600 mutation-positive population, which is the target population for this appraisal. But it also noted that the estimates of comparative efficacy from this analysis were uncertain, and the committee considered that it was not possible to draw robust conclusions from the comparison. This was because the populations in both FLATIRON and cohort\xa0C of BRF113928 were small, and FLATIRON had limited follow up. The committee considered that the comparison of cohort\xa0C from BRF113928 with the BRAF\xa0V600E population from FLATIRON was one of a range of plausible evidence sources to inform clinical efficacy in the model. But, after considering other sources (see sections 3.7 to 3.9) it concluded that FLATIRON was not its preferred evidence source for decision making.\n\n## Assumption of clinical equivalence\n\nThe company also presented an analysis in which it assumed clinical equivalence between dabrafenib plus trametinib and pembrolizumab plus platinum chemotherapy. It said that, in the absence of trial evidence, this was a conservative assumption. The EAG considered that this assumption was not supported by any evidence. It also noted that it would ignore the effects of subsequent treatments, which would differ between the 2\xa0treatments. The committee concluded that assuming clinical equivalence between dabrafenib plus trametinib and pembrolizumab plus chemotherapy was one of a range of plausible assumptions to inform clinical efficacy in the model. But without evidence to support it, this was not its preferred assumption for decision making.\n\n## KEYNOTE-189\n\nThe company also presented data from KEYNOTE‑189. This was a phase\xa03 double-blind randomised controlled trial comparing pembrolizumab plus pemetrexed plus platinum chemotherapy with pemetrexed plus platinum chemotherapy. It included 616\xa0people with advanced or metastatic NSCLC not specific to any driver mutation. Also, KEYNOTE‑189 did not collect data on BRAF mutation status. The EAG suggested that KEYNOTE‑189 could be used to inform the efficacy of the pembrolizumab plus platinum chemotherapy comparator in the model. The company presented analyses using BRF113928 to inform efficacy of dabrafenib plus trametinib, and KEYNOTE‑189 to inform efficacy of pembrolizumab plus platinum chemotherapy. The committee questioned whether the KEYNOTE‑189 data was generalisable to this appraisal because most people in the trial would not have had a BRAF\xa0V600 mutation. It asked if there was any prognostic value of BRAF\xa0V600 mutations. The clinical expert explained that BRAF\xa0V600 mutations can be associated with poorer prognosis after surgery or chemotherapy, but it is less certain if this is the case after immunotherapy. The Cancer Drugs Fund lead considered that BRAF mutations were unlikely to be a strong prognostic factor. Both they and the clinical expert agreed that people in BRF113928 would have been eligible for inclusion in KEYNOTE‑189. Also, they considered that KEYNOTE‑189 was an appropriate data source to inform comparator efficacy in the model. The committee considered that there was mixed evidence on the prognostic value of BRAF mutation status. But it agreed that it had not seen any strong evidence to suggest that it was a strong prognostic factor for progression-free or overall survival. It considered that it would have preferred to see evidence taken from a BRAF\xa0V600-specific population for both arms. It noted that KEYNOTE‑189 was one of a range of plausible evidence sources to inform clinical efficacy in the model. The committee concluded that KEYNOTE‑189 was an acceptable source of comparator clinical efficacy evidence and was its preferred evidence source for decision making.\n\n## Matching-adjusted indirect comparison with KEYNOTE-189\n\nThe company did a matching-adjusted indirect comparison (MAIC) to compare the clinical effectiveness of dabrafenib plus trametinib, using data from cohort\xa0C of BRF113928, with pembrolizumab plus platinum chemotherapy, using data from KEYNOTE‑189. In the MAIC, the BRF113928 population was statistically adjusted to better resemble the KEYNOTE‑189 population. This was to predict the treatment effect if dabrafenib plus trametinib had been evaluated in the KEYNOTE‑189 population. The results of the MAIC are considered to be confidential by the company and cannot be reported here. The EAG noted that the MAIC reduced the effect of cross-trial differences. But it noted that it also reduced the effective sample size of BRF113928 and so increased the uncertainty around the effect estimates. It also observed that the relative effects generated by the MAIC applied to the KEYNOTE‑189 population rather than to the BRF113928 population, which was not representative of the target population for this appraisal. So, the results from the MAIC may not be generalisable to the target population. Finally, the EAG noted that the MAIC was unanchored (which means that the trials had no common comparator). So, the results assumed that all effect modifiers and prognostic factors had been identified. Because the company presented no evidence on potential unidentified covariates, the EAG considered that the results of the MAIC were uncertain. For these reasons, the EAG presented 2\xa0base cases, 1\xa0informed by the MAIC and 1\xa0informed by a naive (no adjustments made) unanchored comparison between BRF113928 and KEYNOTE‑189. The committee understood that a naive comparison would include a larger sample size. But it acknowledged that any estimates of comparative efficacy would still be uncertain because of cross-trial differences and possible confounding. It also recalled that it had seen no strong evidence that BRAF mutation status had prognostic value (see section\xa03.7). The committee considered that the results of the MAIC were uncertain, and noted that there were other plausible sources of clinical evidence (see sections\xa03.5 and 3.6). But it concluded that, despite the limitations of the MAIC, it was an acceptable source of comparator clinical efficacy evidence and was the committee's preferred source for decision making.\n\n## Covariates included in the MAIC\n\nThe company did a sensitivity analysis to explore the impact of adjusting for different covariates on the results of the MAIC. The base-case analysis adjusted for covariates that were found to be statistically significantly associated with either progression-free or overall survival. It also included covariates that were used in MAICs in NICE's technology appraisal guidance on tepotinib, osimertinib, lorlatinib and ceritinib. The company also did a sensitivity analysis that only adjusted for the covariates found to be statistically significantly associated with progression-free or overall survival, and that did not adjust for the covariates identified in the previous appraisals. Both the company and the EAG selected the base-case MAIC for their base-case analyses. The committee understood that the sensitivity MAIC had a larger effective sample size and less uncertain effect estimates than the base-case MAIC. It noted that the sample size of the BRF113928 trial was already small. So, it concluded that it was preferable to use the sensitivity MAIC of BRF113928 with KEYNOTE‑189 to inform the clinical efficacy of dabrafenib plus trametinib and pembrolizumab plus platinum chemotherapy.\n\n# Economic model\n\n## Company's modelling approach\n\nThe company used a partitioned survival model with 3\xa0health states: progression free, progressed disease and death, to model the cost effectiveness of dabrafenib plus trametinib and pembrolizumab plus platinum chemotherapy. The efficacy of the intervention and comparator was informed by the base-case MAIC (see sections\xa03.8 and 3.9). In the model, health state utilities were taken from NICE's technology appraisal guidance on pralsetinib and adverse event disutilities from NICE's technology appraisal guidance on tepotinib. The committee considered that this approach was in line with other similar appraisals in the same disease area, but noted that there was uncertainty around the modelling of an intravenous infusion disutility (see section\xa03.13). The committee concluded that the model was acceptable for decision making.\n\n# Costs\n\n## Costs of BRAF V600 mutation testing\n\nThe company did not include the costs of genomic testing of tumours for a BRAF\xa0V600 mutation in its base case because it said this test is already done in routine practice. The EAG questioned whether BRAF\xa0V600 mutation testing was routine practice, given that its continued use would depend on NICE recommending dabrafenib plus trametinib. The Cancer Drugs Fund lead explained that dabrafenib plus trametinib has been widely used in practice to treat advanced NSCLC since 2020 (see section\xa03.2) and that the BRAF\xa0V600 test is in NHS England's National Genomic Test Directory and is considered part of routine testing. But the Cancer Drugs Fund lead and the clinical expert noted that there is some variation in access to the testing, and delays in some areas (see section\xa03.3). The committee concluded that BRAF\xa0V600 mutation testing is routine practice and that, in line with NICE methodology, it was not appropriate to include the costs of these tests in the cost-effectiveness analysis.\n\n## Discounting\n\nThe company chose to model discounting of future costs discretely from the beginning of the second year of the model. The EAG adopted a different approach, choosing to discount costs continuously from the outset of the model. The committee questioned why the company and the EAG had taken different approaches. The EAG explained that, in its approach, the discount rate was updated every cycle. In the company's approach the discount rate was updated annually and no discounting was applied until a full year had elapsed. This placed a greater weight on short-term costs and benefits. The EAG noted that both methods were valid. The company agreed that both methods were appropriate. The committee understood that the choice of discounting method only had a small effect on the cost-effectiveness estimates. It also noted that the EAG's method had been used more frequently in previous NICE technology appraisal models. The committee concluded that it was preferable to model discounting of future costs continuously from the outset of the model.\n\n# Utility values\n\n## Modelling intravenous disutility\n\nThe company modelled a disutility decrement for intravenous infusion of 0.023 per cycle for people having pembrolizumab plus platinum chemotherapy. This value came from a study that assessed the negative effect of having an intravenous infusion on quality of life. The EAG noted that this value was double that which had been applied in the model for a person being hospitalised with pneumonia. It also explained that the study used a method of obtaining a utility estimate that was not in line with NICE's reference case, which specifies that the EQ‑5D should be used. The EAG also noted that it was done in the UK general population, not a NSCLC-specific population. It considered that this decrement was too high and should either be removed completely or reduced. The company modified the decrement so that it was only incurred in every model cycle in which people had had an intravenous infusion, instead of in every model cycle. The EAG did not include a disutility decrement in its base case. The clinical expert considered that it is plausible that intravenous infusions can have a negative effect on health-related quality of life, especially considering the additional appointments that people would need. Also, capacity issues in NHS chemotherapy centres mean that some people may have to wait before having a scheduled intravenous infusion of pembrolizumab plus chemotherapy. This wait could also have a negative effect on health-related quality of life. The Cancer Drugs Fund lead noted that people having an oral treatment would usually still need to travel to the hospital pharmacy to collect the treatment. The patient organisation submission noted that intravenous infusions have a negative impact on quality of life. But it noted that the perceived effect on quality of life was reduced by the anticancer effects of the treatments. The patient organisation submission explained that most people would prefer an oral treatment but also noted that some people may prefer to have an intravenous infusion because this allows them to have a month's treatment in 1\xa0day. The committee considered that most people would be more likely to prefer an oral treatment, but that there would be a smaller number who would choose intravenous treatment options. It noted that in previous appraisals in NSCLC that compared an oral drug with an intravenous-administered comparator, disutility associated with intravenous infusion was rarely modelled explicitly. The committee understood that previous committees had sometimes considered such effects qualitatively when coming to conclusions on cost-effectiveness thresholds. It considered that, while it was plausible that there was a disutility associated with intravenous infusion, the size of the effect was difficult to quantify. It also noted that some people may prefer to have an intravenous infusion. So, the committee concluded that it preferred not to include an explicit modelling of disutility in the base case, but noted that it would consider this as a potentially uncaptured health benefit in its decision making.\n\n## Adherence to oral therapies\n\nThe EAG noted that there are possible drawbacks to oral therapies when compared with intravenous infusions, such as non-adherence. It noted that these could have a negative and unmodelled effect on efficacy. The company considered that any effect of non-adherence would be included in the model through its effect on progression-free and overall survival in the trial. It considered that it would also be included in the cost calculations, which take into account relative dose intensity. It noted that most instances of non-adherence in the trial were because of dose escalation, or interruption or reduction in response to adverse events. The clinical expert commented that there were minimal drawbacks to oral therapies compared with intravenous infusion, and they expected adherence to be high in practice. The committee concluded that any non-adherence to an oral therapy was adequately accounted for in the cost-effectiveness modelling.\n\n# Cost-effectiveness estimates\n\n## Using dabrafenib plus trametinib second line\n\nThe committee noted that the company had not submitted any cost-effectiveness modelling for using dabrafenib plus trametinib second line. The company said that most people with advanced NSCLC with a BRAF\xa0V600 mutation would have dabrafenib plus trametinib first line. It explained that the main reason for people with a BRAF\xa0V600 mutation not having dabrafenib plus trametinib at first line is a delay in getting their genomic screening results (see section\xa03.3). It said that only a few people with a BRAF\xa0V600 mutation have delayed screening results and start a treatment other than dabrafenib plus trametinib first line. The company said that delays in testing are being resolved, so it expects that the number of people affected will decrease. The committee noted that the NHS England Blueteq data showed there are some people who are eligible for dabrafenib plus trametinib but who have other therapies for untreated NSCLC. The exact numbers are considered confidential and cannot be reported here. The clinical expert agreed with the company that many of these people would have had other therapies because of genomic testing delays, and that these delays are likely to fall substantially in the coming years. So, they agreed that the second-line population would fall over time. The clinical expert also noted that, for untreated NSCLC, some clinicians may prefer to use immunotherapy and some people may not be able to have dabrafenib plus trametinib because of technical errors. The Cancer Drugs Fund lead confirmed that, at the time of writing, most eligible people have dabrafenib plus trametinib first line. They also noted that dabrafenib plus trametinib appeared to be as effective when used second line as when used first line. The company presented hazard ratios and Kaplan–Meier graphs that compared cohort\xa0B (previously treated cancer) of BRF113928 with a subgroup of the FLATIRON database that had a BRAF\xa0V600E mutation (see section\xa03.5) and had chemotherapy second line. The EAG said that the results from cohort\xa0B of BRF113928 were broadly similar to those of cohort\xa0C. So, it considered that it was feasible that dabrafenib plus trametinib had similar effectiveness when used first or second line. But it noted that the sample numbers included in this analysis were very small and that cohort\xa0B had previous treatment with chemotherapy, not immunochemotherapy. So, it considered that the second-line effectiveness of dabrafenib plus trametinib was uncertain. The committee considered that the size of the population having previous treatment was likely to fall substantially. It also noted that it was plausible that dabrafenib plus trametinib was similarly effective when used first and second line. But it had not seen any cost-effectiveness evidence to support using dabrafenib plus trametinib in previously treated NSCLC, so was unable to consider this population further.\n\n## Acceptable ICER\n\nNICE's health technology evaluations manual states that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of the technology as an effective use of NHS resources will consider the degree of uncertainty around the ICER and any benefits of the technology that were not captured in the QALY calculations. The committee will be more cautious about recommending a technology if it is less certain about the evidence presented. The committee recalled that the results of the MAIC that informed the cost-effectiveness estimates were very uncertain (see section\xa03.8). It also recalled that clinicians and people with NSCLC may prefer oral therapies and that there were potential disadvantages associated with an intravenous therapy when compared with an oral therapy, which were not captured in the QALY calculations (see section\xa03.13). After taking these into account, the committee considered that the maximum acceptable ICER would be at the lower end of the £20,000 to £30,000 range normally considered a cost-effective use of NHS resources.\n\n## Committee's preferred assumptions\n\nThe committee considered a range of plausible evidence sources to inform clinical efficacy in the model and all of these were associated with substantial uncertainty (see sections\xa03.5 to 3.9). It concluded that its preferred assumptions for the cost-effectiveness modelling of dabrafenib plus trametinib compared with pembrolizumab plus platinum chemotherapy were to:\n\nuse KEYNOTE‑189 to inform the efficacy of pembrolizumab plus chemotherapy (see section\xa03.7)\n\nuse the sensitivity MAIC with KEYNOTE‑189 to inform the efficacy of dabrafenib plus trametinib and pembrolizumab plus platinum chemotherapy (see section\xa03.9)\n\nmodel discounting continuously from the model outset (see section\xa03.12)\n\nnot include the cost of BRAF V600 mutation testing in the model (see section\xa03.11)\n\nnot explicitly model a disutility decrement for intravenous infusion (see section\xa03.13).\n\n## Cost-effectiveness estimates\n\nThe committee considered the cost-effectiveness estimates generated by its preferred assumptions. Because there are confidential commercial arrangements for the treatments and comparators, the exact ICERs cannot be reported here. But the committee noted that, after considering the uncertainty in the cost-effectiveness analysis, the most plausible ICER is within the range that NICE usually considers a cost-effective use of NHS resources.\n\n# Conclusion\n\n## Recommendation\n\nThe committee concluded that there was substantial uncertainty in the cost-effectiveness estimates, so considered that the maximum acceptable ICER would be at the lower end of the £20,000 to £30,000 range normally considered a cost-effective use of NHS resources. It considered that when its preferred assumptions are incorporated, the cost-effectiveness estimates for dabrafenib plus trametinib are within what NICE considers a cost-effective use of NHS resources. So, dabrafenib plus trametinib is recommended as an option for treating BRAF V600 mutation-positive advanced NSCLC that has not been treated at the advanced stage."}	https://www.nice.org.uk/guidance/ta898	Evidence-based recommendations on dabrafenib (Tafinlar) plus trametinib (Mekinist) for BRAF V600 mutation-positive advanced non-small-cell lung cancer in adults.
55a7ca5426ef5cb68810cc42e321ef572cdfcb7b	nice	Tixagevimab plus cilgavimab for preventing COVID-19	Tixagevimab plus cilgavimab for preventing COVID-19 Evidence-based recommendations on tixagevimab plus cilgavimab (Evusheld) for preventing COVID‑19 in adults. # Recommendations Tixagevimab plus cilgavimab is not recommended, within its marketing authorisation, for the pre‑exposure prophylaxis of COVID‑19 in adults who are not currently infected with SARS‑CoV‑2 and who have not had a known recent exposure to someone infected with SARS‑CoV‑2, and: who are unlikely to have an adequate immune response to COVID‑19 vaccination, or for whom COVID‑19 vaccination is not recommended. Why the committee made this recommendation The results of clinical studies of tixagevimab plus cilgavimab suggest it reduces infection with SARS‑CoV‑2 (the virus that causes COVID‑19) compared with no preventative treatment. But these studies were done early in the pandemic when different variants of the virus were circulating. More recent studies done in laboratories report that tixagevimab plus cilgavimab is unlikely to prevent infection with most of the variants circulating when this guidance was produced. Because of the lack of evidence of clinical effectiveness, the cost-effectiveness estimates for tixagevimab plus cilgavimab are highly uncertain. They are also likely to be much higher than what NICE considers an acceptable use of NHS resources. So, tixagevimab plus cilgavimab is not recommended. Further research is recommended to address some of the uncertainties in this rapidly changing disease area (see section 4).# Information about tixagevimab plus cilgavimab # Marketing authorisation indication Tixagevimab plus cilgavimab (Evusheld, AstraZeneca) has a conditional marketing authorisation for 'the pre‑exposure prophylaxis of COVID‑19 in adults who are not currently infected with SARS‑CoV‑2 and who have not had a known recent exposure to an individual infected with SARS‑CoV‑2 and: who are unlikely to mount an adequate immune response to COVID‑19 vaccination, or for whom COVID‑19 vaccination is not recommended.' # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for tixagevimab plus cilgavimab. # Price The list price of tixagevimab plus cilgavimab is £800 per 300 mg dose and £1,600 per 600 mg dose (excluding VAT; prices provided by company). The company has a commercial arrangement, which would have applied if tixagevimab plus cilgavimab had been recommended.# Committee discussion The evaluation committee considered evidence submitted by AstraZeneca, a review of this submission by the external assessment group (EAG), a report developed by an in vitro advisory group and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## COVID-19 COVID‑19 is an acute respiratory illness caused by the SARS‑CoV‑2 virus. Symptoms range from mild and self-limiting to severe with a risk of hospitalisation or death. After the initial SARS‑CoV‑2 infection, people may have ongoing symptoms (long COVID). Some people remain at high risk of serious illness from COVID‑19, despite the availability of vaccines. These are generally people who would not benefit from vaccination or in whom there is not a good enough response to vaccination. This includes people: who have had a transplant with genetic disorders, some cancers, kidney or liver disease, or immune system disorders whose immune response is affected by the drug used to treat their condition. ## Changing variants of concern The virus that causes COVID‑19 (SARS‑CoV‑2) has evolved over the course of the pandemic. Throughout most of 2021, Alpha and Delta were the main circulating variants. From late 2021 onwards, the Omicron variant began to dominate. Since then, the Omicron variant has continued to evolve into subvariants, each with different mutations on the spike protein. These changes can affect the continued efficacy of existing treatments, particularly neutralising monoclonal antibodies, because the ability of the treatment to bind to the virus is reduced. The UK Health Security Agency (UKHSA) publishes a monthly technical briefing document, which reports variant prevalence. NICE used the data published in the UKHSA's March 2023 technical briefing 51 (based on all of the UK sequenced samples from 20 to 26 February 2023) to determine the variants circulating at the time of this evaluation. Most new cases were the Omicron subvariants BQ.1 and CH.1.1, or XBB lineage subvariants. The committee considered that SARS‑CoV‑2 is rapidly evolving and acknowledged that this makes assessing neutralising monoclonal antibodies difficult. It recalled from the in vitro advisory group report (see section 3.11) that the virus evolves in 2 different ways: Frequent small changes of the virus: new mutations on the spike protein may lead to incremental changes that incorporate many of the same mutations as before. This could be driven by selection pressure, so that viruses with mutations enabling them to evade neutralisation will proliferate. Infrequent larger shifts of the virus: older versions of the virus may be incubating (for example, in people who are immunocompromised, for whom viral clearance may be slower) and mutate to have an advantage over currently circulating variants (for example, the large change that occurred with the Omicron wave).The committee considered it most likely that new variants would be related to currently circulating variants unless there was a larger shift in the virus. It also considered the possibility that neutralising monoclonal antibodies which currently have low efficacy regain their efficacy against future variants. But it noted that the World Health Organization therapeutics and COVID-19 living guideline states that 'the likelihood of COVID‑19 caused by former variants was extremely low'. So, it considered that the effectiveness of tixagevimab plus cilgavimab (from now, tix–cil) over the appropriate time period for this evaluation would be best indicated by neutralisation potential against currently dominant circulating variants and variants that are currently growing the fastest. The committee noted substantial uncertainty in estimating efficacy for future variants, given the current understanding of COVID‑19 and the rapidly evolving virus. It understood from studies such as OpenSAFELY that, broadly, COVD‑19 is waning in its severity. It understood that this was because immunity to SARS‑CoV‑2 has increased in the general population through vaccination and natural exposure, and because later variants of the virus have reduced in pathogenicity. This means that the risks are now very low for the general population and substantially reduced for most people eligible for tix–cil compared with earlier in the COVID‑19 pandemic. But the committee noted that the risks have not reduced for some groups such as people who have had transplants. # Patient perspectives ## Ongoing impact of COVID-19 The patient experts described the ongoing impact of COVID‑19 on their lives and the lives of others with a high risk of severe SARS‑CoV‑2 infection. One patient expert described how modifying their behaviour was mentally and physically exhausting, needing extensive planning for simple tasks like shopping. They described how nothing had changed for them since the start of the pandemic. In fact, they added, the situation had worsened for them because the rest of the country has returned to normal, meaning protective measures are no longer in place. They described how removing measures for limiting viral spread, such as mask wearing, working from home and social distancing, has placed all the responsibility for protection on individuals. They added that people who are immunocompromised need to navigate multiple environments that no longer have the COVID‑19 mitigation measures that they value. Another patient expert described how they are only able to leave the house for routine medical appointments, and are on high alert to minimise the risk of infection whenever possible. Both patient experts also highlighted that the burden of responsibility extends to household family members, and affects work life and family relationships. People reported that their finances had been affected because of a lack of government support and increased costs of shielding. For people with children, there were concerns about the disruption of education on life chances and the long-lasting impact of this. They said that the availability of a preventative treatment that reduces infection risk could reduce the need for exhausting and isolating behavioural changes. The committee agreed that there is an urgent unmet need for a preventative therapy that would reduce the risk of SARS‑CoV‑2 infection for people at high risk of severe infection for whom vaccination is not suitable or does not provide sufficient protection. ## Benefits of tix–cil The patient experts discussed their experiences of having tix–cil. One described their relief after having it. They explained that, even after treatment with tix–cil, they continued to be careful and still maintained social distancing. They acknowledged that tix–cil may not stop all SARS‑CoV‑2 infections, and that returning to normal would be a gradual process as their confidence in the treatment increased. Another patient expert agreed and added that, since having tix–cil, they have met people face to face, but continue to wear a mask and avoid crowded spaces. They added that, even with tix–cil, and with treatments for severe SARS‑CoV‑2 infection now available, this is not enough for them to abandon all caution. # Decision problem ## Eligible population The company explained in its original submission that it was positioning tix–cil in a narrower population than that of the marketing authorisation and the final NICE scope. That is, it positioned it in people who are at the 'highest risk of an adverse COVID‑19 outcome'. In the original company submission, the company referred to the report produced by the independent advisory group set up by the Department of Health and Social Care (DHSC) to identify people at the very highest risk of an adverse COVID‑19 outcome for treatment with antivirals and neutralising monoclonal antibodies. See the DHSC's independent report on the highest-risk subgroups with SARS-CoV-2 when considering neutralising monoclonal antibodies and antiviral drugs (from now, referred to as the McInnes report). The committee noted that a similar report, the independent advisory group report concerning the use of COVID-19 directed antibodies in the prophylaxis setting in the highest-risk clinical subgroups, had been produced by the same group. This stratified cohorts in order of risk. The committee recalled that the wording in the marketing authorisation for tix–cil included 'those unlikely to mount an adequate immune response to COVID‑19'. It considered that this would include people in groups A1, A2 and B of the independent advisory group's report. In response to consultation, the company considered that its target population should include people in groups A1 and A2, and people in group B without a serological response to vaccination. The clinical experts broadly agreed that the groups in the independent advisory group report aligned with the expected level of antibody response to vaccination. They also thought that people in groups A1 and A2 were likely to have the poorest response and so be at the greatest risk of severe SARS‑CoV‑2 infection. But they cautioned that the groups represent a spectrum of risk and that there was likely to be substantial heterogeneity within groups as well as across groups. The clinical experts added that some people may have poor outcomes despite having a response to vaccination. At the second meeting, the clinical experts and NHS England commissioning expert confirmed that serological testing to check response to vaccination is not done routinely in the NHS. So, they thought it was unclear how this would work in clinical practice for people in group B. The committee noted that, in people having a treatment that would place them in group B in the MELODY study, between 7.6% and 13.5% had no detectable antibodies after vaccination. So, the committee concluded that many people in group B would have to be tested to identify a single person eligible for treatment. It considered that the costs of this would be significant and had not been included in the company's model. The EAG noted that many of the inputs in the economic analysis were selected to reflect particular groups. So, it thought that they did not represent the eligible population as a whole and did not capture the heterogeneity within the eligible population. The committee agreed with the EAG that estimates of clinical and cost effectiveness would vary across different risk-based groups because of heterogeneity. At consultation, it was highlighted that certain groups may be at a higher risk of hospitalisation or death than the eligible population as a whole. For example, people with solid organ transplants may have more severe consequences of SARS‑CoV‑2 infection, such as transplant failure. The committee acknowledged the higher risk and costs in these groups. It considered that focusing on the most severe subgroups would reduce the decision risk. The committee added that, ideally, heterogeneity could be explored by considering separate subgroups in the economic model. But it noted that it had not seen evidence of differential clinical or cost effectiveness to rule out other groups covered by the marketing authorisation. So, it maintained that the eligible population should be all groups covered by the marketing authorisation. ## Treatment schedule The summary of product characteristics for tix–cil recommends a dose of 300 mg. It states that a higher dose of 600 mg may be more appropriate for some SARS‑CoV‑2 variants (such as Omicron BA.1 and BA1.1) that show reduced susceptibility to tix–cil in vitro. So, the company used the cost of the higher 600 mg dose in its economic analysis. The summary of product characteristics also states that tix–cil may be effective for pre‑exposure prophylaxis for 6 months after administration. In its original submission, the company assumed that the initial 600 mg dose was followed 6 months later by a second 600 mg dose. The EAG noted that this was not aligned with the summary of product characteristics. This says that tix–cil has only been studied in single-dose studies, and that no safety and efficacy data is available for repeat dosing. The committee was aware that the Medicines and Healthcare products Regulatory Agency (MHRA) had clarified to NICE that repeat dosing of tix–cil is outside the marketing authorisation and would be off-label use. Technology appraisal guidance recommendations must be within the marketing authorisation, so the committee concluded that the economic analysis should only include a single dose of tix–cil. In response to consultation, the company updated its model to only include a single dose of tix–cil. The committee was satisfied with the updated approach. # Clinical effectiveness ## Outcomes The company presented treatment outcomes in line with the NICE scope. These included reduction in risk and severity of SARS‑CoV‑2 infection, and improvements in anxiety, depression and health-related quality of life. The committee considered these appropriate outcomes for a preventative treatment. But the committee noted that there were interactions between outcomes that had not been considered by the company, including: The interaction between the perceived efficacy of treatment and direct utility gain resulting from a reduction in shielding: the committee considered that, as perceived efficacy reduces, the reduction in shielding will also likely reduce, resulting in a reduced direct utility gain. The interaction between the extent of shielding and the risk of infection and severe outcomes: the committee considered that, as shielding reduces, the risk of infection and severe outcomes will increase.The patient experts at the first committee meeting explained that some shielding behaviours such as social distancing were likely to continue to some extent after having tix–cil (see section 3.4). They said that individual decisions about shielding behaviours can take into account many different factors. These factors include the risk from their underlying condition, the current risk posed by SARS‑CoV‑2 and other viruses, and the trust in the effectiveness of the treatment against current variants. People may also take into account the time of year, whether they have upcoming medical appointments and societal attitudes towards protective behaviour (such as mask wearing on public transport and using lateral flow tests). The committee considered that any change in shielding will depend on an individual's estimate of the risk reduction available from tix–cil and their degree of risk aversion. It noted that it is also important to understand how much shielding is because of COVID‑19 risks and how much is related to other factors. The committee considered that, for people who are not shielding, having an effective preventative treatment would reduce the risk of severe illness and death but not result in any quality-of-life benefit from stopping shielding. Whereas, for people who are fully shielding, it thought that having an effective preventative treatment would allow them to stop shielding so their quality of life would be improved but their overall risk of infection would be the same. The committee considered that there would be many people who have a mixture of both direct utility gain and a reduced risk of infection. For example, this would be the case if they are partially shielding or cannot shield and this causes them anxiety. But the committee concluded that no one would have the full benefit of risk reduction and the full direct utility gain from stopping shielding, as was assumed by the company. The committee considered that the company's model may have double counted the benefit of treatment. This was because it incorporated a reduction in risk for people who are fully and effectively shielding (and who are not at risk) as well as a direct utility benefit. It noted that the company had not provided any data on the relationship between efficacy, direct utility gain, shielding behaviours and increased infection risk. It also noted that the company had not modelled this relationship, so the impact on cost-effectiveness estimates could not be explored. The committee concluded that the company's model likely overestimated the benefit of treatment. ## PROVENT trial The company presented evidence from a phase 3, randomised, double-blind, placebo-controlled trial (PROVENT, Levin et al. 2022). PROVENT compared tix–cil (n=3,460) with placebo (n=1,737) for preventing SARS‑CoV‑2 infection in adults at increased risk of an inadequate response to vaccination or at an increased risk of SARS‑CoV‑2 infection. The results from PROVENT showed that tix–cil was associated with a statistically significant reduction in the incidence of COVID‑19 (reverse transcription polymerase chain reaction-positive symptomatic illness) compared with placebo, with a relative risk reduction of 76.7% (equating to an absolute risk reduction of 0.8%). The company noted several limitations with the PROVENT trial: most participants were not at high risk of a severe COVID‑19 outcome participants were unvaccinated it took place before there were significant levels of natural immunity in the population from prior infection it took place when earlier variants of COVID‑19 were prevalent and before newer variants emerged.Because of these limitations, the company did not include efficacy data from PROVENT in its economic model, despite using it as the randomised evidence for efficacy for its marketing authorisation application. The EAG also had other concerns, including: the overall small number of infection events the small proportion of participants on immunosuppressive treatments or with immunosuppressive disease the need for all participants to have a negative point-of-care COVID‑19 test, which is not expected in clinical practice.The committee noted that the context of the disease was very different at the time of the PROVENT trial. It also noted that there was no information reported about how people in either arm modified their behaviour during the trial, which is particularly important for preventative treatments. ## Observational evidence The company presented data from 2 observational evidence studies, Young-Xu et al. (2022) and Kertes et al. (2022). Young-Xu et al. was a retrospective cohort study in US veterans who were immunocompromised (92%) or otherwise at high risk of COVID‑19 (8%). People were recruited between January and April 2022, at the time when Omicron variants BA.1, BA.2 and BA.2.12.1 were circulating. A total of 1,733 people had tix–cil. One 600 mg dose of tix–cil was given to 83% of participants; the rest had a 300 mg dose. The outcomes of the study were SARS‑CoV‑2 infection, COVID‑19-related hospitalisation and all‑cause mortality. To generate estimates of comparative effectiveness, the study compared outcomes for people on tix–cil with propensity-matched controls (n=6,354). The resulting hazard ratios were 0.34 (95% confidence interval 0.13 to 0.87) for SARS‑CoV‑2 infection; 0.13 (95% CI 0.02 to 0.99) for COVID‑19-related hospitalisation and 0.36 (95% CI 0.18 to 0.73) for all‑cause mortality. Kertes et al. was a retrospective cohort study done in people who were immunocompromised and considered at high risk for SARS‑CoV‑2 infection and complications. People were recruited to the study between February and May 2022 at the time when Omicron variants BA.1 and BA.2 were circulating. A total of 825 people had one 300 mg dose of tix–cil. Compared with 4,299 people who did not have tix–cil, the odds ratio of SARS‑CoV‑2 infection was 0.51. The company considered that Young-Xu et al. provided the most robust evidence, and so used it for its base case for the economic model. The EAG had concerns about the methods and generalisability of both observational studies. It highlighted the wide confidence intervals and potential for residual confounding for Young-Xu et al. It added that most of the US veterans were men and older, so the population may not be generalisable to that likely to be offered tix–cil in the UK. For Kertes et al., the EAG had concerns about the potential for selection bias, residual confounding and the shorter follow up in the treatment group than in the control group. The committee noted these limitations. It added that, for both studies, there would likely be systematic differences between people who sought tix–cil treatment and people in the control group who were eligible for tix–cil but did not have treatment. ## Generalisability to the current circulating SARS-CoV-2 variants In addition to the generalisability concerns discussed in section 3.8 and section 3.9, the committee had concerns about generalisability of the company's evidence to the current circulating SARS‑CoV‑2 variants. None of the clinical studies included evidence of efficacy against variants around at the time of this evaluation because of the rapidly evolving nature of the SARS‑CoV‑2 virus. The observational studies were done when the early Omicron variants BA.1, BA.2 and BA.2.12.1 were circulating, so their generalisability to the current UK context is unclear. The committee acknowledged the difficulties in doing trials in a rapidly evolving disease area, but it still considered that the evidence was too uncertain. It considered that in vitro data (from laboratory studies) may provide additional information as to whether there was a realistic clinical possibility of the technology retaining efficacy against currently circulating variants (see section 3.12). ## In vitro advisory group Neutralising monoclonal antibodies such as tixagevimab and cilgavimab target the spike protein of the SARS‑CoV‑2 virus. Mutations on the spike protein can quickly reduce the effectiveness of such treatments. This means that clinical trials done when older variants of SARS‑CoV‑2 were circulating may no longer apply in the current setting, so other types of evidence are needed. In vitro neutralisation assays can be used to assess whether treatments neutralise new variants, and so whether they retain clinical effectiveness over time as the virus evolves. An advantage of in vitro evidence is that it can be generated much faster than it takes to do clinical trials. But NICE's technology appraisal committees are not used to interpreting and appraising in vitro data. Because of this, NICE commissioned an in vitro advisory group made up of experts in infectious disease, virology, vaccine epidemiology, immunology and pharmacology. They developed a decision framework to link the in vitro neutralisation data to clinical outcomes, and their report (the in vitro advisory group report in NICE's draft guidance consultation committee papers) provided guidance on interpreting in vitro evidence. ## In vitro studies Guided by the in vitro advisory group, the committee identified 5 studies that investigated tix–cil's ability in vitro to neutralise a range of SARS‑CoV‑2 variants and subvariants, including some of those circulating at the time of the evaluation. Because the landscape is rapidly evolving, a systematic review of the in vitro data was not possible. Studies by Cao et al. (2022) and Wang et al. (2022) reported no neutralisation activity for tix–cil against the Omicron subvariant BQ.1. Studies by Wang et al. (2023), Cao et al. (2023) and Imai et al. (2023) reported no neutralisation activity of tix–cil against XBB. During the first committee meeting, the committee recalled from the in vitro advisory group report that, if there was no neutralisation activity in vitro, this would suggest no clinical efficacy in people. The company and clinical experts considered that tix–cil may not be clinically effective against many new variants but considered that it could still be effective against some of them. One clinical expert also noted that it was possible that tix–cil may regain efficacy against future variants. The committee noted the company's and experts' views. But it considered that the prevalence of older variants against which tix–cil had shown in vitro efficacy (BA.5 and BA.2) was low and decreasing over time because of the relative speed of growth of other subvariants. The committee noted that subvariants that were not investigated in the in vitro studies, such as CH.1.1, had specific mutations that would likely be associated with reduced or no neutralisation activity of tix–cil. The committee acknowledged that there was the possibility for tix–cil to regain activity against future variants, but considered that the likelihood of this was low. In response to consultation, the company proposed that an appropriate threshold for neutralisation in vitro equating to clinical effectiveness in vivo should be an IC50 of less than 10,000 nanograms per millilitre. The committee recalled the in vitro advisory group's conclusions in circumstances when there is a substantial change in neutralisation activity but some neutralisation is retained in vitro. In these circumstances, the advisory group concluded pharmacokinetic and pharmacodynamic (PK/PD) data is needed to try to link in vitro neutralisation data to clinical outcomes. Without PK/PD data, it is not possible to determine how a change in neutralisation activity may be associated with clinical outcomes. So, the committee did not consider the company's proposal to be appropriate for decision making. Full details are in the in vitro advisory group report in NICE's draft guidance consultation committee papers. The committee noted a recent update from the European Medicines Agency's emergency task force, which cautioned that neutralising monoclonal antibodies currently authorised for COVID‑19 are unlikely to be effective against emerging strains of SARS‑CoV‑2. Shortly after the first committee meeting, the US Food and Drug Administration (FDA) also announced that tix–cil was no longer authorised for emergency use in the US. This was because it was unlikely to be effective against the variants responsible for more than 90% of infections. At the first meeting, the committee concluded that tix–cil was unlikely to retain sufficient neutralisation activity against most variants circulating at the time this guidance was produced. The committee noted there was uncertainty in relying solely on in vitro evidence. It would have preferred to triangulate the data with real-world evidence. But, in the context of changing variants, it considered the in vitro data for current variants more relevant to decision making than the older real-world studies in the company's submission. In response to consultation, the company acknowledged that it was reasonable to assume that total loss of neutralisation in vitro would mean no clinical effect. At the second meeting, the committee considered data from the UKHSA's March 2023 technical briefing 51. This briefing showed that there were only around 3% of circulating variants (BA.2 and BA.5) that tix–cil may be effective against. So, the committee concluded that there was no evidence that tix–cil would neutralise at least 97% of circulating variants as of March 2023. ## Rapid evaluation process During the first committee meeting, the patient experts expressed frustration that the COVID‑19 virus is evolving rapidly. They said that there needs to be a faster mechanism to ensure effective preventative medicines are available when needed, particularly in winter when meeting people outside is more difficult. During consultation, the company and stakeholders agreed that a more flexible and responsive evaluation process is needed. They also thought that a system needs to be in place to monitor current variant mix because tix–cil may regain efficacy against future variants. The company suggested that an approach similar to that of the FDA should be adopted. The FDA has limited tix–cil's use to when the combined frequency of non-susceptible SARS‑CoV‑2 variants nationally is less than or equal to 90% (that is, when 10% or more variants are susceptible to neutralisation by tix–cil). The committee considered that, under the current single technology appraisal process, it could only make decisions based on the data available at the time of the committee meeting. But it noted that a more flexible evaluation process for COVID‑19 technologies is currently being developed by NICE. Further details of the proposed process are provided in NICE's consultation document for the COVID-19 technology appraisal recommendations: surveillance and rapid update process statement. # Cost effectiveness ## Economic model The company's economic model consisted of a decision tree followed by a Markov model. The decision tree captured the impact of tix–cil on COVID‑19 over the 6 months after preventative treatment and the 29‑day (acute) period for anyone who was infected. The Markov model extrapolated survival and quality of life over the person's lifetime. The model assumed a direct utility benefit for everyone in the tix–cil arm, and an efficacy benefit from a reduced risk of SARS‑CoV‑2 infection and a reduced COVID-19 severity. The EAG considered the model structure to be appropriate, except for the company's handling of COVID‑19 cases occurring after the initial treatment period. The model structure did not allow for these people developing long COVID. The EAG thought that it would have been better if the company had attempted to model COVID‑19 cases occurring after the initial treatment period using a model structure that tracked the number of people remaining at risk of long COVID over time. It thought that the company's model structure may have overestimated the benefit of tix–cil. This was because the model assumed that people who avoid COVID‑19 during the initial treatment period by having tix–cil are then subsequently protected from long COVID. The committee noted the uncertainties in the model structure, particularly the challenge of considering a lifetime time horizon despite the uncertain natural history of COVID‑19 and future variants. It acknowledged that it would be difficult to model the impact of COVID‑19 accurately after the initial treatment period because SARS‑CoV‑2 is constantly evolving. The committee considered the model structure to be broadly appropriate. But it considered that key model inputs were highly uncertain, and that this resulted in highly uncertain cost-effectiveness estimates (see sections 3.16 to 3.20). The committee also noted that the interaction between many parameters had not been accounted for in the company's model (see section 3.7 and section 3.16). ## Efficacy In its original submission, the company used efficacy data from the observational evidence study by Young-Xu et al. (2022; see section 3.9). This study showed that tix–cil reduced the risk of symptomatic SARS‑CoV‑2 infection and hospitalisation related to COVID‑19. In response to consultation, the company acknowledged the in vitro data discussed in section 3.12. It agreed that it had to be reasonable to assume that total loss of neutralisation in vitro would mean no clinical effect. But the company suggested that a more flexible approach was needed and that tix–cil should be recommended if it shows activity against a specific threshold of circulating SARS‑CoV‑2 variants. This approach is discussed further in section 3.13. The company suggested a hypothetical threshold for neutralisation against circulating variants of 10% in line with the FDA's approach. To implement this in the model, the company assumed that the relative risk reduction for SARS‑CoV‑2 infection based on Young-Xu et al. was reduced to 10% of its original value, resulting in a relative risk reduction for infection of 6.6%. The EAG preferred to apply the 10% multiplier to the relative risk reduction for both infection and hospitalisation. This was because the company's base case still assumed a treatment effect based on Young-Xu et al. for the relative risk reduction of hospitalisation. The committee preferred the EAG's approach. But it noted that the 10% multiplier applied by both the company and EAG was still only hypothetical and much higher than the efficacy at the time of the second committee meeting (around 3%; see section 3.12). ## Evidence for a direct utility gain The company did a utility study to investigate the impact of the pandemic on people who are immunocompromised (Gallop et al. 2022). Subgroups in the study included people who were fully shielding, partially shielding and no longer shielding. The study collected quality-of-life data using the EQ‑5D‑5L questionnaire from people who were immunocompromised and had not had a preventative treatment (untreated group). The EQ‑5D‑5L rating for each state was scored for UK preference weights, using a mapping function to map from EQ‑5D‑5L to EQ‑5D‑3L. The study compared results with a hypothetical treated group using a vignette (a set of short statements describing the experience of a typical person having treatment). The vignette asked people to imagine a medicine that gives them 'a level of protection from COVID‑19 which is similar to that given by vaccination in individuals who have a healthy immune system'. The utility gain for each subgroup was calculated as the difference between utility scores for the untreated and treated groups. The resulting utility gains were weighted according to the proportions shielding and partially shielding based on a survey by the Office for National Statistics. This gave a final utility gain of 0.098. In its updated model, the company applied the direct utility gain to everyone having tix–cil for 6 months after treatment (3 months for people who were infected with SARS‑CoV‑2, to account for their loss of confidence in protective treatment). The EAG highlighted several limitations with the company's vignette study. It considered that the vignette used in the study did not align with the effectiveness evidence for tix–cil. This was because there was no evidence that tix–cil provides comparable efficacy to vaccination in people with a healthy immune system. In response to consultation, the company provided supportive evidence for the direct utility gain from an academic-in-confidence study. The EAG noted multiple issues with the company's supportive evidence. The committee agreed with the EAG's concerns about the company's evidence for direct utility gain. The committee recalled the patient experts' comments that some shielding behaviours were likely to continue to some extent after having tix–cil (see section 3.7). So, it concluded that the magnitude of the utility gain based on the company's evidence was not reflective of the anticipated utility gain for the group likely to have tix–cil in clinical practice. ## Application of direct utility gain in the economic model In its original submission, the company assumed that the direct utility gain should apply to everyone, regardless of whether they are shielding, partially shielding or not shielding. At consultation, the company updated its base case to apply the utility gain to the 82% of people shielding or partially shielding only, based on the survey by the Office for National Statistics. This was to align with the EAG's preference at the time of the first committee meeting. In its critique of the company's consultation response, the EAG noted that the company's vignette study reported that 50% of people would return to their pretreatment behaviour if there was a new variant against which tix–cil was not effective. The EAG noted that the in vitro data presented at the first committee meeting showed no neutralisation for tix–cil against most circulating variants. So, the EAG updated its base case to apply direct utility gain to only 50% of people. The EAG noted that the company's utility study did not specify a situation in which there could be no efficacy against 90% of circulating variants (as per the company's hypothetical base case). The EAG considered that, if tix–cil were to be offered when it was known to neutralise only 10% of circulating variants, this may not provide sufficient reassurance for most people to stop shielding. So, the EAG explored a scenario assuming that only 10% of people experience a direct utility gain. The patient experts at the second committee meeting considered that they would still have a utility benefit from treatment in situations in which tix–cil is only effective against 10% of circulating variants. At consultation, patient groups considered that even people who are not currently shielding because they are unable to could also benefit from prophylaxis because it could reduce anxiety. The committee considered that there was a complex relationship between the perceived efficacy of tix–cil, the direct utility gain through reducing shielding and the increased risk of infection that would result from reducing shielding (see section 3.7). This relationship had not been modelled by the company. The committee considered that the extent of the direct utility gain would likely differ across patient groups. But it considered that most people would be reluctant to change their behaviour if they were told that treatment would only prevent 1 out of 10 infections, with the additional uncertainty that any remaining benefit of treatment could reduce as variants evolve. The committee concluded that the direct utility gain had been overestimated in both the company's and EAG's base cases. The committee considered the EAG's scenario in which direct utility gain was applied to only 10% of people to be more appropriate than both base cases. But the committee concluded that many people may not feel confident enough in treatment to change their behaviour in the company's hypothetical situation in which tix–cil is effective against 10% of variants. It thought that this could result in no direct utility gain. At the time of the second committee meeting, the committee considered that there was no evidence of effectiveness against 97% of circulating variants. This meant that the actual utility gain would have been much lower and the incremental cost-effectiveness ratio (ICER) would have been much higher than in the EAG's scenario. ## Administration costs In its original submission, the company said that tix–cil should be offered as part of routine outpatient appointments or through secondary care-led community services. It originally assumed a cost per administration of £41, based on 1 hour of band 5 hospital nurse time. It later updated its administration cost to £216 per administration based on the cost used by NHS England in the budget impact assessment for tix–cil. During the meeting, the company revised its suggested cost for administration to be half of this. The company explained that this was because the cost of £216 is for 2 doses of tix–cil, but tix–cil is given as a single dose. The EAG did not think that the cost of delivering tix–cil had been properly accounted for by the company. This was because it was not clear whether everyone who was eligible would be having routine appointments often enough to have tix–cil in such an appointment soon after it became available. Also, it thought that the 1‑hour observation period after administration required by the marketing authorisation may be impractical in a hospital setting. The EAG preferred to use a cost based on administration in COVID‑19 Medicine Delivery Units (CMDUs). It considered the CMDU unit cost of £410 per administration of an oral antiviral to better reflect the cost for administering tix–cil. This was because it thought that a similar bespoke system would be needed to implement tix–cil in the NHS. At the first meeting, an integrated care system commissioning expert explained that their preference was for tix–cil to be delivered in primary care. This was because administration is relatively simple and there is additional complexity implementing the treatment in secondary care. At the second meeting, the NHS England expert explained that the setting in which tix–cil would be given is unclear. They advised that the committee should consider both the company's and EAG's estimates for the cost of administration. The committee concluded that the administration setting for tix–cil is uncertain. It considered both the company's and EAG's administration costs in its decision making. ## Infection risk without tix–cil To generate estimates of comparative effectiveness, the company estimated the risk of SARS‑CoV‑2 infection for people who did not have tix–cil. The relative risk reduction associated with treatment was applied to this risk to calculate the risk of infection for people having tix–cil. The company assumed the risk of symptomatic infection for people not having tix–cil was 22.58% annually. This was based on the average 7‑day risk of reporting a positive test for SARS‑CoV‑2 in the general population of England between August 2021 and August 2022. The EAG highlighted that historical risks may not reflect current or future risks because this depends on circulating variants and protection offered by vaccines. It added that data for the general population may not be generalisable to people likely to have tix–cil. The committee initially considered it likely that the risk of infection in people eligible for tix–cil may be lower than the general population. This is because they modify their behaviour, which remains an effective way to reduce risk of infection, despite the substantial burden. It added that it was uncertain how risk may vary across different risk-based groups. The committee considered that further research is needed to understand the background risk of infection in different populations. It considered that in the interim, a range of scenario analyses would help inform the sensitivity of the model to changes in the background risk of infection. In response to consultation, the company provided scenario analyses varying the risk of symptomatic infection in people not having tix–cil by 20% above and below the value used in its base case. The EAG did not consider this sufficient to cover the broad uncertainty about future risk of infection. The EAG added that the period used to estimate risk included the large peak of cases in late 2021 and early 2022. Restricting this period to estimate the risk in the last 3 months of data provided by the company (May to August 2022) provided an annualised risk of 8%. This was much lower than the lower bound estimate tested in the company's scenario analysis. The EAG explored the impact of scenarios halving and doubling the risk assumed in the company's base case. During the second meeting, the patient experts explained that a lack information to help them assess risk (outbreaks, case numbers) in local areas makes it more challenging for people who are immunocompromised to avoid infection. The committee acknowledged that testing for SARS‑CoV‑2 has now been significantly reduced. This means general population data may no longer be representative of actual case numbers. It also heard that patterns of infection in the general population are different now that COVID‑19 is endemic. This is because rate of infection is driven by population-level resistance to mutations rather than the population transmission seen earlier in the pandemic that led to distinct waves of infection. The committee noted that the company had not provided any new data for the target population for the risk of infection in people not having tix–cil, so the risk was still uncertain. It concluded that, given the high uncertainty, both of the EAG's scenarios (halving and doubling the risk) should be considered in decision making. ## Hospitalisation risk without tix–cil The company estimated the risk of hospitalisation caused by COVID‑19 for people who have not had tix–cil. The company's preferred source of data to estimate this risk was a study by Shields et al. (2022). This study assessed how vaccination affected hospitalisation and mortality for people with primary and secondary immunodeficiency in the UK. Based on Shields et al., the hospitalisation rate for SARS‑CoV‑2 infection in the Omicron wave for people who did not have treatment was 15.9%. At the first meeting, the committee noted that the Shields et al. estimate was much higher than an estimate from Patel et al. (2022), which was considered in NICE's technology appraisal guidance on casirivimab plus imdevimab, nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19. Patel et al. was a retrospective cohort study of people who had early treatment for, or who were diagnosed with, COVID‑19 between 1 December 2021 and 31 May 2022. The study reported that 2.8% of people who had not had treatment were hospitalised with COVID‑19 as the primary diagnosis. The committee concluded that Patel et al. included people eligible for COVID‑19 treatment under the criteria defined by the McInnes report (see section 3.5). These criteria better aligned with the full marketing authorisation for tix–cil, but not with the subgroup used in the economic modelling. In response to consultation, the company stated that Patel et al. considered a broader population than the company are targeting. In addition, the company and other stakeholders highlighted that certain groups such as people with solid organ transplants or people with lymphoma or leukaemia may be at a much higher risk of hospitalisation or death due to COVID-19 than the eligible population as a whole. Stakeholders emphasised the need for separate analyses in these subgroups. In its critique of the company's response to consultation, the EAG acknowledged that specific patient groups are likely to have a higher hospitalisation risk. It noted that the company's model did not consider specific subgroups. So, it considered that the best approach was to use the average risk reported across the population in the marketing authorisation as provided by Patel et al. The EAG assumed a hospitalisation risk of 2.8% based on Patel et al. in its base case. But it explored higher rates of hospitalisation in its scenario analysis to reflect the potential higher risk in some specific groups. The committee had seen evidence from the OpenSAFELY study that validated the Patel et al study. OpenSAFELY calculated the hospitalisation rate for people at highest risk of hospitalisation (as outlined in the McInnes report) to be about 2.4%. It also calculated the hospitalisation rate for a subgroup of this group with renal impairment to be about 4.0%. During the second committee meeting, the clinical experts explained that SARS‑CoV‑2 has become less pathogenic and has caused less severe COVID‑19 as it has mutated. They noted that people with COVID‑19 are now more likely to present with upper rather than lower respiratory tract infections, and that these are less severe. The committee considered that this meant that changes in the pathogenicity of the virus will result in changes to the hospitalisation rate. It concluded that the rate of hospitalisation is uncertain, but the estimate based on Shields et al. was high. The committee added that the estimate in Shields et al. was unlikely to represent the current risk of hospitalisation for most people eligible for treatment according to the marketing authorisation. The committee preferred to assume a hospitalisation rate closer to Patel et al., but noted that the rate would be dependent on the risk group under consideration (see section 3.5). ## Long COVID There were several differences between the company's and EAG's base case for long-COVID parameters. The cumulative impact of these assumptions on the ICER was substantial. Compared with the company's submission, the EAG preferred to assume a: lower risk of long COVID for people not hospitalised shorter duration of long COVID lower cost of managing long COVID smaller impact of long COVID on long-term utility.In response to consultation, the company updated its base case to align with the EAG's preference for the cost and utility impact of long COVID. But the risk of long COVID for people not hospitalised and the duration of long COVID remained the same as for the first committee meeting. The committee considered that there was substantial uncertainty about the effects of long COVID. It also thought that it was unclear how long-COVID assumptions interact with the other modelled elements, for example, the risk of infection. It preferred the EAG's estimates because these were more closely aligned with the estimates used in NICE's technology appraisal guidance on casirivimab plus imdevimab, nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19. ## Invasive mechanical ventilation To determine hospitalisation costs for acute COVID‑19, estimates of the distribution across levels of hospitalisation care are needed. The company's model assumed that this distribution is the same for anyone hospitalised, regardless of whether they had prophylaxis with tix–cil. Levels of hospitalisation care included in the model were 'no oxygen', 'low-flow oxygen', 'non-invasive ventilation or high-flow oxygen' and 'invasive mechanical ventilation (IMV) or extra corporeal membrane oxygenation (ECMO)'. The company used a study by Cusinato et al. (2022), which considered data from a single UK hospital averaged across the first and second waves of COVID‑19. Based on Cusinato et al., the proportion needing IMV was 15.40%. The EAG noted that Cusinato et al. provided data estimated separately for the first and second waves of COVID‑19 and that the proportion needing IMV during the second (Omicron) wave was much lower than during the first wave. In its base case, the EAG preferred to use an estimate for the proportion needing IMV based on data for the general population. Based on this data, the proportion needing IMV was 4.92% for the year up to October 2022 and 2.51% for the most recent 3 months (August to October 2022). The EAG preferred to use the upper estimate of 4.92% because it acknowledged that the proportion of people on IMV may be higher in the population likely to be eligible for tix–cil. The committee agreed with the EAG that the risk of needing IMV had reduced since the start of the pandemic, and that data from the Omicron wave was more generalisable to the current situation. The clinical experts explained that the risk of needing IMV may be lower in people who are immunocompromised than in the general population. This is because of a reduced risk of hyperinflammatory reactions. The committee noted that, in NICE's technology appraisal guidance on casirivimab plus imdevimab, nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19, the proportion needing IMV was 4.12%, which is closer to the EAG's preferred base case. It concluded that the EAG's estimate for the proportion needing IMV was preferred. # Cost-effectiveness estimates ## Committee's preferred estimates With the patient access scheme discount for tix–cil applied, the company's base case deterministic ICER was £15,201 per quality-adjusted life year (QALY) gained. This was on the hypothetical condition that tix–cil has neutralisation activity against 10% of circulating variants. The committee considered the company's hypothetical scenario to be outside of the single technology appraisal process. The committee can only consider efficacy estimates based on the available evidence at the point of decision making. The committee noted that, at the time of evaluation, tix–cil only likely retained neutralisation activity against around 3% of circulating variants. But it also noted that the company's scenario was relevant for future NICE processes (see section 3.13). It also noted that most of the QALY gain in the company's model came from the direct utility gain that was applied independently of efficacy. The EAG's base case of £54,668 per QALY gained included an assumption that the direct utility gain only applied to 50% of people. The EAG also provided a scenario in which the direct utility gain applied to only 10% of people, resulting in an ICER of £242,097 per QALY gained. But the committee considered the EAG's scenario with the direct utility benefit applied to 10% of people to be the most appropriate of the scenarios it had seen. This resulted in an ICER that would not be in a range that would usually be considered a cost-effective use of NHS resources. It was also conditional on tix–cil having evidence of effectiveness against 10% of circulating variants, which was not the case at the time of the evaluation. The committee thought that there was substantial uncertainty around important elements of the model. So, it was unable to conclude what the preferred ICER range was for tix–cil compared with no preventative treatment. Additionally, the committee was concerned that the uncertainty around the administration setting for tix–cil would mean that the benefit of the confidential patient access scheme may not be realised by all parts of the NHS. # Other factors ## Equality issues The committee discussed the potential equality issues raised during the evaluation. It noted comments from stakeholders that: People eligible for tix–cil are likely to be covered under the Equality Act 2010 because of long-term health problems and disabilities. It may also be harder for people with learning disabilities to implement and maintain protective measures against SARS‑CoV‑2 infection. Some minority ethnic groups are less likely to opt in for vaccination or post-exposure treatments, and are more likely to have health conditions that put them at greater risk of severe COVID‑19. A disproportionate number of people unable to shield are from minority ethnic groups because of the higher likelihood that they are in employment without remote working options. People eligible for tix–cil are also more likely to experience mobility difficulties or be resident in health and social care settings. Travel to treatment centres may be an additional barrier.The committee considered that these were important issues. But its decision was based on a lack of expected clinical effectiveness and so very high ICERs. The committee did not expect its conclusions to differ across these groups. At consultation, patient groups emphasised that people who are immunocompromised should be able to have the same level of protection from COVID‑19 as the general population has through vaccines. They added that immunocompromised people still cannot return to a more normal life, and that addressing the risk of COVID‑19 in people who are immunocompromised must be prioritised. The committee acknowledged there was an unmet need for an effective prophylactic treatment in high-risk groups. But it considered that tix–cil could not meet this need because there was no evidence that it worked against 97% of circulating variants when guidance was produced. ## Severity The company did not make the case for the severity modifier, and the committee agreed that NICE's advice about conditions with a high degree of severity did not apply. ## Uncaptured benefits The committee considered whether there were any benefits not captured by the QALY calculations. The clinical experts noted that, if tix–cil were effective, it may reduce the number of people who are immunocompromised and have COVID‑19. This could ultimately reduce the rate of variant change and mean fewer people being infected. The committee agreed that this was a theoretical benefit of treatment. But it concluded that clinical efficacy with tix–cil had to have been shown to justify this benefit. So, it did not consider that this benefit was relevant for decision making. # Conclusion ## Recommendation The committee agreed that there is an urgent unmet need for an effective prophylactic treatment for people who do not have an adequate response to vaccination. But the committee concluded that tix–cil should not be recommended because it is unlikely to be effective against most of the relevant variants at the time this guidance was produced. For this reason, the committee also considered that managed access was not appropriate. Instead, it concluded that further data collection would be a more appropriate way to resolve the key uncertainties (see section 4).# Recommendations for research The committee acknowledged the need for tix–cil to be evaluated quickly against all new variants. It also suggested that the company enter tix–cil into ongoing platform trials. This would create a real-time link between in vitro and in vivo data. The committee noted the lack of evidence on how the availability of a preventative treatment would affect shielding behaviours, and subsequently affect treatment efficacy. It also noted a lack of data on the relationship between perceived efficacy and direct utility gain. It considered that further research into these areas would be useful.	{'Recommendations': 'Tixagevimab plus cilgavimab is not recommended, within its marketing authorisation, for the pre‑exposure prophylaxis of COVID‑19 in adults who are not currently infected with SARS‑CoV‑2 and who have not had a known recent exposure to someone infected with SARS‑CoV‑2, and:\n\nwho are unlikely to have an adequate immune response to COVID‑19 vaccination, or\n\nfor whom COVID‑19 vaccination is not recommended.\n\nWhy the committee made this recommendation\n\nThe results of clinical studies of tixagevimab plus cilgavimab suggest it reduces infection with SARS‑CoV‑2 (the virus that causes COVID‑19) compared with no preventative treatment. But these studies were done early in the pandemic when different variants of the virus were circulating. More recent studies done in laboratories report that tixagevimab plus cilgavimab is unlikely to prevent infection with most of the variants circulating when this guidance was produced.\n\nBecause of the lack of evidence of clinical effectiveness, the cost-effectiveness estimates for tixagevimab plus cilgavimab are highly uncertain. They are also likely to be much higher than what NICE considers an acceptable use of NHS resources. So, tixagevimab plus cilgavimab is not recommended. Further research is recommended to address some of the uncertainties in this rapidly changing disease area (see section\xa04).', 'Information about tixagevimab plus cilgavimab': "# Marketing authorisation indication\n\nTixagevimab plus cilgavimab (Evusheld, AstraZeneca) has a conditional marketing authorisation for 'the pre‑exposure prophylaxis of COVID‑19 in adults who are not currently infected with SARS‑CoV‑2 and who have not had a known recent exposure to an individual infected with SARS‑CoV‑2 and:\n\nwho are unlikely to mount an adequate immune response to COVID‑19 vaccination, or\n\nfor whom COVID‑19 vaccination is not recommended.'\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for tixagevimab plus cilgavimab.\n\n# Price\n\nThe list price of tixagevimab plus cilgavimab is £800 per 300\xa0mg dose and £1,600 per 600\xa0mg dose (excluding VAT; prices provided by company).\n\nThe company has a commercial arrangement, which would have applied if tixagevimab plus cilgavimab had been recommended.", 'Committee discussion': "The evaluation committee considered evidence submitted by AstraZeneca, a review of this submission by the external assessment group (EAG), a report developed by an in vitro advisory group and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## COVID-19\n\nCOVID‑19 is an acute respiratory illness caused by the SARS‑CoV‑2 virus. Symptoms range from mild and self-limiting to severe with a risk of hospitalisation or death. After the initial SARS‑CoV‑2 infection, people may have ongoing symptoms (long COVID). Some people remain at high risk of serious illness from COVID‑19, despite the availability of vaccines. These are generally people who would not benefit from vaccination or in whom there is not a good enough response to vaccination. This includes people:\n\nwho have had a transplant\n\nwith genetic disorders, some cancers, kidney or liver disease, or immune system disorders\n\nwhose immune response is affected by the drug used to treat their condition.\n\n## Changing variants of concern\n\nThe virus that causes COVID‑19 (SARS‑CoV‑2) has evolved over the course of the pandemic. Throughout most of 2021, Alpha and Delta were the main circulating variants. From late 2021 onwards, the Omicron variant began to dominate. Since then, the Omicron variant has continued to evolve into subvariants, each with different mutations on the spike protein. These changes can affect the continued efficacy of existing treatments, particularly neutralising monoclonal antibodies, because the ability of the treatment to bind to the virus is reduced. The UK Health Security Agency (UKHSA) publishes a monthly technical briefing document, which reports variant prevalence. NICE used the data published in the UKHSA's March 2023 technical briefing 51 (based on all of the UK sequenced samples from 20\xa0to 26\xa0February\xa02023) to determine the variants circulating at the time of this evaluation. Most new cases were the Omicron subvariants BQ.1 and CH.1.1, or XBB lineage subvariants. The committee considered that SARS‑CoV‑2 is rapidly evolving and acknowledged that this makes assessing neutralising monoclonal antibodies difficult. It recalled from the in vitro advisory group report (see section\xa03.11) that the virus evolves in 2\xa0different ways:\n\nFrequent small changes of the virus: new mutations on the spike protein may lead to incremental changes that incorporate many of the same mutations as before. This could be driven by selection pressure, so that viruses with mutations enabling them to evade neutralisation will proliferate.\n\nInfrequent larger shifts of the virus: older versions of the virus may be incubating (for example, in people who are immunocompromised, for whom viral clearance may be slower) and mutate to have an advantage over currently circulating variants (for example, the large change that occurred with the Omicron wave).The committee considered it most likely that new variants would be related to currently circulating variants unless there was a larger shift in the virus. It also considered the possibility that neutralising monoclonal antibodies which currently have low efficacy regain their efficacy against future variants. But it noted that the World Health Organization therapeutics and COVID-19 living guideline states that 'the likelihood of COVID‑19 caused by former variants was extremely low'. So, it considered that the effectiveness of tixagevimab plus cilgavimab (from now, tix–cil) over the appropriate time period for this evaluation would be best indicated by neutralisation potential against currently dominant circulating variants and variants that are currently growing the fastest. The committee noted substantial uncertainty in estimating efficacy for future variants, given the current understanding of COVID‑19 and the rapidly evolving virus. It understood from studies such as OpenSAFELY that, broadly, COVD‑19 is waning in its severity. It understood that this was because immunity to SARS‑CoV‑2 has increased in the general population through vaccination and natural exposure, and because later variants of the virus have reduced in pathogenicity. This means that the risks are now very low for the general population and substantially reduced for most people eligible for tix–cil compared with earlier in the COVID‑19 pandemic. But the committee noted that the risks have not reduced for some groups such as people who have had transplants.\n\n# Patient perspectives\n\n## Ongoing impact of COVID-19\n\nThe patient experts described the ongoing impact of COVID‑19 on their lives and the lives of others with a high risk of severe SARS‑CoV‑2 infection. One patient expert described how modifying their behaviour was mentally and physically exhausting, needing extensive planning for simple tasks like shopping. They described how nothing had changed for them since the start of the pandemic. In fact, they added, the situation had worsened for them because the rest of the country has returned to normal, meaning protective measures are no longer in place. They described how removing measures for limiting viral spread, such as mask wearing, working from home and social distancing, has placed all the responsibility for protection on individuals. They added that people who are immunocompromised need to navigate multiple environments that no longer have the COVID‑19 mitigation measures that they value. Another patient expert described how they are only able to leave the house for routine medical appointments, and are on high alert to minimise the risk of infection whenever possible. Both patient experts also highlighted that the burden of responsibility extends to household family members, and affects work life and family relationships. People reported that their finances had been affected because of a lack of government support and increased costs of shielding. For people with children, there were concerns about the disruption of education on life chances and the long-lasting impact of this. They said that the availability of a preventative treatment that reduces infection risk could reduce the need for exhausting and isolating behavioural changes. The committee agreed that there is an urgent unmet need for a preventative therapy that would reduce the risk of SARS‑CoV‑2 infection for people at high risk of severe infection for whom vaccination is not suitable or does not provide sufficient protection.\n\n## Benefits of tix–cil\n\nThe patient experts discussed their experiences of having tix–cil. One described their relief after having it. They explained that, even after treatment with tix–cil, they continued to be careful and still maintained social distancing. They acknowledged that tix–cil may not stop all SARS‑CoV‑2 infections, and that returning to normal would be a gradual process as their confidence in the treatment increased. Another patient expert agreed and added that, since having tix–cil, they have met people face to face, but continue to wear a mask and avoid crowded spaces. They added that, even with tix–cil, and with treatments for severe SARS‑CoV‑2 infection now available, this is not enough for them to abandon all caution.\n\n# Decision problem\n\n## Eligible population\n\nThe company explained in its original submission that it was positioning tix–cil in a narrower population than that of the marketing authorisation and the final NICE scope. That is, it positioned it in people who are at the 'highest risk of an adverse COVID‑19 outcome'. In the original company submission, the company referred to the report produced by the independent advisory group set up by the Department of Health and Social Care (DHSC) to identify people at the very highest risk of an adverse COVID‑19 outcome for treatment with antivirals and neutralising monoclonal antibodies. See the DHSC's independent report on the highest-risk subgroups with SARS-CoV-2 when considering neutralising monoclonal antibodies and antiviral drugs (from now, referred to as the McInnes report). The committee noted that a similar report, the independent advisory group report concerning the use of COVID-19 directed antibodies in the prophylaxis setting in the highest-risk clinical subgroups, had been produced by the same group. This stratified cohorts in order of risk. The committee recalled that the wording in the marketing authorisation for tix–cil included 'those unlikely to mount an adequate immune response to COVID‑19'. It considered that this would include people in groups\xa0A1, A2\xa0and\xa0B of the independent advisory group's report. In response to consultation, the company considered that its target population should include people in groups\xa0A1 and\xa0A2, and people in group\xa0B without a serological response to vaccination. The clinical experts broadly agreed that the groups in the independent advisory group report aligned with the expected level of antibody response to vaccination. They also thought that people in groups\xa0A1 and\xa0A2 were likely to have the poorest response and so be at the greatest risk of severe SARS‑CoV‑2 infection. But they cautioned that the groups represent a spectrum of risk and that there was likely to be substantial heterogeneity within groups as well as across groups. The clinical experts added that some people may have poor outcomes despite having a response to vaccination. At the second meeting, the clinical experts and NHS England commissioning expert confirmed that serological testing to check response to vaccination is not done routinely in the NHS. So, they thought it was unclear how this would work in clinical practice for people in group\xa0B. The committee noted that, in people having a treatment that would place them in group\xa0B in the MELODY study, between 7.6% and 13.5% had no detectable antibodies after vaccination. So, the committee concluded that many people in group\xa0B would have to be tested to identify a single person eligible for treatment. It considered that the costs of this would be significant and had not been included in the company's model. The EAG noted that many of the inputs in the economic analysis were selected to reflect particular groups. So, it thought that they did not represent the eligible population as a whole and did not capture the heterogeneity within the eligible population. The committee agreed with the EAG that estimates of clinical and cost effectiveness would vary across different risk-based groups because of heterogeneity. At consultation, it was highlighted that certain groups may be at a higher risk of hospitalisation or death than the eligible population as a whole. For example, people with solid organ transplants may have more severe consequences of SARS‑CoV‑2 infection, such as transplant failure. The committee acknowledged the higher risk and costs in these groups. It considered that focusing on the most severe subgroups would reduce the decision risk. The committee added that, ideally, heterogeneity could be explored by considering separate subgroups in the economic model. But it noted that it had not seen evidence of differential clinical or cost effectiveness to rule out other groups covered by the marketing authorisation. So, it maintained that the eligible population should be all groups covered by the marketing authorisation.\n\n## Treatment schedule\n\nThe summary of product characteristics for tix–cil recommends a dose of 300\xa0mg. It states that a higher dose of 600\xa0mg may be more appropriate for some SARS‑CoV‑2 variants (such as Omicron BA.1 and BA1.1) that show reduced susceptibility to tix–cil in vitro. So, the company used the cost of the higher 600\xa0mg dose in its economic analysis. The summary of product characteristics also states that tix–cil may be effective for pre‑exposure prophylaxis for 6\xa0months after administration. In its original submission, the company assumed that the initial 600\xa0mg dose was followed 6\xa0months later by a second 600\xa0mg dose. The EAG noted that this was not aligned with the summary of product characteristics. This says that tix–cil has only been studied in single-dose studies, and that no safety and efficacy data is available for repeat dosing. The committee was aware that the Medicines and Healthcare products Regulatory Agency (MHRA) had clarified to NICE that repeat dosing of tix–cil is outside the marketing authorisation and would be off-label use. Technology appraisal guidance recommendations must be within the marketing authorisation, so the committee concluded that the economic analysis should only include a single dose of tix–cil. In response to consultation, the company updated its model to only include a single dose of tix–cil. The committee was satisfied with the updated approach.\n\n# Clinical effectiveness\n\n## Outcomes\n\nThe company presented treatment outcomes in line with the NICE scope. These included reduction in risk and severity of SARS‑CoV‑2 infection, and improvements in anxiety, depression and health-related quality of life. The committee considered these appropriate outcomes for a preventative treatment. But the committee noted that there were interactions between outcomes that had not been considered by the company, including:\n\nThe interaction between the perceived efficacy of treatment and direct utility gain resulting from a reduction in shielding: the committee considered that, as perceived efficacy reduces, the reduction in shielding will also likely reduce, resulting in a reduced direct utility gain.\n\nThe interaction between the extent of shielding and the risk of infection and severe outcomes: the committee considered that, as shielding reduces, the risk of infection and severe outcomes will increase.The patient experts at the first committee meeting explained that some shielding behaviours such as social distancing were likely to continue to some extent after having tix–cil (see section\xa03.4). They said that individual decisions about shielding behaviours can take into account many different factors. These factors include the risk from their underlying condition, the current risk posed by SARS‑CoV‑2 and other viruses, and the trust in the effectiveness of the treatment against current variants. People may also take into account the time of year, whether they have upcoming medical appointments and societal attitudes towards protective behaviour (such as mask wearing on public transport and using lateral flow tests). The committee considered that any change in shielding will depend on an individual's estimate of the risk reduction available from tix–cil and their degree of risk aversion. It noted that it is also important to understand how much shielding is because of COVID‑19 risks and how much is related to other factors. The committee considered that, for people who are not shielding, having an effective preventative treatment would reduce the risk of severe illness and death but not result in any quality-of-life benefit from stopping shielding. Whereas, for people who are fully shielding, it thought that having an effective preventative treatment would allow them to stop shielding so their quality of life would be improved but their overall risk of infection would be the same. The committee considered that there would be many people who have a mixture of both direct utility gain and a reduced risk of infection. For example, this would be the case if they are partially shielding or cannot shield and this causes them anxiety. But the committee concluded that no one would have the full benefit of risk reduction and the full direct utility gain from stopping shielding, as was assumed by the company. The committee considered that the company's model may have double counted the benefit of treatment. This was because it incorporated a reduction in risk for people who are fully and effectively shielding (and who are not at risk) as well as a direct utility benefit. It noted that the company had not provided any data on the relationship between efficacy, direct utility gain, shielding behaviours and increased infection risk. It also noted that the company had not modelled this relationship, so the impact on cost-effectiveness estimates could not be explored. The committee concluded that the company's model likely overestimated the benefit of treatment.\n\n## PROVENT trial\n\nThe company presented evidence from a phase\xa03, randomised, double-blind, placebo-controlled trial (PROVENT, Levin et al. 2022). PROVENT compared tix–cil (n=3,460) with placebo (n=1,737) for preventing SARS‑CoV‑2 infection in adults at increased risk of an inadequate response to vaccination or at an increased risk of SARS‑CoV‑2 infection. The results from PROVENT showed that tix–cil was associated with a statistically significant reduction in the incidence of COVID‑19 (reverse transcription polymerase chain reaction-positive symptomatic illness) compared with placebo, with a relative risk reduction of 76.7% (equating to an absolute risk reduction of 0.8%). The company noted several limitations with the PROVENT trial:\n\nmost participants were not at high risk of a severe COVID‑19 outcome\n\nparticipants were unvaccinated\n\nit took place before there were significant levels of natural immunity in the population from prior infection\n\nit took place when earlier variants of COVID‑19 were prevalent and before newer variants emerged.Because of these limitations, the company did not include efficacy data from PROVENT in its economic model, despite using it as the randomised evidence for efficacy for its marketing authorisation application. The EAG also had other concerns, including:\n\nthe overall small number of infection events\n\nthe small proportion of participants on immunosuppressive treatments or with immunosuppressive disease\n\nthe need for all participants to have a negative point-of-care COVID‑19 test, which is not expected in clinical practice.The committee noted that the context of the disease was very different at the time of the PROVENT trial. It also noted that there was no information reported about how people in either arm modified their behaviour during the trial, which is particularly important for preventative treatments.\n\n## Observational evidence\n\nThe company presented data from 2\xa0observational evidence studies, Young-Xu et al. (2022) and Kertes et al. (2022). Young-Xu et al. was a retrospective cohort study in US veterans who were immunocompromised (92%) or otherwise at high risk of COVID‑19 (8%). People were recruited between January\xa0and April\xa02022, at the time when Omicron variants BA.1, BA.2 and BA.2.12.1 were circulating. A total of 1,733\xa0people had tix–cil. One 600\xa0mg dose of tix–cil was given to 83% of participants; the rest had a 300\xa0mg dose. The outcomes of the study were SARS‑CoV‑2 infection, COVID‑19-related hospitalisation and all‑cause mortality. To generate estimates of comparative effectiveness, the study compared outcomes for people on tix–cil with propensity-matched controls (n=6,354). The resulting hazard ratios were 0.34 (95% confidence interval [CI] 0.13\xa0to\xa00.87) for SARS‑CoV‑2 infection; 0.13 (95%\xa0CI 0.02 to\xa00.99) for COVID‑19-related hospitalisation and 0.36 (95%\xa0CI 0.18\xa0to\xa00.73) for all‑cause mortality. Kertes et al. was a retrospective cohort study done in people who were immunocompromised and considered at high risk for SARS‑CoV‑2 infection and complications. People were recruited to the study between February\xa0and May\xa02022 at the time when Omicron variants BA.1 and BA.2 were circulating. A total of 825\xa0people had one 300\xa0mg dose of tix–cil. Compared with 4,299\xa0people who did not have tix–cil, the odds ratio of SARS‑CoV‑2 infection was 0.51. The company considered that Young-Xu et al. provided the most robust evidence, and so used it for its base case for the economic model. The EAG had concerns about the methods and generalisability of both observational studies. It highlighted the wide confidence intervals and potential for residual confounding for Young-Xu et al. It added that most of the US veterans were men and older, so the population may not be generalisable to that likely to be offered tix–cil in the UK. For Kertes et al., the EAG had concerns about the potential for selection bias, residual confounding and the shorter follow up in the treatment group than in the control group. The committee noted these limitations. It added that, for both studies, there would likely be systematic differences between people who sought tix–cil treatment and people in the control group who were eligible for tix–cil but did not have treatment.\n\n## Generalisability to the current circulating SARS-CoV-2 variants\n\nIn addition to the generalisability concerns discussed in section\xa03.8 and section\xa03.9, the committee had concerns about generalisability of the company's evidence to the current circulating SARS‑CoV‑2 variants. None of the clinical studies included evidence of efficacy against variants around at the time of this evaluation because of the rapidly evolving nature of the SARS‑CoV‑2 virus. The observational studies were done when the early Omicron variants BA.1, BA.2 and BA.2.12.1 were circulating, so their generalisability to the current UK context is unclear. The committee acknowledged the difficulties in doing trials in a rapidly evolving disease area, but it still considered that the evidence was too uncertain. It considered that in vitro data (from laboratory studies) may provide additional information as to whether there was a realistic clinical possibility of the technology retaining efficacy against currently circulating variants (see section\xa03.12).\n\n## In vitro advisory group\n\nNeutralising monoclonal antibodies such as tixagevimab and cilgavimab target the spike protein of the SARS‑CoV‑2 virus. Mutations on the spike protein can quickly reduce the effectiveness of such treatments. This means that clinical trials done when older variants of SARS‑CoV‑2 were circulating may no longer apply in the current setting, so other types of evidence are needed. In vitro neutralisation assays can be used to assess whether treatments neutralise new variants, and so whether they retain clinical effectiveness over time as the virus evolves. An advantage of in vitro evidence is that it can be generated much faster than it takes to do clinical trials. But NICE's technology appraisal committees are not used to interpreting and appraising in vitro data. Because of this, NICE commissioned an in vitro advisory group made up of experts in infectious disease, virology, vaccine epidemiology, immunology and pharmacology. They developed a decision framework to link the in vitro neutralisation data to clinical outcomes, and their report (the in vitro advisory group report in NICE's draft guidance consultation committee papers) provided guidance on interpreting in vitro evidence.\n\n## In vitro studies\n\nGuided by the in vitro advisory group, the committee identified 5\xa0studies that investigated tix–cil's ability in vitro to neutralise a range of SARS‑CoV‑2 variants and subvariants, including some of those circulating at the time of the evaluation. Because the landscape is rapidly evolving, a systematic review of the in vitro data was not possible. Studies by Cao et al. (2022) and Wang et al. (2022) reported no neutralisation activity for tix–cil against the Omicron subvariant BQ.1. Studies by Wang et al. (2023), Cao et al. (2023) and Imai et al. (2023) reported no neutralisation activity of tix–cil against XBB. During the first committee meeting, the committee recalled from the in vitro advisory group report that, if there was no neutralisation activity in vitro, this would suggest no clinical efficacy in people. The company and clinical experts considered that tix–cil may not be clinically effective against many new variants but considered that it could still be effective against some of them. One clinical expert also noted that it was possible that tix–cil may regain efficacy against future variants. The committee noted the company's and experts' views. But it considered that the prevalence of older variants against which tix–cil had shown in vitro efficacy (BA.5 and BA.2) was low and decreasing over time because of the relative speed of growth of other subvariants. The committee noted that subvariants that were not investigated in the in vitro studies, such as CH.1.1, had specific mutations that would likely be associated with reduced or no neutralisation activity of tix–cil. The committee acknowledged that there was the possibility for tix–cil to regain activity against future variants, but considered that the likelihood of this was low. In response to consultation, the company proposed that an appropriate threshold for neutralisation in vitro equating to clinical effectiveness in vivo should be an IC50 of less than 10,000\xa0nanograms per millilitre. The committee recalled the in vitro advisory group's conclusions in circumstances when there is a substantial change in neutralisation activity but some neutralisation is retained in vitro. In these circumstances, the advisory group concluded pharmacokinetic and pharmacodynamic (PK/PD) data is needed to try to link in vitro neutralisation data to clinical outcomes. Without PK/PD data, it is not possible to determine how a change in neutralisation activity may be associated with clinical outcomes. So, the committee did not consider the company's proposal to be appropriate for decision making. Full details are in the in vitro advisory group report in NICE's draft guidance consultation committee papers. The committee noted a recent update from the European Medicines Agency's emergency task force, which cautioned that neutralising monoclonal antibodies currently authorised for COVID‑19 are unlikely to be effective against emerging strains of SARS‑CoV‑2. Shortly after the first committee meeting, the US Food and Drug Administration (FDA) also announced that tix–cil was no longer authorised for emergency use in the US. This was because it was unlikely to be effective against the variants responsible for more than 90% of infections. At the first meeting, the committee concluded that tix–cil was unlikely to retain sufficient neutralisation activity against most variants circulating at the time this guidance was produced. The committee noted there was uncertainty in relying solely on in vitro evidence. It would have preferred to triangulate the data with real-world evidence. But, in the context of changing variants, it considered the in vitro data for current variants more relevant to decision making than the older real-world studies in the company's submission. In response to consultation, the company acknowledged that it was reasonable to assume that total loss of neutralisation in vitro would mean no clinical effect. At the second meeting, the committee considered data from the UKHSA's March 2023 technical briefing 51. This briefing showed that there were only around 3% of circulating variants (BA.2 and BA.5) that tix–cil may be effective against. So, the committee concluded that there was no evidence that tix–cil would neutralise at least 97% of circulating variants as of March\xa02023.\n\n## Rapid evaluation process\n\nDuring the first committee meeting, the patient experts expressed frustration that the COVID‑19 virus is evolving rapidly. They said that there needs to be a faster mechanism to ensure effective preventative medicines are available when needed, particularly in winter when meeting people outside is more difficult. During consultation, the company and stakeholders agreed that a more flexible and responsive evaluation process is needed. They also thought that a system needs to be in place to monitor current variant mix because tix–cil may regain efficacy against future variants. The company suggested that an approach similar to that of the FDA should be adopted. The FDA has limited tix–cil's use to when the combined frequency of non-susceptible SARS‑CoV‑2 variants nationally is less than or equal to 90% (that is, when 10% or more variants are susceptible to neutralisation by tix–cil). The committee considered that, under the current single technology appraisal process, it could only make decisions based on the data available at the time of the committee meeting. But it noted that a more flexible evaluation process for COVID‑19 technologies is currently being developed by NICE. Further details of the proposed process are provided in NICE's consultation document for the COVID-19 technology appraisal recommendations: surveillance and rapid update process statement.\n\n# Cost effectiveness\n\n## Economic model\n\nThe company's economic model consisted of a decision tree followed by a Markov model. The decision tree captured the impact of tix–cil on COVID‑19 over the 6\xa0months after preventative treatment and the 29‑day (acute) period for anyone who was infected. The Markov model extrapolated survival and quality of life over the person's lifetime. The model assumed a direct utility benefit for everyone in the tix–cil arm, and an efficacy benefit from a reduced risk of SARS‑CoV‑2 infection and a reduced COVID-19 severity. The EAG considered the model structure to be appropriate, except for the company's handling of COVID‑19 cases occurring after the initial treatment period. The model structure did not allow for these people developing long COVID. The EAG thought that it would have been better if the company had attempted to model COVID‑19 cases occurring after the initial treatment period using a model structure that tracked the number of people remaining at risk of long COVID over time. It thought that the company's model structure may have overestimated the benefit of tix–cil. This was because the model assumed that people who avoid COVID‑19 during the initial treatment period by having tix–cil are then subsequently protected from long COVID. The committee noted the uncertainties in the model structure, particularly the challenge of considering a lifetime time horizon despite the uncertain natural history of COVID‑19 and future variants. It acknowledged that it would be difficult to model the impact of COVID‑19 accurately after the initial treatment period because SARS‑CoV‑2 is constantly evolving. The committee considered the model structure to be broadly appropriate. But it considered that key model inputs were highly uncertain, and that this resulted in highly uncertain cost-effectiveness estimates (see sections\xa03.16 to\xa03.20). The committee also noted that the interaction between many parameters had not been accounted for in the company's model (see section\xa03.7 and section\xa03.16).\n\n## Efficacy\n\nIn its original submission, the company used efficacy data from the observational evidence study by Young-Xu et al. (2022; see section\xa03.9). This study showed that tix–cil reduced the risk of symptomatic SARS‑CoV‑2 infection and hospitalisation related to COVID‑19. In response to consultation, the company acknowledged the in vitro data discussed in section\xa03.12. It agreed that it had to be reasonable to assume that total loss of neutralisation in vitro would mean no clinical effect. But the company suggested that a more flexible approach was needed and that tix–cil should be recommended if it shows activity against a specific threshold of circulating SARS‑CoV‑2 variants. This approach is discussed further in section\xa03.13. The company suggested a hypothetical threshold for neutralisation against circulating variants of 10% in line with the FDA's approach. To implement this in the model, the company assumed that the relative risk reduction for SARS‑CoV‑2 infection based on Young-Xu et al. was reduced to 10% of its original value, resulting in a relative risk reduction for infection of 6.6%. The EAG preferred to apply the 10% multiplier to the relative risk reduction for both infection and hospitalisation. This was because the company's base case still assumed a treatment effect based on Young-Xu et al. for the relative risk reduction of hospitalisation. The committee preferred the EAG's approach. But it noted that the 10% multiplier applied by both the company and EAG was still only hypothetical and much higher than the efficacy at the time of the second committee meeting (around 3%; see section\xa03.12).\n\n## Evidence for a direct utility gain\n\nThe company did a utility study to investigate the impact of the pandemic on people who are immunocompromised (Gallop et al. 2022). Subgroups in the study included people who were fully shielding, partially shielding and no longer shielding. The study collected quality-of-life data using the EQ‑5D‑5L questionnaire from people who were immunocompromised and had not had a preventative treatment (untreated group). The EQ‑5D‑5L rating for each state was scored for UK preference weights, using a mapping function to map from EQ‑5D‑5L to EQ‑5D‑3L. The study compared results with a hypothetical treated group using a vignette (a set of short statements describing the experience of a typical person having treatment). The vignette asked people to imagine a medicine that gives them 'a level of protection from COVID‑19 which is similar to that given by vaccination in individuals who have a healthy immune system'. The utility gain for each subgroup was calculated as the difference between utility scores for the untreated and treated groups. The resulting utility gains were weighted according to the proportions shielding and partially shielding based on a survey by the Office for National Statistics. This gave a final utility gain of 0.098. In its updated model, the company applied the direct utility gain to everyone having tix–cil for 6\xa0months after treatment (3\xa0months for people who were infected with SARS‑CoV‑2, to account for their loss of confidence in protective treatment). The EAG highlighted several limitations with the company's vignette study. It considered that the vignette used in the study did not align with the effectiveness evidence for tix–cil. This was because there was no evidence that tix–cil provides comparable efficacy to vaccination in people with a healthy immune system. In response to consultation, the company provided supportive evidence for the direct utility gain from an academic-in-confidence study. The EAG noted multiple issues with the company's supportive evidence. The committee agreed with the EAG's concerns about the company's evidence for direct utility gain. The committee recalled the patient experts' comments that some shielding behaviours were likely to continue to some extent after having tix–cil (see section\xa03.7). So, it concluded that the magnitude of the utility gain based on the company's evidence was not reflective of the anticipated utility gain for the group likely to have tix–cil in clinical practice.\n\n## Application of direct utility gain in the economic model\n\nIn its original submission, the company assumed that the direct utility gain should apply to everyone, regardless of whether they are shielding, partially shielding or not shielding. At consultation, the company updated its base case to apply the utility gain to the 82% of people shielding or partially shielding only, based on the survey by the Office for National Statistics. This was to align with the EAG's preference at the time of the first committee meeting. In its critique of the company's consultation response, the EAG noted that the company's vignette study reported that 50% of people would return to their pretreatment behaviour if there was a new variant against which tix–cil was not effective. The EAG noted that the in vitro data presented at the first committee meeting showed no neutralisation for tix–cil against most circulating variants. So, the EAG updated its base case to apply direct utility gain to only 50% of people. The EAG noted that the company's utility study did not specify a situation in which there could be no efficacy against 90% of circulating variants (as per the company's hypothetical base case). The EAG considered that, if tix–cil were to be offered when it was known to neutralise only 10% of circulating variants, this may not provide sufficient reassurance for most people to stop shielding. So, the EAG explored a scenario assuming that only 10% of people experience a direct utility gain. The patient experts at the second committee meeting considered that they would still have a utility benefit from treatment in situations in which tix–cil is only effective against 10% of circulating variants. At consultation, patient groups considered that even people who are not currently shielding because they are unable to could also benefit from prophylaxis because it could reduce anxiety. The committee considered that there was a complex relationship between the perceived efficacy of tix–cil, the direct utility gain through reducing shielding and the increased risk of infection that would result from reducing shielding (see section\xa03.7). This relationship had not been modelled by the company. The committee considered that the extent of the direct utility gain would likely differ across patient groups. But it considered that most people would be reluctant to change their behaviour if they were told that treatment would only prevent 1\xa0out of 10\xa0infections, with the additional uncertainty that any remaining benefit of treatment could reduce as variants evolve. The committee concluded that the direct utility gain had been overestimated in both the company's and EAG's base cases. The committee considered the EAG's scenario in which direct utility gain was applied to only 10% of people to be more appropriate than both base cases. But the committee concluded that many people may not feel confident enough in treatment to change their behaviour in the company's hypothetical situation in which tix–cil is effective against 10% of variants. It thought that this could result in no direct utility gain. At the time of the second committee meeting, the committee considered that there was no evidence of effectiveness against 97% of circulating variants. This meant that the actual utility gain would have been much lower and the incremental cost-effectiveness ratio (ICER) would have been much higher than in the EAG's scenario.\n\n## Administration costs\n\nIn its original submission, the company said that tix–cil should be offered as part of routine outpatient appointments or through secondary care-led community services. It originally assumed a cost per administration of £41, based on 1\xa0hour of band\xa05 hospital nurse time. It later updated its administration cost to £216 per administration based on the cost used by NHS England in the budget impact assessment for tix–cil. During the meeting, the company revised its suggested cost for administration to be half of this. The company explained that this was because the cost of £216 is for 2\xa0doses of tix–cil, but tix–cil is given as a single dose. The EAG did not think that the cost of delivering tix–cil had been properly accounted for by the company. This was because it was not clear whether everyone who was eligible would be having routine appointments often enough to have tix–cil in such an appointment soon after it became available. Also, it thought that the 1‑hour observation period after administration required by the marketing authorisation may be impractical in a hospital setting. The EAG preferred to use a cost based on administration in COVID‑19 Medicine Delivery Units (CMDUs). It considered the CMDU unit cost of £410 per administration of an oral antiviral to better reflect the cost for administering tix–cil. This was because it thought that a similar bespoke system would be needed to implement tix–cil in the NHS. At the first meeting, an integrated care system commissioning expert explained that their preference was for tix–cil to be delivered in primary care. This was because administration is relatively simple and there is additional complexity implementing the treatment in secondary care. At the second meeting, the NHS England expert explained that the setting in which tix–cil would be given is unclear. They advised that the committee should consider both the company's and EAG's estimates for the cost of administration. The committee concluded that the administration setting for tix–cil is uncertain. It considered both the company's and EAG's administration costs in its decision making.\n\n## Infection risk without tix–cil\n\nTo generate estimates of comparative effectiveness, the company estimated the risk of SARS‑CoV‑2 infection for people who did not have tix–cil. The relative risk reduction associated with treatment was applied to this risk to calculate the risk of infection for people having tix–cil. The company assumed the risk of symptomatic infection for people not having tix–cil was 22.58% annually. This was based on the average 7‑day risk of reporting a positive test for SARS‑CoV‑2 in the general population of England between August\xa02021 and August\xa02022. The EAG highlighted that historical risks may not reflect current or future risks because this depends on circulating variants and protection offered by vaccines. It added that data for the general population may not be generalisable to people likely to have tix–cil. The committee initially considered it likely that the risk of infection in people eligible for tix–cil may be lower than the general population. This is because they modify their behaviour, which remains an effective way to reduce risk of infection, despite the substantial burden. It added that it was uncertain how risk may vary across different risk-based groups. The committee considered that further research is needed to understand the background risk of infection in different populations. It considered that in the interim, a range of scenario analyses would help inform the sensitivity of the model to changes in the background risk of infection. In response to consultation, the company provided scenario analyses varying the risk of symptomatic infection in people not having tix–cil by 20% above and below the value used in its base case. The EAG did not consider this sufficient to cover the broad uncertainty about future risk of infection. The EAG added that the period used to estimate risk included the large peak of cases in late\xa02021 and early\xa02022. Restricting this period to estimate the risk in the last 3\xa0months of data provided by the company (May\xa0to August\xa02022) provided an annualised risk of 8%. This was much lower than the lower bound estimate tested in the company's scenario analysis. The EAG explored the impact of scenarios halving and doubling the risk assumed in the company's base case. During the second meeting, the patient experts explained that a lack information to help them assess risk (outbreaks, case numbers) in local areas makes it more challenging for people who are immunocompromised to avoid infection. The committee acknowledged that testing for SARS‑CoV‑2 has now been significantly reduced. This means general population data may no longer be representative of actual case numbers. It also heard that patterns of infection in the general population are different now that COVID‑19 is endemic. This is because rate of infection is driven by population-level resistance to mutations rather than the population transmission seen earlier in the pandemic that led to distinct waves of infection. The committee noted that the company had not provided any new data for the target population for the risk of infection in people not having tix–cil, so the risk was still uncertain. It concluded that, given the high uncertainty, both of the EAG's scenarios (halving and doubling the risk) should be considered in decision making.\n\n## Hospitalisation risk without tix–cil\n\nThe company estimated the risk of hospitalisation caused by COVID‑19 for people who have not had tix–cil. The company's preferred source of data to estimate this risk was a study by Shields et al. (2022). This study assessed how vaccination affected hospitalisation and mortality for people with primary and secondary immunodeficiency in the UK. Based on Shields et al., the hospitalisation rate for SARS‑CoV‑2 infection in the Omicron wave for people who did not have treatment was 15.9%. At the first meeting, the committee noted that the Shields et al. estimate was much higher than an estimate from Patel et al. (2022), which was considered in NICE's technology appraisal guidance on casirivimab plus imdevimab, nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19. Patel et al. was a retrospective cohort study of people who had early treatment for, or who were diagnosed with, COVID‑19 between 1\xa0December\xa02021 and 31\xa0May\xa02022. The study reported that 2.8% of people who had not had treatment were hospitalised with COVID‑19 as the primary diagnosis. The committee concluded that Patel et al. included people eligible for COVID‑19 treatment under the criteria defined by the McInnes report (see section\xa03.5). These criteria better aligned with the full marketing authorisation for tix–cil, but not with the subgroup used in the economic modelling. In response to consultation, the company stated that Patel et al. considered a broader population than the company are targeting. In addition, the company and other stakeholders highlighted that certain groups such as people with solid organ transplants or people with lymphoma or leukaemia may be at a much higher risk of hospitalisation or death due to COVID-19 than the eligible population as a whole. Stakeholders emphasised the need for separate analyses in these subgroups. In its critique of the company's response to consultation, the EAG acknowledged that specific patient groups are likely to have a higher hospitalisation risk. It noted that the company's model did not consider specific subgroups. So, it considered that the best approach was to use the average risk reported across the population in the marketing authorisation as provided by Patel et al. The EAG assumed a hospitalisation risk of 2.8% based on Patel et al. in its base case. But it explored higher rates of hospitalisation in its scenario analysis to reflect the potential higher risk in some specific groups. The committee had seen evidence from the OpenSAFELY study that validated the Patel et al study. OpenSAFELY calculated the hospitalisation rate for people at highest risk of hospitalisation (as outlined in the McInnes report) to be about 2.4%. It also calculated the hospitalisation rate for a subgroup of this group with renal impairment to be about 4.0%. During the second committee meeting, the clinical experts explained that SARS‑CoV‑2 has become less pathogenic and has caused less severe COVID‑19 as it has mutated. They noted that people with COVID‑19 are now more likely to present with upper rather than lower respiratory tract infections, and that these are less severe. The committee considered that this meant that changes in the pathogenicity of the virus will result in changes to the hospitalisation rate. It concluded that the rate of hospitalisation is uncertain, but the estimate based on Shields et al. was high. The committee added that the estimate in Shields et al. was unlikely to represent the current risk of hospitalisation for most people eligible for treatment according to the marketing authorisation. The committee preferred to assume a hospitalisation rate closer to Patel et al., but noted that the rate would be dependent on the risk group under consideration (see section\xa03.5).\n\n## Long COVID\n\nThere were several differences between the company's and EAG's base case for long-COVID parameters. The cumulative impact of these assumptions on the ICER was substantial. Compared with the company's submission, the EAG preferred to assume a:\n\nlower risk of long COVID for people not hospitalised\n\nshorter duration of long COVID\n\nlower cost of managing long COVID\n\nsmaller impact of long COVID on long-term utility.In response to consultation, the company updated its base case to align with the EAG's preference for the cost and utility impact of long COVID. But the risk of long COVID for people not hospitalised and the duration of long COVID remained the same as for the first committee meeting. The committee considered that there was substantial uncertainty about the effects of long COVID. It also thought that it was unclear how long-COVID assumptions interact with the other modelled elements, for example, the risk of infection. It preferred the EAG's estimates because these were more closely aligned with the estimates used in NICE's technology appraisal guidance on casirivimab plus imdevimab, nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19.\n\n## Invasive mechanical ventilation\n\nTo determine hospitalisation costs for acute COVID‑19, estimates of the distribution across levels of hospitalisation care are needed. The company's model assumed that this distribution is the same for anyone hospitalised, regardless of whether they had prophylaxis with tix–cil. Levels of hospitalisation care included in the model were 'no oxygen', 'low-flow oxygen', 'non-invasive ventilation or high-flow oxygen' and 'invasive mechanical ventilation (IMV) or extra corporeal membrane oxygenation (ECMO)'. The company used a study by Cusinato et al. (2022), which considered data from a single UK\xa0hospital averaged across the first and second waves of COVID‑19. Based on Cusinato et al., the proportion needing IMV was 15.40%. The EAG noted that Cusinato et al. provided data estimated separately for the first and second waves of COVID‑19 and that the proportion needing IMV during the second (Omicron) wave was much lower than during the first wave. In its base case, the EAG preferred to use an estimate for the proportion needing IMV based on data for the general population. Based on this data, the proportion needing IMV was 4.92% for the year up to October\xa02022 and 2.51% for the most recent 3\xa0months (August\xa0to October\xa02022). The EAG preferred to use the upper estimate of 4.92% because it acknowledged that the proportion of people on IMV may be higher in the population likely to be eligible for tix–cil. The committee agreed with the EAG that the risk of needing IMV had reduced since the start of the pandemic, and that data from the Omicron wave was more generalisable to the current situation. The clinical experts explained that the risk of needing IMV may be lower in people who are immunocompromised than in the general population. This is because of a reduced risk of hyperinflammatory reactions. The committee noted that, in NICE's technology appraisal guidance on casirivimab plus imdevimab, nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19, the proportion needing IMV was 4.12%, which is closer to the EAG's preferred base case. It concluded that the EAG's estimate for the proportion needing IMV was preferred.\n\n# Cost-effectiveness estimates\n\n## Committee's preferred estimates\n\nWith the patient access scheme discount for tix–cil applied, the company's base case deterministic ICER was £15,201 per quality-adjusted life year (QALY) gained. This was on the hypothetical condition that tix–cil has neutralisation activity against 10% of circulating variants. The committee considered the company's hypothetical scenario to be outside of the single technology appraisal process. The committee can only consider efficacy estimates based on the available evidence at the point of decision making. The committee noted that, at the time of evaluation, tix–cil only likely retained neutralisation activity against around 3% of circulating variants. But it also noted that the company's scenario was relevant for future NICE processes (see section\xa03.13). It also noted that most of the QALY gain in the company's model came from the direct utility gain that was applied independently of efficacy. The EAG's base case of £54,668 per QALY gained included an assumption that the direct utility gain only applied to 50% of people. The EAG also provided a scenario in which the direct utility gain applied to only 10% of people, resulting in an ICER of £242,097 per QALY gained. But the committee considered the EAG's scenario with the direct utility benefit applied to 10% of people to be the most appropriate of the scenarios it had seen. This resulted in an ICER that would not be in a range that would usually be considered a cost-effective use of NHS resources. It was also conditional on tix–cil having evidence of effectiveness against 10% of circulating variants, which was not the case at the time of the evaluation. The committee thought that there was substantial uncertainty around important elements of the model. So, it was unable to conclude what the preferred ICER range was for tix–cil compared with no preventative treatment. Additionally, the committee was concerned that the uncertainty around the administration setting for tix–cil would mean that the benefit of the confidential patient access scheme may not be realised by all parts of the NHS.\n\n# Other factors\n\n## Equality issues\n\nThe committee discussed the potential equality issues raised during the evaluation. It noted comments from stakeholders that:\n\nPeople eligible for tix–cil are likely to be covered under the Equality Act\xa02010 because of long-term health problems and disabilities. It may also be harder for people with learning disabilities to implement and maintain protective measures against SARS‑CoV‑2 infection.\n\nSome minority ethnic groups are less likely to opt in for vaccination or post-exposure treatments, and are more likely to have health conditions that put them at greater risk of severe COVID‑19.\n\nA disproportionate number of people unable to shield are from minority ethnic groups because of the higher likelihood that they are in employment without remote working options.\n\nPeople eligible for tix–cil are also more likely to experience mobility difficulties or be resident in health and social care settings. Travel to treatment centres may be an additional barrier.The committee considered that these were important issues. But its decision was based on a lack of expected clinical effectiveness and so very high ICERs. The committee did not expect its conclusions to differ across these groups. At consultation, patient groups emphasised that people who are immunocompromised should be able to have the same level of protection from COVID‑19 as the general population has through vaccines. They added that immunocompromised people still cannot return to a more normal life, and that addressing the risk of COVID‑19 in people who are immunocompromised must be prioritised. The committee acknowledged there was an unmet need for an effective prophylactic treatment in high-risk groups. But it considered that tix–cil could not meet this need because there was no evidence that it worked against 97% of circulating variants when guidance was produced.\n\n## Severity\n\nThe company did not make the case for the severity modifier, and the committee agreed that NICE's advice about conditions with a high degree of severity did not apply.\n\n## Uncaptured benefits\n\nThe committee considered whether there were any benefits not captured by the QALY calculations. The clinical experts noted that, if tix–cil were effective, it may reduce the number of people who are immunocompromised and have COVID‑19. This could ultimately reduce the rate of variant change and mean fewer people being infected. The committee agreed that this was a theoretical benefit of treatment. But it concluded that clinical efficacy with tix–cil had to have been shown to justify this benefit. So, it did not consider that this benefit was relevant for decision making.\n\n# Conclusion\n\n## Recommendation\n\nThe committee agreed that there is an urgent unmet need for an effective prophylactic treatment for people who do not have an adequate response to vaccination. But the committee concluded that tix–cil should not be recommended because it is unlikely to be effective against most of the relevant variants at the time this guidance was produced. For this reason, the committee also considered that managed access was not appropriate. Instead, it concluded that further data collection would be a more appropriate way to resolve the key uncertainties (see section\xa04).", 'Recommendations for research': 'The committee acknowledged the need for tix–cil to be evaluated quickly against all new variants. It also suggested that the company enter tix–cil into ongoing platform trials. This would create a real-time link between in vitro and in vivo data.\n\nThe committee noted the lack of evidence on how the availability of a preventative treatment would affect shielding behaviours, and subsequently affect treatment efficacy. It also noted a lack of data on the relationship between perceived efficacy and direct utility gain. It considered that further research into these areas would be useful.'}	https://www.nice.org.uk/guidance/ta900	Evidence-based recommendations on tixagevimab plus cilgavimab (Evusheld) for preventing COVID‑19 in adults.
35ceb798e8816603cddcecdd497ac75228b604b0	nice	Brexucabtagene autoleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 26 years and over	Brexucabtagene autoleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 26 years and over Evidence-based recommendations on brexucabtagene autoleucel (Tecartus) for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 26 years and over. # Recommendations Brexucabtagene autoleucel is recommended for use within the Cancer Drugs Fund as an option for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people 26 years and over. It is recommended only if the conditions in the managed access agreement for brexucabtagene autoleucel are followed. This recommendation is not intended to affect treatment with brexucabtagene autoleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard treatment for B‑cell acute lymphoblastic leukaemia includes inotuzumab, blinatumomab, and ponatinib. This can be followed by an allogeneic stem cell transplant for some people. Brexucabtagene autoleucel would be offered as an additional treatment option. Evidence from a study of brexucabtagene autoleucel does not compare the treatment with anything else. It suggests that people having the treatment may live longer and have more time before their disease relapses, but this is uncertain. There is also not enough evidence to tell if this treatment can cure B‑cell acute lymphoblastic leukaemia. The most likely cost-effectiveness estimates are uncertain, and some of them are higher than what NICE considers an acceptable use of NHS resources. So brexucabtagene autoleucel cannot be recommended for routine use. Evidence collected in the Cancer Drugs Fund would help reduce some of the uncertainties in the clinical evidence. Brexucabtagene autoleucel has the potential to be cost effective, so it is recommended for use in the Cancer Drugs Fund.# Information about brexucabtagene autoleucel # Marketing authorisation indication Brexucabtagene autoleucel (Tecartus, Kite) is indicated for 'the treatment of adult patients 26 years of age and above with relapsed or refractory B cell precursor acute lymphoblastic leukaemia'. The dosage schedule is available in the summary of product characteristics for brexucabtagene autoleucel. # Price The list price for single infusion is £316,118 (excluding VAT, MIMS online, accessed February 2023). The company has a commercial arrangement. This makes brexucabtagene autoleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Kite, a Gilead company, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Treatment pathway and clinical practice ## People with relapsed or refractory B-cell acute lymphoblastic leukaemia would welcome a new treatment Outcomes for people with relapsed or refractory B‑cell acute lymphoblastic leukaemia are poor. The disease has low levels of response to treatment and is associated with limited survival. Common symptoms include fatigue, breathlessness, infections, bleeding, bruising, fever and sweating. The clinical and patient experts noted that people with relapsed or refractory B‑cell acute lymphoblastic leukaemia have limited treatment options. This is because the current treatments do not provide a cure and can only extend life for less than a year. This has a serious impact on the quality of life of people with the disease, and could affect their families. The only potentially curative option is an allogeneic stem cell transplant (allo‑SCT), which not many people can have because of the eligibility requirements such as remission, age, fitness levels and donor availability. They further explained that stem cell transplants are associated with a slow and laborious recovery over around a year. The clinical expert explained that people from minority ethnic family backgrounds are less likely to find a matching donor. Chimeric antigen receptor (CAR) T‑cell therapies are a new generation of personalised cancer immunotherapies in which the patients' own immune cells are collected and modified to treat their cancer. The clinical expert said that CAR T‑cell therapy causes less severe, short-term and more manageable side effects than allo‑SCT. They also said that the technology could potentially lead to a cure in some people. This type of technology is currently recommended for people 25 years and under (see NICE technology appraisal guidance on tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years). So, there is an unmet need for people older than 25. The clinical expert explained that clinicians in the UK are in a difficult position when treating B‑cell acute lymphoblastic leukaemia in people 26 years and over, because there are no CAR T‑cell therapy options for this population. The committee concluded that people with relapsed or refractory B‑cell acute lymphoblastic leukaemia, especially those 26 years and over, would welcome new treatment options such as CAR T‑cell therapies that improve the chance of survival. ## The company's positioning of brexucabtagene autoleucel in the treatment pathway is appropriate The company proposed 3 potential positions for brexucabtagene autoleucel in the treatment pathway; specifically, for people 26 years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia: whose disease has relapsed after an allo‑SCT or who are ineligible for an allo‑SCT or who are unlikely to reach a point at which they can have an allo‑SCT via existing bridging therapies.The clinical experts stated that currently there are no curative treatment options for people 26 years and over whose disease has relapsed after having an allo‑SCT. CAR T‑cell therapy is not available for this group of people in the NHS. They also explained that in the UK, clinicians would not give a second allo‑SCT and that allo‑SCT use may decrease in favour of CAR T‑cell therapy. This is because allo‑SCT is a highly toxic treatment and can lead to graft-versus-host disease (an immune-mediated condition resulting from a complex interaction between donor and recipient adaptive immunity). The clinical experts also stressed the importance of having this treatment option for people who are ineligible for allo‑SCT. The committee noted that the treatment pathway proposed by the company included Philadelphia chromosome-negative and Philadelphia chromosome-positive relapsed or refractory B‑cell acute lymphoblastic leukaemia. It further noted that the marketing authorisation covered people both with and without the Philadelphia chromosome. The committee concluded that the company's positioning of brexucabtagene autoleucel in the treatment pathway was appropriate. ## The relevant comparators are inotuzumab, blinatumomab and ponatinib The company compared brexucabtagene autoleucel with all comparators in the NICE scope, that is, FLAG‑IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), inotuzumab, blinatumomab and tyrosine kinase inhibitors (ponatinib). Based on clinical advice, the company refined the list of comparators and categorised them by treatment group: overall population (irrespective of Philadelphia chromosome status), Philadelphia chromosome negative, and Philadelphia chromosome positive. The clinical experts explained that FLAG‑IDA-based chemotherapy is rarely used in the UK because of its toxicity, poor tolerance and poor outcomes. They further explained that inotuzumab is given to both subgroups (Philadelphia chromosome-negative and -positive), whereas blinatumomab is restricted to Philadelphia chromosome-negative relapsed or refractory B‑cell acute lymphoblastic leukaemia. Ponatinib is restricted to Philadelphia chromosome-positive relapsed or refractory B‑cell acute lymphoblastic leukaemia in people whose disease does not respond or who cannot tolerate a tyrosine kinase inhibitor before having an allo‑SCT. The committee discussed if FLAG‑IDA should be included as a comparator in light of the clinical experts' comments. It agreed that since FLAG‑IDA is rarely used in clinical practice, it should not be included as a comparator. The committee concluded that inotuzumab, blinatumomab and ponatinib were the appropriate comparators for people 26 years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia. # Clinical effectiveness ## Brexucabtagene autoleucel could be clinically effective, but a curative treatment effect is uncertain The clinical-effectiveness evidence for brexucabtagene autoleucel came from ZUMA‑3, a single-arm open-label study of relapsed or refractory B‑cell acute lymphoblastic leukaemia. The trial recruited people from 32 centres across 5 countries, but there were no centres in the UK. A total of 78 people with relapsed or refractory B‑cell acute lymphoblastic leukaemia were included in the final analysis, which provided the clinical evidence for the company's base-case cost-effectiveness analysis. The trial population included people under 26 years, so restricting the analysis to people covered by the marketing authorisation reduced the number of people included. The exact number is confidential so cannot be shown here. The primary outcome of the trial was overall complete remission. Secondary outcomes included overall survival and relapse-free survival. The median overall survival and relapse-free survival results are considered confidential by the company, so they cannot be shown here. The results for overall survival suggested that brexucabtagene autoleucel could be potentially curative. The ERG explained that the results supporting an assumption of cure with brexucabtagene autoleucel were uncertain. It explained that, over time, relapse-free survival decreased, and that this indicated that brexucabtagene autoleucel may not be curative. It also noted that because the analyses did not distinguish between people who had an allo‑SCT before treatment and those who did not, it was unclear if any of the survival benefit resulted from allo‑SCT treatment before treatment with brexucabtagene autoleucel. The clinical experts were concerned about how to interpret the relapse-free survival curve given the uncertainties. They noted that it was unlikely that survival after treatment with brexucabtagene autoleucel would be influenced by prior allo‑SCT. They added that curative outcomes can be seen in real-world evidence from people with relapsed or refractory B‑cell acute lymphoblastic leukaemia who have had multiple different treatments before the CAR T‑cell therapy. One of the clinical experts stressed that relapses after 12 months are infrequent and that this should be considered. The committee concluded that treatment with brexucabtagene autoleucel could be clinically effective, but a curative treatment effect is uncertain. ## Brexucabtagene autoleucel is expected to be equally effective in both subgroups The company proposed brexucabtagene autoleucel for treating Philadelphia chromosome-positive and -negative relapsed or refractory B‑cell acute lymphoblastic leukaemia. The clinical experts stated that the treatment is expected to have similar efficacy in both populations. This is because the mechanism of action is not related to Philadelphia chromosome status. They noted that tisagenlecleucel is equally clinically effective in Philadelphia chromosome-negative and -positive disease. The committee concluded that brexucabtagene autoleucel is expected to be equally effective in both Philadelphia chromosome-negative and Philadelphia chromosome-positive disease. ## For the comparison with blinatumomab and ponatinib, the company and ERG's methods are acceptable Because ZUMA‑3 is a single-arm trial, an indirect treatment comparison was needed to estimate the efficacy of brexucabtagene autoleucel compared with the comparators. ZUMA‑3 was used as the evidence source for brexucabtagene autoleucel. The evidence sources for blinatumomab were TOWER and SCHOLAR‑3, and the evidence source for ponatinib was PACE. For the comparison with blinatumomab, the company presented: a matched comparison via SCHOLAR‑3, using the synthetic control arm from SCHOLAR‑3 to compare brexucabtagene autoleucel with blinatumomab (used in its base-case economic analysis) a naive unadjusted comparison a matching-adjusted indirect comparison (MAIC).The ERG used the company's matched comparison via SCHOLAR‑3 for the comparison with blinatumomab in its base case. But it highlighted that the company did this analysis with ZUMA‑3 phase 2 data only, and matching with pooled phase 1 and 2 data would have been preferred. For the comparison with ponatinib, the company presented a naive unadjusted comparison only and used this in its base case. The company deemed a MAIC against ponatinib unsuitable because of the small numbers of people with Philadelphia chromosome-positive disease in ZUMA‑3. The ERG agreed that a MAIC against ponatinib was unsuitable and that a naive comparison was needed. The committee considered that the treatment comparisons indicated that brexucabtagene autoleucel could potentially improve event-free and overall survival compared with blinatumomab and improve overall survival compared with ponatinib, but this was uncertain. It concluded that the company's and the ERG's methods of using a matched comparison via SCHOLAR‑3 for blinatumomab and an unadjusted comparison for ponatinib were acceptable. ## For the comparison with inotuzumab, the inverse hazard ratio analysis is preferred For the comparison with inotuzumab, the company presented a naive unadjusted comparison and a MAIC. It used ZUMA‑3 as the evidence source for brexucabtagene autoleucel and INO‑VATE as the evidence source for inotuzumab. The company's base case used the naive unadjusted comparison. It preferred this comparison because it believed ZUMA‑3 was more aligned with the target population in UK practice, whereas INO‑VATE was not. It said that using a MAIC would not adjust to the population of interest. The ERG noted that the population in INO‑VATE was different to that in ZUMA‑3, and so a naive comparison would be at a high risk of bias. So, this comparison would not reflect the true relative treatment effect. It preferred a MAIC approach to adjust for the differences between the trials. The company used the overall population data for the MAIC, so the ERG was not able to look at the MAIC analysis for the Philadelphia chromosome-positive and -negative subgroups. This is because it did not have subgroup data from the INO‑VATE study. So the ERG had to adjust the MAIC analysis to the ZUMA‑3 study data. The ERG also suggested using inverse hazard ratios derived from the MAIC analysis applied to the ZUMA‑3 arm as baseline (an inverse hazard ratio method). This was an alternative method to minimise bias associated with the other analysis methods. The ERG considered this a reasonable approach because the company believed that matching patients to studies other than ZUMA‑3 would be inappropriate. The ERG had not been given enough time to review this analysis before the first committee meeting, but was able to review it before the second meeting. At the second committee meeting, the ERG's base-case economic analysis used the inverse hazard ratio method for the comparison with inotuzumab. The committee considered that brexucabtagene autoleucel could potentially improve event-free survival compared with inotuzumab, but that this was uncertain. It concluded that it preferred the inverse of the hazard ratios method for the comparison with inotuzumab, over the MAIC and naive comparisons. # The company's economic model ## The company's economic model is appropriate for decision making The company used a partitioned survival model that included 3 mutually exclusive health states: event-free, progressed disease and death. The company modelled the cost effectiveness of treatment with brexucabtagene autoleucel using data from ZUMA‑3 and data from INO‑VATE, TOWER, PACE and SCHOLAR‑3 for the comparators. After technical engagement the company updated its economic model to include a recent data cut of ZUMA‑3, revised clinical-effectiveness data for people 26 years and over (the population in the marketing authorisation) and data from SCHOLAR‑3. The committee agreed that the model was appropriate for decision making. ## A standardised mortality ratio of 3 is appropriate in the absence of evidence, but this is highly uncertain The company's model assumed a standardised mortality ratio of 1.09 to model the mortality risk of people whose cancer was considered cured after 3 years of relapse-free survival. This was compared with the mortality of the age- and sex-matched general population in the UK. The ERG considered this to be an underestimate. It noted that this value was from a study of people with diffuse large B‑cell lymphoma rather than B‑cell acute lymphoblastic leukaemia. The ERG proposed a standardised mortality ratio of 4, sourced from Martin et al. (2010), which included people with relapsed or refractory B‑cell acute lymphoblastic leukaemia in which the mortality risk ranged between 4 and 9. It noted that it had chosen the lowest value in the study, which was a conservative approach. The company noted that the Martin et al. study was in people who had allo‑SCT, which is more burdensome and has longer-term treatment requirements than CAR T‑cell therapy. During consultation, the company provided a scenario using a standardised mortality ratio of 2.2. This was a weighted average based on the proportion of people who had received allo‑SCT before brexucabtagene autoleucel in ZUMA‑3, with a standardised mortality ratio of 4 applied to people who had received an allo‑SCT and 1.09 applied to the remaining proportion. The ERG also provided a threshold analysis that applied various standardised mortality ratios to the ERG base case, ranging from 1.09 to 4. The clinical experts explained that there is no long-term survival data for people with relapsed or refractory B‑cell acute lymphoblastic leukaemia who have had brexucabtagene autoleucel. But they expected it to be similar to the data for tisagenlecleucel, for which many people have been followed up for 5 to 10 years. The clinical experts highlighted that the main risk of the disease relapsing is during the first year after treatment, and that after that, relapse is unlikely. They further explained that the increased risk of dying was associated with having an allo‑SCT. This is because of the risk of graft-versus-host disease. The clinical experts added that it is rare that people who have had a CAR T‑cell therapy develop graft-versus-host disease. They suggested that the appropriate standardised mortality ratio was highly uncertain, but that it was likely to be greater than 1.09 and lower than 4, and likely closer to the ERG's estimate than the company's. The committee understood that the risk of dying was linked to allo‑SCT before the CAR T‑cell therapy and that the population in Martin et al. included only people who had had allo‑SCT. So the population in Martin et al. was likely to be at a higher risk of death than the population who would be treated in clinical practice, who would not all have had allo‑SCT. But the committee also noted that the ERG had used the lower end of the range of the standardised mortality ratio in Martin et al., which may be appropriate given the differences in the populations. The committee considered the company's weighted average standardised mortality ratio of 2.2. There was no evidence from people with B‑cell acute lymphoblastic leukaemia that supported using a standardised mortality ratio of 1.09 in the weighted average for people who have not had an allo‑SCT. So this was highly uncertain. The committee also noted that the standardised mortality ratio of 4 applied in the weighted average to people who have had allo‑SCT was at the lower end of the range in Martin et al. and so may be an underestimate for this population. Given this, and the high level of uncertainty, the committee agreed that it was appropriate to consider a standardised mortality ratio higher than 2.2. It concluded that in this case and given the lack of evidence, a standardised mortality ratio of 3 was appropriate, as this was the midpoint between the company's scenario analysis of 2.2 and the ERG's base-case value of 4. It further concluded that the true standardised mortality ratio for this population was highly uncertain and may be as high as the ERG's estimate of 4. ## People who have had brexucabtagene autoleucel do not have the same health-related quality of life as the general population The company's model assumed that people who had brexucabtagene autoleucel and whose disease had not progressed after 3 years of treatment would have the same health-related quality of life as that of the same age- and sex-matched general population in the UK. The ERG had received clinical advice that there is cumulative toxicity from previous therapies, and that the disease itself reduced health-related quality of life. So the ERG proposed applying a utility multiplier of 0.92 to the general population utility values to adjust for lower quality of life. This was calculated from a ratio between the utility value reported in ZUMA‑3 after the infusion and before relapse (0.82), and the general population of a similar age (0.89). The ERG also noted that if a standardised mortality ratio was being applied to account for an increased risk of death in this population (see section 3.9), it was logical to also assume a decrease in health-related quality of life. The company disagreed that mortality and health-related quality of life would be correlated, because acute events that do not affect quality of life may lead to death. It also stated that the ERG's approach underestimated the health-related quality of life of the cured population, because it was partly based on utility values measured shortly after CAR T‑cell treatment, which would be lower than the utility values expected 3 years after treatment. The company also noted that the general population included people who had weakened immune systems and who have had cancer, and so the general population utility values reflected the population whose relapsed or refractory acute lymphoblastic leukaemia was cured. The ERG explained that the proportion of people with a weakened immune system or who have had cancer was much lower in the general population than it would be in this population. The clinical experts explained that there is not enough evidence in CAR T‑cell therapies to support either approach. But they explained that reduced quality of life in this population is likely to be related to previous treatments. People can live a near-normal life after treatment with the new technology and can return to daily activities soon after having a CAR T‑cell therapy. The clinical experts also explained that CAR T‑cell therapy can lead to better quality of life than other treatments, because it is given in an outpatient setting and so people need less time in hospital. The patient expert stated that the condition had a huge emotional and financial impact on them and their family after they were diagnosed. They explained that they have a sustained risk from infections and so have to have regular follow-up appointments. However, this monitoring provides reassurance and does not affect the ability to perform daily activities. They stated that the benefits of treatment outweighed the negative impacts. The committee understood that people whose disease has not progressed after 3 years will have a worse health-related quality of life than the general population, even though CAR T‑cell treatment is better tolerated than some other treatments for acute lymphoblastic leukaemia. This is because of the risks associated with CAR T‑cell treatments, the effect of previous therapies including chemotherapy and allo‑SCT, and the effects from the disease itself, all of which are more prevalent in this population than in the general population. It noted that the ERG's approach appeared plausible and that the company had not provided an analysis during consultation using a utility value based on trial data recorded after a longer follow up. It concluded that people having brexucabtagene autoleucel do not have the same quality of life as the general population, and the ERG approach should be used in decision making. ## Allo-SCT costs and QALY loss should be included in the model for people having brexucabtagene autoleucel In ZUMA‑3, 14 out of 78 (18%) people had an allo‑SCT. But the company did not account for the costs or quality-adjusted life year (QALY) impact of allo‑SCT use in this proportion of people in the brexucabtagene autoleucel arm in the economic model. The company stated that the technology is not planned to be used before an allo‑SCT in UK clinical practice. It had done a sensitivity analysis adjusting for overall survival, censoring for allo‑SCT, and no statistical difference was found. The ERG stated that the sensitivity analysis was not sufficiently powered to detect a difference. So it could not be determined if an allo‑SCT could have provided a survival advantage to the people who had had one. The ERG stated that it was therefore also appropriate to include the associated costs and QALYs in the model for the 18% who received brexucabtagene autoleucel in ZUMA‑3 and went on to receive allo‑SCT. The clinical experts stated that allo‑SCT after CAR T‑cell treatment would not be standard practice, and that brexucabtagene autoleucel would likely be used as a standalone therapy. The committee noted that it was unclear how often allo‑SCT would be used in practice. But it noted the ERG's opinion that because the clinical-effectiveness evidence in the model included some people who received allo‑SCT after CAR T‑cell treatment, the associated costs and QALYs of allo‑SCT should also be included. The committee concluded that allo‑SCT costs and a QALY loss should be included in the model for people having brexucabtagene autoleucel. ## CAR T-cell delivery costs of £41,101 are most appropriate for decision making NHS England has established a single tariff to capture the costs of delivering CAR T‑cell therapy. The tariff was developed after NICE recommended the first CAR T‑cell therapy, tisagenlecleucel, for use in the Cancer Drugs Fund in December 2018. NHS England explained that the tariff includes all costs of care from the decision to have CAR T‑cell therapy to 100 days after the infusion. NHS England explained that there is not a healthcare resource group (HRG) code that adequately captures the administration of CAR T‑cell therapies. As part of the NICE technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies (TA872), the company (also the company in this appraisal) submitted an analysis using a CAR T‑cell therapy delivery cost of £41,101. This was informed by an ERG scenario analysis in the NICE technology appraisal guidance on axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy. NHS England considered that, although the company's cost of £41,101 differs from the NHS England tariff for CAR T‑cell therapy, it was an acceptable cost to use in the cost-effectiveness analysis. This is because although the NHS England tariff represents the high hospital costs of establishing the infrastructure of a CAR T‑cell therapy service and delivering a relatively new type of treatment, economies of scale may be expected over time, particularly with clinical developments that reduce toxicity and the intensity of monitoring and treatment. At the second committee meeting, the company included the CAR T‑cell delivery cost of £41,101 in its base case, and excluded the costs for the following from the model, which it believed should be covered by the delivery cost: leukapheresis CAR T‑cell administration adverse events monitoring training conditioning and bridging chemotherapy acquisition, administration and delivery.NHS England's clinical lead for the Cancer Drugs Fund noted that the costs of conditioning and bridging chemotherapy are not included in the £41,101 delivery cost. The ERG also included the CAR T‑cell delivery cost of £41,101 in its base case and excluded most of the same costs that the company excluded. But the ERG included the costs of conditioning and bridging chemotherapy separately in the model. NHS England confirmed that the ERG's approach was appropriate and in line with the approach agreed for TA872. The committee noted NHS England's comments and was satisfied that the ERG's costs were a reasonable projection of the cost to the NHS of delivering CAR T‑cell therapy. # End of life ## Brexucabtagene autoleucel meets the criteria to be considered a life-extending treatment at the end of life The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The literature showed that median overall survival with the comparator treatments ranged from 5.3 to 8 months. The clinical experts stated that life expectancy is the same for people with Philadelphia chromosome-negative and -positive disease. The company's model predicted that mean overall survival with the comparator treatments was more than 24 months, but the percentage of people alive at 2 years ranged from 13% to 22%. So the committee was persuaded that people are unlikely to live for longer than 24 months and that the short life expectancy criterion was met. The clinical experts explained that it is likely that brexucabtagene autoleucel will extend life for more than 3 months. Also, the model estimated a mean overall survival gain for brexucabtagene autoleucel compared with the comparators of more than 3 months. The exact data is confidential and so cannot be shown here. The committee concluded that the end of life criteria were met for people 26 years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia. # Cost-effectiveness estimate ## Because of the uncertainty, the maximum acceptable ICER would be substantially less than £50,000 per QALY gained NICE's guide to the methods of technology appraisal (section 6) notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, decisions about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically associated with: the clinical-effectiveness estimates and the assumption of cure (see section 3.4) long-term mortality rates compared with the general population (see section 3.9) long-term quality of life compared with the general population (see section 3.10).The committee also agreed that the end of life criteria applied, which allows it to consider ICERs of up to £50,000 per QALY gained (see section 3.13). NICE's guide to the methods of technology appraisal also notes that the appraisal committee does not use a precise maximum acceptable ICER. Given the level of uncertainty, the committee concluded that the maximum acceptable ICER for routine commissioning would be substantially lower than £50,000 per QALY gained. ## Brexucabtagene autoleucel is not recommended for routine use in the NHS The committee noted that the ERG's base-case analysis was more closely aligned with its preferred assumptions for both Philadelphia chromosome subgroups, specifically: using the inverse of hazard ratios derived from the MAIC analysis to model inotuzumab in the ZUMA‑3 population (see section 3.7) including costs and QALY loss associated with allo‑SCT for people who have brexucabtagene autoleucel (see section 3.11) applying a utility multiplier of 0.92, to age and sex-matched general population utilities (see section 3.10) assuming adverse event-related costs for brexucabtagene autoleucel would be the same as those for inotuzumab removing the costs of FLAG‑IDA for people having ponatinib assuming a CAR T‑cell delivery cost of £41,101 plus the costs associated with conditioning and bridging chemotherapy (see section 3.12).The committee also concluded that it was appropriate to apply a standardised mortality ratio to the general population mortality rate after 3 years in the model. It was highly uncertain what the true standardised mortality ratio should be. It concluded that it was appropriate to consider a value of 3 for decision making, noting that it could plausibly be as high as 4 (see section 3.9). The committee considered the ICERs using standardised mortality ratios of 3 and 4 applied to the ERG's base case, using the confidential discounts for brexucabtagene autoleucel and the comparator treatments. Because there are confidential discounts, the exact ICERs cannot be reported here. The committee noted that the ICERs were not all substantially below £50,000 per QALY gained in deterministic analysis, compared with both comparators, in the Philadelphia-positive and -negative subgroups. It noted that the ICER was highest when using a standardised mortality ratio of 4. The ERG highlighted that these ICERs were based on deterministic analyses and that it was likely that the probabilistic ICERs in a fully incremental analysis would be higher. The committee recalled that a maximum acceptable ICER for routine commissioning would be substantially below £50,000 per QALY gained (see section 3.14). Given the high levels of uncertainty in the model and the fact that the ICERs using the committee's preferred assumptions were not all substantially below £50,000 per QALY gained, the committee concluded that brexucabtagene autoleucel could not be recommended for routine use in the NHS. # Cancer Drugs Fund ## Brexucabtagene autoleucel meets the criteria for inclusion in the Cancer Drugs Fund The committee considered if brexucabtagene autoleucel could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016. The committee discussed if the uncertainties identified in the company's cost-effectiveness evidence could be addressed by collecting more data in the Cancer Drugs Fund. The ongoing single-arm ZUMA‑3 trial will provide further data on the follow up of people having brexucabtagene autoleucel and may help resolve some clinical uncertainties around overall survival, relapse-free survival and whether this treatment is curative. The committee noted that even with further data collection from ZUMA‑3, there would still be uncertainty in the comparative clinical-effectiveness evidence. This was because ZUMA‑3 was a single-arm study and so comparative evidence relied on indirect treatment comparisons. Other issues, such as the uncertainties in the standardised mortality ratio value (see section 3.9) and the utility value (see section 3.10), would be unlikely to be resolved through further data collection in the Cancer Drugs Fund. The committee noted that brexucabtagene autoleucel does have the potential to be cost effective because some plausible scenarios resulted in ICERs below what NICE considers an acceptable use of NHS resources (see section 3.15). It concluded that brexucabtagene autoleucel did meet the criteria for inclusion in the Cancer Drugs Fund. # Equality issues ## With the evidence available, this technology appraisal cannot address the equalities issues The committee considered multiple equalities issues: The clinical experts noted that people from minority ethnic family backgrounds can have difficulty finding a suitable match for a curative allo‑SCT. They also noted that older people are less likely to be eligible for allo‑SCT, but could be eligible for brexucabtagene autoleucel. For people who are unable to have an allo‑SCT, brexucabtagene autoleucel could offer improved outcomes over existing treatments. The committee noted that this was a population with a particular unmet need. But it was not presented with any clinical or cost-effectiveness evidence allowing this population to be considered separately. So it was only able to make a decision based on the full population in the decision problem. The committee agreed that this could not be addressed in this technology appraisal given the information available. The committee noted that the marketing authorisation states that this technology is for people 26 years and over. The patient and clinical experts noted that if this technology is not recommended, it would leave people above this age without access to a potentially curative treatment option. They highlighted that a different CAR T‑cell treatment (tisagenlecleucel) is available through the Cancer Drugs Fund for people aged under 26. The committee acknowledged this issue and that people 26 years and over have a particular unmet need. It noted that the decision to recommend brexucabtagene autoleucel was based on the clinical and cost-effectiveness evidence available for this appraisal. The committee concluded that it could not recommend a technology for a particular population based on the fact that another technology appraisal did not include that population. The committee was also aware that some religious groups such as Jehovah's witnesses may not accept technologies or procedures derived from blood (such as allo‑SCT). These people would normally have best supportive care. The committee acknowledged that if brexucabtagene autoleucel does become available, some people may choose not to have this treatment because it contains human blood products. So, this is not viewed as an equality issue in this appraisal.The committee concluded that given the information available, the equality issues cannot be addressed through this technology appraisal. # Conclusion ## Brexucabtagene autoleucel is recommended for use in the Cancer Drugs Fund The committee recalled the uncertainties in the evidence for this technology (see section 3.14) and that the population has high unmet needs (see section 3.1). Taking this into account, the ICERs based on its preferred assumptions were still higher that what was considered cost effective. So, it concluded that brexucabtagene autoleucel could not be recommended for routine use. But, the committee considered that brexucabtagene autoleucel did have plausible potential to be cost effective, and that some of the clinical uncertainties may be resolved with further data collection (see section 3.16). So brexucabtagene autoleucel is recommended for use in the Cancer Drugs Fund for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people 26 years and over.# Review of guidance The data collection period is expected to end as outlined in the data collection arrangement, when more data from the ZUMA‑3 trial is available. Once enough evidence is available, the process for exiting the Cancer Drugs Fund will begin at this point and the review of the NICE guidance will start. As part of the managed access agreement, the technology will continue to be available through the Cancer Drugs Fund after the data collection period has ended and while the guidance is being reviewed. This assumes that the data collection period ends as planned and the review of guidance follows the standard timelines described in section 6 of NICE's guide to the processes of technology appraisal. Stephen O'BrienChair, appraisal committeeMarch 2023	{'Recommendations': 'Brexucabtagene autoleucel is recommended for use within the Cancer Drugs Fund as an option for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people 26\xa0years and over. It is recommended only if the conditions in the managed access agreement for brexucabtagene autoleucel are followed.\n\nThis recommendation is not intended to affect treatment with brexucabtagene autoleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard treatment for B‑cell acute lymphoblastic leukaemia includes inotuzumab, blinatumomab, and ponatinib. This can be followed by an allogeneic stem cell transplant for some people. Brexucabtagene autoleucel would be offered as an additional treatment option.\n\nEvidence from a study of brexucabtagene autoleucel does not compare the treatment with anything else. It suggests that people having the treatment may live longer and have more time before their disease relapses, but this is uncertain. There is also not enough evidence to tell if this treatment can cure B‑cell acute lymphoblastic leukaemia.\n\nThe most likely cost-effectiveness estimates are uncertain, and some of them are higher than what NICE considers an acceptable use of NHS resources. So brexucabtagene autoleucel cannot be recommended for routine use.\n\nEvidence collected in the Cancer Drugs Fund would help reduce some of the uncertainties in the clinical evidence. Brexucabtagene autoleucel has the potential to be cost effective, so it is recommended for use in the Cancer Drugs Fund.', 'Information about brexucabtagene autoleucel': "# Marketing authorisation indication\n\nBrexucabtagene autoleucel (Tecartus, Kite) is indicated for 'the treatment of adult patients 26\xa0years of age and above with relapsed or refractory B\xa0cell precursor acute lymphoblastic leukaemia'.\n\nThe dosage schedule is available in the summary of product characteristics for brexucabtagene autoleucel.\n\n# Price\n\nThe list price for single infusion is £316,118 (excluding VAT, MIMS [Monthly Index of Medical Specialities] online, accessed February 2023).\n\nThe company has a commercial arrangement. This makes brexucabtagene autoleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Kite, a Gilead company, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway and clinical practice\n\n## People with relapsed or refractory B-cell acute lymphoblastic leukaemia would welcome a new treatment\n\nOutcomes for people with relapsed or refractory B‑cell acute lymphoblastic leukaemia are poor. The disease has low levels of response to treatment and is associated with limited survival. Common symptoms include fatigue, breathlessness, infections, bleeding, bruising, fever and sweating. The clinical and patient experts noted that people with relapsed or refractory B‑cell acute lymphoblastic leukaemia have limited treatment options. This is because the current treatments do not provide a cure and can only extend life for less than a year. This has a serious impact on the quality of life of people with the disease, and could affect their families. The only potentially curative option is an allogeneic stem cell transplant (allo‑SCT), which not many people can have because of the eligibility requirements such as remission, age, fitness levels and donor availability. They further explained that stem cell transplants are associated with a slow and laborious recovery over around a year. The clinical expert explained that people from minority ethnic family backgrounds are less likely to find a matching donor. Chimeric antigen receptor (CAR) T‑cell therapies are a new generation of personalised cancer immunotherapies in which the patients' own immune cells are collected and modified to treat their cancer. The clinical expert said that CAR\xa0T‑cell therapy causes less severe, short-term and more manageable side effects than allo‑SCT. They also said that the technology could potentially lead to a cure in some people. This type of technology is currently recommended for people 25\xa0years and under (see NICE technology appraisal guidance on tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25\xa0years). So, there is an unmet need for people older than 25. The clinical expert explained that clinicians in the UK are in a difficult position when treating B‑cell acute lymphoblastic leukaemia in people 26\xa0years and over, because there are no CAR\xa0T‑cell therapy options for this population. The committee concluded that people with relapsed or refractory B‑cell acute lymphoblastic leukaemia, especially those 26\xa0years and over, would welcome new treatment options such as CAR\xa0T‑cell therapies that improve the chance of survival.\n\n## The company's positioning of brexucabtagene autoleucel in the treatment pathway is appropriate\n\nThe company proposed 3 potential positions for brexucabtagene autoleucel in the treatment pathway; specifically, for people 26\xa0years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia:\n\nwhose disease has relapsed after an allo‑SCT or\n\nwho are ineligible for an allo‑SCT or\n\nwho are unlikely to reach a point at which they can have an allo‑SCT via existing bridging therapies.The clinical experts stated that currently there are no curative treatment options for people 26\xa0years and over whose disease has relapsed after having an allo‑SCT. CAR\xa0T‑cell therapy is not available for this group of people in the NHS. They also explained that in the UK, clinicians would not give a second allo‑SCT and that allo‑SCT use may decrease in favour of CAR\xa0T‑cell therapy. This is because allo‑SCT is a highly toxic treatment and can lead to graft-versus-host disease (an immune-mediated condition resulting from a complex interaction between donor and recipient adaptive immunity). The clinical experts also stressed the importance of having this treatment option for people who are ineligible for allo‑SCT. The committee noted that the treatment pathway proposed by the company included Philadelphia chromosome-negative and Philadelphia chromosome-positive relapsed or refractory B‑cell acute lymphoblastic leukaemia. It further noted that the marketing authorisation covered people both with and without the Philadelphia chromosome. The committee concluded that the company's positioning of brexucabtagene autoleucel in the treatment pathway was appropriate.\n\n## The relevant comparators are inotuzumab, blinatumomab and ponatinib\n\nThe company compared brexucabtagene autoleucel with all comparators in the NICE scope, that is, FLAG‑IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), inotuzumab, blinatumomab and tyrosine kinase inhibitors (ponatinib). Based on clinical advice, the company refined the list of comparators and categorised them by treatment group: overall population (irrespective of Philadelphia chromosome status), Philadelphia chromosome negative, and Philadelphia chromosome positive. The clinical experts explained that FLAG‑IDA-based chemotherapy is rarely used in the UK because of its toxicity, poor tolerance and poor outcomes. They further explained that inotuzumab is given to both subgroups (Philadelphia chromosome-negative and -positive), whereas blinatumomab is restricted to Philadelphia chromosome-negative relapsed or refractory B‑cell acute lymphoblastic leukaemia. Ponatinib is restricted to Philadelphia chromosome-positive relapsed or refractory B‑cell acute lymphoblastic leukaemia in people whose disease does not respond or who cannot tolerate a tyrosine kinase inhibitor before having an allo‑SCT. The committee discussed if FLAG‑IDA should be included as a comparator in light of the clinical experts' comments. It agreed that since FLAG‑IDA is rarely used in clinical practice, it should not be included as a comparator. The committee concluded that inotuzumab, blinatumomab and ponatinib were the appropriate comparators for people 26\xa0years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia.\n\n# Clinical effectiveness\n\n## Brexucabtagene autoleucel could be clinically effective, but a curative treatment effect is uncertain\n\nThe clinical-effectiveness evidence for brexucabtagene autoleucel came from ZUMA‑3, a single-arm open-label study of relapsed or refractory B‑cell acute lymphoblastic leukaemia. The trial recruited people from 32\xa0centres across 5\xa0countries, but there were no centres in the UK. A total of 78\xa0people with relapsed or refractory B‑cell acute lymphoblastic leukaemia were included in the final analysis, which provided the clinical evidence for the company's base-case cost-effectiveness analysis. The trial population included people under 26\xa0years, so restricting the analysis to people covered by the marketing authorisation reduced the number of people included. The exact number is confidential so cannot be shown here. The primary outcome of the trial was overall complete remission. Secondary outcomes included overall survival and relapse-free survival. The median overall survival and relapse-free survival results are considered confidential by the company, so they cannot be shown here. The results for overall survival suggested that brexucabtagene autoleucel could be potentially curative. The ERG explained that the results supporting an assumption of cure with brexucabtagene autoleucel were uncertain. It explained that, over time, relapse-free survival decreased, and that this indicated that brexucabtagene autoleucel may not be curative. It also noted that because the analyses did not distinguish between people who had an allo‑SCT before treatment and those who did not, it was unclear if any of the survival benefit resulted from allo‑SCT treatment before treatment with brexucabtagene autoleucel. The clinical experts were concerned about how to interpret the relapse-free survival curve given the uncertainties. They noted that it was unlikely that survival after treatment with brexucabtagene autoleucel would be influenced by prior allo‑SCT. They added that curative outcomes can be seen in real-world evidence from people with relapsed or refractory B‑cell acute lymphoblastic leukaemia who have had multiple different treatments before the CAR\xa0T‑cell therapy. One of the clinical experts stressed that relapses after 12\xa0months are infrequent and that this should be considered. The committee concluded that treatment with brexucabtagene autoleucel could be clinically effective, but a curative treatment effect is uncertain.\n\n## Brexucabtagene autoleucel is expected to be equally effective in both subgroups\n\nThe company proposed brexucabtagene autoleucel for treating Philadelphia chromosome-positive and -negative relapsed or refractory B‑cell acute lymphoblastic leukaemia. The clinical experts stated that the treatment is expected to have similar efficacy in both populations. This is because the mechanism of action is not related to Philadelphia chromosome status. They noted that tisagenlecleucel is equally clinically effective in Philadelphia chromosome-negative and -positive disease. The committee concluded that brexucabtagene autoleucel is expected to be equally effective in both Philadelphia chromosome-negative and Philadelphia chromosome-positive disease.\n\n## For the comparison with blinatumomab and ponatinib, the company and ERG's methods are acceptable\n\nBecause ZUMA‑3 is a single-arm trial, an indirect treatment comparison was needed to estimate the efficacy of brexucabtagene autoleucel compared with the comparators. ZUMA‑3 was used as the evidence source for brexucabtagene autoleucel. The evidence sources for blinatumomab were TOWER and SCHOLAR‑3, and the evidence source for ponatinib was PACE. For the comparison with blinatumomab, the company presented:\n\na matched comparison via SCHOLAR‑3, using the synthetic control arm from SCHOLAR‑3 to compare brexucabtagene autoleucel with blinatumomab (used in its base-case economic analysis)\n\na naive unadjusted comparison\n\na matching-adjusted indirect comparison (MAIC).The ERG used the company's matched comparison via SCHOLAR‑3 for the comparison with blinatumomab in its base case. But it highlighted that the company did this analysis with ZUMA‑3 phase\xa02 data only, and matching with pooled phase\xa01 and 2 data would have been preferred. For the comparison with ponatinib, the company presented a naive unadjusted comparison only and used this in its base case. The company deemed a MAIC against ponatinib unsuitable because of the small numbers of people with Philadelphia chromosome-positive disease in ZUMA‑3. The ERG agreed that a MAIC against ponatinib was unsuitable and that a naive comparison was needed. The committee considered that the treatment comparisons indicated that brexucabtagene autoleucel could potentially improve event-free and overall survival compared with blinatumomab and improve overall survival compared with ponatinib, but this was uncertain. It concluded that the company's and the ERG's methods of using a matched comparison via SCHOLAR‑3 for blinatumomab and an unadjusted comparison for ponatinib were acceptable.\n\n## For the comparison with inotuzumab, the inverse hazard ratio analysis is preferred\n\nFor the comparison with inotuzumab, the company presented a naive unadjusted comparison and a MAIC. It used ZUMA‑3 as the evidence source for brexucabtagene autoleucel and INO‑VATE as the evidence source for inotuzumab. The company's base case used the naive unadjusted comparison. It preferred this comparison because it believed ZUMA‑3 was more aligned with the target population in UK practice, whereas INO‑VATE was not. It said that using a MAIC would not adjust to the population of interest. The ERG noted that the population in INO‑VATE was different to that in ZUMA‑3, and so a naive comparison would be at a high risk of bias. So, this comparison would not reflect the true relative treatment effect. It preferred a MAIC approach to adjust for the differences between the trials. The company used the overall population data for the MAIC, so the ERG was not able to look at the MAIC analysis for the Philadelphia chromosome-positive and -negative subgroups. This is because it did not have subgroup data from the INO‑VATE study. So the ERG had to adjust the MAIC analysis to the ZUMA‑3 study data. The ERG also suggested using inverse hazard ratios derived from the MAIC analysis applied to the ZUMA‑3 arm as baseline (an inverse hazard ratio method). This was an alternative method to minimise bias associated with the other analysis methods. The ERG considered this a reasonable approach because the company believed that matching patients to studies other than ZUMA‑3 would be inappropriate. The ERG had not been given enough time to review this analysis before the first committee meeting, but was able to review it before the second meeting. At the second committee meeting, the ERG's base-case economic analysis used the inverse hazard ratio method for the comparison with inotuzumab. The committee considered that brexucabtagene autoleucel could potentially improve event-free survival compared with inotuzumab, but that this was uncertain. It concluded that it preferred the inverse of the hazard ratios method for the comparison with inotuzumab, over the MAIC and naive comparisons.\n\n# The company's economic model\n\n## The company's economic model is appropriate for decision making\n\nThe company used a partitioned survival model that included 3 mutually exclusive health states: event-free, progressed disease and death. The company modelled the cost effectiveness of treatment with brexucabtagene autoleucel using data from ZUMA‑3 and data from INO‑VATE, TOWER, PACE and SCHOLAR‑3 for the comparators. After technical engagement the company updated its economic model to include a recent data cut of ZUMA‑3, revised clinical-effectiveness data for people 26\xa0years and over (the population in the marketing authorisation) and data from SCHOLAR‑3. The committee agreed that the model was appropriate for decision making.\n\n## A standardised mortality ratio of 3 is appropriate in the absence of evidence, but this is highly uncertain\n\nThe company's model assumed a standardised mortality ratio of 1.09 to model the mortality risk of people whose cancer was considered cured after 3\xa0years of relapse-free survival. This was compared with the mortality of the age- and sex-matched general population in the UK. The ERG considered this to be an underestimate. It noted that this value was from a study of people with diffuse large B‑cell lymphoma rather than B‑cell acute lymphoblastic leukaemia. The ERG proposed a standardised mortality ratio of 4, sourced from Martin et al. (2010), which included people with relapsed or refractory B‑cell acute lymphoblastic leukaemia in which the mortality risk ranged between 4 and 9. It noted that it had chosen the lowest value in the study, which was a conservative approach. The company noted that the Martin et al. study was in people who had allo‑SCT, which is more burdensome and has longer-term treatment requirements than CAR\xa0T‑cell therapy. During consultation, the company provided a scenario using a standardised mortality ratio of 2.2. This was a weighted average based on the proportion of people who had received allo‑SCT before brexucabtagene autoleucel in ZUMA‑3, with a standardised mortality ratio of 4 applied to people who had received an allo‑SCT and 1.09 applied to the remaining proportion. The ERG also provided a threshold analysis that applied various standardised mortality ratios to the ERG base case, ranging from 1.09 to 4. The clinical experts explained that there is no long-term survival data for people with relapsed or refractory B‑cell acute lymphoblastic leukaemia who have had brexucabtagene autoleucel. But they expected it to be similar to the data for tisagenlecleucel, for which many people have been followed up for 5 to 10\xa0years. The clinical experts highlighted that the main risk of the disease relapsing is during the first year after treatment, and that after that, relapse is unlikely. They further explained that the increased risk of dying was associated with having an allo‑SCT. This is because of the risk of graft-versus-host disease. The clinical experts added that it is rare that people who have had a CAR\xa0T‑cell therapy develop graft-versus-host disease. They suggested that the appropriate standardised mortality ratio was highly uncertain, but that it was likely to be greater than 1.09 and lower than 4, and likely closer to the ERG's estimate than the company's. The committee understood that the risk of dying was linked to allo‑SCT before the CAR\xa0T‑cell therapy and that the population in Martin et al. included only people who had had allo‑SCT. So the population in Martin et al. was likely to be at a higher risk of death than the population who would be treated in clinical practice, who would not all have had allo‑SCT. But the committee also noted that the ERG had used the lower end of the range of the standardised mortality ratio in Martin et al., which may be appropriate given the differences in the populations. The committee considered the company's weighted average standardised mortality ratio of 2.2. There was no evidence from people with B‑cell acute lymphoblastic leukaemia that supported using a standardised mortality ratio of 1.09 in the weighted average for people who have not had an allo‑SCT. So this was highly uncertain. The committee also noted that the standardised mortality ratio of 4 applied in the weighted average to people who have had allo‑SCT was at the lower end of the range in Martin et al. and so may be an underestimate for this population. Given this, and the high level of uncertainty, the committee agreed that it was appropriate to consider a standardised mortality ratio higher than 2.2. It concluded that in this case and given the lack of evidence, a standardised mortality ratio of 3 was appropriate, as this was the midpoint between the company's scenario analysis of 2.2 and the ERG's base-case value of 4. It further concluded that the true standardised mortality ratio for this population was highly uncertain and may be as high as the ERG's estimate of 4.\n\n## People who have had brexucabtagene autoleucel do not have the same health-related quality of life as the general population\n\nThe company's model assumed that people who had brexucabtagene autoleucel and whose disease had not progressed after 3\xa0years of treatment would have the same health-related quality of life as that of the same age- and sex-matched general population in the UK. The ERG had received clinical advice that there is cumulative toxicity from previous therapies, and that the disease itself reduced health-related quality of life. So the ERG proposed applying a utility multiplier of 0.92 to the general population utility values to adjust for lower quality of life. This was calculated from a ratio between the utility value reported in ZUMA‑3 after the infusion and before relapse (0.82), and the general population of a similar age (0.89). The ERG also noted that if a standardised mortality ratio was being applied to account for an increased risk of death in this population (see section 3.9), it was logical to also assume a decrease in health-related quality of life. The company disagreed that mortality and health-related quality of life would be correlated, because acute events that do not affect quality of life may lead to death. It also stated that the ERG's approach underestimated the health-related quality of life of the cured population, because it was partly based on utility values measured shortly after CAR\xa0T‑cell treatment, which would be lower than the utility values expected 3\xa0years after treatment. The company also noted that the general population included people who had weakened immune systems and who have had cancer, and so the general population utility values reflected the population whose relapsed or refractory acute lymphoblastic leukaemia was cured. The ERG explained that the proportion of people with a weakened immune system or who have had cancer was much lower in the general population than it would be in this population. The clinical experts explained that there is not enough evidence in CAR\xa0T‑cell therapies to support either approach. But they explained that reduced quality of life in this population is likely to be related to previous treatments. People can live a near-normal life after treatment with the new technology and can return to daily activities soon after having a CAR\xa0T‑cell therapy. The clinical experts also explained that CAR\xa0T‑cell therapy can lead to better quality of life than other treatments, because it is given in an outpatient setting and so people need less time in hospital. The patient expert stated that the condition had a huge emotional and financial impact on them and their family after they were diagnosed. They explained that they have a sustained risk from infections and so have to have regular follow-up appointments. However, this monitoring provides reassurance and does not affect the ability to perform daily activities. They stated that the benefits of treatment outweighed the negative impacts. The committee understood that people whose disease has not progressed after 3\xa0years will have a worse health-related quality of life than the general population, even though CAR\xa0T‑cell treatment is better tolerated than some other treatments for acute lymphoblastic leukaemia. This is because of the risks associated with CAR\xa0T‑cell treatments, the effect of previous therapies including chemotherapy and allo‑SCT, and the effects from the disease itself, all of which are more prevalent in this population than in the general population. It noted that the ERG's approach appeared plausible and that the company had not provided an analysis during consultation using a utility value based on trial data recorded after a longer follow up. It concluded that people having brexucabtagene autoleucel do not have the same quality of life as the general population, and the ERG approach should be used in decision making.\n\n## Allo-SCT costs and QALY loss should be included in the model for people having brexucabtagene autoleucel\n\nIn ZUMA‑3, 14 out of 78 (18%) people had an allo‑SCT. But the company did not account for the costs or quality-adjusted life year (QALY) impact of allo‑SCT use in this proportion of people in the brexucabtagene autoleucel arm in the economic model. The company stated that the technology is not planned to be used before an allo‑SCT in UK clinical practice. It had done a sensitivity analysis adjusting for overall survival, censoring for allo‑SCT, and no statistical difference was found. The ERG stated that the sensitivity analysis was not sufficiently powered to detect a difference. So it could not be determined if an allo‑SCT could have provided a survival advantage to the people who had had one. The ERG stated that it was therefore also appropriate to include the associated costs and QALYs in the model for the 18% who received brexucabtagene autoleucel in ZUMA‑3 and went on to receive allo‑SCT. The clinical experts stated that allo‑SCT after CAR\xa0T‑cell treatment would not be standard practice, and that brexucabtagene autoleucel would likely be used as a standalone therapy. The committee noted that it was unclear how often allo‑SCT would be used in practice. But it noted the ERG's opinion that because the clinical-effectiveness evidence in the model included some people who received allo‑SCT after CAR\xa0T‑cell treatment, the associated costs and QALYs of allo‑SCT should also be included. The committee concluded that allo‑SCT costs and a QALY loss should be included in the model for people having brexucabtagene autoleucel.\n\n## CAR T-cell delivery costs of £41,101 are most appropriate for decision making\n\nNHS England has established a single tariff to capture the costs of delivering CAR\xa0T‑cell therapy. The tariff was developed after NICE recommended the first CAR\xa0T‑cell therapy, tisagenlecleucel, for use in the Cancer Drugs Fund in December 2018. NHS England explained that the tariff includes all costs of care from the decision to have CAR\xa0T‑cell therapy to 100\xa0days after the infusion. NHS England explained that there is not a healthcare resource group (HRG) code that adequately captures the administration of CAR\xa0T‑cell therapies. As part of the NICE technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies (TA872), the company (also the company in this appraisal) submitted an analysis using a CAR\xa0T‑cell therapy delivery cost of £41,101. This was informed by an ERG scenario analysis in the NICE technology appraisal guidance on axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy. NHS England considered that, although the company's cost of £41,101 differs from the NHS England tariff for CAR\xa0T‑cell therapy, it was an acceptable cost to use in the cost-effectiveness analysis. This is because although the NHS England tariff represents the high hospital costs of establishing the infrastructure of a CAR\xa0T‑cell therapy service and delivering a relatively new type of treatment, economies of scale may be expected over time, particularly with clinical developments that reduce toxicity and the intensity of monitoring and treatment. At the second committee meeting, the company included the CAR\xa0T‑cell delivery cost of £41,101 in its base case, and excluded the costs for the following from the model, which it believed should be covered by the delivery cost:\n\nleukapheresis\n\nCAR\xa0T‑cell administration\n\nadverse events\n\nmonitoring\n\ntraining\n\nconditioning and bridging chemotherapy acquisition, administration and delivery.NHS England's clinical lead for the Cancer Drugs Fund noted that the costs of conditioning and bridging chemotherapy are not included in the £41,101 delivery cost. The ERG also included the CAR\xa0T‑cell delivery cost of £41,101 in its base case and excluded most of the same costs that the company excluded. But the ERG included the costs of conditioning and bridging chemotherapy separately in the model. NHS England confirmed that the ERG's approach was appropriate and in line with the approach agreed for TA872. The committee noted NHS England's comments and was satisfied that the ERG's costs were a reasonable projection of the cost to the NHS of delivering CAR\xa0T‑cell therapy.\n\n# End of life\n\n## Brexucabtagene autoleucel meets the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The literature showed that median overall survival with the comparator treatments ranged from 5.3 to 8\xa0months. The clinical experts stated that life expectancy is the same for people with Philadelphia chromosome-negative and -positive disease. The company's model predicted that mean overall survival with the comparator treatments was more than 24\xa0months, but the percentage of people alive at 2\xa0years ranged from 13% to 22%. So the committee was persuaded that people are unlikely to live for longer than 24\xa0months and that the short life expectancy criterion was met. The clinical experts explained that it is likely that brexucabtagene autoleucel will extend life for more than 3\xa0months. Also, the model estimated a mean overall survival gain for brexucabtagene autoleucel compared with the comparators of more than 3\xa0months. The exact data is confidential and so cannot be shown here. The committee concluded that the end of life criteria were met for people 26\xa0years and over with relapsed or refractory B‑cell acute lymphoblastic leukaemia.\n\n# Cost-effectiveness estimate\n\n## Because of the uncertainty, the maximum acceptable ICER would be substantially less than £50,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal (section 6) notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, decisions about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically associated with:\n\nthe clinical-effectiveness estimates and the assumption of cure (see section\xa03.4)\n\nlong-term mortality rates compared with the general population (see section\xa03.9)\n\nlong-term quality of life compared with the general population (see section\xa03.10).The committee also agreed that the end of life criteria applied, which allows it to consider ICERs of up to £50,000 per QALY gained (see section 3.13). NICE's guide to the methods of technology appraisal also notes that the appraisal committee does not use a precise maximum acceptable ICER. Given the level of uncertainty, the committee concluded that the maximum acceptable ICER for routine commissioning would be substantially lower than £50,000 per QALY gained.\n\n## Brexucabtagene autoleucel is not recommended for routine use in the NHS\n\nThe committee noted that the ERG's base-case analysis was more closely aligned with its preferred assumptions for both Philadelphia chromosome subgroups, specifically:\n\nusing the inverse of hazard ratios derived from the MAIC analysis to model inotuzumab in the ZUMA‑3 population (see section\xa03.7)\n\nincluding costs and QALY loss associated with allo‑SCT for people who have brexucabtagene autoleucel (see section\xa03.11)\n\napplying a utility multiplier of 0.92, to age and sex-matched general population utilities (see section\xa03.10)\n\nassuming adverse event-related costs for brexucabtagene autoleucel would be the same as those for inotuzumab\n\nremoving the costs of FLAG‑IDA for people having ponatinib\n\nassuming a CAR\xa0T‑cell delivery cost of £41,101 plus the costs associated with conditioning and bridging chemotherapy (see section\xa03.12).The committee also concluded that it was appropriate to apply a standardised mortality ratio to the general population mortality rate after 3\xa0years in the model. It was highly uncertain what the true standardised mortality ratio should be. It concluded that it was appropriate to consider a value of 3\xa0for decision making, noting that it could plausibly be as high as 4 (see section 3.9). The committee considered the ICERs using standardised mortality ratios of 3 and 4 applied to the ERG's base case, using the confidential discounts for brexucabtagene autoleucel and the comparator treatments. Because there are confidential discounts, the exact ICERs cannot be reported here. The committee noted that the ICERs were not all substantially below £50,000 per QALY gained in deterministic analysis, compared with both comparators, in the Philadelphia-positive and -negative subgroups. It noted that the ICER was highest when using a standardised mortality ratio of 4. The ERG highlighted that these ICERs were based on deterministic analyses and that it was likely that the probabilistic ICERs in a fully incremental analysis would be higher. The committee recalled that a maximum acceptable ICER for routine commissioning would be substantially below £50,000 per QALY gained (see section 3.14). Given the high levels of uncertainty in the model and the fact that the ICERs using the committee's preferred assumptions were not all substantially below £50,000 per QALY gained, the committee concluded that brexucabtagene autoleucel could not be recommended for routine use in the NHS.\n\n# Cancer Drugs Fund\n\n## Brexucabtagene autoleucel meets the criteria for inclusion in the Cancer Drugs Fund\n\nThe committee considered if brexucabtagene autoleucel could be recommended for use within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016. The committee discussed if the uncertainties identified in the company's cost-effectiveness evidence could be addressed by collecting more data in the Cancer Drugs Fund. The ongoing single-arm ZUMA‑3 trial will provide further data on the follow up of people having brexucabtagene autoleucel and may help resolve some clinical uncertainties around overall survival, relapse-free survival and whether this treatment is curative. The committee noted that even with further data collection from ZUMA‑3, there would still be uncertainty in the comparative clinical-effectiveness evidence. This was because ZUMA‑3 was a single-arm study and so comparative evidence relied on indirect treatment comparisons. Other issues, such as the uncertainties in the standardised mortality ratio value (see section\xa03.9) and the utility value (see section\xa03.10), would be unlikely to be resolved through further data collection in the Cancer Drugs Fund. The committee noted that brexucabtagene autoleucel does have the potential to be cost effective because some plausible scenarios resulted in ICERs below what NICE considers an acceptable use of NHS resources (see section\xa03.15). It concluded that brexucabtagene autoleucel did meet the criteria for inclusion in the Cancer Drugs Fund.\n\n# Equality issues\n\n## With the evidence available, this technology appraisal cannot address the equalities issues\n\nThe committee considered multiple equalities issues:\n\nThe clinical experts noted that people from minority ethnic family backgrounds can have difficulty finding a suitable match for a curative allo‑SCT. They also noted that older people are less likely to be eligible for allo‑SCT, but could be eligible for brexucabtagene autoleucel. For people who are unable to have an allo‑SCT, brexucabtagene autoleucel could offer improved outcomes over existing treatments. The committee noted that this was a population with a particular unmet need. But it was not presented with any clinical or cost-effectiveness evidence allowing this population to be considered separately. So it was only able to make a decision based on the full population in the decision problem. The committee agreed that this could not be addressed in this technology appraisal given the information available.\n\nThe committee noted that the marketing authorisation states that this technology is for people 26\xa0years and over. The patient and clinical experts noted that if this technology is not recommended, it would leave people above this age without access to a potentially curative treatment option. They highlighted that a different CAR\xa0T‑cell treatment (tisagenlecleucel) is available through the Cancer Drugs Fund for people aged under 26. The committee acknowledged this issue and that people 26\xa0years and over have a particular unmet need. It noted that the decision to recommend brexucabtagene autoleucel was based on the clinical and cost-effectiveness evidence available for this appraisal. The committee concluded that it could not recommend a technology for a particular population based on the fact that another technology appraisal did not include that population.\n\nThe committee was also aware that some religious groups such as Jehovah's witnesses may not accept technologies or procedures derived from blood (such as allo‑SCT). These people would normally have best supportive care. The committee acknowledged that if brexucabtagene autoleucel does become available, some people may choose not to have this treatment because it contains human blood products. So, this is not viewed as an equality issue in this appraisal.The committee concluded that given the information available, the equality issues cannot be addressed through this technology appraisal.\n\n# Conclusion\n\n## Brexucabtagene autoleucel is recommended for use in the Cancer Drugs Fund\n\nThe committee recalled the uncertainties in the evidence for this technology (see section\xa03.14) and that the population has high unmet needs (see section 3.1). Taking this into account, the ICERs based on its preferred assumptions were still higher that what was considered cost effective. So, it concluded that brexucabtagene autoleucel could not be recommended for routine use. But, the committee considered that brexucabtagene autoleucel did have plausible potential to be cost effective, and that some of the clinical uncertainties may be resolved with further data collection (see section 3.16). So brexucabtagene autoleucel is recommended for use in the Cancer Drugs Fund for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people 26\xa0years and over.", 'Review of guidance': "The data collection period is expected to end as outlined in the data collection arrangement, when more data from the ZUMA‑3 trial is available. Once enough evidence is available, the process for exiting the Cancer Drugs Fund will begin at this point and the review of the NICE guidance will start.\n\nAs part of the managed access agreement, the technology will continue to be available through the Cancer Drugs Fund after the data collection period has ended and while the guidance is being reviewed. This assumes that the data collection period ends as planned and the review of guidance follows the standard timelines described in section 6 of NICE's guide to the processes of technology appraisal.\n\nStephen O'BrienChair, appraisal committeeMarch 2023"}	https://www.nice.org.uk/guidance/ta893	Evidence-based recommendations on brexucabtagene autoleucel (Tecartus) for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 26 years and over.
a6460b61ba37d399c8cd9fdc01c02b8f7c12597a	nice	Axicabtagene ciloleucel for treating relapsed or refractory follicular lymphoma	Axicabtagene ciloleucel for treating relapsed or refractory follicular lymphoma Evidence-based recommendations on axicabtagene ciloleucel (Yescarta) for relapsed or refractory follicular lymphoma in adults. # Recommendations Axicabtagene ciloleucel is not recommended, within its marketing authorisation, for treating relapsed or refractory follicular lymphoma after 3 or more systemic treatments in adults. This recommendation is not intended to affect treatment with axicabtagene ciloleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations There is no established treatment for relapsed or refractory follicular lymphoma after 3 or more systemic treatments. Treatment can involve trying previous treatments again. Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T‑cell therapy. The therapy uses the person's immune system cells (T cells), which have been modified to attach to and kill cancer cells. The clinical evidence is from a small study that suggests that axicabtagene ciloleucel increases the amount of time people have before their condition gets worse and how long they live, but it is uncertain by how much. Axicabtagene ciloleucel does not meet NICE's criteria to be considered a life-extending treatment at the end of life. This is because people having standard treatments for relapsed or refractory follicular lymphoma after 3 or more systemic treatments are likely to live longer than 2 years. Because there are uncertainties in the economic model, the cost-effectiveness estimates are also uncertain. They are also all above the range NICE normally considers to be an acceptable use of NHS resources. So, axicabtagene ciloleucel is not recommended for routine use in the NHS. The evidence suggests that axicabtagene ciloleucel is not likely to be cost effective. So, axicabtagene ciloleucel is not recommended for use in the Cancer Drugs Fund.# Information about axicabtagene ciloleucel # Marketing authorisation indication Axicabtagene ciloleucel (Yescarta, Kite) is indicated for 'the treatment of adult patients with r/r follicular lymphoma (FL) after three or more lines of systemic therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for axicabtagene ciloleucel. # Price The list price of axicabtagene ciloleucel for a single infusion including shipping, engineering and generation of chimeric antigen receptor (CAR) T cells is £280,451 (company submission). The company has a commercial arrangement. This makes axicabtagene ciloleucel available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Kite, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Living with relapsed or refractory follicular lymphoma is physically and emotionally challenging The clinical and patient expert statements highlighted that follicular lymphoma can have a significant effect on the quality of life of people with the condition and their carers. They explained that people with follicular lymphoma are concerned about relapse, and that the need for repeated courses of treatment is physically and psychologically challenging. They explained that the symptoms and unpredictable nature of the disease have a profound and devastating impact on all aspects of a person's life. People experience a wide variety of symptoms including enlarged lymph nodes, weight loss, fever, night sweats, constant itching, fatigue, neutropenia, anaemia and thrombocytopenia. Low-grade lymphoma can transform into high-grade lymphoma, which can have serious symptoms requiring urgent treatment. These symptoms can lead to not being able to work, focus or concentrate and can affect mood and the ability to exercise, socialise and have a relationship. They explained that people feel exhausted, tire easily and are unable to do daily activities. The committee understood that people with the disease often have difficulty doing day-to-day tasks, and they fear relapse. In addition, treatment options become limited as the disease advances, so courses of previous treatments are often repeated. There can be a negative impact on self-esteem and difficulties in having relationships. A clinical expert explained that with more effective treatment, there was potential for people with the condition to live longer and have a better quality of life. In addition, the patient expert statement highlighted that caring for someone with follicular lymphoma is emotionally, practically and financially challenging. For example, carers often provide transport to and from hospital appointments and treatment sessions, requiring time off work. They also provide emotional support, while trying to deal with an emotionally difficult situation themselves. The committee concluded that living with the condition and caring for people with relapsed or refractory follicular lymphoma is physically and emotionally challenging. ## People with relapsed or refractory follicular lymphoma would welcome a new treatment option The clinical and patient experts explained that there is an unmet need for effective new treatments for people with relapsed or refractory follicular lymphoma. This is because for many people their disease does not respond well after 3 or more treatments. The only option for them is to repeat courses of previous treatments. These can have significant side effects which may affect their daily activities. The clinical and patient experts explained that if multiple treatments are available in the treatment pathway, it allows them to identify the best option as quickly as possible to achieve complete remission. The committee concluded that clinicians and people with the condition would welcome a new treatment option. # The treatment pathway ## The proposed positioning of axicabtagene ciloleucel is appropriate Follicular lymphoma is the most common type of indolent (low-grade) non-Hodgkin lymphoma and is not considered curable. Treatment aims to induce response, and control disease progression for as long as possible. The clinical experts explained that treatment is characterised by multiple lines of treatment as the disease responds and relapses. Rituximab monotherapy is used as a first-line treatment option for the treatment of asymptomatic advanced (stage 3 or 4) disease. For symptomatic advanced follicular lymphoma, NICE's technology appraisal guidance on rituximab for the first-line treatment of stage 3 to 4 follicular lymphoma recommends first-line treatment with rituximab in combination with either: cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) cyclophosphamide, vincristine and prednisolone (CVP) mitoxantrone, chlorambucil and prednisolone (MCP) cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-alfa (CHVPi), or chlorambucil.At first relapse, if the disease had a good response to initial treatment, people are offered a different rituximab–chemotherapy combination followed by rituximab maintenance treatments. If the disease does not respond adequately or if response is lost, lenalidomide with rituximab, or obinutuzumab with bendamustine is offered. The clinical experts explained that if the disease relapses after obinutuzumab with chemotherapy it may be treated with a rituximab–chemotherapy combination. They explained that it may be treated with rituximab alone if there is resistance or intolerance to chemotherapy. The clinical experts also explained that when the disease becomes refractory, the available treatment options are limited, and people have a poor prognosis. Treatments are chosen based on the person's previous treatment and fitness level. Rechallenge or reintroduction of previously used treatments is a relatively common practice. The committee acknowledged that there is no established standard care for people with relapsed or refractory follicular lymphoma after 3 or more systemic treatments. The committee agreed with the company's positioning of axicabtagene ciloleucel after 3 or more previous treatments. ## The company's blended comparator approach is acceptable for decision making The company compared axicabtagene ciloleucel with various treatments based on SCHOLAR‑5. This was an international external control cohort study that was generated to provide comparative evidence in relapsed or refractory follicular lymphoma (see section 3.7). Treatments in the blended comparator included rituximab with chemotherapy (CHOP, CVP or bendamustine), rituximab with lenalidomide, and obinutuzumab with bendamustine (from now on referred to as the blended comparator). A blended comparator was used because there is no established standard treatment after 3 or more systemic treatments. The company considered that rituximab monotherapy and best supportive care were not relevant comparators. This was because these treatments would likely be used to treat people who are not well enough to have axicabtagene ciloleucel. So, rituximab monotherapy and best supportive care were excluded from the list of comparators. The ERG and clinical experts broadly agreed that the company's blended comparator reflected clinical practice, but they highlighted a few differences. For example, in some cases CVP may be used after 3 treatments in clinical practice. The committee concluded that the company's blended comparator approach, and the treatments included in it, were suitable for decision making in the context of this appraisal. # Clinical evidence ## The results of ZUMA-5 are generalisable to NHS clinical practice The clinical evidence for axicabtagene ciloleucel came from ZUMA‑5, a single-arm, open-label, phase 2 study. The study was in people with relapsed or refractory B‑cell indolent non-Hodgkin lymphoma (follicular lymphoma or marginal zone lymphoma). It included 125 people with relapsed or refractory follicular lymphoma. The committee noted that ZUMA‑5 included people with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. This means that their activities are relatively unrestricted by their disease. The clinical experts highlighted that the relevant population in the NHS is likely to be older and less fit than the trial population. But they considered that the population included in ZUMA‑5 would be generalisable to the people who would have treatment with axicabtagene ciloleucel in clinical practice. The committee concluded that ZUMA‑5 is broadly generalisable to NHS clinical practice and is appropriate for decision making. ## Axicabtagene ciloleucel is likely to be clinically effective, but survival data is immature and the long-term treatment effect is uncertain The primary outcome of ZUMA‑5 was objective response rate. The secondary outcomes relevant to this appraisal were objective response rate, complete response, duration of response, best objective response, progression-free survival and overall survival. Efficacy data was presented for people with follicular lymphoma after 2 treatments because this was the predefined primary efficacy analysis set. But to align with the marketing authorisation and decision problem, efficacy data was also presented for people with follicular lymphoma after 3 or more treatments. Results showed that people with relapsed or refractory follicular lymphoma who had axicabtagene ciloleucel after 3 or more treatments, had a high objective response rate and complete response. The results, including median overall survival and median progression-free survival, are academic in confidence and cannot be reported here. The committee noted that there is no evidence on the effectiveness of axicabtagene ciloleucel directly compared with standard care. At the latest data cut, the median follow up in ZUMA‑5 was short and the survival data was immature, so there was uncertainty in the robustness of the results. The committee was aware that no plateau was observed in the Kaplan–Meier curves for overall survival and progression-free survival. It also noted that the curves were based on very few people having experienced an event by the data cut-off, which means that the long-term outcomes are very uncertain. The committee also noted that some people included in ZUMA‑5 had an allogeneic stem cell transplant after treatment with axicabtagene ciloleucel. The committee was aware that this may affect the overall mean survival for ZUMA‑5. The number of people who had allogeneic stem cell transplant is academic in confidence so cannot be reported here. At the first meeting, the committee concluded that axicabtagene ciloleucel is likely to be clinically effective. But the size of this benefit is uncertain. This is because of the immature survival data, the inclusion of subsequent treatments (such as allogenic stem cell transplant) in the trial, and the lack of comparator data. In response to consultation, the company presented an updated analysis of data from ZUMA‑5 (referred to as the 36‑month data cut). The company also presented a post-hoc analysis that explored the potential impact of allogenic stem cell transplant. The analysis censored data for people at the time of subsequent transplant and compared the 24‑month overall-survival rate estimate with the main analysis. The company explained that the results indicated a plateau, and subsequent stem cell treatment does not have a positive impact on overall survival. The results are also academic in confidence and cannot be reported here. The ERG explained that the Kaplan–Meier curves of overall survival and progression-free survival from the ZUMA‑5 36‑month data cut were broadly aligned with the company's extrapolation to 5 years. But the median progression-free survival was slightly underestimated in the model. The ERG noted that there were also signs that the Kaplan–Meier curves were flattening from 3 years, but the data was affected by heavy censoring. The ERG also explained that 24 months is too early to determine if subsequent treatment has a positive impact on overall survival, and highlighted that longer-term follow up is needed. The committee noted the sustained benefit shown from the 36‑month data cut and the relatively short follow up of the trial. It concluded that while the data indicates that axicabtagene ciloleucel reduces the risk of disease progression in people with relapsed or refractory follicular lymphoma, its long-term treatment effect is uncertain. ## ZUMA-5 is a single-arm study, so comparator data was taken from the SCHOLAR-5 study Because ZUMA‑5 was a single-arm study, the company used data from the SCHOLAR‑5 study to inform comparative effectiveness. SCHOLAR‑5 was a retrospective study with pooled data from 3 cohorts (A, B and C). Cohorts A and B included retrospective medical records from 7 sites in the UK, France, Spain, Portugal and the US. Cohort C included a single-arm, open-label phase 2 study (DELTA) for people: with relapsed or refractory follicular lymphoma whose disease did not respond adequately or was refractory to rituximab and an alkylating agent, and who had previously had treatment with idelalisib. The cohorts were restricted to people with follicular lymphoma who had previous treatment after at least 3 prior treatments, in line with the anticipated marketing authorisation for axicabtagene ciloleucel. More treatments were included in SCHOLAR‑5 than in the blended comparator (see section 3.4). Idelalisib, radioimmunotherapy, CVP and experimental treatments were excluded from the blended comparator because they were not considered representative of treatments used in the NHS. The committee noted the ERG's concerns that comparative effectiveness results derived from single-arm studies were prone to bias because of the lack of randomised comparators in the clinical data. The committee was aware that because of the lack of data for relapsed or refractory follicular lymphoma after 3 or more treatments, the company had used a propensity-score-weighted indirect comparison (see section 3.8). The committee concluded that using data from the SCHOLAR‑5 study was acceptable to inform comparative effectiveness. ## The company's approach to adjusting the SCHOLAR-5 data is highly complex Clinical inputs for the comparator arm, for treatment options after 3 or more treatments, were derived using the propensity-score-weighted data from the SCHOLAR‑5 study. To address the baseline imbalances between the ZUMA‑5 and SCHOLAR‑5 studies and to reduce bias in comparative effectiveness, the company applied propensity scoring methods using standardised mortality ratio (SMR) weighting. The ERG commented that it was not transparent how the SMR weighting had been applied to the propensity scoring. But it considered that the weighting improved comparability between ZUMA‑5 and SCHOLAR‑5. The results of pre-weighting and post-weighting baseline characteristics are academic in confidence and cannot be reported here. The committee noted that the company had access to individual patient data from both the ZUMA‑5 and SCHOLAR‑5 studies, so other methods may have been more appropriate (as documented in the NICE Decision Support Unit Technical Support Document 18). The company also did an unanchored indirect comparison using both propensity-score-weighting and propensity-score-matching methods. The committee agreed with the ERG that propensity-score weighting improved the comparability. But the committee noted that some covariates had been excluded from the weighting: for example, follicular lymphoma subtype (grade 1, grade 2 and grade 3a), for which a large standardised mean difference was observed. The committee noted that stronger assumptions need to be met for an unanchored comparison. It also noted that propensity-score-weighting methods should adjust for all treatment effect modifiers and prognostic variables to better predict outcomes. At the first meeting, the committee concluded that the company's approach and use of the propensity-score-weighting method was highly uncertain. It would have liked to see other methods explored in more detail or the uncertainties of the unanchored indirect comparison addressed. In response to consultation, the company explained that its approach for the SCHOLAR‑5 analyses was based on NICE DSU Technical Support Document 18 and more recent developments in the literature. The company said that the propensity-score-weighting methods should adjust for all treatment effect modifiers and prognostic variables which must also be balanced with the sample size. So, it had focused on the covariates strongly correlated with outcomes. The ERG highlighted that generating comparative effectiveness estimates from real-world data is challenging when sample sizes are limited and not all prognostic and effect-modifying variables can be adjusted for. The ERG noted that in addition to the follicular lymphoma subtype, there were some other lower grade subtypes in SCHOLAR‑5 than in ZUMA‑5. It noted that failure to adjust for these may have biased in favour of current fourth line care. The committee understood that propensity-score weighting should ideally adjust for all prognostic and effect modifiers but noted the concerns raised about small sample sizes. The committee was aware that the company had done sensitivity analyses using propensity-score matching and inverse-probability treatment weighting. It noted that the company had also explored alternative methods, including G-estimation and the E‑value, which provided consistent results in line with the company's original base case. The committee concluded that the adjustment method used by the company is highly complex. # Economic model ## The company's model is appropriate for decision making The company used a partitioned survival model to estimate the cost effectiveness of axicabtagene ciloleucel compared with standard care. It included 3 health states: pre-progression, progressed and death. The company's model structure was similar to those used in previous appraisals for relapsed or refractory follicular lymphoma. The ERG explained that the company had captured all relevant health states and that its model structure was appropriate. But it noted some uncertainties in the assumptions used in its model, for example, the long-term survivor assumption (see section 3.11). The committee questioned whether the company had explored a mixture-cure modelling approach. The company explained that because of the immaturity of the data it was not possible to use a mixture-cure model or a spline model. The committee concluded that the company's model was appropriate for its decision making. ## Extrapolations for progression-free and overall survival benefits from SCHOLAR-5 for standard care are uncertain The committee was aware that the company used SCHOLAR‑5 data to model survival for the blended comparator. Because there was no date of progression for people having the index therapy in the DELTA cohort, the ERG noted that these people were excluded from the progression-free survival analysis. This resulted in fewer people to inform progression-free survival, post weighting. The ERG explained that the results from SCHOLAR‑5 could overestimate overall-survival time in the post-progression state for standard care. At technical engagement, the company removed the DELTA cohort from the SCHOLAR‑5 data before propensity weighting, which improved the comparability with ZUMA‑5. The committee noted the minimal impact of removing the DELTA cohort on the progression-free survival curves and that the company had selected gamma extrapolation in line with its original base case. The ERG explained that people from the DELTA cohort were included in SCHOLAR‑5 from the point of their progression. So, this cohort represented people who had previous treatment with idelalisib but who were not having idelalisib as fourth line treatment. The ERG considered the generalised gamma, log-logistic and log-normal distributions to provide the best statistical fits. The estimates of survival extrapolation for people with relapsed or refractory follicular lymphoma after 3 or more previous treatments in the NHS in England and Wales were noted by the ERG to be highly uncertain. The committee noted that the company did not justify using a gamma extrapolation as its chosen parametric curve. It also noted that removing the DELTA cohort from SCHOLAR‑5 had a large effect on cost-effectiveness results. The committee concluded that although extrapolation of progression-free survival and overall survival for standard care after 3 or more treatments is uncertain, it preferred the exponential distribution for progression-free survival and the gamma distribution for overall survival. ## The committee considered both the company's and the ERG's approaches in its decision making Progression-free survival and overall survival were the main effectiveness inputs included in the company's economic model. Progression-free survival and overall survival for axicabtagene ciloleucel and standard care after 3 or more treatments, were estimated using time-to-event data from ZUMA‑5 and SCHOLAR‑5 respectively. The committee noted that both the company's and ERG's models assumed that a proportion of people who had axicabtagene ciloleucel could be considered long-term survivors from a future time point and thereafter experience zero risk of progression. The long-term survivors were also assumed to have a 9% higher probability of death than the general population from year 5 onwards. The company base-case assumption was that 25% of people who had treatment with axicabtagene ciloleucel were long-term survivors, and these extrapolation assumptions were applied from 5 years. Non-long-term survivors continued to follow the hazards of progression and death based on a Weibull distribution fitted to the full ZUMA‑5 dataset. The committee noted that the company's approach reflects a homogenous cohort of people, which is used at all time points for non-long-term survivors, but that this is overridden by cure assumptions in the long-term survivor group from 5 years. The company clarified that based on clinical opinion and clinical validation of survival curves, it assumed that 25% of people who had axicabtagene ciloleucel were long-term survivors. The ERG agreed with the company that it was not possible to use a mixture-cure model because the data from ZUMA‑5 was immature. The ERG considered that because of the unique mechanism of action of axicabtagene ciloleucel, it would expect a proportion of people to be long-term survivors but that the proportion could not be validated because of the lack of data after 3 treatments. The committee was aware that both the company and the ERG also presented scenario analyses with long-term survival proportions which varied up to 25%. The committee noted that the long-term survivor proportion assumption had little effect on the cost-effectiveness results. The committee noted that the company did not clearly present the model predictions for long-term survivors and non-long-term survivors separately. At the first meeting, the committee concluded that based on the immature survival data from ZUMA‑5 and the uncertainties in the SCHOLAR‑5 data, it was uncertain if the company's long-term survival assumptions were appropriate. In response to consultation, the company presented a graph of the modelled overall survival stratified by long-term survivors and non-long-term survivors to address the committee's concerns. The ERG noted that the hazard of death remained lower in non-long-term survivors compared with those having standard care after 3 or more treatments. It used a Weibull distribution to extrapolate the hazard of mortality for non-long-term survival. This was adjusted to remain 1.2 times higher than that of the general population matched for age and sex. The ERG further explored scenarios by increasing this adjustment to 1.5 times and 2 times higher than that of the general population matched for age and sex. It also presented a pessimistic scenario using the generalised gamma distribution for extrapolation of axicabtagene ciloleucel overall survival, but without upward adjustment of the extrapolated mortality hazard for non-long-term survivors. The committee noted that this predicted a steeper overall-survival curve for non-long-term survivors, with the hazard of mortality exceeding that of the standard care arm. The committee took both the company's and the ERG's approaches into account in its decision making. It noted that the presented analyses did not resolve the issues with the company's long-term and non-long-term survivor assumptions. ## The ERG's approach for health state utility values is more appropriate In ZUMA‑5 and SCHOLAR‑5, no health-related quality-of-life data was collected. The committee noted that the company used health state utility values in the economic model from NICE's technology appraisal guidance on lenalidomide with rituximab for previously treated follicular lymphoma which were based on the AUGMENT study. The committee was aware that other sources of health state utilities were also available. But the ERG was concerned that because most people in the AUGMENT study were at an earlier stage in the disease pathway, they would be expected to have a higher quality of life than people having treatment after 3 or more treatments. So, the ERG preferred to use utility values from Wild et al. (2006) in its base case, in which EQ‑5D data was collected from people with relapsed or refractory follicular lymphoma. Long-term survivors (that is, people who were alive and free of progression at 5 years and beyond) were assumed to have a utility decrement compared with the general population for the rest of their life. The ERG highlighted the limitations of the Wild et al. study but considered that it better reflected the likely quality of life of people after 3 treatments than the AUGMENT study. In response to technical engagement, the company agreed with the ERG and updated its base case using utility values from Wild et al. The company explained that it considered that health-related quality of life for long-term survivors would be equal to that of the general population in line with previous NICE technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies and autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory mantle cell lymphoma. To address the uncertainty, the company also presented a scenario that assumed the health state utility value for long-term survivors after axicabtagene ciloleucel treatment to be halfway between the Wild et al. progression-free estimate and the general population. The ERG broadly agreed with the company's updated base case. But it considered it unlikely that long-term survivors would attain a health state utility in line with the general population while experiencing an elevated mortality risk. Given the uncertainty, the ERG considered it important to consider the range of assumptions around long-term survivors' utility values. The committee noted that the source of utility values had a small effect on the cost-effectiveness results. At the first meeting, the committee concluded that the ERG's approach of using a utility decrement for long-term survivors was more appropriate, and it would consider other scenarios presented in its decision making. In response to consultation, the company clarified that its assumptions were based on previous NICE technology appraisal guidance which were accepted by the committee. The clinical experts explained that they would expect a minor decrement in the utilities after chimeric antigen receptor (CAR) T‑cell therapy because of the higher risk of infections and relapse. They explained that if people do not have any infections and do not relapse, they would expect health-related quality of life to be near to that of the general population. The committee recognised that there are some uncertainties with this approach. The committee concluded that the ERG's approach of using a utility decrement for long-term survivors was more appropriate. The committee also noted that the assumption of a rebound to general-population utility for long-term survivors favoured axicabtagene ciloleucel. ## Time on treatment and subsequent treatment costs for comparators used in the model are acceptable In its original model, for treatments used in the blended comparator, the company used the median number of treatment cycles reported in the relevant summary of product characteristics. The company fitted an exponential distribution in its model to estimate time on comparator treatments. For simplicity, the company assumed equal subsequent treatment costs in both arms of the model. The ERG noted that the time-on-treatment curves were not consistent with the derived progression-free survival and overall survival curves for the comparator arm. The ERG highlighted that the company capped the time on treatment so it could not exceed overall survival, assuming that treatment may continue beyond progression. The clinical experts explained that treatment was unlikely to continue beyond progression. At technical engagement, the company agreed with the ERG that allowing treatment beyond progression while applying subsequent treatment costs at the point of progression may overestimate the costs of standard care in the comparator arm of the model. So, in its updated base case, the company capped time on treatment for the comparator treatments at the point of progression. The ERG explained that it was broadly satisfied with the company's updated base case. But time on comparator treatments for people with relapsed or refractory follicular lymphoma after 3 or more previous treatments remains uncertain because of limited data. The committee was aware that time on comparator treatments and subsequent treatment costs had a large impact on cost-effectiveness results. Despite the uncertainty in the estimation of time on comparator treatments, the committee concluded that it would accept the approach for decision making in the context of this appraisal. ## The infusion, monitoring and hospitalisation costs in the company's original model may not reflect NHS practice The company explained that axicabtagene ciloleucel is given as a single infusion within 30 minutes. It explained that in line with previous appraisals for CAR T‑cell therapies (NICE technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies and autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory mantle cell lymphoma), people are monitored in an elective inpatient setting. To account for this, the company applied daily hospitalisation costs of £903 to the mean duration of hospitalisation observed after axicabtagene ciloleucel treatment in ZUMA‑5. The mean duration of hospitalisation is academic in confidence and cannot be reported here. The NHS England Cancer Drugs Fund clinical lead (from now, Cancer Drugs Fund lead) explained that NHS England provides the infrastructure to CAR T‑cell therapy centres for them to deliver the entire treatment, including infusion and monitoring. NHS England has established a single delivery tariff for the cost of delivering current CAR T‑cell therapies. The 2022 to 2023 tariff for CAR T‑cell therapy delivery in people aged 19 years and over is £96,016, subject to ongoing review and period updates. The committee noted that the tariff cost was higher than the costs calculated by the company. The clinical experts also explained that they would expect intravenous immunoglobulin to be used for longer than the company's modelled time of 12 months. They also explained that in clinical practice the costs are higher than the company's estimates used in the model but are well below the NHS tariff. The committee noted that it was not provided with full details about how the NHS tariff was derived. It noted the need for greater transparency as to what the tariff cost included, to explore potential issues of double counting or undercounting costs. At the first meeting, the committee concluded that the tariff was the best available source to inform the cost that the NHS is paying currently. In response to consultation, the company explained that it had followed recommended NICE methods and its model included the best estimate of the cost of delivering CAR T‑cell therapy. It highlighted that using the NHS tariff in decision making would be procedurally unfair and unreasonable, because of the lack of transparency in how it is derived. The ERG also agreed with the company that transparency would be beneficial to estimate the true costs. The company also presented evidence from a real-world point-in-time survey of clinicians and people with diffuse large B-cell lymphoma (DLBCL) in the UK, Germany, Spain, Italy, France and Canada in 2021 (the Adelphi DLBCL Disease Specific Programme ). This survey considered the 100 days after CAR T‑cell therapy which showed a similar average hospitalisation duration (measured in days) to those used in the company's model, resulting in identical CAR T‑cell therapy infusion, monitoring and hospitalisation costs. The results of Adelphi DLBCL DSP are academic in confidence so cannot be reported here. During the second committee meeting, the Cancer Drugs Fund lead explained that the NHS tariff may have overestimated the true cost to the NHS, but also considered that the company's approach is an underestimate of the true cost. The committee noted that NHS England and the company did urgent work to provide alternative costs to NICE after the second committee meeting. ## CAR T-cell therapy delivery costs of £41,101 are most appropriate for decision making Additional information and clarification on costs were provided by NHS England after the second committee meeting. Based on this new information, the company used a 'bottom-up' costing approach to calculate the cost of delivering axicabtagene ciloleucel treatment in the NHS. The company included the costs of: infusion, monitoring and hospitalisation leukapheresis conditioning chemotherapy bridging therapy.The company considered each cost category individually and combined them to give an estimate for the cost of delivering axicabtagene ciloleucel in the NHS. The committee understood that NHS England had established a single tariff to capture these costs. The tariff was developed after NICE recommended the first CAR T‑cell therapy, tisagenlecleucel, for use in the Cancer Drugs Fund in December 2018. NHS England explained that the tariff includes all costs of care from the decision for the person to have CAR T‑cell therapy to 100 days after infusion. NHS England explained that there is not currently an HRG (healthcare resource group) code that adequately captures the administration of CAR T‑cell therapies. It also commented that a key difference between its tariff and the company's costs is the time and number of staff needed to look after people who have had CAR T‑cell therapy. The company commented that it is not appropriate to use the tariff in the modelling. This is because it is a mechanism for NHS England to fund hospitals to provide CAR T‑cell therapy and is not designed for health technology evaluation. It was concerned that the evidence underlying the tariff had not been transparently shared and that it may include costs that are not relevant. The ERG was also concerned about the methods used by NHS England to derive the tariff. It was unclear how individual trusts estimated expenditure and how this corresponded to quantities of resource use. But the ERG also commented that the company's approach likely underestimated the true cost of delivering CAR T‑cell therapy. After the second appraisal committee meeting the company submitted a further analysis using a CAR T‑cell therapy delivery cost of £41,101, informed by an ERG scenario analysis. This accounted for the impact of increased staffing needs associated with providing CAR T‑cell therapy. The updated company analysis consisted of a one-off cost of £41,101 for the first 100 days as well as the costs of conditioning chemotherapy drugs, stem cell transplantation and intravenous immunoglobulin. These 3 costs are reimbursed separately by NHS England. NHS England considered that, although the company's cost differs from the tariff for CAR T‑cell therapy, it was an acceptable cost to use in the cost-effectiveness analysis. This is because the current tariff represents the high hospital costs of establishing the infrastructure of a CAR T‑cell therapy service and delivering a relatively new type of treatment, but economies of scale may be expected over time. Costs may also reduce with clinical developments in care that reduce toxicity and so reduce the need for more intense monitoring and treatment. The committee noted NHS England's comments and was satisfied that the company's costs adequately captured a reasonable projection of the cost to the NHS of delivering CAR T‑cell therapy. # End of life ## Axicabtagene ciloleucel does not meet the criteria to be considered a life-extending treatment at the end of life The committee considered the advice about life-extending treatments for people with a short life expectancy in section 6 of NICE's guide to the methods of technology appraisal 2013. This states that a treatment can be considered as a life-extending treatment at the end of life if: it is indicated for people with a short life expectancy (normally less than 24 months), and it offers an extension to life (normally a mean value of at least an additional 3 months compared with current NHS treatment). The committee noted that both the company and the ERG agreed that axicabtagene ciloleucel did not meet the criteria for end of life. The company explained that axicabtagene ciloleucel would be used by clinicians as an end of life treatment for people with relapsed or refractory follicular lymphoma who had 3 or more systemic treatments. The clinical experts highlighted that they would expect people having standard care to live for between approximately 30 and 36 months. In response to consultation, a consultee highlighted that they would expect people having standard care to live for 24 months or less. This is because of a lack of data for people with relapsed or refractory follicular lymphoma after 3 or more treatments. The committee noted that the median life expectancies from the treatment comparisons from both the company's and the ERG's models were higher than 24 months. The median life expectancies are academic in confidence and cannot be reported here. The committee was aware that both the company's and the ERG's base cases supported a mean survival gain of greater than 3 months. But the committee considered that the short life expectancy criterion of less than 24 months was not met because the life expectancy of people who would have axicabtagene ciloleucel would normally be longer than 24 months. The committee concluded that axicabtagene ciloleucel does not meet the criteria to be considered a life-extending treatment at the end of life. # Cost-effectiveness estimates ## An acceptable ICER would be within the range normally considered a cost-effective use of NHS resources Section 6 of NICE's guide to the methods of technology appraisal 2013 notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee noted that data is immature for overall survival, and extrapolations from the model are uncertain. So, the committee agreed that an acceptable ICER would be within the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). ## Axicabtagene ciloleucel is not recommended for routine use Both the company's deterministic and probabilistic base cases showed that ICERs for axicabtagene ciloleucel compared with standard care were over £40,000 per QALY gained. The committee noted the high level of uncertainty in the model, particularly about: immature overall-survival data from ZUMA‑5 (see section 3.6) no direct comparative efficacy data for axicabtagene ciloleucel compared with standard care (see sections 3.7 and 3.8) long-term survivor proportion assumptions (see section 3.11) limited available evidence to inform time on treatment for comparator treatments in the company's model for people having treatment after 3 treatments (see section 3.13).The committee preferred the following assumptions: using a Weibull distribution for overall survival and generalised gamma distribution for progression-free survival in the axicabtagene ciloleucel arm (see section 3.11) using a gamma distribution for overall survival and exponential distribution for progression-free survival in the standard care arm including a utility decrement for long-term survivors after axicabtagene ciloleucel treatment (see section 3.12) a CAR T‑cell therapy administration cost of £41,101 (see section 3.15).Because of confidential commercial arrangements for axicabtagene ciloleucel and comparator treatments, the exact ICERs cannot be reported here. Taking into account all confidential discounts, the committee noted that the company's cost-effectiveness estimates for axicabtagene ciloleucel compared with standard care were above the range NICE normally considers a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee recognised the need for new effective treatments for relapsed or refractory follicular lymphoma. The committee took into account the innovative nature of axicabtagene ciloleucel and the additional benefits not captured in the model (see section 3.20). But axicabtagene ciloleucel was not shown to be a cost-effective use of NHS resources in any of the analyses presented and the evidence was highly uncertain. So, axicabtagene ciloleucel is not recommended for routine use in the NHS. # Cancer Drugs Fund ## Axicabtagene ciloleucel is not recommended for use in the Cancer Drugs Fund Having concluded that axicabtagene ciloleucel could not be recommended for routine use in the NHS, the committee then considered if it could be recommended for treating relapsed or refractory follicular lymphoma after 3 or more systemic treatments within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund process and methods guide. The committee recognised that people with relapsed or refractory follicular lymphoma have a high unmet need, and the availability of new treatments is very important. The committee was aware that the company had expressed an interest in the treatment being considered for funding through the Cancer Drugs Fund. It understood that ZUMA‑5 (a single-arm, phase 2 study) is ongoing and that a further study for axicabtagene ciloleucel is also planned (ZUMA‑22, a phase 3 study). The committee noted that these studies are likely to provide further evidence on survival but may not fully resolve some of the key uncertainties affecting the cost-effectiveness results, such as: immature overall-survival data from ZUMA‑5 no direct comparative efficacy data for axicabtagene ciloleucel compared with standard care.The committee also noted that the evidence suggests that axicabtagene ciloleucel is not likely to be a cost-effective use of NHS resources (see section 3.18). The committee concluded that axicabtagene ciloleucel did not meet the criteria to be recommended for use in the Cancer Drugs Fund. # Innovation ## Axicabtagene ciloleucel is an innovative treatment and the benefits may not be fully captured in the model The company considered axicabtagene ciloleucel to be innovative because of its mechanism of action in which a person's T cells are modified to target and kill cancer cells. The company explained that it was the first of the breakthrough class of CAR T‑cell therapies to be licensed for use in Europe and the US. The clinical experts explained that a single infusion may benefit some people with this condition. The committee acknowledged both the benefits offered and the innovative nature of axicabtagene ciloleucel. It concluded that there could be some additional carer benefits not fully captured in the model but noted that additional evidence had not been provided in the submission. # Equalities There were no equality issues identified.	{'Recommendations': "Axicabtagene ciloleucel is not recommended, within its marketing authorisation, for treating relapsed or refractory follicular lymphoma after 3\xa0or more systemic treatments in adults.\n\nThis recommendation is not intended to affect treatment with axicabtagene ciloleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere is no established treatment for relapsed or refractory follicular lymphoma after 3\xa0or more systemic treatments. Treatment can involve trying previous treatments again. Axicabtagene ciloleucel is a chimeric antigen receptor (CAR)\xa0T‑cell therapy. The therapy uses the person's immune system cells (T\xa0cells), which have been modified to attach to and kill cancer cells.\n\nThe clinical evidence is from a small study that suggests that axicabtagene ciloleucel increases the amount of time people have before their condition gets worse and how long they live, but it is uncertain by how much.\n\nAxicabtagene ciloleucel does not meet NICE's criteria to be considered a life-extending treatment at the end of life. This is because people having standard treatments for relapsed or refractory follicular lymphoma after 3\xa0or more systemic treatments are likely to live longer than 2\xa0years.\n\nBecause there are uncertainties in the economic model, the cost-effectiveness estimates are also uncertain. They are also all above the range NICE normally considers to be an acceptable use of NHS resources. So, axicabtagene ciloleucel is not recommended for routine use in the NHS.\n\nThe evidence suggests that axicabtagene ciloleucel is not likely to be cost effective. So, axicabtagene ciloleucel is not recommended for use in the Cancer Drugs Fund.", 'Information about axicabtagene ciloleucel': "# Marketing authorisation indication\n\nAxicabtagene ciloleucel (Yescarta, Kite) is indicated for 'the treatment of adult patients with r/r [relapsed or refractory] follicular lymphoma (FL) after three or more lines of systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for axicabtagene ciloleucel.\n\n# Price\n\nThe list price of axicabtagene ciloleucel for a single infusion including shipping, engineering and generation of chimeric antigen receptor (CAR)\xa0T cells is £280,451 (company submission). The company has a commercial arrangement. This makes axicabtagene ciloleucel available to the NHS with a discount and it would have also applied to this indication if the technology had been recommended. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Kite, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Living with relapsed or refractory follicular lymphoma is physically and emotionally challenging\n\nThe clinical and patient expert statements highlighted that follicular lymphoma can have a significant effect on the quality of life of people with the condition and their carers. They explained that people with follicular lymphoma are concerned about relapse, and that the need for repeated courses of treatment is physically and psychologically challenging. They explained that the symptoms and unpredictable nature of the disease have a profound and devastating impact on all aspects of a person's life. People experience a wide variety of symptoms including enlarged lymph nodes, weight loss, fever, night sweats, constant itching, fatigue, neutropenia, anaemia and thrombocytopenia. Low-grade lymphoma can transform into high-grade lymphoma, which can have serious symptoms requiring urgent treatment. These symptoms can lead to not being able to work, focus or concentrate and can affect mood and the ability to exercise, socialise and have a relationship. They explained that people feel exhausted, tire easily and are unable to do daily activities. The committee understood that people with the disease often have difficulty doing day-to-day tasks, and they fear relapse. In addition, treatment options become limited as the disease advances, so courses of previous treatments are often repeated. There can be a negative impact on self-esteem and difficulties in having relationships. A clinical expert explained that with more effective treatment, there was potential for people with the condition to live longer and have a better quality of life. In addition, the patient expert statement highlighted that caring for someone with follicular lymphoma is emotionally, practically and financially challenging. For example, carers often provide transport to and from hospital appointments and treatment sessions, requiring time off work. They also provide emotional support, while trying to deal with an emotionally difficult situation themselves. The committee concluded that living with the condition and caring for people with relapsed or refractory follicular lymphoma is physically and emotionally challenging.\n\n## People with relapsed or refractory follicular lymphoma would welcome a new treatment option\n\nThe clinical and patient experts explained that there is an unmet need for effective new treatments for people with relapsed or refractory follicular lymphoma. This is because for many people their disease does not respond well after 3\xa0or more treatments. The only option for them is to repeat courses of previous treatments. These can have significant side effects which may affect their daily activities. The clinical and patient experts explained that if multiple treatments are available in the treatment pathway, it allows them to identify the best option as quickly as possible to achieve complete remission. The committee concluded that clinicians and people with the condition would welcome a new treatment option.\n\n# The treatment pathway\n\n## The proposed positioning of axicabtagene ciloleucel is appropriate\n\nFollicular lymphoma is the most common type of indolent (low-grade) non-Hodgkin lymphoma and is not considered curable. Treatment aims to induce response, and control disease progression for as long as possible. The clinical experts explained that treatment is characterised by multiple lines of treatment as the disease responds and relapses. Rituximab monotherapy is used as a first-line treatment option for the treatment of asymptomatic advanced (stage\xa03 or\xa04) disease. For symptomatic advanced follicular lymphoma, NICE's technology appraisal guidance on rituximab for the first-line treatment of stage\xa03 to\xa04 follicular lymphoma recommends first-line treatment with rituximab in combination with either:\n\ncyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)\n\ncyclophosphamide, vincristine and prednisolone (CVP)\n\nmitoxantrone, chlorambucil and prednisolone (MCP)\n\ncyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-alfa (CHVPi), or\n\nchlorambucil.At first relapse, if the disease had a good response to initial treatment, people are offered a different rituximab–chemotherapy combination followed by rituximab maintenance treatments. If the disease does not respond adequately or if response is lost, lenalidomide with rituximab, or obinutuzumab with bendamustine is offered. The clinical experts explained that if the disease relapses after obinutuzumab with chemotherapy it may be treated with a rituximab–chemotherapy combination. They explained that it may be treated with rituximab alone if there is resistance or intolerance to chemotherapy. The clinical experts also explained that when the disease becomes refractory, the available treatment options are limited, and people have a poor prognosis. Treatments are chosen based on the person's previous treatment and fitness level. Rechallenge or reintroduction of previously used treatments is a relatively common practice. The committee acknowledged that there is no established standard care for people with relapsed or refractory follicular lymphoma after 3\xa0or more systemic treatments. The committee agreed with the company's positioning of axicabtagene ciloleucel after 3\xa0or more previous treatments.\n\n## The company's blended comparator approach is acceptable for decision making\n\nThe company compared axicabtagene ciloleucel with various treatments based on SCHOLAR‑5. This was an international external control cohort study that was generated to provide comparative evidence in relapsed or refractory follicular lymphoma (see section\xa03.7). Treatments in the blended comparator included rituximab with chemotherapy (CHOP, CVP or bendamustine), rituximab with lenalidomide, and obinutuzumab with bendamustine (from now on referred to as the blended comparator). A blended comparator was used because there is no established standard treatment after 3\xa0or more systemic treatments. The company considered that rituximab monotherapy and best supportive care were not relevant comparators. This was because these treatments would likely be used to treat people who are not well enough to have axicabtagene ciloleucel. So, rituximab monotherapy and best supportive care were excluded from the list of comparators. The ERG and clinical experts broadly agreed that the company's blended comparator reflected clinical practice, but they highlighted a few differences. For example, in some cases CVP may be used after 3\xa0treatments in clinical practice. The committee concluded that the company's blended comparator approach, and the treatments included in it, were suitable for decision making in the context of this appraisal.\n\n# Clinical evidence\n\n## The results of ZUMA-5 are generalisable to NHS clinical practice\n\nThe clinical evidence for axicabtagene ciloleucel came from ZUMA‑5, a single-arm, open-label, phase\xa02 study. The study was in people with relapsed or refractory B‑cell indolent non-Hodgkin lymphoma (follicular lymphoma or marginal zone lymphoma). It included 125\xa0people with relapsed or refractory follicular lymphoma. The committee noted that ZUMA‑5 included people with an Eastern Cooperative Oncology Group (ECOG) performance status of\xa00 or\xa01. This means that their activities are relatively unrestricted by their disease. The clinical experts highlighted that the relevant population in the NHS is likely to be older and less fit than the trial population. But they considered that the population included in ZUMA‑5 would be generalisable to the people who would have treatment with axicabtagene ciloleucel in clinical practice. The committee concluded that ZUMA‑5 is broadly generalisable to NHS clinical practice and is appropriate for decision making.\n\n## Axicabtagene ciloleucel is likely to be clinically effective, but survival data is immature and the long-term treatment effect is uncertain\n\nThe primary outcome of ZUMA‑5 was objective response rate. The secondary outcomes relevant to this appraisal were objective response rate, complete response, duration of response, best objective response, progression-free survival and overall survival. Efficacy data was presented for people with follicular lymphoma after 2\xa0treatments because this was the predefined primary efficacy analysis set. But to align with the marketing authorisation and decision problem, efficacy data was also presented for people with follicular lymphoma after 3\xa0or more treatments. Results showed that people with relapsed or refractory follicular lymphoma who had axicabtagene ciloleucel after 3\xa0or more treatments, had a high objective response rate and complete response. The results, including median overall survival and median progression-free survival, are academic in confidence and cannot be reported here. The committee noted that there is no evidence on the effectiveness of axicabtagene ciloleucel directly compared with standard care. At the latest data cut, the median follow up in ZUMA‑5 was short and the survival data was immature, so there was uncertainty in the robustness of the results. The committee was aware that no plateau was observed in the Kaplan–Meier curves for overall survival and progression-free survival. It also noted that the curves were based on very few people having experienced an event by the data cut-off, which means that the long-term outcomes are very uncertain. The committee also noted that some people included in ZUMA‑5 had an allogeneic stem cell transplant after treatment with axicabtagene ciloleucel. The committee was aware that this may affect the overall mean survival for ZUMA‑5. The number of people who had allogeneic stem cell transplant is academic in confidence so cannot be reported here. At the first meeting, the committee concluded that axicabtagene ciloleucel is likely to be clinically effective. But the size of this benefit is uncertain. This is because of the immature survival data, the inclusion of subsequent treatments (such as allogenic stem cell transplant) in the trial, and the lack of comparator data. In response to consultation, the company presented an updated analysis of data from ZUMA‑5 (referred to as the 36‑month data cut). The company also presented a post-hoc analysis that explored the potential impact of allogenic stem cell transplant. The analysis censored data for people at the time of subsequent transplant and compared the 24‑month overall-survival rate estimate with the main analysis. The company explained that the results indicated a plateau, and subsequent stem cell treatment does not have a positive impact on overall survival. The results are also academic in confidence and cannot be reported here. The ERG explained that the Kaplan–Meier curves of overall survival and progression-free survival from the ZUMA‑5 36‑month data cut were broadly aligned with the company's extrapolation to 5\xa0years. But the median progression-free survival was slightly underestimated in the model. The ERG noted that there were also signs that the Kaplan–Meier curves were flattening from 3\xa0years, but the data was affected by heavy censoring. The ERG also explained that 24\xa0months is too early to determine if subsequent treatment has a positive impact on overall survival, and highlighted that longer-term follow up is needed. The committee noted the sustained benefit shown from the 36‑month data cut and the relatively short follow up of the trial. It concluded that while the data indicates that axicabtagene ciloleucel reduces the risk of disease progression in people with relapsed or refractory follicular lymphoma, its long-term treatment effect is uncertain.\n\n## ZUMA-5 is a single-arm study, so comparator data was taken from the SCHOLAR-5 study\n\nBecause ZUMA‑5 was a single-arm study, the company used data from the SCHOLAR‑5 study to inform comparative effectiveness. SCHOLAR‑5 was a retrospective study with pooled data from 3\xa0cohorts (A,\xa0B and\xa0C). Cohorts\xa0A and\xa0B included retrospective medical records from 7\xa0sites in the UK, France, Spain, Portugal and the US. Cohort\xa0C included a single-arm, open-label phase\xa02 study (DELTA) for people:\n\nwith relapsed or refractory follicular lymphoma\n\nwhose disease did not respond adequately or was refractory to rituximab and an alkylating agent, and\n\nwho had previously had treatment with idelalisib. The cohorts were restricted to people with follicular lymphoma who had previous treatment after at least 3\xa0prior treatments, in line with the anticipated marketing authorisation for axicabtagene ciloleucel. More treatments were included in SCHOLAR‑5 than in the blended comparator (see section\xa03.4). Idelalisib, radioimmunotherapy, CVP and experimental treatments were excluded from the blended comparator because they were not considered representative of treatments used in the NHS. The committee noted the ERG's concerns that comparative effectiveness results derived from single-arm studies were prone to bias because of the lack of randomised comparators in the clinical data. The committee was aware that because of the lack of data for relapsed or refractory follicular lymphoma after 3\xa0or more treatments, the company had used a propensity-score-weighted indirect comparison (see section\xa03.8). The committee concluded that using data from the SCHOLAR‑5 study was acceptable to inform comparative effectiveness.\n\n## The company's approach to adjusting the SCHOLAR-5 data is highly complex\n\nClinical inputs for the comparator arm, for treatment options after 3\xa0or more treatments, were derived using the propensity-score-weighted data from the SCHOLAR‑5 study. To address the baseline imbalances between the ZUMA‑5 and SCHOLAR‑5 studies and to reduce bias in comparative effectiveness, the company applied propensity scoring methods using standardised mortality ratio (SMR) weighting. The ERG commented that it was not transparent how the SMR weighting had been applied to the propensity scoring. But it considered that the weighting improved comparability between ZUMA‑5 and SCHOLAR‑5. The results of pre-weighting and post-weighting baseline characteristics are academic in confidence and cannot be reported here. The committee noted that the company had access to individual patient data from both the ZUMA‑5 and SCHOLAR‑5 studies, so other methods may have been more appropriate (as documented in the NICE Decision Support Unit [DSU] Technical Support Document\xa018). The company also did an unanchored indirect comparison using both propensity-score-weighting and propensity-score-matching methods. The committee agreed with the ERG that propensity-score weighting improved the comparability. But the committee noted that some covariates had been excluded from the weighting: for example, follicular lymphoma subtype (grade\xa01, grade\xa02 and grade\xa03a), for which a large standardised mean difference was observed. The committee noted that stronger assumptions need to be met for an unanchored comparison. It also noted that propensity-score-weighting methods should adjust for all treatment effect modifiers and prognostic variables to better predict outcomes. At the first meeting, the committee concluded that the company's approach and use of the propensity-score-weighting method was highly uncertain. It would have liked to see other methods explored in more detail or the uncertainties of the unanchored indirect comparison addressed. In response to consultation, the company explained that its approach for the SCHOLAR‑5 analyses was based on NICE DSU Technical Support Document\xa018 and more recent developments in the literature. The company said that the propensity-score-weighting methods should adjust for all treatment effect modifiers and prognostic variables which must also be balanced with the sample size. So, it had focused on the covariates strongly correlated with outcomes. The ERG highlighted that generating comparative effectiveness estimates from real-world data is challenging when sample sizes are limited and not all prognostic and effect-modifying variables can be adjusted for. The ERG noted that in addition to the follicular lymphoma subtype, there were some other lower grade subtypes in SCHOLAR‑5 than in ZUMA‑5. It noted that failure to adjust for these may have biased in favour of current fourth line care. The committee understood that propensity-score weighting should ideally adjust for all prognostic and effect modifiers but noted the concerns raised about small sample sizes. The committee was aware that the company had done sensitivity analyses using propensity-score matching and inverse-probability treatment weighting. It noted that the company had also explored alternative methods, including G-estimation and the E‑value, which provided consistent results in line with the company's original base case. The committee concluded that the adjustment method used by the company is highly complex.\n\n# Economic model\n\n## The company's model is appropriate for decision making\n\nThe company used a partitioned survival model to estimate the cost effectiveness of axicabtagene ciloleucel compared with standard care. It included 3\xa0health states: pre-progression, progressed and death. The company's model structure was similar to those used in previous appraisals for relapsed or refractory follicular lymphoma. The ERG explained that the company had captured all relevant health states and that its model structure was appropriate. But it noted some uncertainties in the assumptions used in its model, for example, the long-term survivor assumption (see section\xa03.11). The committee questioned whether the company had explored a mixture-cure modelling approach. The company explained that because of the immaturity of the data it was not possible to use a mixture-cure model or a spline model. The committee concluded that the company's model was appropriate for its decision making.\n\n## Extrapolations for progression-free and overall survival benefits from SCHOLAR-5 for standard care are uncertain\n\nThe committee was aware that the company used SCHOLAR‑5 data to model survival for the blended comparator. Because there was no date of progression for people having the index therapy in the DELTA cohort, the ERG noted that these people were excluded from the progression-free survival analysis. This resulted in fewer people to inform progression-free survival, post weighting. The ERG explained that the results from SCHOLAR‑5 could overestimate overall-survival time in the post-progression state for standard care. At technical engagement, the company removed the DELTA cohort from the SCHOLAR‑5 data before propensity weighting, which improved the comparability with ZUMA‑5. The committee noted the minimal impact of removing the DELTA cohort on the progression-free survival curves and that the company had selected gamma extrapolation in line with its original base case. The ERG explained that people from the DELTA cohort were included in SCHOLAR‑5 from the point of their progression. So, this cohort represented people who had previous treatment with idelalisib but who were not having idelalisib as fourth line treatment. The ERG considered the generalised gamma, log-logistic and log-normal distributions to provide the best statistical fits. The estimates of survival extrapolation for people with relapsed or refractory follicular lymphoma after 3\xa0or more previous treatments in the NHS in England and Wales were noted by the ERG to be highly uncertain. The committee noted that the company did not justify using a gamma extrapolation as its chosen parametric curve. It also noted that removing the DELTA cohort from SCHOLAR‑5 had a large effect on cost-effectiveness results. The committee concluded that although extrapolation of progression-free survival and overall survival for standard care after 3\xa0or more treatments is uncertain, it preferred the exponential distribution for progression-free survival and the gamma distribution for overall survival.\n\n## The committee considered both the company's and the ERG's approaches in its decision making\n\nProgression-free survival and overall survival were the main effectiveness inputs included in the company's economic model. Progression-free survival and overall survival for axicabtagene ciloleucel and standard care after 3\xa0or more treatments, were estimated using time-to-event data from ZUMA‑5 and SCHOLAR‑5 respectively. The committee noted that both the company's and ERG's models assumed that a proportion of people who had axicabtagene ciloleucel could be considered long-term survivors from a future time point and thereafter experience zero risk of progression. The long-term survivors were also assumed to have a 9% higher probability of death than the general population from year\xa05\xa0onwards. The company base-case assumption was that 25% of people who had treatment with axicabtagene ciloleucel were long-term survivors, and these extrapolation assumptions were applied from 5\xa0years. Non-long-term survivors continued to follow the hazards of progression and death based on a Weibull distribution fitted to the full ZUMA‑5 dataset. The committee noted that the company's approach reflects a homogenous cohort of people, which is used at all time points for non-long-term survivors, but that this is overridden by cure assumptions in the long-term survivor group from 5\xa0years. The company clarified that based on clinical opinion and clinical validation of survival curves, it assumed that 25% of people who had axicabtagene ciloleucel were long-term survivors. The ERG agreed with the company that it was not possible to use a mixture-cure model because the data from ZUMA‑5 was immature. The ERG considered that because of the unique mechanism of action of axicabtagene ciloleucel, it would expect a proportion of people to be long-term survivors but that the proportion could not be validated because of the lack of data after 3\xa0treatments. The committee was aware that both the company and the ERG also presented scenario analyses with long-term survival proportions which varied up to 25%. The committee noted that the long-term survivor proportion assumption had little effect on the cost-effectiveness results. The committee noted that the company did not clearly present the model predictions for long-term survivors and non-long-term survivors separately. At the first meeting, the committee concluded that based on the immature survival data from ZUMA‑5 and the uncertainties in the SCHOLAR‑5 data, it was uncertain if the company's long-term survival assumptions were appropriate. In response to consultation, the company presented a graph of the modelled overall survival stratified by long-term survivors and non-long-term survivors to address the committee's concerns. The ERG noted that the hazard of death remained lower in non-long-term survivors compared with those having standard care after 3\xa0or more treatments. It used a Weibull distribution to extrapolate the hazard of mortality for non-long-term survival. This was adjusted to remain 1.2\xa0times higher than that of the general population matched for age and sex. The ERG further explored scenarios by increasing this adjustment to 1.5\xa0times and 2\xa0times higher than that of the general population matched for age and sex. It also presented a pessimistic scenario using the generalised gamma distribution for extrapolation of axicabtagene ciloleucel overall survival, but without upward adjustment of the extrapolated mortality hazard for non-long-term survivors. The committee noted that this predicted a steeper overall-survival curve for non-long-term survivors, with the hazard of mortality exceeding that of the standard care arm. The committee took both the company's and the ERG's approaches into account in its decision making. It noted that the presented analyses did not resolve the issues with the company's long-term and non-long-term survivor assumptions.\n\n## The ERG's approach for health state utility values is more appropriate\n\nIn ZUMA‑5 and SCHOLAR‑5, no health-related quality-of-life data was collected. The committee noted that the company used health state utility values in the economic model from NICE's technology appraisal guidance on lenalidomide with rituximab for previously treated follicular lymphoma which were based on the AUGMENT study. The committee was aware that other sources of health state utilities were also available. But the ERG was concerned that because most people in the AUGMENT study were at an earlier stage in the disease pathway, they would be expected to have a higher quality of life than people having treatment after 3\xa0or more treatments. So, the ERG preferred to use utility values from Wild et al. (2006) in its base case, in which EQ‑5D data was collected from people with relapsed or refractory follicular lymphoma. Long-term survivors (that is, people who were alive and free of progression at 5\xa0years and beyond) were assumed to have a utility decrement compared with the general population for the rest of their life. The ERG highlighted the limitations of the Wild et al. study but considered that it better reflected the likely quality of life of people after 3\xa0treatments than the AUGMENT study. In response to technical engagement, the company agreed with the ERG and updated its base case using utility values from Wild et al. The company explained that it considered that health-related quality of life for long-term survivors would be equal to that of the general population in line with previous NICE technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2\xa0or more systemic therapies and autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory mantle cell lymphoma. To address the uncertainty, the company also presented a scenario that assumed the health state utility value for long-term survivors after axicabtagene ciloleucel treatment to be halfway between the Wild et al. progression-free estimate and the general population. The ERG broadly agreed with the company's updated base case. But it considered it unlikely that long-term survivors would attain a health state utility in line with the general population while experiencing an elevated mortality risk. Given the uncertainty, the ERG considered it important to consider the range of assumptions around long-term survivors' utility values. The committee noted that the source of utility values had a small effect on the cost-effectiveness results. At the first meeting, the committee concluded that the ERG's approach of using a utility decrement for long-term survivors was more appropriate, and it would consider other scenarios presented in its decision making. In response to consultation, the company clarified that its assumptions were based on previous NICE technology appraisal guidance which were accepted by the committee. The clinical experts explained that they would expect a minor decrement in the utilities after chimeric antigen receptor (CAR)\xa0T‑cell therapy because of the higher risk of infections and relapse. They explained that if people do not have any infections and do not relapse, they would expect health-related quality of life to be near to that of the general population. The committee recognised that there are some uncertainties with this approach. The committee concluded that the ERG's approach of using a utility decrement for long-term survivors was more appropriate. The committee also noted that the assumption of a rebound to general-population utility for long-term survivors favoured axicabtagene ciloleucel.\n\n## Time on treatment and subsequent treatment costs for comparators used in the model are acceptable\n\nIn its original model, for treatments used in the blended comparator, the company used the median number of treatment cycles reported in the relevant summary of product characteristics. The company fitted an exponential distribution in its model to estimate time on comparator treatments. For simplicity, the company assumed equal subsequent treatment costs in both arms of the model. The ERG noted that the time-on-treatment curves were not consistent with the derived progression-free survival and overall survival curves for the comparator arm. The ERG highlighted that the company capped the time on treatment so it could not exceed overall survival, assuming that treatment may continue beyond progression. The clinical experts explained that treatment was unlikely to continue beyond progression. At technical engagement, the company agreed with the ERG that allowing treatment beyond progression while applying subsequent treatment costs at the point of progression may overestimate the costs of standard care in the comparator arm of the model. So, in its updated base case, the company capped time on treatment for the comparator treatments at the point of progression. The ERG explained that it was broadly satisfied with the company's updated base case. But time on comparator treatments for people with relapsed or refractory follicular lymphoma after 3\xa0or more previous treatments remains uncertain because of limited data. The committee was aware that time on comparator treatments and subsequent treatment costs had a large impact on cost-effectiveness results. Despite the uncertainty in the estimation of time on comparator treatments, the committee concluded that it would accept the approach for decision making in the context of this appraisal.\n\n## The infusion, monitoring and hospitalisation costs in the company's original model may not reflect NHS practice\n\nThe company explained that axicabtagene ciloleucel is given as a single infusion within 30\xa0minutes. It explained that in line with previous appraisals for CAR\xa0T‑cell therapies (NICE technology appraisal guidance on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2\xa0or more systemic therapies and autologous anti-CD19-transduced CD3+ cells for treating relapsed or refractory mantle cell lymphoma), people are monitored in an elective inpatient setting. To account for this, the company applied daily hospitalisation costs of £903 to the mean duration of hospitalisation observed after axicabtagene ciloleucel treatment in ZUMA‑5. The mean duration of hospitalisation is academic in confidence and cannot be reported here. The NHS England Cancer Drugs Fund clinical lead (from now, Cancer Drugs Fund lead) explained that NHS England provides the infrastructure to CAR\xa0T‑cell therapy centres for them to deliver the entire treatment, including infusion and monitoring. NHS England has established a single delivery tariff for the cost of delivering current CAR\xa0T‑cell therapies. The 2022 to 2023 tariff for CAR\xa0T‑cell therapy delivery in people aged 19\xa0years and over is £96,016, subject to ongoing review and period updates. The committee noted that the tariff cost was higher than the costs calculated by the company. The clinical experts also explained that they would expect intravenous immunoglobulin to be used for longer than the company's modelled time of 12\xa0months. They also explained that in clinical practice the costs are higher than the company's estimates used in the model but are well below the NHS tariff. The committee noted that it was not provided with full details about how the NHS tariff was derived. It noted the need for greater transparency as to what the tariff cost included, to explore potential issues of double counting or undercounting costs. At the first meeting, the committee concluded that the tariff was the best available source to inform the cost that the NHS is paying currently. In response to consultation, the company explained that it had followed recommended NICE methods and its model included the best estimate of the cost of delivering CAR\xa0T‑cell therapy. It highlighted that using the NHS tariff in decision making would be procedurally unfair and unreasonable, because of the lack of transparency in how it is derived. The ERG also agreed with the company that transparency would be beneficial to estimate the true costs. The company also presented evidence from a real-world point-in-time survey of clinicians and people with diffuse large B-cell lymphoma (DLBCL) in the UK, Germany, Spain, Italy, France and Canada in 2021 (the Adelphi DLBCL Disease Specific Programme [DSP]). This survey considered the 100\xa0days after CAR\xa0T‑cell therapy which showed a similar average hospitalisation duration (measured in days) to those used in the company's model, resulting in identical CAR\xa0T‑cell therapy infusion, monitoring and hospitalisation costs. The results of Adelphi DLBCL DSP are academic in confidence so cannot be reported here. During the second committee meeting, the Cancer Drugs Fund lead explained that the NHS tariff may have overestimated the true cost to the NHS, but also considered that the company's approach is an underestimate of the true cost. The committee noted that NHS England and the company did urgent work to provide alternative costs to NICE after the second committee meeting.\n\n## CAR T-cell therapy delivery costs of £41,101 are most appropriate for decision making\n\nAdditional information and clarification on costs were provided by NHS England after the second committee meeting. Based on this new information, the company used a 'bottom-up' costing approach to calculate the cost of delivering axicabtagene ciloleucel treatment in the NHS. The company included the costs of:\n\ninfusion, monitoring and hospitalisation\n\nleukapheresis\n\nconditioning chemotherapy\n\nbridging therapy.The company considered each cost category individually and combined them to give an estimate for the cost of delivering axicabtagene ciloleucel in the NHS. The committee understood that NHS England had established a single tariff to capture these costs. The tariff was developed after NICE recommended the first CAR\xa0T‑cell therapy, tisagenlecleucel, for use in the Cancer Drugs Fund in December\xa02018. NHS England explained that the tariff includes all costs of care from the decision for the person to have CAR\xa0T‑cell therapy to 100\xa0days after infusion. NHS England explained that there is not currently an HRG (healthcare resource group) code that adequately captures the administration of CAR\xa0T‑cell therapies. It also commented that a key difference between its tariff and the company's costs is the time and number of staff needed to look after people who have had CAR\xa0T‑cell therapy. The company commented that it is not appropriate to use the tariff in the modelling. This is because it is a mechanism for NHS England to fund hospitals to provide CAR\xa0T‑cell therapy and is not designed for health technology evaluation. It was concerned that the evidence underlying the tariff had not been transparently shared and that it may include costs that are not relevant. The ERG was also concerned about the methods used by NHS England to derive the tariff. It was unclear how individual trusts estimated expenditure and how this corresponded to quantities of resource use. But the ERG also commented that the company's approach likely underestimated the true cost of delivering CAR\xa0T‑cell therapy. After the second appraisal committee meeting the company submitted a further analysis using a CAR\xa0T‑cell therapy delivery cost of £41,101, informed by an ERG scenario analysis. This accounted for the impact of increased staffing needs associated with providing CAR\xa0T‑cell therapy. The updated company analysis consisted of a one-off cost of £41,101 for the first 100\xa0days as well as the costs of conditioning chemotherapy drugs, stem cell transplantation and intravenous immunoglobulin. These 3\xa0costs are reimbursed separately by NHS England. NHS England considered that, although the company's cost differs from the tariff for CAR\xa0T‑cell therapy, it was an acceptable cost to use in the cost-effectiveness analysis. This is because the current tariff represents the high hospital costs of establishing the infrastructure of a CAR\xa0T‑cell therapy service and delivering a relatively new type of treatment, but economies of scale may be expected over time. Costs may also reduce with clinical developments in care that reduce toxicity and so reduce the need for more intense monitoring and treatment. The committee noted NHS England's comments and was satisfied that the company's costs adequately captured a reasonable projection of the cost to the NHS of delivering CAR\xa0T‑cell therapy.\n\n# End of life\n\n## Axicabtagene ciloleucel does not meet the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in section\xa06 of NICE's guide to the methods of technology appraisal 2013. This states that a treatment can be considered as a life-extending treatment at the end of life if:\n\nit is indicated for people with a short life expectancy (normally less than 24\xa0months), and\n\nit offers an extension to life (normally a mean value of at least an additional 3\xa0months compared with current NHS treatment). The committee noted that both the company and the ERG agreed that axicabtagene ciloleucel did not meet the criteria for end of life. The company explained that axicabtagene ciloleucel would be used by clinicians as an end of life treatment for people with relapsed or refractory follicular lymphoma who had 3\xa0or more systemic treatments. The clinical experts highlighted that they would expect people having standard care to live for between approximately 30\xa0and 36\xa0months. In response to consultation, a consultee highlighted that they would expect people having standard care to live for 24\xa0months or less. This is because of a lack of data for people with relapsed or refractory follicular lymphoma after 3\xa0or more treatments. The committee noted that the median life expectancies from the treatment comparisons from both the company's and the ERG's models were higher than 24\xa0months. The median life expectancies are academic in confidence and cannot be reported here. The committee was aware that both the company's and the ERG's base cases supported a mean survival gain of greater than 3\xa0months. But the committee considered that the short life expectancy criterion of less than 24\xa0months was not met because the life expectancy of people who would have axicabtagene ciloleucel would normally be longer than 24\xa0months. The committee concluded that axicabtagene ciloleucel does not meet the criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness estimates\n\n## An acceptable ICER would be within the range normally considered a cost-effective use of NHS resources\n\nSection\xa06 of NICE's guide to the methods of technology appraisal 2013 notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee noted that data is immature for overall survival, and extrapolations from the model are uncertain. So, the committee agreed that an acceptable ICER would be within the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained).\n\n## Axicabtagene ciloleucel is not recommended for routine use\n\nBoth the company's deterministic and probabilistic base cases showed that ICERs for axicabtagene ciloleucel compared with standard care were over £40,000 per QALY gained. The committee noted the high level of uncertainty in the model, particularly about:\n\nimmature overall-survival data from ZUMA‑5 (see section\xa03.6)\n\nno direct comparative efficacy data for axicabtagene ciloleucel compared with standard care (see sections\xa03.7 and\xa03.8)\n\nlong-term survivor proportion assumptions (see section\xa03.11)\n\nlimited available evidence to inform time on treatment for comparator treatments in the company's model for people having treatment after 3\xa0treatments (see section\xa03.13).The committee preferred the following assumptions:\n\nusing a Weibull distribution for overall survival and generalised gamma distribution for progression-free survival in the axicabtagene ciloleucel arm (see section\xa03.11)\n\nusing a gamma distribution for overall survival and exponential distribution for progression-free survival in the standard care arm\n\nincluding a utility decrement for long-term survivors after axicabtagene ciloleucel treatment (see section\xa03.12)\n\na CAR\xa0T‑cell therapy administration cost of £41,101 (see section\xa03.15).Because of confidential commercial arrangements for axicabtagene ciloleucel and comparator treatments, the exact ICERs cannot be reported here. Taking into account all confidential discounts, the committee noted that the company's cost-effectiveness estimates for axicabtagene ciloleucel compared with standard care were above the range NICE normally considers a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee recognised the need for new effective treatments for relapsed or refractory follicular lymphoma. The committee took into account the innovative nature of axicabtagene ciloleucel and the additional benefits not captured in the model (see section\xa03.20). But axicabtagene ciloleucel was not shown to be a cost-effective use of NHS resources in any of the analyses presented and the evidence was highly uncertain. So, axicabtagene ciloleucel is not recommended for routine use in the NHS.\n\n# Cancer Drugs Fund\n\n## Axicabtagene ciloleucel is not recommended for use in the Cancer Drugs Fund\n\nHaving concluded that axicabtagene ciloleucel could not be recommended for routine use in the NHS, the committee then considered if it could be recommended for treating relapsed or refractory follicular lymphoma after 3\xa0or more systemic treatments within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund process and methods guide. The committee recognised that people with relapsed or refractory follicular lymphoma have a high unmet need, and the availability of new treatments is very important. The committee was aware that the company had expressed an interest in the treatment being considered for funding through the Cancer Drugs Fund. It understood that ZUMA‑5 (a single-arm, phase\xa02 study) is ongoing and that a further study for axicabtagene ciloleucel is also planned (ZUMA‑22, a phase\xa03 study). The committee noted that these studies are likely to provide further evidence on survival but may not fully resolve some of the key uncertainties affecting the cost-effectiveness results, such as:\n\nimmature overall-survival data from ZUMA‑5\n\nno direct comparative efficacy data for axicabtagene ciloleucel compared with standard care.The committee also noted that the evidence suggests that axicabtagene ciloleucel is not likely to be a cost-effective use of NHS resources (see section\xa03.18). The committee concluded that axicabtagene ciloleucel did not meet the criteria to be recommended for use in the Cancer Drugs Fund.\n\n# Innovation\n\n## Axicabtagene ciloleucel is an innovative treatment and the benefits may not be fully captured in the model\n\nThe company considered axicabtagene ciloleucel to be innovative because of its mechanism of action in which a person's T\xa0cells are modified to target and kill cancer cells. The company explained that it was the first of the breakthrough class of CAR\xa0T‑cell therapies to be licensed for use in Europe and the US. The clinical experts explained that a single infusion may benefit some people with this condition. The committee acknowledged both the benefits offered and the innovative nature of axicabtagene ciloleucel. It concluded that there could be some additional carer benefits not fully captured in the model but noted that additional evidence had not been provided in the submission.\n\n# Equalities\n\nThere were no equality issues identified."}	https://www.nice.org.uk/guidance/ta894	Evidence-based recommendations on axicabtagene ciloleucel (Yescarta) for relapsed or refractory follicular lymphoma in adults.
8c299a26d68496c5c38399290cba02af63aa474d	nice	Axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy	Axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy Evidence-based recommendations on axicabtagene ciloleucel (Yescarta) for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy. # Recommendations Axicabtagene ciloleucel is recommended for use within the Cancer Drugs Fund as an option for treating diffuse large B‑cell lymphoma in adults when an autologous stem cell transplant is suitable if it: has relapsed within 12 months after first-line chemoimmunotherapy or is refractory to first-line chemoimmunotherapy. It is recommended only if the conditions in the managed access agreement for axicabtagene ciloleucel are followed. This recommendation is not intended to affect treatment with axicabtagene ciloleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard care for relapsed or refractory diffuse large B‑cell lymphoma after first-line chemoimmunotherapy is chemotherapy followed by high-dose chemotherapy and an autologous stem cell transplant. Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T‑cell therapy. It uses the person's own immune system cells (T‑cells) that have been modified to attach to and kill cancer cells. It would be used as an alternative to standard care. Clinical trial evidence suggests that, when an autologous stem cell transplant is suitable, axicabtagene ciloleucel increases how long people live compared with standard care. But it is uncertain by how much because the trial is still ongoing. Some people in the trial who had standard care went on to have a CAR T‑cell therapy. This is not standard care in the NHS, so adjusting the data to reflect this also adds uncertainty. Also, another treatment that is used during CAR T‑cell therapy in the NHS was not used in the trial. This adds uncertainty because it is not clear if the results from the trial fully reflect what would happen when using axicabtagene ciloleucel in the NHS. Axicabtagene ciloleucel meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources for end of life treatments. But, because of the uncertainty, an acceptable cost-effectiveness estimate would need to be at the lower end of the range. The cost-effectiveness estimate for axicabtagene ciloleucel is above the lower end of the range, so it cannot be recommended for routine use in the NHS. Axicabtagene ciloleucel has the potential to be cost effective, but more evidence is needed to reduce the uncertainties. Evidence from the trial and from NHS practice could help address these. So, axicabtagene ciloleucel is recommended for use in the Cancer Drugs Fund.# Information about axicabtagene ciloleucel # Marketing authorisation indication Axicabtagene ciloleucel (Yescarta, Kite) is indicated for 'the treatment of adult patients with diffuse large B‑cell lymphoma (DLBCL) and high-grade B‑cell lymphoma (HGBL) that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for axicabtagene ciloleucel. # Price The list price of axicabtagene ciloleucel for a single infusion including shipping, engineering and generation of chimeric antigen receptor (CAR) T‑cells is £280,451 (company submission). The company has a commercial arrangement. This makes axicabtagene ciloleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Kite, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need and treatment pathway ## Disease burden Diffuse large B‑cell lymphoma (DLBCL) is an aggressive type of cancer of the lymphatic system. People with DLBCL can experience swollen lymph nodes, bone pain, night sweats, fever, weight loss and itching. Patient experts commented that in addition to physical symptoms, many people also experience significant mental health challenges. They explained that disease relapse can be particularly difficult both physically and emotionally. Patient experts also commented that relapsed or refractory DLBCL has a large impact on daily life. They explained that people with DLBCL may spend several weeks in hospital, which impacts their ability to work and spend time with friends and family. They also commented that many people need a carer, which is often a family member, in the weeks after they have axicabtagene ciloleucel. If people do not have a carer, they may stay in hospital for the first 28 days after they have axicabtagene ciloleucel. The committee recognised that relapsed or refractory DLBCL after first-line chemoimmunotherapy has a large disease burden. ## Treatment options Clinical experts said that in current practice, people with DLBCL are usually offered rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP) as initial treatment. For DLBCL that is relapsed or refractory to R‑CHOP, clinicians offer salvage chemotherapy. If the disease responds, clinicians then offer high-dose chemotherapy and an autologous stem cell transplant, for those who are able to have one. Transplant suitability is based on the person's tolerance of intensive treatment and is usually only offered to people aged under 70. Patient experts commented on the side effects of intensive chemotherapy, including sickness, diarrhoea, hair loss and neutropenia. Patient and clinical experts also said that there is a need for treatments that could improve survival for people with relapsed or refractory DLBCL. The committee concluded that people with DLBCL and clinicians would welcome a new treatment option. ## Proposed positioning The company proposed axicabtagene ciloleucel for a narrower population than its marketing authorisation. It focused on adults with DLBCL that is primary refractory or early relapsed within 12 months of treatment, and who are intended for an autologous stem cell transplant. This narrowed the population to those who would have been considered for an autologous stem cell transplant. This was to align with the key clinical trial, ZUMA‑7 (see section 3.5). Clinical experts commented that people who cannot have an autologous stem cell transplant have worse outcomes than those who can have one. They explained that it would be beneficial to have an additional treatment option for these people. They also added that there were effectively 3 groups of people: those who could tolerate either an autologous stem cell transplant or axicabtagene ciloleucel, those who could not tolerate transplant but could tolerate axicabtagene ciloleucel and those who could not tolerate either. They were mindful that people who were not well enough to have an autologous stem cell transplant but who could tolerate axicabtagene ciloleucel would not be offered treatment based on the company's proposed positioning. But the clinical experts also highlighted that there was no evidence for axicabtagene ciloleucel in this population because they were not included in ZUMA‑7. So the committee agreed that it was appropriate to position axicabtagene ciloleucel for the narrower population. ## Comparator The committee recalled that relapsed or refractory DLBCL after first-line chemoimmunotherapy is usually treated with salvage chemotherapy, high-dose chemotherapy and an autologous stem cell transplant (from now, called standard care). The company used clinical expert opinion to estimate the chemotherapy regimens in standard care as 50% R‑ICE (rituximab, ifosfamide, carboplatin and etoposide) and 50% R‑GDP (rituximab, gemcitabine, dexamethasone and cisplatin). The committee concluded that standard care including salvage chemotherapy, high-dose chemotherapy and an autologous stem cell transplant was the relevant comparator. # Clinical evidence ## ZUMA-7 trial The company provided evidence for axicabtagene ciloleucel compared with standard care from ZUMA‑7, which is ongoing. This is a phase 3, randomised, open-label trial in adults with primary refractory or early relapse (within 12 months of first-line treatment) DLBCL after chemoimmunotherapy who are intended for transplant. Standard care was defined as platinum-based chemoimmunotherapy, and if the condition responded, then high-dose chemotherapy and an autologous stem cell transplantation. The primary endpoint was event-free survival defined as time from randomisation to the earliest date of disease progression, start of new lymphoma treatment, death, or best disease response of stable disease. Best disease response of stable disease is the best response for DLBCL that is not growing or shrinking. One clinical expert commented that event-free survival was not an appropriate primary endpoint for a trial investigating second-line treatment. They said that people who went on to have third-line axicabtagene ciloleucel would not be captured in event-free survival. But the company confirmed that starting a new lymphoma treatment included off-protocol subsequent chimeric antigen receptor (CAR) T‑cell therapy, so it was a component of event-free survival. Another clinical expert noted that event-free survival is increasingly used as a primary endpoint because it effectively measures the impact of the intervention. ZUMA‑7 had 1 to 1 randomisation and included a total of 359 people. The median age of people in the trial was 59 and in the overall trial group 66% were men. About three quarters of people in the trial (74%) had primary refractory disease and about one quarter (26%) had disease relapse within 12 months of first-line treatment at study entry. Crossover between treatment arms was not included in the trial. But if a person's disease did not respond to standard care, then they could have subsequent CAR T‑cell therapy off protocol. In the standard care arm, 56% of people had subsequent CAR T‑cell therapy. The committee acknowledged the experts' concerns but concluded that ZUMA‑7 provided the best available evidence for axicabtagene ciloleucel compared with standard care. ## Chemotherapy bridging At the first committee meeting, the clinical experts noted that chemotherapy bridging, which is chemotherapy offered between T‑cell collection and reinfusion, was not included in ZUMA‑7 but is commonly used in NHS practice. They commented that this might have made clinicians less likely to offer enrolment to people with fast-progressing disease in the trial. They explained that it was difficult to estimate the impact this would have on the comparative effectiveness. At the second committee meeting, the NHS England Cancer Drugs Fund clinical lead (from here, Cancer Drugs Fund lead) commented that in NHS clinical practice 75% of people have bridging therapy. Clinicians believe that this has resulted in a reduced incidence of grade 3 or more cytokine release syndrome (CRS) and neurotoxicity. The Cancer Drugs Fund lead noted that recent evidence has shown that people who experience CRS and neurotoxicity have a higher median metabolic tumour volume. This has been shown to correlate with clinical outcomes in third-line CAR T‑cell treatment. In a recent clinical trial for another CAR T‑cell therapy, used in the same position as axicabtagene ciloleucel in the treatment pathway, 63% of people who had CAR T‑cell therapy also had bridging chemotherapy. They explained that because bridging chemotherapy was not included in ZUMA‑7 but would be commonly used with axicabtagene ciloleucel in NHS practice, the generalisability of the results from ZUMA‑7 to NHS practice was very uncertain. But, this uncertainty could be reduced with Cancer Drug Fund data collection. The committee acknowledged the issues of generalisability to NHS practice, and that this increases uncertainty in the clinical and cost-effectiveness results. It concluded that collecting data on treatment that reflects NHS clinical practice could reduce the uncertainty. ## Adverse events Clinical and patient experts explained that current standard care can be associated with adverse events, but the types of adverse events and how they are treated is different for axicabtagene ciloleucel. Two of the key adverse events associated with axicabtagene ciloleucel are CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). In ZUMA‑7, 92% of people who had axicabtagene ciloleucel had CRS of any grade and 6% had CRS of grade 3 or higher. Also in the trial, more people who had axicabtagene ciloleucel had a serious neurological event compared with those who had standard care. The patient expert said that during their treatment with axicabtagene ciloleucel they experienced severely reduced mental abilities. The nursing expert also commented that neurological adverse events can develop within minutes. They explained that this is much faster than typical adverse events associated with standard care. They added that because of the risk of rapid deterioration, people who have had CAR T‑cell therapy need more monitoring, and potentially 1 to 1 nursing even if they are not in intensive care. The committee understood the potential adverse events associated with axicabtagene ciloleucel and considered the implications for the cost of managing these in the NHS (see section 3.12). # Economic model ## Model structure The company provided a partitioned survival model to compare the cost effectiveness of axicabtagene ciloleucel with standard care. The model had 3 health states: event free, post event and death. Health state occupancy was determined by mixture cure models fitted to ZUMA‑7 overall survival, event-free survival and time to next treatment curves. The model structure was similar to those used in previous CAR T‑cell NICE appraisals. The company justified using event-free survival, instead of progression-free survival, because it was the primary endpoint in ZUMA‑7 and it is clinically relevant given the curative intent of treatment. The model assumed that people who were alive and event free at 5 years in both the axicabtagene ciloleucel and standard care arms had a quality of life equal to the general population because they were considered effectively cured. The ERG commented that, on balance, it was satisfied that the modelling approach was appropriate but that the model had a limited capacity to consider more than 1 post-event round of treatment. The committee concluded the model was appropriate for decision making. ## Axicabtagene ciloleucel overall survival extrapolation The company used the most recent data cut from ZUMA‑7 to inform axicabtagene ciloleucel overall survival. This provided data for approximately 2 years of follow up that the company then fitted a range of mixture cure models to. Its preferred model was the generalised gamma distribution because it had good statistical fit and was validated by clinical experts. The ERG noted that all curves fit relatively well to the trial data, but the log-logistic curve had marginally better statistical fit. Because the trial data is immature and the long-term survival for axicabtagene ciloleucel is uncertain, the ERG preferred the log-logistic curve. This provided slightly more conservative overall survival extrapolations. In its response to consultation, the company said that they were concerned with the clinical plausibility of the survival estimates produced by the log-logistic extrapolation. It provided a naive unadjusted comparison of 5‑year overall survival, comparing the observed results from ZUMA‑1 (a single-arm study of axicabtagene ciloleucel for treating relapsed or refractory DLBCL at third line or later) and the estimates from the log-logistic and generalised gamma extrapolations. The company explained that people having treatment at second line would be expected to be more well and have better outcomes than those having treatment at third line or later. The company considered that the log-logistic extrapolation gave a smaller difference in overall survival than would be expected at 5 years when compared with the observed overall survival difference between ZUMA‑1 and ZUMA‑7 at 2 years. The ERG noted that the follow-up data from ZUMA‑7 was still relatively immature, which increased uncertainty around long-term survival extrapolations. It commented that any models predicting overall survival greater than the ZUMA‑1 observed values were clinically plausible considering the overall uncertainty. The ERG maintained its preference for the log-logistic model. The committee concluded that both the generalised gamma and log-logistic curves appeared plausible and agreed that the log-logistic model was appropriate given the uncertainty. ## Standard care overall survival At the time of the second committee meeting, axicabtagene ciloleucel after 2 or more systemic therapies had only been provisionally recommended for routine commissioning and the recommendation was still subject to appeal (see NICE's technology appraisal guidance on axicabtagene ciloleucel). Axicabtagene ciloleucel after 2 or more systemic therapies is not considered to be established practice until after the final guidance is published, so for the purpose of this appraisal it was not considered a relevant subsequent treatment. In ZUMA‑7, 56% of people in the standard care group had third-line CAR T‑cell therapy (see section 3.5). The company explored adjusting the standard care overall survival to remove the benefit of subsequent CAR T‑cell therapy, which the committee agreed was necessary. Its base case treatment-switching adjustment method was the rank preserving structural failure time (RPSFT) model with full re-censoring of data for all people having standard care. This analysis gave a hazard ratio, which the company applied to the axicabtagene ciloleucel overall survival curve. The company also explored RPSFT models with different types of censoring and the inverse probability of censoring weighting method. During technical engagement, the company updated the survival analysis to recategorise 4 people in the standard care arm whose data was originally censored as lost to follow up but were confirmed to have died during the study period. This reanalysis was originally requested by the US Food and Drug Administration. The updated overall survival hazard ratio for using the RPSFT model with full re-censoring was 0.42. At the second committee meeting the Cancer Drugs Fund lead noted the results from a clinical trial for another CAR T‑cell therapy in the same position in the treatment pathway as axicabtagene ciloleucel. The trial also included treatment switching and chemotherapy bridging and showed that survival benefit for people having CAR T‑cell therapy was lower in longer-term follow up compared with earlier results. They advised this increased uncertainty around the long-term survival benefit of other CAR T‑cell therapies such as axicabtagene ciloleucel. The committee agreed that the RPSFT model with full re-censoring was suitable. But, it added uncertainty that cannot be resolved until there is longer-term overall survival data collection. ## Crossover analysis clinical plausibility The company compared the updated survival estimates from the different treatment-switching adjustment methods with those from SCHOLAR‑1 and the comparator arm of the ORCHARRD study. SCHOLAR‑1 was a retrospective evaluation of outcomes in people with refractory DLBCL and included both observational and randomised controlled trial data. ORCHARRD was a study of ofatumumab compared with rituximab, dexamethasone, cytarabine and cisplatin (R‑DHAP) salvage treatment, followed by an autologous stem cell transplant. Clinical experts advised the company that overall survival for people having standard care would likely be above the SCHOLAR‑1 estimates but below the ORCHARRD estimates. The company noted that the only adjustment method that met the clinician's expectations, was the RPSFT model with full re-censoring. The ERG agreed that the company's preferred adjustment was the most appropriate method but cautioned that there was remaining uncertainty about standard care overall survival. The committee questioned whether it was appropriate to apply a hazard ratio to the axicabtagene ciloleucel overall survival mixture cure model. It was concerned that standard care overall survival was disadvantaged after 5 years. Clinical expectation is that if people are alive and event free at 5 years, regardless of the treatment they had, they are effectively cured. But, applying a hazard ratio implies that the standard care survival would be proportional to axicabtagene ciloleucel even after the cure point, which may not reflect clinical expectation. The committee concluded that the company's standard care overall survival extrapolation was acceptable, but that there was remaining uncertainty in long-term survival, which could be favourable to axicabtagene ciloleucel. ## CAR T-cell therapy delivery costs The company used a 'bottom-up' costing approach to calculate the cost of delivering axicabtagene ciloleucel treatment in the NHS. The company included the costs of: hospital administration leukapheresis conditioning chemotherapy bridging therapy treating adverse events.The company considered each cost category individually and combined them to give an estimate for the cost of delivering axicabtagene ciloleucel in the NHS. The committee understood that NHS England had established a single tariff to capture these costs. The tariff was developed after NICE recommended the first CAR T‑cell therapy, tisagenlecleucel, for use in the Cancer Drugs Fund in December 2018. NHS England explained that the tariff includes all costs of care from the decision for the person to have CAR T‑cell therapy to 100 days after infusion. NHS England explained that there is not currently a healthcare resource group (HRG) code that adequately captures the administration of CAR T‑cell therapies. It also commented that a key difference between its tariff and the company's costs is the time and number of staff needed to look after people who have had CAR T‑cell therapy. The company commented that it is not appropriate to use the tariff in the modelling. This is because it is a mechanism for NHS England to fund hospitals to provide CAR T‑cell therapy and is not designed for health technology evaluation. It was concerned that the evidence underlying the tariff has not been transparently shared and that it may include costs that are not relevant. The ERG was also concerned about the methods used by NHS England to derive the tariff. It was unclear how individual trusts estimated expenditure and how this corresponded to quantities of resource use. However, the ERG also commented that the company's approach likely underestimated the true cost of delivering CAR T‑cell therapy. After the first appraisal committee meeting the company submitted a further analysis using a CAR T‑cell therapy delivery cost of £41,101, informed by an ERG scenario analysis. This accounted for the impact of increased staffing needs associated with providing CAR T‑cell therapy. The updated company analysis consisted of a one-off cost of £41,101 for the first 100 days as well as the costs of conditioning chemotherapy drugs and intravenous immunoglobulin (IVIg). These 3 costs are reimbursed separately by NHS England. NHS England considered that, although the company's cost differs from the tariff for CAR T‑cell therapy, it was an acceptable cost to use in the cost-effectiveness analysis. This is because the current tariff represents the high hospital costs of establishing the infrastructure of a CAR T‑cell therapy service and delivering a relatively new type of treatment, but economies of scale may be expected over time. Costs may also reduce with clinical developments in care that reduce toxicity and so reduce the need for more intense monitoring and treatment. The committee noted NHS England's comments and was satisfied that the company's costs adequately captured a reasonable projection of the cost to the NHS of delivering CAR T‑cell therapy. ## Autologous stem cell transplant costs As part of current standard care for relapsed or refractory DLBCL, people are offered an autologous stem cell transplant. The company included a cost of £37,736 for this procedure. This was the value used in NICE's Guideline on non-Hodgkin's lymphoma: diagnosis and management inflated to 2020 to 2021 values. The ERG noted that this cost was not transparent and preferred to use the HRG for 'Peripheral Blood Stem Cell Transplant, Autologous, 19 years and over' inflated to £17,181. The company was concerned that the ERG's approach did not include follow-up costs. It cited a study by Wang et al. (2016) of people with DLBCL in the Haematological Malignancy Research Network, which reported the cost of autologous stem cell transplants to be about £42,000. The Cancer Drugs Fund lead commented that the company's estimate appeared more consistent with the cost of the procedure in the NHS than the ERG's. The committee concluded that there was some uncertainty about the true cost of autologous stem cell transplants in the NHS, but that the company's estimate was more appropriate. ## Retreatment costs The company noted that a small proportion of people in ZUMA‑7 had retreatment with axicabtagene ciloleucel (the company considers the value to be confidential, so it cannot be reported here). It explained that retreatment was not part of the marketing authorisation and would not occur in clinical practice, so it did not include those costs. It also added that the clinical benefit for people who had retreatment was small and unlikely to impact the cost-effectiveness estimates. The ERG was concerned that excluding retreatment costs would mean that modelled treatment benefit and modelled costs were not aligned. It preferred to include retreatment costs because there is no robust way of removing treatment benefit. The committee noted the benefit of retreatment was uncertain. NHS England confirmed that it would not commission retreatment. The committee agreed with the ERG that it was important to align modelled costs and benefits. So it concluded that it was appropriate to include axicabtagene ciloleucel retreatment costs. # End of life ## Life-extending treatment criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal 2013. The company proposed that axicabtagene ciloleucel met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24 months). The committee noted that using its preferred RPSFT model with full re-censoring adjustment, the mean life years for the standard care arm was more than 24 months, but the median overall survival was less than 24 months (the company considers the exact values to be confidential, so they cannot be reported here). The model also predicted that less than one third of people in the standard care arm would be alive at 24 months (the company considers the exact value to be confidential, so it cannot be reported here). The clinical experts agreed that they would expect 20% to 30% of people in this population to be alive at 24 months with current standard care. The committee recalled that CAR T‑cell therapy is not considered established practice so could not be considered part of standard care (see section 3.10). The committee agreed that although there was some uncertainty, the short life expectancy criterion was met. It then considered if axicabtagene ciloleucel was associated with a gain in overall survival of at least 3 months. When using its preferred assumptions, the model predicted axicabtagene ciloleucel would extend life by more than 3 months (the company considers the exact value to be confidential, so it cannot be reported here). The committee concluded that axicabtagene ciloleucel met both of NICE's criteria to be considered a life-extending treatment at the end of life. # Cost-effectiveness estimate ## Preferred ICER The committee considered the deterministic incremental cost-effectiveness ratios (ICERs) for axicabtagene ciloleucel compared with standard care. Because of confidential commercial arrangements for comparator treatments, the exact cost-effectiveness results cannot be reported here. The committee's preferred cost-effectiveness estimate included: a log-logistic mixture cure model for axicabtagene ciloleucel overall survival (see section 3.9) CAR T‑cell delivery costs of £41,101 (see section 3.12) autologous stem cell transplant costs from NICE's Guideline on Non-Hodgkin's lymphoma: diagnosis and management (see section 3.13) retreatment costs for axicabtagene ciloleucel (see section 3.14) post-event treatment distributions from ZUMA‑7 post-event utility values from ZUMA‑1 (a single-arm study of axicabtagene ciloleucel for relapsed or refractory DLBCL at third line or later; pre-progression values) rather than JULIET (a single-arm study of tisagenlecleucel for relapsed or refractory DLBCL) the cost of an additional consultation for neurological adverse events. ## Uncertainty NICE's guide to the methods of technology appraisal 2013 notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically: long-term overall survival in people having treatment with axicabtagene ciloleucel and standard care, including: immature trial data and the distribution used to extrapolate overall survival for people having treatment with axicabtagene ciloleucel in ZUMA‑7 (see section 3.9) the crossover adjustment needed to adjust for the use of third-line CAR T‑cell therapy in ZUMA‑7 (see section 3.11) generalisability of the results from ZUMA‑7 to NHS practice because chemotherapy bridging was not used in the trial (see section 3.6).The committee agreed that the end of life criteria applies to axicabtagene ciloleucel. This can allow it to consider ICERs of up to £50,000 per QALY gained, when the full weighting is applied to the upper end of the usual cost-effectiveness range (£30,000 per QALY gained). But, because of the uncertainty in this appraisal, the committee expected a maximum acceptable ICER to be around £20,000 per QALY gained. So, when the end of life weighting is applied, the maximum acceptable ICER is substantially less than £50,000 per QALY gained. The committee highlighted that the lower value for an acceptable ICER in this appraisal is based on the substantial levels of uncertainty associated with the evidence from ZUMA-7. When confidential commercial arrangements were included, the committee's most plausible ICER was less than £50,000 per QALY gained (the exact ICER cannot be reported because of the confidential comparator discounts). But the ICER was above what the committee considered to be their maximum acceptable ICER with the high level of uncertainty. So, the committee concluded that it could not recommend axicabtagene ciloleucel for routine use in the NHS. # Cancer Drugs Fund ## Criteria for Cancer Drugs Fund Having concluded that axicabtagene ciloleucel could not be recommended for routine use, the committee then considered if it could be recommended for treating DLBCL after first-line chemoimmunotherapy within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). At the first committee meeting, the company acknowledged that there is uncertainty in the clinical evidence for using axicabtagene ciloleucel in this position, and that it could be a candidate for the Cancer Drugs Fund. The committee noted that ZUMA‑7 is ongoing and further follow up may resolve some uncertainty around long-term survival for people who have axicabtagene ciloleucel and people who have standard care. During the second committee meeting, the Cancer Drugs Fund lead also commented that if axicabtagene ciloleucel was available in the Cancer Drugs Fund it would also help reduce uncertainty around the generalisability of the evidence from ZUMA‑7 because of the absence of chemotherapy bridging (see section 3.6). This is because Systemic Anti-Cancer Therapy (SACT) data would be collected from people having treatment in the NHS. The committee agreed that reducing the uncertainty by having a longer period of data collection in the NHS would support the case for axicabtagene ciloleucel to be recommended for routine commissioning. The committee also considered that axicabtagene ciloleucel has the plausible potential to be cost-effective, if further data collection validates the current cost-effectiveness estimates. The committee concluded that axicabtagene ciloleucel met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended axicabtagene ciloleucel for use within the Cancer Drugs Fund as an option for treating DLBCL that has relapsed within 12 months after first-line chemoimmunotherapy, or is refractory to first-line chemoimmunotherapy, in adults when an autologous stem cell transplant is suitable. # Other factors ## Innovation The company commented that axicabtagene ciloleucel is a personalised, transformative and innovative treatment. It also noted that there may be potential benefits of axicabtagene ciloleucel treatment that were not fully captured in the QALY calculations. It stated that the true benefit of cure was likely underestimated. It also stated that there may be benefits associated with axicabtagene ciloleucel because it is a single infusion, compared with multiple cycles of chemotherapy followed by high-dose treatment and an autologous stem cell transplant. The committee recognised that there may be these benefits to people but concluded that it had not seen evidence of these benefits over those already included in the QALY calculations. ## Equality The committee recalled that current standard care includes an autologous stem cell transplant. The company and clinical experts explained that people 70 years and older are not usually offered stem cell transplant. The company explained that because axicabtagene ciloleucel would not have an age restriction, it could help reduce the age inequality. Age is a protected characteristic under the Equality Act 2010. The committee was aware that NICE makes recommendations for technologies within their marketing authorisations. However, the committee recalled that the company positioned axicabtagene ciloleucel only for people for whom an autologous stem cell transplant is suitable, which is usually people aged under 70. The committee considered the evidence that had been submitted. It noted that it had not seen evidence for axicabtagene ciloleucel for treating relapsed or refractory DLBCL in people for whom autologous stem cell transplant is not suitable, who are usually older and less well. The committee was aware of the need for new treatments in this population and was disappointed the company chose to position axicabtagene ciloleucel for the transplant eligible population only. A research organisation also commented that there is a geographic inequality because CAR T‑cell therapy is only provided at 10 designated centres. The clinical experts explained that there are plans to deliver CAR T‑cell therapy at more centres in more locations, which may mitigate this issue. The committee noted these concerns but concluded that its recommendation for axicabtagene ciloleucel would not adversely affect people protected by the equality legislation.	{'Recommendations': "Axicabtagene ciloleucel is recommended for use within the Cancer Drugs Fund as an option for treating diffuse large B‑cell lymphoma in adults when an autologous stem cell transplant is suitable if it:\n\nhas relapsed within 12\xa0months after first-line chemoimmunotherapy or\n\nis refractory to first-line chemoimmunotherapy. It is recommended only if the conditions in the managed access agreement for axicabtagene ciloleucel are followed.\n\nThis recommendation is not intended to affect treatment with axicabtagene ciloleucel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for relapsed or refractory diffuse large B‑cell lymphoma after first-line chemoimmunotherapy is chemotherapy followed by high-dose chemotherapy and an autologous stem cell transplant. Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T‑cell therapy. It uses the person's own immune system cells (T‑cells) that have been modified to attach to and kill cancer cells. It would be used as an alternative to standard care.\n\nClinical trial evidence suggests that, when an autologous stem cell transplant is suitable, axicabtagene ciloleucel increases how long people live compared with standard care. But it is uncertain by how much because the trial is still ongoing. Some people in the trial who had standard care went on to have a CAR\xa0T‑cell therapy. This is not standard care in the NHS, so adjusting the data to reflect this also adds uncertainty. Also, another treatment that is used during CAR T‑cell therapy in the NHS was not used in the trial. This adds uncertainty because it is not clear if the results from the trial fully reflect what would happen when using axicabtagene ciloleucel in the NHS.\n\nAxicabtagene ciloleucel meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources for end of life treatments. But, because of the uncertainty, an acceptable cost-effectiveness estimate would need to be at the lower end of the range. The cost-effectiveness estimate for axicabtagene ciloleucel is above the lower end of the range, so it cannot be recommended for routine use in the NHS.\n\nAxicabtagene ciloleucel has the potential to be cost effective, but more evidence is needed to reduce the uncertainties. Evidence from the trial and from NHS practice could help address these. So, axicabtagene ciloleucel is recommended for use in the Cancer Drugs Fund.", 'Information about axicabtagene ciloleucel': "# Marketing authorisation indication\n\nAxicabtagene ciloleucel (Yescarta, Kite) is indicated for 'the treatment of adult patients with diffuse large B‑cell lymphoma (DLBCL) and high-grade B‑cell lymphoma (HGBL) that relapses within 12\xa0months from completion of, or is refractory to, first-line chemoimmunotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for axicabtagene ciloleucel.\n\n# Price\n\nThe list price of axicabtagene ciloleucel for a single infusion including shipping, engineering and generation of chimeric antigen receptor (CAR)\xa0T‑cells is £280,451 (company submission).\n\nThe company has a commercial arrangement. This makes axicabtagene ciloleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Kite, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## Disease burden\n\nDiffuse large B‑cell lymphoma (DLBCL) is an aggressive type of cancer of the lymphatic system. People with DLBCL can experience swollen lymph nodes, bone pain, night sweats, fever, weight loss and itching. Patient experts commented that in addition to physical symptoms, many people also experience significant mental health challenges. They explained that disease relapse can be particularly difficult both physically and emotionally. Patient experts also commented that relapsed or refractory DLBCL has a large impact on daily life. They explained that people with DLBCL may spend several weeks in hospital, which impacts their ability to work and spend time with friends and family. They also commented that many people need a carer, which is often a family member, in the weeks after they have axicabtagene ciloleucel. If people do not have a carer, they may stay in hospital for the first 28\xa0days after they have axicabtagene ciloleucel. The committee recognised that relapsed or refractory DLBCL after first-line\xa0chemoimmunotherapy has a large disease burden.\n\n## Treatment options\n\nClinical experts said that in current practice, people with DLBCL are usually offered rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP) as initial treatment. For DLBCL that is relapsed or refractory to R‑CHOP, clinicians offer salvage chemotherapy. If the disease responds, clinicians then offer high-dose chemotherapy and an autologous stem cell transplant, for those who are able to have one. Transplant suitability is based on the person's tolerance of intensive treatment and is usually only offered to people aged under\xa070. Patient experts commented on the side effects of intensive chemotherapy, including sickness, diarrhoea, hair loss and neutropenia. Patient and clinical experts also said that there is a need for treatments that could improve survival for people with relapsed or refractory DLBCL. The committee concluded that people with DLBCL and clinicians would welcome a new treatment option.\n\n## Proposed positioning\n\nThe company proposed axicabtagene ciloleucel for a narrower population than its marketing authorisation. It focused on adults with DLBCL that is primary refractory or early relapsed within 12\xa0months of treatment, and who are intended for an autologous stem cell transplant. This narrowed the population to those who would have been considered for an autologous stem cell transplant. This was to align with the key clinical trial, ZUMA‑7 (see section\xa03.5). Clinical experts commented that people who cannot have an autologous stem cell transplant have worse outcomes than those who can have one. They explained that it would be beneficial to have an additional treatment option for these people. They also added that there were effectively 3\xa0groups of people: those who could tolerate either an autologous stem cell transplant or axicabtagene ciloleucel, those who could not tolerate transplant but could tolerate axicabtagene ciloleucel and those who could not tolerate either. They were mindful that people who were not well enough to have an autologous stem cell transplant but who could tolerate axicabtagene ciloleucel would not be offered treatment based on the company's proposed positioning. But the clinical experts also highlighted that there was no evidence for axicabtagene ciloleucel in this population because they were not included in ZUMA‑7. So the committee agreed that it was appropriate to position axicabtagene ciloleucel for the narrower population.\n\n## Comparator\n\nThe committee recalled that relapsed or refractory DLBCL after first-line chemoimmunotherapy is usually treated with salvage chemotherapy, high-dose chemotherapy and an autologous stem cell transplant (from now, called standard care). The company used clinical expert opinion to estimate the chemotherapy regimens in standard care as 50% R‑ICE (rituximab, ifosfamide, carboplatin and etoposide) and 50% R‑GDP (rituximab, gemcitabine, dexamethasone and cisplatin). The committee concluded that standard care including salvage chemotherapy, high-dose chemotherapy and an autologous stem cell transplant was the relevant comparator.\n\n# Clinical evidence\n\n## ZUMA-7 trial\n\nThe company provided evidence for axicabtagene ciloleucel compared with standard care from ZUMA‑7, which is ongoing. This is a phase\xa03, randomised, open-label trial in adults with primary refractory or early relapse (within 12\xa0months of first-line treatment) DLBCL after chemoimmunotherapy who are intended for transplant. Standard care was defined as platinum-based chemoimmunotherapy, and if the condition responded, then high-dose chemotherapy and an autologous stem cell transplantation. The primary endpoint was event-free survival defined as time from randomisation to the earliest date of disease progression, start of new lymphoma treatment, death, or best disease response of stable disease. Best disease response of stable disease is the best response for DLBCL that is not growing or shrinking. One clinical expert commented that event-free survival was not an appropriate primary endpoint for a trial investigating second-line treatment. They said that people who went on to have third-line axicabtagene ciloleucel would not be captured in event-free survival. But the company confirmed that starting a new lymphoma treatment included off-protocol subsequent chimeric antigen receptor (CAR)\xa0T‑cell therapy, so it was a component of event-free survival. Another clinical expert noted that event-free survival is increasingly used as a primary endpoint because it effectively measures the impact of the intervention. ZUMA‑7 had 1\xa0to\xa01 randomisation and included a total of 359\xa0people. The median age of people in the trial was 59 and in the overall trial group 66% were men. About three quarters of people in the trial (74%) had primary refractory disease and about one quarter (26%) had disease relapse within 12\xa0months of first-line treatment at study entry. Crossover between treatment arms was not included in the trial. But if a person's disease did not respond to standard care, then they could have subsequent CAR\xa0T‑cell therapy off protocol. In the standard care arm, 56% of people had subsequent CAR\xa0T‑cell therapy. The committee acknowledged the experts' concerns but concluded that ZUMA‑7 provided the best available evidence for axicabtagene ciloleucel compared with standard care.\n\n## Chemotherapy bridging\n\nAt the first committee meeting, the clinical experts noted that chemotherapy bridging, which is chemotherapy offered between T‑cell collection and reinfusion, was not included in ZUMA‑7 but is commonly used in NHS practice. They commented that this might have made clinicians less likely to offer enrolment to people with fast-progressing disease in the trial. They explained that it was difficult to estimate the impact this would have on the comparative effectiveness. At the second committee meeting, the NHS England Cancer Drugs Fund clinical lead (from here, Cancer Drugs Fund lead) commented that in NHS clinical practice 75% of people have bridging therapy. Clinicians believe that this has resulted in a reduced incidence of grade\xa03\xa0or\xa0more cytokine release syndrome (CRS) and neurotoxicity. The Cancer Drugs Fund lead noted that recent evidence has shown that people who experience CRS and neurotoxicity have a higher median metabolic tumour volume. This has been shown to correlate with clinical outcomes in third-line CAR\xa0T‑cell treatment. In a recent clinical trial for another CAR\xa0T‑cell therapy, used in the same position as axicabtagene ciloleucel in the treatment pathway, 63% of people who had CAR\xa0T‑cell therapy also had bridging chemotherapy. They explained that because bridging chemotherapy was not included in ZUMA‑7 but would be commonly used with axicabtagene ciloleucel in NHS practice, the generalisability of the results from ZUMA‑7 to NHS practice was very uncertain. But, this uncertainty could be reduced with Cancer Drug Fund data collection. The committee acknowledged the issues of generalisability to NHS practice, and that this increases uncertainty in the clinical and cost-effectiveness results. It concluded that collecting data on treatment that reflects NHS clinical practice could reduce the uncertainty.\n\n## Adverse events\n\nClinical and patient experts explained that current standard care can be associated with adverse events, but the types of adverse events and how they are treated is different for axicabtagene ciloleucel. Two of the key adverse events associated with axicabtagene ciloleucel are CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). In ZUMA‑7, 92% of people who had axicabtagene ciloleucel had CRS of any grade and 6% had CRS of grade 3\xa0or\xa0higher. Also in the trial, more people who had axicabtagene ciloleucel had a serious neurological event compared with those who had standard care. The patient expert said that during their treatment with axicabtagene ciloleucel they experienced severely reduced mental abilities. The nursing expert also commented that neurological adverse events can develop within minutes. They explained that this is much faster than typical adverse events associated with standard care. They added that because of the risk of rapid deterioration, people who have had CAR\xa0T‑cell therapy need more monitoring, and potentially 1\xa0to\xa01 nursing even if they are not in intensive care. The committee understood the potential adverse events associated with axicabtagene ciloleucel and considered the implications for the cost of managing these in the NHS (see section\xa03.12).\n\n# Economic model\n\n## Model structure\n\nThe company provided a partitioned survival model to compare the cost effectiveness of axicabtagene ciloleucel with standard care. The model had 3\xa0health states: event free, post event and death. Health state occupancy was determined by mixture cure models fitted to ZUMA‑7 overall survival, event-free survival and time to next treatment curves. The model structure was similar to those used in previous CAR\xa0T‑cell NICE appraisals. The company justified using event-free survival, instead of progression-free survival, because it was the primary endpoint in ZUMA‑7 and it is clinically relevant given the curative intent of treatment. The model assumed that people who were alive and event free at 5\xa0years in both the axicabtagene ciloleucel and standard care arms had a quality of life equal to the general population because they were considered effectively cured. The ERG commented that, on balance, it was satisfied that the modelling approach was appropriate but that the model had a limited capacity to consider more than 1\xa0post-event round of treatment. The committee concluded the model was appropriate for decision making.\n\n## Axicabtagene ciloleucel overall survival extrapolation\n\nThe company used the most recent data cut from ZUMA‑7 to inform axicabtagene ciloleucel overall survival. This provided data for approximately 2\xa0years of follow up that the company then fitted a range of mixture cure models to. Its preferred model was the generalised gamma distribution because it had good statistical fit and was validated by clinical experts. The ERG noted that all curves fit relatively well to the trial data, but the log-logistic curve had marginally better statistical fit. Because the trial data is immature and the long-term survival for axicabtagene ciloleucel is uncertain, the ERG preferred the log-logistic curve. This provided slightly more conservative overall survival extrapolations. In its response to consultation, the company said that they were concerned with the clinical plausibility of the survival estimates produced by the log-logistic extrapolation. It provided a naive unadjusted comparison of 5‑year overall survival, comparing the observed results from ZUMA‑1 (a single-arm study of axicabtagene ciloleucel for treating relapsed or refractory DLBCL at third line or later) and the estimates from the log-logistic and generalised gamma extrapolations. The company explained that people having treatment at second line would be expected to be more well and have better outcomes than those having treatment at third line or later. The company considered that the log-logistic extrapolation gave a smaller difference in overall survival than would be expected at 5\xa0years when compared with the observed overall survival difference between ZUMA‑1 and ZUMA‑7 at 2\xa0years. The ERG noted that the follow-up data from ZUMA‑7 was still relatively immature, which increased uncertainty around long-term survival extrapolations. It commented that any models predicting overall survival greater than the ZUMA‑1 observed values were clinically plausible considering the overall uncertainty. The ERG maintained its preference for the log-logistic model. The committee concluded that both the generalised gamma and log-logistic curves appeared plausible and agreed that the log-logistic model was appropriate given the uncertainty.\n\n## Standard care overall survival\n\nAt the time of the second committee meeting, axicabtagene ciloleucel after 2\xa0or\xa0more systemic therapies had only been provisionally recommended for routine commissioning and the recommendation was still subject to appeal (see NICE's technology appraisal guidance on axicabtagene ciloleucel). Axicabtagene ciloleucel after 2\xa0or\xa0more systemic therapies is not considered to be established practice until after the final guidance is published, so for the purpose of this appraisal it was not considered a relevant subsequent treatment. In ZUMA‑7, 56% of people in the standard care group had third-line CAR\xa0T‑cell therapy (see section\xa03.5). The company explored adjusting the standard care overall survival to remove the benefit of subsequent CAR\xa0T‑cell therapy, which the committee agreed was necessary. Its base case treatment-switching adjustment method was the rank preserving structural failure time (RPSFT) model with full re-censoring of data for all people having standard care. This analysis gave a hazard ratio, which the company applied to the axicabtagene ciloleucel overall survival curve. The company also explored RPSFT models with different types of censoring and the inverse probability of censoring weighting method. During technical engagement, the company updated the survival analysis to recategorise 4\xa0people in the standard care arm whose data was originally censored as lost to follow up but were confirmed to have died during the study period. This reanalysis was originally requested by the US Food and Drug Administration. The updated overall survival hazard ratio for using the RPSFT model with full re-censoring was 0.42. At the second committee meeting the Cancer Drugs Fund lead noted the results from a clinical trial for another CAR\xa0T‑cell therapy in the same position in the treatment pathway as axicabtagene ciloleucel. The trial also included treatment switching and chemotherapy bridging and showed that survival benefit for people having CAR\xa0T‑cell therapy was lower in longer-term follow up compared with earlier results. They advised this increased uncertainty around the long-term survival benefit of other CAR\xa0T‑cell therapies such as axicabtagene ciloleucel. The committee agreed that the RPSFT model with full re-censoring was suitable. But, it added uncertainty that cannot be resolved until there is longer-term overall survival data collection.\n\n## Crossover analysis clinical plausibility\n\nThe company compared the updated survival estimates from the different treatment-switching adjustment methods with those from SCHOLAR‑1 and the comparator arm of the ORCHARRD study. SCHOLAR‑1 was a retrospective evaluation of outcomes in people with refractory DLBCL and included both observational and randomised controlled trial data. ORCHARRD was a study of ofatumumab compared with rituximab, dexamethasone, cytarabine and cisplatin (R‑DHAP) salvage treatment, followed by an autologous stem cell transplant. Clinical experts advised the company that overall survival for people having standard care would likely be above the SCHOLAR‑1 estimates but below the ORCHARRD estimates. The company noted that the only adjustment method that met the clinician's expectations, was the RPSFT model with full re-censoring. The ERG agreed that the company's preferred adjustment was the most appropriate method but cautioned that there was remaining uncertainty about standard care overall survival. The committee questioned whether it was appropriate to apply a hazard ratio to the axicabtagene ciloleucel overall survival mixture cure model. It was concerned that standard care overall survival was disadvantaged after 5\xa0years. Clinical expectation is that if people are alive and event free at 5\xa0years, regardless of the treatment they had, they are effectively cured. But, applying a hazard ratio implies that the standard care survival would be proportional to axicabtagene ciloleucel even after the cure point, which may not reflect clinical expectation. The committee concluded that the company's standard care overall survival extrapolation was acceptable, but that there was remaining uncertainty in long-term survival, which could be favourable to axicabtagene ciloleucel.\n\n## CAR T-cell therapy delivery costs\n\nThe company used a 'bottom-up' costing approach to calculate the cost of delivering axicabtagene ciloleucel treatment in the NHS. The company included the costs of:\n\nhospital administration\n\nleukapheresis\n\nconditioning chemotherapy\n\nbridging therapy\n\ntreating adverse events.The company considered each cost category individually and combined them to give an estimate for the cost of delivering axicabtagene ciloleucel in the NHS. The committee understood that NHS England had established a single tariff to capture these costs. The tariff was developed after NICE recommended the first CAR\xa0T‑cell therapy, tisagenlecleucel, for use in the Cancer Drugs Fund in December\xa02018. NHS England explained that the tariff includes all costs of care from the decision for the person to have CAR\xa0T‑cell therapy to 100\xa0days after infusion. NHS England explained that there is not currently a healthcare resource group (HRG) code that adequately captures the administration of CAR\xa0T‑cell therapies. It also commented that a key difference between its tariff and the company's costs is the time and number of staff needed to look after people who have had CAR\xa0T‑cell therapy. The company commented that it is not appropriate to use the tariff in the modelling. This is because it is a mechanism for NHS England to fund hospitals to provide CAR\xa0T‑cell therapy and is not designed for health technology evaluation. It was concerned that the evidence underlying the tariff has not been transparently shared and that it may include costs that are not relevant. The ERG was also concerned about the methods used by NHS England to derive the tariff. It was unclear how individual trusts estimated expenditure and how this corresponded to quantities of resource use. However, the ERG also commented that the company's approach likely underestimated the true cost of delivering CAR\xa0T‑cell therapy. After the first appraisal committee meeting the company submitted a further analysis using a CAR\xa0T‑cell therapy delivery cost of £41,101, informed by an ERG scenario analysis. This accounted for the impact of increased staffing needs associated with providing CAR\xa0T‑cell therapy. The updated company analysis consisted of a one-off cost of £41,101 for the first 100\xa0days as well as the costs of conditioning chemotherapy drugs and intravenous immunoglobulin (IVIg). These 3\xa0costs are reimbursed separately by NHS England. NHS England considered that, although the company's cost differs from the tariff for CAR\xa0T‑cell therapy, it was an acceptable cost to use in the cost-effectiveness analysis. This is because the current tariff represents the high hospital costs of establishing the infrastructure of a CAR\xa0T‑cell therapy service and delivering a relatively new type of treatment, but economies of scale may be expected over time. Costs may also reduce with clinical developments in care that reduce toxicity and so reduce the need for more intense monitoring and treatment. The committee noted NHS England's comments and was satisfied that the company's costs adequately captured a reasonable projection of the cost to the NHS of delivering CAR\xa0T‑cell therapy.\n\n## Autologous stem cell transplant costs\n\nAs part of current standard care for relapsed or refractory DLBCL, people are offered an autologous stem cell transplant. The company included a cost of £37,736 for this procedure. This was the value used in NICE's Guideline on non-Hodgkin's lymphoma: diagnosis and management inflated to 2020\xa0to\xa02021 values. The ERG noted that this cost was not transparent and preferred to use the HRG for 'Peripheral Blood Stem Cell Transplant, Autologous, 19\xa0years and over' inflated to £17,181. The company was concerned that the ERG's approach did not include follow-up costs. It cited a study by Wang et al. (2016) of people with DLBCL in the Haematological Malignancy Research Network, which reported the cost of autologous stem cell transplants to be about £42,000. The Cancer Drugs Fund lead commented that the company's estimate appeared more consistent with the cost of the procedure in the NHS than the ERG's. The committee concluded that there was some uncertainty about the true cost of autologous stem cell transplants in the NHS, but that the company's estimate was more appropriate.\n\n## Retreatment costs\n\nThe company noted that a small proportion of people in ZUMA‑7 had retreatment with axicabtagene ciloleucel (the company considers the value to be confidential, so it cannot be reported here). It explained that retreatment was not part of the marketing authorisation and would not occur in clinical practice, so it did not include those costs. It also added that the clinical benefit for people who had retreatment was small and unlikely to impact the cost-effectiveness estimates. The ERG was concerned that excluding retreatment costs would mean that modelled treatment benefit and modelled costs were not aligned. It preferred to include retreatment costs because there is no robust way of removing treatment benefit. The committee noted the benefit of retreatment was uncertain. NHS England confirmed that it would not commission retreatment. The committee agreed with the ERG that it was important to align modelled costs and benefits. So it concluded that it was appropriate to include axicabtagene ciloleucel retreatment costs.\n\n# End of life\n\n## Life-extending treatment criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal 2013. The company proposed that axicabtagene ciloleucel met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24\xa0months). The committee noted that using its preferred RPSFT model with full re-censoring adjustment, the mean life years for the standard care arm was more than 24\xa0months, but the median overall survival was less than 24\xa0months (the company considers the exact values to be confidential, so they cannot be reported here). The model also predicted that less than one third of people in the standard care arm would be alive at 24\xa0months (the company considers the exact value to be confidential, so it cannot be reported here). The clinical experts agreed that they would expect 20% to 30% of people in this population to be alive at 24\xa0months with current standard care. The committee recalled that CAR\xa0T‑cell therapy is not considered established practice so could not be considered part of standard care (see section\xa03.10). The committee agreed that although there was some uncertainty, the short life expectancy criterion was met. It then considered if axicabtagene ciloleucel was associated with a gain in overall survival of at least 3\xa0months. When using its preferred assumptions, the model predicted axicabtagene ciloleucel would extend life by more than 3\xa0months (the company considers the exact value to be confidential, so it cannot be reported here). The committee concluded that axicabtagene ciloleucel met both of NICE's criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness estimate\n\n## Preferred ICER\n\nThe committee considered the deterministic incremental cost-effectiveness ratios (ICERs) for axicabtagene ciloleucel compared with standard care. Because of confidential commercial arrangements for comparator treatments, the exact cost-effectiveness results cannot be reported here. The committee's preferred cost-effectiveness estimate included:\n\na log-logistic mixture cure model for axicabtagene ciloleucel overall survival (see section\xa03.9)\n\nCAR\xa0T‑cell delivery costs of £41,101 (see section\xa03.12)\n\nautologous stem cell transplant costs from NICE's Guideline on Non-Hodgkin's lymphoma: diagnosis and management (see section\xa03.13)\n\nretreatment costs for axicabtagene ciloleucel (see section\xa03.14)\n\npost-event treatment distributions from ZUMA‑7\n\npost-event utility values from ZUMA‑1 (a single-arm study of axicabtagene ciloleucel for relapsed or refractory DLBCL at third line or later; pre-progression values) rather than JULIET (a single-arm study of tisagenlecleucel for relapsed or refractory DLBCL)\n\nthe cost of an additional consultation for neurological adverse events.\n\n## Uncertainty\n\nNICE's guide to the methods of technology appraisal 2013 notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically:\n\nlong-term overall survival in people having treatment with axicabtagene ciloleucel and standard care, including:\n\n\n\nimmature trial data and the distribution used to extrapolate overall survival for people having treatment with axicabtagene ciloleucel in ZUMA‑7 (see section\xa03.9)\n\nthe crossover adjustment needed to adjust for the use of third-line CAR\xa0T‑cell therapy in ZUMA‑7 (see section\xa03.11)\n\n\n\ngeneralisability of the results from ZUMA‑7 to NHS practice because chemotherapy bridging was not used in the trial (see section\xa03.6).The committee agreed that the end of life criteria applies to axicabtagene ciloleucel. This can allow it to consider ICERs of up to £50,000\xa0per QALY gained, when the full weighting is applied to the upper end of the usual cost-effectiveness range (£30,000\xa0per QALY gained). But, because of the uncertainty in this appraisal, the committee expected a maximum acceptable ICER to be around £20,000\xa0per QALY gained. So, when the end of life weighting is applied, the maximum acceptable ICER is substantially less than £50,000\xa0per QALY gained. The committee highlighted that the lower value for an acceptable ICER in this appraisal is based on the substantial levels of uncertainty associated with the evidence from ZUMA-7. When confidential commercial arrangements were included, the committee's most plausible ICER was less than £50,000\xa0per QALY gained (the exact ICER cannot be reported because of the confidential comparator discounts). But the ICER was above what the committee considered to be their maximum acceptable ICER with the high level of uncertainty. So, the committee concluded that it could not recommend axicabtagene ciloleucel for routine use in the NHS.\n\n# Cancer Drugs Fund\n\n## Criteria for Cancer Drugs Fund\n\nHaving concluded that axicabtagene ciloleucel could not be recommended for routine use, the committee then considered if it could be recommended for treating DLBCL after first-line\xa0chemoimmunotherapy within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). At the first committee meeting, the company acknowledged that there is uncertainty in the clinical evidence for using axicabtagene ciloleucel in this position, and that it could be a candidate for the Cancer Drugs Fund. The committee noted that ZUMA‑7 is ongoing and further follow up may resolve some uncertainty around long-term survival for people who have axicabtagene ciloleucel and people who have standard care. During the second committee meeting, the Cancer Drugs Fund lead also commented that if axicabtagene ciloleucel was available in the Cancer Drugs Fund it would also help reduce uncertainty around the generalisability of the evidence from ZUMA‑7 because of the absence of chemotherapy bridging (see section\xa03.6). This is because Systemic Anti-Cancer Therapy (SACT) data would be collected from people having treatment in the NHS. The committee agreed that reducing the uncertainty by having a longer period of data collection in the NHS would support the case for axicabtagene ciloleucel to be recommended for routine commissioning. The committee also considered that axicabtagene ciloleucel has the plausible potential to be cost-effective, if further data collection validates the current cost-effectiveness estimates. The committee concluded that axicabtagene ciloleucel met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended axicabtagene ciloleucel for use within the Cancer Drugs Fund as an option for treating DLBCL that has relapsed within 12\xa0months after first-line chemoimmunotherapy, or is refractory to first-line chemoimmunotherapy, in adults when an autologous stem cell transplant is suitable.\n\n# Other factors\n\n## Innovation\n\nThe company commented that axicabtagene ciloleucel is a personalised, transformative and innovative treatment. It also noted that there may be potential benefits of axicabtagene ciloleucel treatment that were not fully captured in the QALY calculations. It stated that the true benefit of cure was likely underestimated. It also stated that there may be benefits associated with axicabtagene ciloleucel because it is a single infusion, compared with multiple cycles of chemotherapy followed by high-dose treatment and an autologous stem cell transplant. The committee recognised that there may be these benefits to people but concluded that it had not seen evidence of these benefits over those already included in the QALY calculations.\n\n## Equality\n\nThe committee recalled that current standard care includes an autologous stem cell transplant. The company and clinical experts explained that people 70\xa0years and older are not usually offered stem cell transplant. The company explained that because axicabtagene ciloleucel would not have an age restriction, it could help reduce the age inequality. Age is a protected characteristic under the Equality Act\xa02010. The committee was aware that NICE makes recommendations for technologies within their marketing authorisations. However, the committee recalled that the company positioned axicabtagene ciloleucel only for people for whom an autologous stem cell transplant is suitable, which is usually people aged under\xa070. The committee considered the evidence that had been submitted. It noted that it had not seen evidence for axicabtagene ciloleucel for treating relapsed or refractory DLBCL in people for whom autologous stem cell transplant is not suitable, who are usually older and less well. The committee was aware of the need for new treatments in this population and was disappointed the company chose to position axicabtagene ciloleucel for the transplant eligible population only. A research organisation also commented that there is a geographic inequality because CAR\xa0T‑cell therapy is only provided at 10\xa0designated centres. The clinical experts explained that there are plans to deliver CAR\xa0T‑cell therapy at more centres in more locations, which may mitigate this issue. The committee noted these concerns but concluded that its recommendation for axicabtagene ciloleucel would not adversely affect people protected by the equality legislation."}	https://www.nice.org.uk/guidance/ta895	Evidence-based recommendations on axicabtagene ciloleucel (Yescarta) for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy.
d6038e9f97deb8728e0aa6b4b22ce79aeba208c3	nice	Bulevirtide for treating chronic hepatitis D	Bulevirtide for treating chronic hepatitis D Evidence-based recommendations on bulevirtide (Hepcludex) for chronic hepatitis D in adults. # Recommendations Bulevirtide is recommended as an option for treating chronic hepatitis D in adults with compensated liver disease only if: there is evidence of significant fibrosis (METAVIR stage F2 or above or Ishak stage 3 or above) and their hepatitis has not responded to peginterferon alfa‑2a (PEG‑IFN) or they cannot have interferon-based therapy.Bulevirtide is only recommended if the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with bulevirtide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations People with hepatitis D also have hepatitis B. There are no other licensed treatments specifically for hepatitis D. Standard care usually involves treating symptoms and the hepatitis B. People with significant fibrosis (scarring) in their liver can be offered PEG‑IFN, but it is not licensed for this use. The company positioned bulevirtide for people with chronic hepatitis D who have tried PEG‑IFN and whose condition did not respond to it, or for people who cannot have interferon-based therapy. The company also only positioned it for METAVIR stage F2 or above (which means they have significant fibrosis). Testing for METAVIR stage usually involves a biopsy, which is invasive and may have side effects, and many people decline it. But NICE's guideline on diagnosing and managing chronic hepatitis B recommends transient elastography (FibroScan), which is a non-invasive assessment. It also recommends that hepatitis D with significant fibrosis is defined by a METAVIR stage of F2 or above, or an Ishak stage of 3 or above. Clinical trial evidence shows that bulevirtide is effective compared with standard care despite some uncertainties around how long it works for. Despite the uncertainties in the clinical trial evidence, the cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources. So bulevirtide is recommended.# Information about bulevirtide # Marketing authorisation indication Bulevirtide (Hepcludex, Gilead) has a conditional marketing authorisation 'for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV RNA positive adult patients with compensated liver disease'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for bulevirtide. # Price The list price of 2 milligram vials of bulevirtide is £6,500 for 30 vials (excluding VAT; BNF online accessed May 2023). The company has a commercial arrangement. This makes bulevirtide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Gilead, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition, treatment pathway and positioning ## Hepatitis D disease burden Hepatitis D is an infectious disease of the liver caused by the hepatitis delta virus (HDV). Around half of all people who acquire HDV will develop chronic hepatitis D, defined as an infection lasting longer than 6 months. Hepatitis D only affects people who are already infected with the hepatitis B virus (HBV) because HDV needs the hepatitis B surface antigen to complete its replication. The patient expert explained the significant impact co-infection with hepatitis B and D has on their physical and mental health. They emphasised that the extreme lethargy associated with the condition affects their day-to-day functioning and ability to walk short distances. They also explained that changes to their lifestyle such as stopping smoking or eating healthily have had limited impact on improving the symptoms of their condition, which have been a constant burden for over 10 years. The committee noted the high disease burden of chronic hepatitis D. ## Treatment pathway and unmet need The treatment options for people with chronic hepatitis D are limited. Clinical experts explained that people with hepatitis D would have treatment according to the recommendations in NICE's guideline on diagnosing and managing chronic hepatitis B. People co-infected with hepatitis D, with evidence of significant fibrosis, can be offered a 48‑week course of peginterferon alfa‑2a (PEG‑IFN). The clinical experts explained that using PEG‑IFN to treat hepatitis D is off label, can have serious side effects, and is not effective for most people. They also said that a large proportion of people would also have antivirals (tenofovir and entecavir) for their underlying hepatitis B infection. If hepatitis B is cured, the hepatitis D virus cannot survive. But hepatitis B has a low chance of being cured with current treatments. The clinical experts explained that bulevirtide is a first-in-class medicine that addresses an unmet need for effective and well-tolerated treatments. They added that there is regional variation in providing tests for HDV, even though NICE's guideline on diagnosing and managing chronic hepatitis B recommends that everyone with HBV should have one. The clinical experts added that even if bulevirtide was available, there may still be undiagnosed hepatitis D in people with undiagnosed hepatitis B. They also noted the limited number of laboratories testing for hepatitis D. But, if bulevirtide was available, there would be an extra incentive to identify people with HDV, which may arguably make access to diagnosis more equal across the country. The committee concluded that there is a significant unmet need for effective treatments in this population because the current options are limited. ## Positioning of bulevirtide in the treatment pathway The clinical evidence presented for bulevirtide came from MYR 301, a phase 3, multicentre, open-label, randomised trial evaluating the clinical efficacy and safety of bulevirtide in people with chronic hepatitis D and compensated liver disease. The marketing authorisation also specifies that bulevirtide should be considered for people with chronic hepatitis D and compensated liver disease. But the company positioned bulevirtide for a narrower population as a treatment for chronic hepatitis D with compensated liver disease and evidence of significant fibrosis, which it defined as a METAVIR fibrosis score of F2 or above. The condition should also have not responded well enough to PEG‑IFN, or the person with hepatitis D should not be able to tolerate PEG‑IFN or should have a contraindication. The company clarified that most people in MYR 301 had already had interferon treatment, and those who had not were likely to have a contraindication or not be able to tolerate it. The EAG accepted this but was concerned that the company's evidence included people not relevant to the decision problem it had specified. The company presented data from the full analysis set from MYR 301, which included people with all METAVIR fibrosis stages (F0 to F4). It explained that its positioning addressed the area of highest unmet need. The clinical experts said that everyone with hepatitis D has an unmet need for treatments that prevent disease progression, and if bulevirtide was recommended, they would prefer to use it as an alternative to PEG‑IFN. At consultation, the company noted that its proposed positioning aligned with the recommendations in NICE's guideline on diagnosing and managing chronic hepatitis B, which recommends that people with hepatitis D and significant fibrosis (defined by METAVIR stage F2 or above or Ishak stage 3 or above) should be offered a course of PEG‑IFN. The committee considered that this positioning was appropriate. ## Fibrosis staging The clinical experts explained that it would be difficult to identify the company's proposed population in clinical practice. METAVIR staging is done using a liver biopsy, which is invasive and carries a morbidity and mortality risk. So, many people refuse this procedure. The committee agreed that, even if it accepted that it is clinically appropriate to limit bulevirtide to people with significant fibrosis, defined by a liver biopsy, it may not be possible to implement such a rule in practice. NICE's guideline on diagnosing and managing chronic hepatitis B recommends a non-invasive assessment, transient elastography (FibroScan), for everyone with HBV. Liver biopsy is only offered to confirm the level of fibrosis in adults with a transient elastography score of between 6 kPa and 10 kPa. The clinical experts explained that, in practice, clinicians would likely use transient elastography to determine eligibility for bulevirtide, along with serological tests and imaging. The committee heard that the company had collected transient elastography data in MYR 301. It considered that, if it was not possible to position bulevirtide as a first-line treatment, it would be useful for the company to present data using transient elastography rather than liver biopsy (METAVIR staging) to assess fibrosis. This is because this approach more closely reflects current clinical practice for determining fibrosis stage to identify eligible people. At consultation, the company reiterated the positioning in its base-case model of bulevirtide as a treatment for people with chronic hepatitis D, compensated liver disease and evidence of significant fibrosis (defined as a METAVIR score of F2 or above, based on liver biopsy). It identified 3 subgroups in MYR 301 that it considered aligned with a METAVIR fibrosis stage of F2 or above, and 2 transient elastography cut‑off scores that could rule out significant fibrosis. It considered these in a scenario analysis. The company noted that there is no agreement in clinical practice on cut-offs that can rule out significant or advanced fibrosis. So, it used external literature to inform these values. The company used a meta-analysis by Qi et al. (2018) and data from the European Association for the Study of the Liver (EASL; 2021 Clinical Practice Guidelines) to identify 2 transient elastography (FibroScan) thresholds of 7.25 kPa and 8.00 kPa that aligned with a METAVIR fibrosis stage of F2 or above. It applied these thresholds to the transient elastography scores collected in MYR 301. Based on its analyses, the company considered that most people in MYR 301 were in line with its proposed positioning of bulevirtide for a METAVIR fibrosis score of F2 or above. It carried out 3 scenario analyses covering each of the fibrosis stages it had identified. The company considered that these analyses showed that the transient elastography scores in MYR301 aligned with a METAVIR fibrosis staging of F2 or above. The EAG was unable to validate the threshold for the significant fibrosis source used in the EASL guideline. But it did consider that a value of at least 8.0 kPa is the most validated threshold to rule out advanced fibrosis (F3 or above). It was unclear about whether the company had used a systematic approach to identify the thresholds. The company clarified that it had not used a formal consensus approach to gather its clinical feedback on appropriate thresholds. The committee recognised there was still a high level of uncertainty about the most appropriate threshold for transient elastography fibrosis staging. It recalled at the first committee meeting that its preference had been for an elastography-based model (see section 3.8). The committee considered that it had not seen this detail, so this could not inform its decision making. It considered that using a non-invasive assessment through transient elastography (FibroScan) would be better than using an invasive liver biopsy assessment. The EAG noted that transient elastography is not very accurate at diagnosing significant fibrosis, but is likely to be used in clinical practice to identify people that will be eligible for bulevirtide. Because the response data from MYR 301 showed similar results for both subgroups and the full trial population, the EAG considered that this suggested including people with less severe liver disease had limited effects on the response rates. It preferred to use the full trial population. The company later updated its base case to reflect response rates from the full trial population. The committee accepted this. It concluded that response rates should reflect the full trial population, and accepted that in clinical practice, fibrosis could be assessed by either transient elastography or a clinical biopsy. # Clinical effectiveness ## Virological and biochemical response The MYR 301 trial investigated 2 different doses of bulevirtide (2 mg and 10 mg) over 144 weeks and also bulevirtide 10 mg started at 48 weeks (that is, people had standard care until 48 weeks, at which point they started on bulevirtide). The company used 48‑week data from the bulevirtide 2 mg arm and delayed treatment arm to reflect the intervention and comparator. The primary outcome of MYR 301 was combined virological and biochemical response at week 48. Virological response was defined as undetectable HDV RNA or a decrease in HDV RNA levels by 2log10 IU/ml or more from baseline. Biochemical response was defined as alanine aminotransferase (ALT) normalisation, that is, ALT levels in the normal range. In the MYR 301 trial, many more people on bulevirtide had a combined response than people who had standard care at 24 weeks and 48 weeks of treatment. This difference was statistically significant. The committee noted that people in the delayed treatment arm of the trial were allowed to continue with any treatment prescribed for their underlying hepatitis B. It agreed that this arm represented standard care in the UK. The committee acknowledged the large benefit for people who had treatment with bulevirtide at week 48 but noted that the 48‑week treatment period in MYR 301 was quite short. At the second committee meeting, the company reiterated that longer-term data from MYR 301 is due to be published shortly. The committee considered that longer-term data would be useful to determine if response with bulevirtide is sustained beyond the 48‑week treatment period. No additional data was provided by the company at the third committee meeting. The committee concluded that uncertainty still remained in identifying if response to treatment with bulevirtide would continue. ## Surrogate outcomes It is not feasible to assess the long-term complications of hepatitis D, such as decompensated cirrhosis, hepatocellular carcinoma and death directly in clinical trials, because these may take years to develop. Because of this, surrogate outcomes are used. The clinical experts said the surrogate outcomes of virological and biochemical response used in MYR 301 were reasonable markers of disease progression in hepatitis D. But they explained that some people's ALT levels may not normalise with treatment because of other reasons, such as fatty liver disease or alcohol use, and using the combined end point may disadvantage those with raised ALT if treatment was stopped in these people because of it. They added that undetectable HDV was also a good indication of treatment efficacy. The committee concluded that virological and biochemical response can be considered suitable surrogate outcomes for preventing the complications of liver disease. ## Generalisability Because MYR 301 did not include people in the UK, the company assumed that the baseline characteristics of people taking bulevirtide in the NHS would reflect the cohort reported by Spaan et al. (2020), a retrospective analysis of 107 people with hepatitis D in the UK. People in Spaan et al. had a baseline age of 35 years and 60% had cirrhosis. In MYR 301 the baseline age was 42 years and 47% had cirrhosis. The EAG said the baseline characteristics in Spaan et al. and MYR 301 were both clinically plausible, but the model was sensitive to these inputs in terms of the cost‑effectiveness results and the severity modifier applied (see section 3.15). The company also presented data published by Public Health England (now the UK Health Security Agency ) on routine blood-borne virus testing. The median age between 2011 and 2020 was around 37 years. The committee noted that this data was provided after the technical engagement stage, so could not be fully reviewed by the EAG. Further to this, one of the clinical experts explained that they are the lead investigator of a study being done by the UKHSA on the epidemiology of HDV infection in the UK. The study is collecting data from the 10 laboratories doing HDV testing in the UK and data should be available on mean age at baseline. The committee agreed with using UKHSA data but considered that data on mean (rather than median) age and the proportion with cirrhosis on diagnosis would be helpful. At consultation, the company updated its base case to reflect the average age of people diagnosed with hepatitis D in the UK based on the median age (35 years) from the UKHSA study. It considered that this data suggested that most people with chronic hepatitis D in the UK are young at diagnosis, so preferred to use the median age estimate. The EAG preferred the mean age. The committee agreed that the mean was the most appropriate measure of central tendency. The clinical expert noted that people with chronic hepatitis D would also be diagnosed with hepatitis B. The committee considered that relevant data on the age at diagnosis of hepatitis B would therefore help validate its concerns around the mean baseline age of people diagnosed with chronic hepatitis D (see section 3.16). It considered that, until more data becomes available, it was difficult to define the proportion with cirrhosis at baseline. It considered that the UKHSA data based on mean age at diagnosis was the most appropriate source to inform the baseline age. After the second committee meeting, the company updated its base case to reflect the cohort of people with hepatitis D in the UK that are currently alive (n=570). It considered that this reflected the age of people with hepatitis D who would use bulevirtide. The EAG explained that in the UKHSA study, mean age was captured in 2 different ways. It preferred to use the mean age from the full UKHSA dataset of people in the UK that had been diagnosed with hepatitis D, considering that this better reflected the age at diagnosis. The committee concluded that the baseline age that reflected the full UKHSA dataset of people diagnosed with hepatitis D was the most appropriate as it was also a bigger dataset (n=602). # Economic model ## Company's modelling approach The company presented a Markov model to estimate the cost effectiveness of bulevirtide compared with standard care. The model had 10 health states, representing METAVIR fibrosis stages F0 to F4, and more severe disease complications, including decompensated cirrhosis, hepatocellular carcinoma, liver transplant, post-liver transplant and death. The model had a 24‑week cycle length and used a lifetime time horizon. Because the company positioned bulevirtide for people with METAVIR stage F2 and above, the F0 to F1 states in the model were never occupied. The committee noted that using model health states based on METAVIR fibrosis staging may not be appropriate (see sections 3.3 and 3.4). The committee considered that, if the company amended its population and comparators to cover the entire marketing authorisation, then a model structure using METAVIR stages may be acceptable because data from the full trial population could be used. The committee concluded that, if the company is planning to position bulevirtide in a narrower population than the marketing authorisation, an elastography-based model (with effectiveness data from the relevant population alone) was preferred. At the second committee meeting the company maintained its base-case position using METAVIR staging (see section 3.4) and did not change its model to an elastography-based model. The committee concluded that it had not seen the evidence to change its original viewpoint and maintained its preference for an elastography-based model. ## Transition probabilities Initial transition probabilities in the model were determined by response status in MYR 301. Although the company positioned bulevirtide for people with METAVIR stage F2 and above, it used data from the full trial population to estimate probabilities of response, which included people with METAVIR stage F0 to F1. The EAG noted that people with less severe fibrosis may be more likely to have a better response, which may overestimate response rates in a population with METAVIR stage F2 and above. In the longer term, the company assumed that people with a combined response (from now referred to as combined responders) did not progress through fibrosis states or to more severe disease states, such as hepatocellular carcinoma, and could have fibrosis regression from 24 weeks onwards. The company assumed an 8.8% annual probability of regression from F4 to F3, and a 13.3% annual probability of regression from F3 to F2. The company assumed that people with a virological response only (from now referred to as virological responders) could progress, although at a slower rate than people whose condition did not respond to treatment at all (from now referred to as non-responders). The clinical experts agreed with the company that combined responders would have a low risk of progression through fibrosis stages. But they argued that this would not be zero because this group could still have detectable levels of virus. They added that even combined responders may still be at risk of hepatocellular carcinoma. The clinical experts further explained that it is plausible that fibrosis regression could occur in combined responders but added that the company's assumed transition probabilities for fibrosis regression seemed high. The committee agreed with the clinical experts that combined responders would still be at risk of hepatocellular carcinoma and noted that in people with hepatitis B and hepatitis C, viral response reduces, but does not eradicate hepatocellular carcinoma risk. The committee noted that the EAG assumed a residual risk of hepatocellular carcinoma in its base case. It had noted a data analysis directly in people with HDV (Alfaiate et al. 2020) had found that all responders are likely to have hepatocellular carcinoma. This meant that combined and partial responders may have a chance of developing hepatocellular carcinoma. Because the risk for people whose condition responds to treatment is lower than those whose condition does not, the EAG preferred to assume that combined responders and partial responders would have the same probability of developing hepatocellular carcinoma. The committee felt that additional scenario analyses would be helpful to address the remaining uncertainties around transition probabilities. At consultation, the company did 3 exploratory analyses. In these analyses it assumed that progression through fibrosis states and to hepatocellular carcinoma in combined responders was 20% of that for partial responders. This had a small impact on the cost-effectiveness results and the company later included these assumptions in its revised base case. The committee was satisfied that this addressed the uncertainties it originally had around transition probabilities in the model. ## Duration of response The company's assessment of response was based on 48‑week data from MYR 301, extrapolated for 1 additional model cycle to 72 weeks. The EAG preferred to limit the timeframe for assessing response to 48 weeks, without extrapolating data from MYR 301. It argued that the company's extrapolations were uncertain because they assumed that response is maintained for all people who do not stop treatment from 48 weeks onwards. The committee considered the data on response at week 24 and week 48 and noted that some people lost response, while others gained response. But the trend is likely to be for people to lose response over time. The committee heard from the company that additional data from MYR 301, beyond 48 weeks, would soon be available. The committee considered that additional trial data would be helpful in resolving the uncertainty around ongoing response and gave the committee confidence in the response rates seen at 48 weeks. But, until this data is available, the committee agreed with the EAG that response should be limited to 48 weeks because this is aligned with the data currently available. At consultation, the company clarified that its revised base case now included the data from MYR 301 which was not extrapolated beyond 48 weeks. The trial results showed a trend for response rates to increase during the first 48 weeks of treatment, so it had chosen not to extrapolate data beyond 48 weeks. The clinical expert highlighted that it was very difficult to define how long people should be treated for because there was not enough data from the 48‑week treatment period. People with hepatitis might initially see sustained response, but many may later relapse. The committee was still unclear about how long response would be sustained beyond the 48‑week data. It considered that longer-term data would have been helpful to committee decision making and resolving the uncertainty over how long people would maintain a response beyond 48 weeks. ## Treatment duration and stopping rules The summary of product characteristics for bulevirtide says that treatment should be continued for as long as it is associated with a clinical benefit. The company assumed that treatment duration in the model depends on response status. Combined responders were assumed to remain on treatment indefinitely, whereas virological responders and non-responders stopped at 72 weeks and 48 weeks respectively. The EAG highlighted the mismatch between treatment duration in the model and in the trial; everyone in the trial could continue treatment, irrespective of response status. The clinical experts broadly agreed with the company's model assumptions for combined responders and non-responders but were less sure of what would happen for virological responders. One clinical expert explained that if a person had a virological response but high ALT for reasons other than hepatitis, for example fatty liver disease or alcohol use, clinicians would be wary about stopping treatment. The clinical experts added that treatment would also likely continue for combined or virological responders who develop hepatocellular carcinoma, and that for people with convincing evidence of virus eradication, treatment would likely be stopped. The committee agreed with the clinical experts' assumptions. At consultation, the company confirmed its base-case analyses now included the assumption that combined responders with undetectable RNA at 48 weeks would stop treatment 52 weeks later. The committee considered that there was some uncertainty around the company's assumptions. In MYR 301, people could be treated with bulevirtide up to 144 weeks. But the company assumed that partial responders would have treatment for up to 72 weeks, then stop treatment if they had not had a complete response. If the condition had not responded at all to treatment at week 48, treatment was stopped. The committee noted that the study protocol for MYR 301 suggested that partial responders could continue treatment for longer than the 72 weeks assumed by the company. It also noted that there was no clear justification for why, if there was no response, treatment stopped at 48 weeks. The company did 3 exploratory analyses to test the effect of varying stopping rules, all of which increased the company's cost-effectiveness estimates, assuming: partial and non-responders stopped treatment at week 48 partial and non-responders stopped treatment at week 72 non-responders at week 48 would continue to be treated for a further 52 weeks.The committee recognised that there was still ambiguity around how long treatment should be continued and when bulevirtide should stop because of lack of response. The company confirmed that this data had not been collected in MYR 301, so further data analyses would be needed. It later updated its base case so partial and non-responders stopped treatment at week 72. The committee accepted this but concluded that only further data collection would help resolve the uncertainty around treatment duration and stopping rules. ## Utility gain for combined responders The company applied a utility gain for combined responders to capture the benefit of having the combined outcome of virological and biochemical response. The committee noted that the utility gain for combined responders was a key driver of cost effectiveness. The company fitted a Tobit regression model to 48‑week pooled data from MYR 301. Variables included in the model, informed by clinical experts, were cirrhosis status at baseline and response at week 48. The utility gain was applied in addition to utility for the F2 to F4 health states for people with a combined response. The committee heard from the clinical experts that it was plausible for people's symptoms and quality of life to improve with the reduction in viral load. It concluded that it was reasonable to assume a utility gain for combined responders. The committee was less certain about the size of the utility gain that should be applied. It noted the lack of justification for the Tobit approach and highlighted that the resulting utility gain from the regression model was not statistically significant. At consultation, the company explained its decision to use a Tobit regression analysis. It said that a large number of people in MYR 301 had the highest utility index score and this suggested that there was a ceiling effect, so other regression analyses would not be appropriate. The committee accepted this explanation. It recalled that, in previous appraisals of hepatitis C, combined response was associated with a smaller utility gain than assumed by the company. It considered that the size of the utility benefit for combined responders was uncertain and asked the company to explore this uncertainty by testing alternative estimates of utility gain. The company had searched existing NICE technology appraisal guidance on hepatitis B and C and found utility gains for people with a sustained virologic response ranging from 0.03 to 0.05. It did 2 scenario analyses, reducing the utility gain in its base case by 50% and 75%. These had a moderate impact on increasing the cost‑effectiveness estimates. The EAG considered that these were arbitrary values. It preferred to test the impact of using the lowest and highest utility gains identified in previous NICE technology appraisal guidance on hepatitis. The clinical expert noted that hepatitis C and D are very different populations, with different risk factors and manifestations of disease. The committee also noted that there were some differences in the way utility gains had been assessed. In the company's analysis, MYR 301 utility gains were assessed while people were still having treatment, whereas in previous technology appraisals these had been defined after treatment had stopped. The committee concluded that the utility gain for combined responders was still uncertain. It recalled that people's symptoms and quality of life improved as viral load reduced, so it preferred the EAG's scenarios incorporating the maximum utility gain for combined responders from previous technology appraisals. The company later included this in its base-case analyses. ## Health-state utility values The MYR 301 trial collected EQ‑5D‑3L data at baseline, week 24 and week 48. The company argued that the EQ‑5D data did not demonstrate face validity because it did not reflect differences between people with and without compensated cirrhosis. It added that key symptoms of hepatitis such as fatigue, nausea and vomiting are not well reflected by EQ‑5D‑3L. The company could not identify appropriate utility values for people with chronic hepatitis D in the literature, so preferred to use utility values from a meta-analysis of people with chronic hepatitis B. The EAG did not agree with the company's view because the EAG's experts highlighted that the impact of different levels of fibrosis on quality of life is likely to be very small. The committee agreed with the EAG and noted that even histologically advanced liver disease is silent in many people and decompensation is often the presenting event. The committee concluded that utilities based on MYR 301 were appropriate. ## Costs Bulevirtide is available as a 2 mg powder for injection vial, reconstituted and self-administered daily. According to the summary of product characteristics, people self-administering should get training to minimise the risk of injection site reactions. The company explained that it would fund all homecare services, including training to self-administer, so these costs are not included in the model. The committee concluded that the model includes all relevant costs associated with bulevirtide treatment. ## Severity modifier The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company calculated absolute and proportional quality-adjusted life year (QALY) shortfall weights in line with NICE's health technology evaluations manual. Absolute QALY shortfall is the future health, including quality and length of life, that is lost by people living with a condition, compared with the expected future health without the condition over people's remaining lifetime. Proportional QALY shortfall represents the proportion of future health, including quality and length of life, that is lost by people living with the condition. The company estimated that a weight of 1.2 should apply to the QALY. In its calculation of QALYs accrued by a healthy individual in the general population, baseline age was 37 years (based on UKHSA data) and 59% were men (based on baseline characteristics from the MYR 301 study). QALYs for people on standard care were taken from the comparator arm of the model. The EAG considered that the company had calculated the QALY weighting appropriately but noted that the weighting was sensitive to the assumed age at baseline as well as the proportion with cirrhosis. At consultation, the company provided data from the UKHSA study to validate assumptions around age at diagnosis. It considered that applying the UKHSA data did not alter the eligibility for a severity modifier. It preferred to use the mean age from the UKHSA cohort of people in the UK with hepatitis D who are currently alive (see section 3.7). It had not been able to provide updated data on cirrhosis status because this was still being collected by the UKHSA. It carried out a post-hoc analysis of baseline fibrosis distributions from MYR 301 to inform its assumption that 55% of people would have compensated cirrhosis. The EAG preferred to use the estimates from primary data collected in MYR 301, of 47% with compensated cirrhosis. The committee had previously noted that many of the EAG's preferred assumptions around the natural history modelling of chronic hepatitis D may also affect the QALY weighting calculations because they affect QALYs accrued by people having standard care. At the second committee meeting the EAG confirmed that, according to its results for all of its preferred scenarios, the total QALYs for standard care meant that the severity modifier did not apply. The committee had originally requested validation of the model predictions for people on standard care using external literature sources. At consultation, the company also provided sources to validate the outcomes used in its model for compensated cirrhosis, hepatocellular carcinoma and liver‑related mortality. The committee had some concerns about the company's approach. The EAG had not been able to validate this data in the company's model and did not think that the company had used a systematic approach to identify literature to validate the model outcomes. The company had carried out a literature search to identify data on the risk of disease progression in hepatitis D. Because of limitations and heterogeneity in the identified studies, it applied hazard ratios from publications that compared evidence for hepatitis D co-infected with hepatitis B to evidence from people only infected with hepatitis B. The EAG preferred to use alternative sources of data that directly estimated the natural history of disease in hepatitis D. The company noted that hepatitis D is a rare disease and modelling its natural history has not yet been established. The committee preferred the EAG's approach to estimate the natural history of the disease in the population of interest. It recognised the limited evidence for hepatitis D and noted that the NICE health technology evaluations manual states that the committee may be able to make recommendations accepting a higher degree of uncertainty, especially in rare diseases. In the company's sensitivity analyses, the results showed that in all but 1 of the scenarios, the QALY shortfall was over 12 QALYs (see section 3.17). So, the committee agreed the 1.2 severity modifier should be applied. ## Committee's preferred assumptions The committee considered the differences between the company's and the EAG's base-case assumptions. The committee favoured the EAG's assumptions but noted that there were still some concerns around the high level of uncertainty, specifically: response rates beyond 48 weeks in MYR 301 (see section 3.10) treatment duration beyond 48 weeks in MYR 301 (see section 3.11)The committee preferred the EAG's assumptions, which included: using the baseline mean age from the full dataset of people with hepatitis D in the UKHSA study (see section 3.7) % of people with hepatocellular carcinoma will be cured from hepatocellular carcinoma and accrue a utility of 0.81 (see section 3.7) fibrosis regression can only start from 96 weeks (see section 3.7) maximum utility gain for combined responders based on that reported in previous technology appraisals (see section 3.12) natural history modelling of fibrosis progression and hepatocellular carcinoma based on evidence directly in HDV (see section 3.15).In addition, the committee considered that the assumptions should specifically include: combined responders will have a low but not zero probability of hepatocellular carcinoma and probability of fibrosis progression (see section 3.9) baseline cirrhotic distribution based on MYR 301 (see section 3.7). ## Cost-effectiveness estimates The company's deterministic incremental cost-effectiveness ratio (ICER) for bulevirtide compared with standard care was £23,083 per QALY gained, including the commercial discount for bulevirtide and a 1.2 QALY weight (see section 3.15). The EAG presented a range of ICERs using alternative assumptions. The highest ICER presented by the EAG was £33,677. This included the EAG's preferred assumptions, baseline age characteristics for cirrhotic distribution from MYR 301, and the mean age at diagnosis based on the mean from the full UKHSA dataset. The probabilistic ICERs were slightly higher than the deterministic ICERs. NICE's health technology evaluations manual states that above a most plausible ICER of £20,000 per QALY gained, decisions about the acceptability of the technology as an effective use of NHS resources will specifically consider the following factors: the degree of certainty and uncertainty around the ICER aspects that relate to uncaptured benefits and non-health factors.The committee recalled the uncertainty in response rates and response duration beyond 48 weeks. It recognised the small UK population with hepatitis D and noted the benefits of the technology in reducing risks of transmission. It recognised the limited evidence for rare diseases and noted that the NICE health technology evaluations manual states that the committee may be able to make recommendations accepting a higher degree of uncertainty, especially in rare diseases. It considered the results of the company's sensitivity analyses which had explored the impact of the EAG's preferred assumptions on the company's revised cost-effectiveness estimates. It recalled that the results showed that in all but one of the scenarios, the QALY shortfall was over 12 QALYs, so the 1.2 severity modifier should be applied. It further explored the results of each scenario. It accepted most of the EAG's preferred assumptions. These included: response data based on MYR 301 (see section 3.3) the UKHSA data set that reflected all people with hepatitis D (see section 3.7) complete responders having a low probability of fibrosis progression (see section 3.9) the natural history of fibrosis progression and developing hepatocellular carcinoma being based on evidence directly in a hepatitis D population (see section 3.15).The committee considered that the clinical expert opinion that combined responders would have a lower risk of hepatocellular carcinoma was most appropriate. So, it preferred the company's assumption (see section 3.9). It also considered that the baseline fibrosis distribution should be based on that in MYR 301 (see section 3.15). The committee recognised that hepatitis D is a rare disease and that bulevirtide has an orphan designation. But it considered there were still high levels of uncertainty. It noted specifically that the clinical trial had only published data for a period of 48 weeks. It recalled that after the first committee meeting it had asked to see further data on the evolution of response beyond 48 weeks, to help to validate model predictions around ongoing response. The company did not provide an updated analysis from MYR 301. Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be towards the lower end of the £20,000 to £30,000 per QALY gained range normally considered a cost-effective use of NHS resources. Considering the committee's preferred assumptions (see section 3.16), the company's deterministic ICER was £24,853 per QALY gained. So, the committee was satisfied that the most likely cost-effectiveness estimates were within what NICE considers an acceptable use of NHS resources. # Other considerations ## Uncaptured benefits The committee also heard about several benefits of bulevirtide that were not captured by the QALY calculation. It noted the rarity of hepatitis D and that bulevirtide was the first licensed treatment in this area, addressing an unmet need, and was therefore innovative. The clinical experts pointed out that the treatment would reduce the viral load in infected people, prevent the spread of infection and reduce the stigma around this blood-borne virus. The committee noted that these benefits were not captured in the cost-effectiveness analysis. But the committee was satisfied its concerns around the degree of uncertainty around the ICER had been factored into its decision making. ## Equality issues The committee noted that chronic hepatitis D disproportionately affects people from a Black African family background. It heard that migrant HDV infections are increasing and native HDV infections are decreasing because of HBV vaccination programmes. It accepted that bulevirtide would be a welcome option and could address these potential issues. # Conclusion The committee recommended bulevirtide for treating chronic hepatitis D in people with a METAVIR fibrosis stage of F2 or above.	{'Recommendations': "Bulevirtide is recommended as an option for treating chronic hepatitis\xa0D in adults with compensated liver disease only if:\n\nthere is evidence of significant fibrosis (METAVIR stage\xa0F2 or above or Ishak stage\xa03 or above) and\n\ntheir hepatitis has not responded to peginterferon alfa‑2a (PEG‑IFN) or they cannot have interferon-based therapy.Bulevirtide is only recommended if the company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with bulevirtide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with hepatitis\xa0D also have hepatitis\xa0B. There are no other licensed treatments specifically for hepatitis\xa0D. Standard care usually involves treating symptoms and the hepatitis\xa0B. People with significant fibrosis (scarring) in their liver can be offered PEG‑IFN, but it is not licensed for this use.\n\nThe company positioned bulevirtide for people with chronic hepatitis\xa0D who have tried PEG‑IFN and whose condition did not respond to it, or for people who cannot have interferon-based therapy. The company also only positioned it for METAVIR stage\xa0F2 or above (which means they have significant fibrosis). Testing for METAVIR stage usually involves a biopsy, which is invasive and may have side effects, and many people decline it. But NICE's guideline on diagnosing and managing chronic hepatitis\xa0B recommends transient elastography (FibroScan), which is a non-invasive assessment. It also recommends that hepatitis\xa0D with significant fibrosis is defined by a METAVIR stage of\xa0F2 or above, or an Ishak stage of\xa03 or above.\n\nClinical trial evidence shows that bulevirtide is effective compared with standard care despite some uncertainties around how long it works for. Despite the uncertainties in the clinical trial evidence, the cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources. So bulevirtide is recommended.", 'Information about bulevirtide': "# Marketing authorisation indication\n\nBulevirtide (Hepcludex, Gilead) has a conditional marketing authorisation 'for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV RNA positive adult patients with compensated liver disease'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for bulevirtide.\n\n# Price\n\nThe list price of 2\xa0milligram vials of bulevirtide is £6,500 for 30\xa0vials (excluding VAT; BNF online accessed May\xa02023).\n\nThe company has a commercial arrangement. This makes bulevirtide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Gilead, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition, treatment pathway and positioning\n\n## Hepatitis\xa0D disease burden\n\nHepatitis\xa0D is an infectious disease of the liver caused by the hepatitis delta virus (HDV). Around half of all people who acquire HDV will develop chronic hepatitis\xa0D, defined as an infection lasting longer than 6\xa0months. Hepatitis\xa0D only affects people who are already infected with the hepatitis\xa0B virus (HBV) because HDV needs the hepatitis\xa0B surface antigen to complete its replication. The patient expert explained the significant impact co-infection with hepatitis\xa0B and\xa0D has on their physical and mental health. They emphasised that the extreme lethargy associated with the condition affects their day-to-day functioning and ability to walk short distances. They also explained that changes to their lifestyle such as stopping smoking or eating healthily have had limited impact on improving the symptoms of their condition, which have been a constant burden for over 10\xa0years. The committee noted the high disease burden of chronic hepatitis\xa0D.\n\n## Treatment pathway and unmet need\n\nThe treatment options for people with chronic hepatitis\xa0D are limited. Clinical experts explained that people with hepatitis\xa0D would have treatment according to the recommendations in NICE's guideline on diagnosing and managing chronic hepatitis\xa0B. People co-infected with hepatitis\xa0D, with evidence of significant fibrosis, can be offered a 48‑week course of peginterferon alfa‑2a (PEG‑IFN). The clinical experts explained that using PEG‑IFN to treat hepatitis\xa0D is off label, can have serious side effects, and is not effective for most people. They also said that a large proportion of people would also have antivirals (tenofovir and entecavir) for their underlying hepatitis\xa0B infection. If hepatitis\xa0B is cured, the hepatitis\xa0D virus cannot survive. But hepatitis\xa0B has a low chance of being cured with current treatments. The clinical experts explained that bulevirtide is a first-in-class medicine that addresses an unmet need for effective and well-tolerated treatments. They added that there is regional variation in providing tests for HDV, even though NICE's guideline on diagnosing and managing chronic hepatitis\xa0B recommends that everyone with HBV should have one. The clinical experts added that even if bulevirtide was available, there may still be undiagnosed hepatitis\xa0D in people with undiagnosed hepatitis\xa0B. They also noted the limited number of laboratories testing for hepatitis\xa0D. But, if bulevirtide was available, there would be an extra incentive to identify people with HDV, which may arguably make access to diagnosis more equal across the country. The committee concluded that there is a significant unmet need for effective treatments in this population because the current options are limited.\n\n## Positioning of bulevirtide in the treatment pathway\n\nThe clinical evidence presented for bulevirtide came from MYR\xa0301, a phase\xa03, multicentre, open-label, randomised trial evaluating the clinical efficacy and safety of bulevirtide in people with chronic hepatitis\xa0D and compensated liver disease. The marketing authorisation also specifies that bulevirtide should be considered for people with chronic hepatitis\xa0D and compensated liver disease. But the company positioned bulevirtide for a narrower population as a treatment for chronic hepatitis\xa0D with compensated liver disease and evidence of significant fibrosis, which it defined as a METAVIR fibrosis score of\xa0F2 or above. The condition should also have not responded well enough to PEG‑IFN, or the person with hepatitis\xa0D should not be able to tolerate PEG‑IFN or should have a contraindication. The company clarified that most people in MYR\xa0301 had already had interferon treatment, and those who had not were likely to have a contraindication or not be able to tolerate it. The EAG accepted this but was concerned that the company's evidence included people not relevant to the decision problem it had specified. The company presented data from the full analysis set from MYR\xa0301, which included people with all METAVIR fibrosis stages (F0\xa0to\xa0F4). It explained that its positioning addressed the area of highest unmet need. The clinical experts said that everyone with hepatitis\xa0D has an unmet need for treatments that prevent disease progression, and if bulevirtide was recommended, they would prefer to use it as an alternative to PEG‑IFN. At consultation, the company noted that its proposed positioning aligned with the recommendations in NICE's guideline on diagnosing and managing chronic hepatitis\xa0B, which recommends that people with hepatitis\xa0D and significant fibrosis (defined by METAVIR stage\xa0F2 or above or Ishak stage\xa03 or above) should be offered a course of PEG‑IFN. The committee considered that this positioning was appropriate.\n\n## Fibrosis staging\n\nThe clinical experts explained that it would be difficult to identify the company's proposed population in clinical practice. METAVIR staging is done using a liver biopsy, which is invasive and carries a morbidity and mortality risk. So, many people refuse this procedure. The committee agreed that, even if it accepted that it is clinically appropriate to limit bulevirtide to people with significant fibrosis, defined by a liver biopsy, it may not be possible to implement such a rule in practice. NICE's guideline on diagnosing and managing chronic hepatitis\xa0B recommends a non-invasive assessment, transient elastography (FibroScan), for everyone with HBV. Liver biopsy is only offered to confirm the level of fibrosis in adults with a transient elastography score of between 6\xa0kPa and 10\xa0kPa. The clinical experts explained that, in practice, clinicians would likely use transient elastography to determine eligibility for bulevirtide, along with serological tests and imaging. The committee heard that the company had collected transient elastography data in MYR\xa0301. It considered that, if it was not possible to position bulevirtide as a first-line treatment, it would be useful for the company to present data using transient elastography rather than liver biopsy (METAVIR staging) to assess fibrosis. This is because this approach more closely reflects current clinical practice for determining fibrosis stage to identify eligible people. At consultation, the company reiterated the positioning in its base-case model of bulevirtide as a treatment for people with chronic hepatitis\xa0D, compensated liver disease and evidence of significant fibrosis (defined as a METAVIR score of\xa0F2 or above, based on liver biopsy). It identified 3\xa0subgroups in MYR\xa0301 that it considered aligned with a METAVIR fibrosis stage of\xa0F2 or above, and 2\xa0transient elastography cut‑off scores that could rule out significant fibrosis. It considered these in a scenario analysis. The company noted that there is no agreement in clinical practice on cut-offs that can rule out significant or advanced fibrosis. So, it used external literature to inform these values. The company used a meta-analysis by Qi et al. (2018) and data from the European Association for the Study of the Liver (EASL; 2021 Clinical Practice Guidelines) to identify 2\xa0transient elastography (FibroScan) thresholds of 7.25\xa0kPa and 8.00\xa0kPa that aligned with a METAVIR fibrosis stage of\xa0F2 or above. It applied these thresholds to the transient elastography scores collected in MYR\xa0301. Based on its analyses, the company considered that most people in MYR\xa0301 were in line with its proposed positioning of bulevirtide for a METAVIR fibrosis score of\xa0F2 or above. It carried out 3\xa0scenario analyses covering each of the fibrosis stages it had identified. The company considered that these analyses showed that the transient elastography scores in MYR301 aligned with a METAVIR fibrosis staging of\xa0F2 or above. The EAG was unable to validate the threshold for the significant fibrosis source used in the EASL guideline. But it did consider that a value of at least 8.0\xa0kPa is the most validated threshold to rule out advanced fibrosis (F3\xa0or above). It was unclear about whether the company had used a systematic approach to identify the thresholds. The company clarified that it had not used a formal consensus approach to gather its clinical feedback on appropriate thresholds. The committee recognised there was still a high level of uncertainty about the most appropriate threshold for transient elastography fibrosis staging. It recalled at the first committee meeting that its preference had been for an elastography-based model (see section\xa03.8). The committee considered that it had not seen this detail, so this could not inform its decision making. It considered that using a non-invasive assessment through transient elastography (FibroScan) would be better than using an invasive liver biopsy assessment. The EAG noted that transient elastography is not very accurate at diagnosing significant fibrosis, but is likely to be used in clinical practice to identify people that will be eligible for bulevirtide. Because the response data from MYR\xa0301 showed similar results for both subgroups and the full trial population, the EAG considered that this suggested including people with less severe liver disease had limited effects on the response rates. It preferred to use the full trial population. The company later updated its base case to reflect response rates from the full trial population. The committee accepted this. It concluded that response rates should reflect the full trial population, and accepted that in clinical practice, fibrosis could be assessed by either transient elastography or a clinical biopsy.\n\n# Clinical effectiveness\n\n## Virological and biochemical response\n\nThe MYR\xa0301 trial investigated 2\xa0different doses of bulevirtide (2\xa0mg and 10\xa0mg) over 144\xa0weeks and also bulevirtide 10\xa0mg started at 48\xa0weeks (that is, people had standard care until 48\xa0weeks, at which point they started on bulevirtide). The company used 48‑week data from the bulevirtide 2\xa0mg arm and delayed treatment arm to reflect the intervention and comparator. The primary outcome of MYR\xa0301 was combined virological and biochemical response at week\xa048. Virological response was defined as undetectable HDV RNA or a decrease in HDV RNA levels by 2log10\xa0IU/ml or more from baseline. Biochemical response was defined as alanine aminotransferase (ALT) normalisation, that is, ALT levels in the normal range. In the MYR\xa0301 trial, many more people on bulevirtide had a combined response than people who had standard care at 24\xa0weeks and 48\xa0weeks of treatment. This difference was statistically significant. The committee noted that people in the delayed treatment arm of the trial were allowed to continue with any treatment prescribed for their underlying hepatitis\xa0B. It agreed that this arm represented standard care in the UK. The committee acknowledged the large benefit for people who had treatment with bulevirtide at week\xa048 but noted that the 48‑week treatment period in MYR\xa0301 was quite short. At the second committee meeting, the company reiterated that longer-term data from MYR\xa0301 is due to be published shortly. The committee considered that longer-term data would be useful to determine if response with bulevirtide is sustained beyond the 48‑week treatment period. No additional data was provided by the company at the third committee meeting. The committee concluded that uncertainty still remained in identifying if response to treatment with bulevirtide would continue.\n\n## Surrogate outcomes\n\nIt is not feasible to assess the long-term complications of hepatitis\xa0D, such as decompensated cirrhosis, hepatocellular carcinoma and death directly in clinical trials, because these may take years to develop. Because of this, surrogate outcomes are used. The clinical experts said the surrogate outcomes of virological and biochemical response used in MYR\xa0301 were reasonable markers of disease progression in hepatitis\xa0D. But they explained that some people's ALT levels may not normalise with treatment because of other reasons, such as fatty liver disease or alcohol use, and using the combined end point may disadvantage those with raised ALT if treatment was stopped in these people because of it. They added that undetectable HDV was also a good indication of treatment efficacy. The committee concluded that virological and biochemical response can be considered suitable surrogate outcomes for preventing the complications of liver disease.\n\n## Generalisability\n\nBecause MYR\xa0301 did not include people in the UK, the company assumed that the baseline characteristics of people taking bulevirtide in the NHS would reflect the cohort reported by Spaan et al. (2020), a retrospective analysis of 107\xa0people with hepatitis\xa0D in the UK. People in Spaan et al. had a baseline age of 35\xa0years and 60% had cirrhosis. In MYR\xa0301 the baseline age was 42\xa0years and 47% had cirrhosis. The EAG said the baseline characteristics in Spaan et al. and MYR\xa0301 were both clinically plausible, but the model was sensitive to these inputs in terms of the cost‑effectiveness results and the severity modifier applied (see section\xa03.15). The company also presented data published by Public Health England (now the UK Health Security Agency [UKHSA]) on routine blood-borne virus testing. The median age between 2011 and 2020 was around 37\xa0years. The committee noted that this data was provided after the technical engagement stage, so could not be fully reviewed by the EAG. Further to this, one of the clinical experts explained that they are the lead investigator of a study being done by the UKHSA on the epidemiology of HDV infection in the UK. The study is collecting data from the 10\xa0laboratories doing HDV testing in the UK and data should be available on mean age at baseline. The committee agreed with using UKHSA data but considered that data on mean (rather than median) age and the proportion with cirrhosis on diagnosis would be helpful. At consultation, the company updated its base case to reflect the average age of people diagnosed with hepatitis\xa0D in the UK based on the median age (35\xa0years) from the UKHSA study. It considered that this data suggested that most people with chronic hepatitis\xa0D in the UK are young at diagnosis, so preferred to use the median age estimate. The EAG preferred the mean age. The committee agreed that the mean was the most appropriate measure of central tendency. The clinical expert noted that people with chronic hepatitis\xa0D would also be diagnosed with hepatitis\xa0B. The committee considered that relevant data on the age at diagnosis of hepatitis\xa0B would therefore help validate its concerns around the mean baseline age of people diagnosed with chronic hepatitis\xa0D (see section\xa03.16). It considered that, until more data becomes available, it was difficult to define the proportion with cirrhosis at baseline. It considered that the UKHSA data based on mean age at diagnosis was the most appropriate source to inform the baseline age. After the second committee meeting, the company updated its base case to reflect the cohort of people with hepatitis\xa0D in the UK that are currently alive (n=570). It considered that this reflected the age of people with hepatitis\xa0D who would use bulevirtide. The EAG explained that in the UKHSA study, mean age was captured in 2\xa0different ways. It preferred to use the mean age from the full UKHSA dataset of people in the UK that had been diagnosed with hepatitis\xa0D, considering that this better reflected the age at diagnosis. The committee concluded that the baseline age that reflected the full UKHSA dataset of people diagnosed with hepatitis D was the most appropriate as it was also a bigger dataset (n=602).\n\n# Economic model\n\n## Company's modelling approach\n\nThe company presented a Markov model to estimate the cost effectiveness of bulevirtide compared with standard care. The model had 10\xa0health states, representing METAVIR fibrosis stages\xa0F0 to\xa0F4, and more severe disease complications, including decompensated cirrhosis, hepatocellular carcinoma, liver transplant, post-liver transplant and death. The model had a 24‑week cycle length and used a lifetime time horizon. Because the company positioned bulevirtide for people with METAVIR stage\xa0F2 and above, the F0\xa0to\xa0F1 states in the model were never occupied. The committee noted that using model health states based on METAVIR fibrosis staging may not be appropriate (see sections\xa03.3\xa0and\xa03.4). The committee considered that, if the company amended its population and comparators to cover the entire marketing authorisation, then a model structure using METAVIR stages may be acceptable because data from the full trial population could be used. The committee concluded that, if the company is planning to position bulevirtide in a narrower population than the marketing authorisation, an elastography-based model (with effectiveness data from the relevant population alone) was preferred. At the second committee meeting the company maintained its base-case position using METAVIR staging (see section\xa03.4) and did not change its model to an elastography-based model. The committee concluded that it had not seen the evidence to change its original viewpoint and maintained its preference for an elastography-based model.\n\n## Transition probabilities\n\nInitial transition probabilities in the model were determined by response status in MYR\xa0301. Although the company positioned bulevirtide for people with METAVIR stage\xa0F2 and above, it used data from the full trial population to estimate probabilities of response, which included people with METAVIR stage F0\xa0to\xa0F1. The EAG noted that people with less severe fibrosis may be more likely to have a better response, which may overestimate response rates in a population with METAVIR stage\xa0F2 and above. In the longer term, the company assumed that people with a combined response (from now referred to as combined responders) did not progress through fibrosis states or to more severe disease states, such as hepatocellular carcinoma, and could have fibrosis regression from 24\xa0weeks onwards. The company assumed an 8.8% annual probability of regression from F4\xa0to\xa0F3, and a 13.3% annual probability of regression from F3\xa0to\xa0F2. The company assumed that people with a virological response only (from now referred to as virological responders) could progress, although at a slower rate than people whose condition did not respond to treatment at all (from now referred to as non-responders). The clinical experts agreed with the company that combined responders would have a low risk of progression through fibrosis stages. But they argued that this would not be zero because this group could still have detectable levels of virus. They added that even combined responders may still be at risk of hepatocellular carcinoma. The clinical experts further explained that it is plausible that fibrosis regression could occur in combined responders but added that the company's assumed transition probabilities for fibrosis regression seemed high. The committee agreed with the clinical experts that combined responders would still be at risk of hepatocellular carcinoma and noted that in people with hepatitis\xa0B and hepatitis\xa0C, viral response reduces, but does not eradicate hepatocellular carcinoma risk. The committee noted that the EAG assumed a residual risk of hepatocellular carcinoma in its base case. It had noted a data analysis directly in people with HDV (Alfaiate et al. 2020) had found that all responders are likely to have hepatocellular carcinoma. This meant that combined and partial responders may have a chance of developing hepatocellular carcinoma. Because the risk for people whose condition responds to treatment is lower than those whose condition does not, the EAG preferred to assume that combined responders and partial responders would have the same probability of developing hepatocellular carcinoma. The committee felt that additional scenario analyses would be helpful to address the remaining uncertainties around transition probabilities. At consultation, the company did 3\xa0exploratory analyses. In these analyses it assumed that progression through fibrosis states and to hepatocellular carcinoma in combined responders was 20% of that for partial responders. This had a small impact on the cost-effectiveness results and the company later included these assumptions in its revised base case. The committee was satisfied that this addressed the uncertainties it originally had around transition probabilities in the model.\n\n## Duration of response\n\nThe company's assessment of response was based on 48‑week data from MYR\xa0301, extrapolated for 1\xa0additional model cycle to 72\xa0weeks. The EAG preferred to limit the timeframe for assessing response to 48\xa0weeks, without extrapolating data from MYR\xa0301. It argued that the company's extrapolations were uncertain because they assumed that response is maintained for all people who do not stop treatment from 48\xa0weeks onwards. The committee considered the data on response at week\xa024 and week\xa048 and noted that some people lost response, while others gained response. But the trend is likely to be for people to lose response over time. The committee heard from the company that additional data from MYR\xa0301, beyond 48\xa0weeks, would soon be available. The committee considered that additional trial data would be helpful in resolving the uncertainty around ongoing response and gave the committee confidence in the response rates seen at 48\xa0weeks. But, until this data is available, the committee agreed with the EAG that response should be limited to 48\xa0weeks because this is aligned with the data currently available. At consultation, the company clarified that its revised base case now included the data from MYR\xa0301 which was not extrapolated beyond 48\xa0weeks. The trial results showed a trend for response rates to increase during the first 48\xa0weeks of treatment, so it had chosen not to extrapolate data beyond 48\xa0weeks. The clinical expert highlighted that it was very difficult to define how long people should be treated for because there was not enough data from the 48‑week treatment period. People with hepatitis might initially see sustained response, but many may later relapse. The committee was still unclear about how long response would be sustained beyond the 48‑week data. It considered that longer-term data would have been helpful to committee decision making and resolving the uncertainty over how long people would maintain a response beyond 48\xa0weeks.\n\n## Treatment duration and stopping rules\n\nThe summary of product characteristics for bulevirtide says that treatment should be continued for as long as it is associated with a clinical benefit. The company assumed that treatment duration in the model depends on response status. Combined responders were assumed to remain on treatment indefinitely, whereas virological responders and non-responders stopped at 72\xa0weeks and 48\xa0weeks respectively. The EAG highlighted the mismatch between treatment duration in the model and in the trial; everyone in the trial could continue treatment, irrespective of response status. The clinical experts broadly agreed with the company's model assumptions for combined responders and non-responders but were less sure of what would happen for virological responders. One clinical expert explained that if a person had a virological response but high ALT for reasons other than hepatitis, for example fatty liver disease or alcohol use, clinicians would be wary about stopping treatment. The clinical experts added that treatment would also likely continue for combined or virological responders who develop hepatocellular carcinoma, and that for people with convincing evidence of virus eradication, treatment would likely be stopped. The committee agreed with the clinical experts' assumptions. At consultation, the company confirmed its base-case analyses now included the assumption that combined responders with undetectable RNA at 48\xa0weeks would stop treatment 52\xa0weeks later. The committee considered that there was some uncertainty around the company's assumptions. In MYR\xa0301, people could be treated with bulevirtide up to 144\xa0weeks. But the company assumed that partial responders would have treatment for up to 72\xa0weeks, then stop treatment if they had not had a complete response. If the condition had not responded at all to treatment at week\xa048, treatment was stopped. The committee noted that the study protocol for MYR\xa0301 suggested that partial responders could continue treatment for longer than the 72\xa0weeks assumed by the company. It also noted that there was no clear justification for why, if there was no response, treatment stopped at 48\xa0weeks. The company did 3\xa0exploratory analyses to test the effect of varying stopping rules, all of which increased the company's cost-effectiveness estimates, assuming:\n\npartial and non-responders stopped treatment at week\xa048\n\npartial and non-responders stopped treatment at week\xa072\n\nnon-responders at week\xa048 would continue to be treated for a further 52\xa0weeks.The committee recognised that there was still ambiguity around how long treatment should be continued and when bulevirtide should stop because of lack of response. The company confirmed that this data had not been collected in MYR\xa0301, so further data analyses would be needed. It later updated its base case so partial and non-responders stopped treatment at week\xa072. The committee accepted this but concluded that only further data collection would help resolve the uncertainty around treatment duration and stopping rules.\n\n## Utility gain for combined responders\n\nThe company applied a utility gain for combined responders to capture the benefit of having the combined outcome of virological and biochemical response. The committee noted that the utility gain for combined responders was a key driver of cost effectiveness. The company fitted a Tobit regression model to 48‑week pooled data from MYR\xa0301. Variables included in the model, informed by clinical experts, were cirrhosis status at baseline and response at week\xa048. The utility gain was applied in addition to utility for the F2\xa0to\xa0F4 health states for people with a combined response. The committee heard from the clinical experts that it was plausible for people's symptoms and quality of life to improve with the reduction in viral load. It concluded that it was reasonable to assume a utility gain for combined responders. The committee was less certain about the size of the utility gain that should be applied. It noted the lack of justification for the Tobit approach and highlighted that the resulting utility gain from the regression model was not statistically significant. At consultation, the company explained its decision to use a Tobit regression analysis. It said that a large number of people in MYR\xa0301 had the highest utility index score and this suggested that there was a ceiling effect, so other regression analyses would not be appropriate. The committee accepted this explanation. It recalled that, in previous appraisals of hepatitis\xa0C, combined response was associated with a smaller utility gain than assumed by the company. It considered that the size of the utility benefit for combined responders was uncertain and asked the company to explore this uncertainty by testing alternative estimates of utility gain. The company had searched existing NICE technology appraisal guidance on hepatitis\xa0B and\xa0C and found utility gains for people with a sustained virologic response ranging from\xa00.03 to\xa00.05. It did 2\xa0scenario analyses, reducing the utility gain in its base case by 50% and 75%. These had a moderate impact on increasing the cost‑effectiveness estimates. The EAG considered that these were arbitrary values. It preferred to test the impact of using the lowest and highest utility gains identified in previous NICE technology appraisal guidance on hepatitis. The clinical expert noted that hepatitis\xa0C and\xa0D are very different populations, with different risk factors and manifestations of disease. The committee also noted that there were some differences in the way utility gains had been assessed. In the company's analysis, MYR\xa0301 utility gains were assessed while people were still having treatment, whereas in previous technology appraisals these had been defined after treatment had stopped. The committee concluded that the utility gain for combined responders was still uncertain. It recalled that people's symptoms and quality of life improved as viral load reduced, so it preferred the EAG's scenarios incorporating the maximum utility gain for combined responders from previous technology appraisals. The company later included this in its base-case analyses.\n\n## Health-state utility values\n\nThe MYR\xa0301 trial collected EQ‑5D‑3L data at baseline, week\xa024 and week\xa048. The company argued that the EQ‑5D data did not demonstrate face validity because it did not reflect differences between people with and without compensated cirrhosis. It added that key symptoms of hepatitis such as fatigue, nausea and vomiting are not well reflected by EQ‑5D‑3L. The company could not identify appropriate utility values for people with chronic hepatitis\xa0D in the literature, so preferred to use utility values from a meta-analysis of people with chronic hepatitis\xa0B. The EAG did not agree with the company's view because the EAG's experts highlighted that the impact of different levels of fibrosis on quality of life is likely to be very small. The committee agreed with the EAG and noted that even histologically advanced liver disease is silent in many people and decompensation is often the presenting event. The committee concluded that utilities based on MYR\xa0301 were appropriate.\n\n## Costs\n\nBulevirtide is available as a 2\xa0mg powder for injection vial, reconstituted and self-administered daily. According to the summary of product characteristics, people self-administering should get training to minimise the risk of injection site reactions. The company explained that it would fund all homecare services, including training to self-administer, so these costs are not included in the model. The committee concluded that the model includes all relevant costs associated with bulevirtide treatment.\n\n## Severity modifier\n\nThe severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company calculated absolute and proportional quality-adjusted life year (QALY) shortfall weights in line with NICE's health technology evaluations manual. Absolute QALY shortfall is the future health, including quality and length of life, that is lost by people living with a condition, compared with the expected future health without the condition over people's remaining lifetime. Proportional QALY shortfall represents the proportion of future health, including quality and length of life, that is lost by people living with the condition. The company estimated that a weight of\xa01.2 should apply to the QALY. In its calculation of QALYs accrued by a healthy individual in the general population, baseline age was 37\xa0years (based on UKHSA data) and 59% were men (based on baseline characteristics from the MYR\xa0301 study). QALYs for people on standard care were taken from the comparator arm of the model. The EAG considered that the company had calculated the QALY weighting appropriately but noted that the weighting was sensitive to the assumed age at baseline as well as the proportion with cirrhosis. At consultation, the company provided data from the UKHSA study to validate assumptions around age at diagnosis. It considered that applying the UKHSA data did not alter the eligibility for a severity modifier. It preferred to use the mean age from the UKHSA cohort of people in the UK with hepatitis\xa0D who are currently alive (see section\xa03.7). It had not been able to provide updated data on cirrhosis status because this was still being collected by the UKHSA. It carried out a post-hoc analysis of baseline fibrosis distributions from MYR\xa0301 to inform its assumption that 55% of people would have compensated cirrhosis. The EAG preferred to use the estimates from primary data collected in MYR\xa0301, of 47% with compensated cirrhosis. The committee had previously noted that many of the EAG's preferred assumptions around the natural history modelling of chronic hepatitis\xa0D may also affect the QALY weighting calculations because they affect QALYs accrued by people having standard care. At the second committee meeting the EAG confirmed that, according to its results for all of its preferred scenarios, the total QALYs for standard care meant that the severity modifier did not apply. The committee had originally requested validation of the model predictions for people on standard care using external literature sources. At consultation, the company also provided sources to validate the outcomes used in its model for compensated cirrhosis, hepatocellular carcinoma and liver‑related mortality. The committee had some concerns about the company's approach. The EAG had not been able to validate this data in the company's model and did not think that the company had used a systematic approach to identify literature to validate the model outcomes. The company had carried out a literature search to identify data on the risk of disease progression in hepatitis\xa0D. Because of limitations and heterogeneity in the identified studies, it applied hazard ratios from publications that compared evidence for hepatitis\xa0D co-infected with hepatitis\xa0B to evidence from people only infected with hepatitis\xa0B. The EAG preferred to use alternative sources of data that directly estimated the natural history of disease in hepatitis\xa0D. The company noted that hepatitis\xa0D is a rare disease and modelling its natural history has not yet been established. The committee preferred the EAG's approach to estimate the natural history of the disease in the population of interest. It recognised the limited evidence for hepatitis\xa0D and noted that the NICE health technology evaluations manual states that the committee may be able to make recommendations accepting a higher degree of uncertainty, especially in rare diseases. In the company's sensitivity analyses, the results showed that in all but 1 of the scenarios, the QALY shortfall was over 12\xa0QALYs (see section\xa03.17). So, the committee agreed the 1.2\xa0severity modifier should be applied.\n\n## Committee's preferred assumptions\n\nThe committee considered the differences between the company's and the EAG's base-case assumptions. The committee favoured the EAG's assumptions but noted that there were still some concerns around the high level of uncertainty, specifically:\n\nresponse rates beyond 48\xa0weeks in MYR\xa0301 (see section\xa03.10)\n\ntreatment duration beyond 48\xa0weeks in MYR\xa0301 (see section\xa03.11)The committee preferred the EAG's assumptions, which included:\n\nusing the baseline mean age from the full dataset of people with hepatitis\xa0D in the UKHSA study (see section\xa03.7)\n\n% of people with hepatocellular carcinoma will be cured from hepatocellular carcinoma and accrue a utility of\xa00.81 (see section\xa03.7)\n\nfibrosis regression can only start from 96\xa0weeks (see section\xa03.7)\n\nmaximum utility gain for combined responders based on that reported in previous technology appraisals (see section\xa03.12)\n\nnatural history modelling of fibrosis progression and hepatocellular carcinoma based on evidence directly in HDV (see section\xa03.15).In addition, the committee considered that the assumptions should specifically include:\n\ncombined responders will have a low but not zero probability of hepatocellular carcinoma and probability of fibrosis progression (see section\xa03.9)\n\nbaseline cirrhotic distribution based on MYR\xa0301 (see section\xa03.7).\n\n## Cost-effectiveness estimates\n\nThe company's deterministic incremental cost-effectiveness ratio (ICER) for bulevirtide compared with standard care was £23,083 per QALY gained, including the commercial discount for bulevirtide and a 1.2\xa0QALY weight (see section\xa03.15). The EAG presented a range of ICERs using alternative assumptions. The highest ICER presented by the EAG was £33,677. This included the EAG's preferred assumptions, baseline age characteristics for cirrhotic distribution from MYR\xa0301, and the mean age at diagnosis based on the mean from the full UKHSA dataset. The probabilistic ICERs were slightly higher than the deterministic ICERs. NICE's health technology evaluations manual states that above a most plausible ICER of £20,000 per QALY gained, decisions about the acceptability of the technology as an effective use of NHS resources will specifically consider the following factors:\n\nthe degree of certainty and uncertainty around the ICER\n\naspects that relate to uncaptured benefits and non-health factors.The committee recalled the uncertainty in response rates and response duration beyond 48\xa0weeks. It recognised the small UK population with hepatitis\xa0D and noted the benefits of the technology in reducing risks of transmission. It recognised the limited evidence for rare diseases and noted that the NICE health technology evaluations manual states that the committee may be able to make recommendations accepting a higher degree of uncertainty, especially in rare diseases. It considered the results of the company's sensitivity analyses which had explored the impact of the EAG's preferred assumptions on the company's revised cost-effectiveness estimates. It recalled that the results showed that in all but one of the scenarios, the QALY shortfall was over 12\xa0QALYs, so the 1.2\xa0severity modifier should be applied. It further explored the results of each scenario. It accepted most of the EAG's preferred assumptions. These included:\n\nresponse data based on MYR\xa0301 (see section\xa03.3)\n\nthe UKHSA data set that reflected all people with hepatitis\xa0D (see section\xa03.7)\n\ncomplete responders having a low probability of fibrosis progression (see section\xa03.9)\n\nthe natural history of fibrosis progression and developing hepatocellular carcinoma being based on evidence directly in a hepatitis\xa0D population (see section\xa03.15).The committee considered that the clinical expert opinion that combined responders would have a lower risk of hepatocellular carcinoma was most appropriate. So, it preferred the company's assumption (see section\xa03.9). It also considered that the baseline fibrosis distribution should be based on that in MYR\xa0301 (see section\xa03.15). The committee recognised that hepatitis D is a rare disease and that bulevirtide has an orphan designation. But it considered there were still high levels of uncertainty. It noted specifically that the clinical trial had only published data for a period of 48\xa0weeks. It recalled that after the first committee meeting it had asked to see further data on the evolution of response beyond 48\xa0weeks, to help to validate model predictions around ongoing response. The company did not provide an updated analysis from MYR\xa0301. Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be towards the lower end of the £20,000 to £30,000 per QALY gained range normally considered a cost-effective use of NHS resources. Considering the committee's preferred assumptions (see section\xa03.16), the company's deterministic ICER was £24,853 per QALY gained. So, the committee was satisfied that the most likely cost-effectiveness estimates were within what NICE considers an acceptable use of NHS resources.\n\n# Other considerations\n\n## Uncaptured benefits\n\nThe committee also heard about several benefits of bulevirtide that were not captured by the QALY calculation. It noted the rarity of hepatitis\xa0D and that bulevirtide was the first licensed treatment in this area, addressing an unmet need, and was therefore innovative. The clinical experts pointed out that the treatment would reduce the viral load in infected people, prevent the spread of infection and reduce the stigma around this blood-borne virus. The committee noted that these benefits were not captured in the cost-effectiveness analysis. But the committee was satisfied its concerns around the degree of uncertainty around the ICER had been factored into its decision making.\n\n## Equality issues\n\nThe committee noted that chronic hepatitis\xa0D disproportionately affects people from a Black African family background. It heard that migrant HDV infections are increasing and native HDV infections are decreasing because of HBV vaccination programmes. It accepted that bulevirtide would be a welcome option and could address these potential issues.\n\n# Conclusion\n\nThe committee recommended bulevirtide for treating chronic hepatitis\xa0D in people with a METAVIR fibrosis stage of\xa0F2 or above."}	https://www.nice.org.uk/guidance/ta896	Evidence-based recommendations on bulevirtide (Hepcludex) for chronic hepatitis D in adults.
4027bce41f1a4b5b737a38fcb83a0564ed004f85	nice	Atopic eczema in under 12s: diagnosis and management	Atopic eczema in under 12s: diagnosis and management This guideline covers diagnosing and managing atopic eczema in children under 12. It aims to improve care for children with atopic eczema by making detailed recommendations on treatment and specialist referral. The guideline also explains how healthcare professionals should assess the effect eczema has on quality of life, in addition to its physical severity. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Diagnosis Take clinical and drug histories of children with atopic eczema, including questions about: time of onset, pattern and severity of the atopic eczema response to previous and current treatments possible trigger factors (irritant and allergic) the impact of the atopic eczema on the child and their parents or carers dietary history, including any dietary manipulation growth and development personal and family history of atopic conditions. Diagnose atopic eczema when a child has an itchy skin condition plus 3 or more of the following: visible flexural dermatitis involving the skin creases, such as the bends of the elbows or behind the knees (or visible dermatitis on the cheeks and/or extensor areas in children aged 18 months or under) previous flexural dermatitis (or dermatitis on the cheeks and/or extensor areas in children aged 18 months or under) dry skin in the last 12 months asthma or allergic rhinitis (or history of atopic disease in a first-degree relative of children aged under 4 years) -nset of signs and symptoms under the age of 2 years (do not use this criterion in children aged under 4 years).Healthcare professionals should be aware that in Asian, Black Caribbean and Black African children, atopic eczema can affect the extensor surfaces rather than the flexures, and discoid (circular) or follicular (around hair follicles) patterns may be more common. # Assessing severity, psychological and psychosocial wellbeing and quality of life Use a holistic approach when assessing a child's atopic eczema at each consultation, taking into account: the severity of the atopic eczema the child's quality of life, including everyday activities, sleep, and psychosocial wellbeing (see table 1) that there is not necessarily a direct relationship between the severity of the atopic eczema and the impact it has on quality of life. Skin and physical severity Impact on quality of life and psychosocial wellbeing Clear: normal skin, no evidence of active atopic eczema None: no impact on quality of life Mild: areas of dry skin, infrequent itching (with or without small areas of redness) Mild: little impact on everyday activities, sleep and psychosocial wellbeing Moderate: areas of dry skin, frequent itching, redness (with or without excoriation and localised skin thickening) Moderate: moderate impact on everyday activities and psychosocial wellbeing, frequently disturbed sleep Severe: widespread areas of dry skin, incessant itching, redness (with or without excoriation, extensive skin thickening, bleeding, oozing, cracking and alteration of pigmentation) Severe: severe limitation of everyday activities and psychosocial functioning, nightly loss of sleep Explain the physical severity category (see table 1) of the atopic eczema to the child and their parents or carers. Assess whether the child's atopic eczema is consistent in severity, or whether there are areas of differing severity. If there are areas of differing severity, treat each area independently. During an assessment of psychological and psychosocial wellbeing and quality of life, take into account the impact of atopic eczema on parents or carers as well as the child, and provide them with advice and support. When deciding treatment strategies, take into account that all categories of severity of atopic eczema can have a negative impact on psychological and psychosocial wellbeing and quality of life. Consider using the following additional tools to provide objective measures of the severity of atopic eczema, quality of life and response to treatment: visual analogue scales (0 to 10) capturing the child's and/or parents' or carers' assessment of severity, itch and sleep loss over the previous 3 days and nights validated tools: Patient-Oriented Eczema Measure (POEM) for severity Children's Dermatology Life Quality Index (CDLQI), Infants' Dermatitis Quality of Life Index (IDQoL) or Dermatitis Family Impact (DFI) questionnaire for quality of life. # Discussing related conditions and how atopic eczema may change over time Explain to children with atopic eczema and their parents or carers that: the condition often improves with time, but not all children will grow out of atopic eczema and it may get worse in teenage or adult life children with atopic eczema often develop asthma and/or allergic rhinitis sometimes food allergy is associated with atopic eczema, particularly in very young children. # Identifying and managing trigger factors When assessing children with atopic eczema, identify potential trigger factors, including: irritants, for example soaps and detergents (including shampoos, bubble baths, shower gels and washing-up liquids) skin infections contact allergens food allergens inhalant allergens. Consider a diagnosis of food allergy in: children with atopic eczema who have had immediate symptoms from eating a particular food babies and young children with moderate or severe atopic eczema that has not been controlled by optimum management, particularly if associated with gut dysmotility (colic, vomiting, altered bowel habit) or failure to thrive. Consider a diagnosis of inhalant allergy in: children with seasonal flares of atopic eczema children with atopic eczema associated with asthma or allergic rhinitis children aged 3 years or over with atopic eczema on the face, particularly around the eyes. Consider a diagnosis of allergic contact dermatitis in children with: an exacerbation of previously controlled atopic eczema, or reactions to topical treatments. Reassure children with mild atopic eczema and their parents or carers that most children with mild atopic eczema do not need to have tests for allergies. Advise children with atopic eczema and their parents or carers not to use high street or internet allergy tests, because there is no evidence of their value in managing atopic eczema. For bottle-fed babies aged under 6 months with moderate or severe atopic eczema that has not been controlled by optimal treatment with emollients and mild topical corticosteroids, offer a 6‑ to 8‑week trial of an extensively hydrolysed protein formula or amino acid formula in place of cow's milk formula. Refer children with atopic eczema for specialist dietary advice if they have followed a cow's milk-free diet for longer than 8 weeks. Do not use diets based on unmodified proteins of other species' milk (for example, goat's milk or sheep's milk) or partially hydrolysed formulas to manage suspected cow's milk allergy in children with atopic eczema. Offer diets that include soya protein along with specialist dietary advice for children aged 6 months or over. For children who are being breast fed, explain that it is not known whether changing the mother's diet will reduce the severity of the atopic eczema. If food allergy is strongly suspected, consider a trial of an allergen-specific exclusion diet. Explain to children with atopic eczema and their parents or carers that: it is unclear what role factors such as stress, humidity or extremes of temperature have in causing flares of atopic eczema, and they should avoid these factors when possible. # Treatment ## Stepped approach to management Use the stepped approach in table 2 for managing atopic eczema in children. Emollients are the basis of management and should always be used, even when atopic eczema is clear. Management can then be stepped up or down, according to the severity of symptoms, with the addition of the other treatments listed in table 2. Mild atopic eczema emollients mild-potency topical corticosteroids. Moderate atopic eczema emollients moderate-potency topical corticosteroids topical calcineurin inhibitors bandages. Severe atopic eczema emollients potent topical corticosteroids topical calcineurin inhibitors bandages phototherapy systemic therapy. Offer children with atopic eczema and their parents or carers information on how to recognise flares of atopic eczema (increased dryness, itching, redness, swelling and general irritability). Give clear instructions on how to manage flares according to the stepped-care plan, and prescribe treatments that allow children and their parents or carers to follow this plan. Start treatment for flares of atopic eczema as soon as signs and symptoms appear, and continue treatment for approximately 48 hours after symptoms subside. ## Emollients Emollient creams are vital in helping to manage dry skin conditions, but there are Medicines and Healthcare products Regulatory Agency (MHRA) warnings about fire hazards associated with build-up of emollient residue on clothing and bedding. Offer children with atopic eczema a choice of unperfumed emollients to use every day for moisturising. This may be a combination of products or one product for all purposes. Prescribe large quantities of leave-on emollients (250 g to 500 g weekly) that are easily available to use at nursery, pre-school or school. Explain to children with atopic eczema and their parents or carers that they should use emollients: in larger amounts and more often than other treatments -n their whole body, both when the atopic eczema is clear and while using all other treatments. Show children with atopic eczema and their parents or carers how to apply emollients, including how to smooth emollients onto the skin rather than rubbing them in. If their current emollient causes irritation or is not acceptable, offer a different way to apply it or offer an alternative emollient. Review repeat prescriptions of individual products and combinations of products with children with atopic eczema and their parents or carers at least once a year. When children with atopic eczema are using emollients and other topical products at the same time of day, explain that: they should apply one product at a time, and wait several minutes before applying the next product they can choose which product to apply first. Offer personalised advice on washing with emollients or emollient soap substitutes, and explain to children with atopic eczema and their parents or carers that: they should use leave-on emollients or emollient soap substitutes instead of soaps and detergent-based wash products leave-on emollients can be added to bath water children aged under 12 months should use leave-on emollients or emollient soap substitutes instead of shampoos -lder children using shampoo should use a brand that is unperfumed and ideally labelled as suitable for eczema, and they should avoid washing their hair in bath water. Do not offer emollient bath additives to children with atopic eczema. For a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on emollient bath additives . Full details of the evidence and the committee's discussion are in evidence review A: adding bath emollients to the management of atopic eczema in children under 12 years. Loading. Please wait. ## Topical corticosteroids Recommendations 1.5.1.14 and 1.5.1.15 are from NICE's technology appraisal guidance on frequency of application of topical corticosteroids for atopic eczema. Discuss the benefits and harms of treatment with topical corticosteroids with children with atopic eczema and their parents or carers, emphasising that the benefits outweigh possible harms when they are applied correctly. Tailor the potency of topical corticosteroids to the severity of the child's atopic eczema (which may vary according to body site): use mild potency for mild atopic eczema use moderate potency for moderate atopic eczema use potent for severe atopic eczema use mild potency for the face and neck, except for short-term (3 to 5 days) use of moderate potency for severe flares use moderate or potent preparations for short periods only (7 to 14 days) for flares in vulnerable sites such as axillae and groin do not use very potent preparations in children without specialist dermatological advice. It is recommended that topical corticosteroids for atopic eczema should be prescribed for application only once or twice daily. It is recommended that where more than one alternative topical corticosteroid is considered clinically appropriate within a potency class, the drug with the lowest acquisition cost should be prescribed, taking into account pack size and frequency of application. Explain to children with atopic eczema and their parents or carers that they should only apply topical corticosteroids to areas of active atopic eczema (or eczema that has been active within the past 48 hours), which may include areas of broken skin. If a mild or moderately potent topical corticosteroid has not controlled the atopic eczema within 7 to 14 days: exclude secondary bacterial or viral infection for children aged 12 months or over, use potent topical corticosteroids for as short a time as possible (no longer than 14 days, and not on the face or neck) if the atopic eczema is still uncontrolled, review the diagnosis and refer the child for specialist dermatological advice. Do not use potent topical corticosteroids in children aged under 12 months without specialist dermatological supervision. When dispensing topical corticosteroids, apply labels stating the potency class to the container (for example, the tube), not the outer packaging. Once the atopic eczema has been controlled, consider treating problem areas with topical corticosteroids for 2 consecutive days per week to prevent flares in children with frequent flares (2 or 3 per month). Review this strategy within 3 to 6 months. Consider a different topical corticosteroid of the same potency as an alternative to stepping up treatment if tachyphylaxis to a topical corticosteroid is suspected in children with atopic eczema. ## Topical calcineurin inhibitors Recommendations 1.5.1.22 to 1.5.1.26 are from NICE's technology appraisal guidance on tacrolimus and pimecrolimus for atopic eczema. Do not use topical tacrolimus and pimecrolimus for mild atopic eczema, or as first-line treatments for atopic eczema of any severity. Topical tacrolimus is recommended, within its licensed indications, as an option for the second-line treatment of moderate to severe atopic eczema in adults and children aged 2 years and older that has not been controlled by topical corticosteroids (see recommendation 1.5.1.25), where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy. Pimecrolimus is recommended, within its licensed indications, as an option for the second-line treatment of moderate atopic eczema on the face and neck in children aged 2 years to 16 years that has not been controlled by topical corticosteroids (see recommendation 1.5.1.25), where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy. For the purposes of this guidance, atopic eczema that has not been controlled by topical corticosteroids refers to disease that has not shown a satisfactory clinical response to adequate use of the maximum strength and potency that is appropriate for the patient's age and the area being treated. It is recommended that treatment with tacrolimus or pimecrolimus be initiated only by physicians (including general practitioners) with a special interest and experience in dermatology, and only after careful discussion with the patient about the potential risks and benefits of all appropriate second-line treatment options. Explain to children with atopic eczema and their parents or carers that they should only apply topical calcineurin inhibitors to areas of active atopic eczema, which may include areas of broken skin. Do not use topical calcineurin inhibitors under occlusion (bandages and dressings) for treating atopic eczema in children without specialist dermatological advice. For facial atopic eczema in children that requires long-term or frequent use of mild topical corticosteroids, consider stepping up treatment to topical calcineurin inhibitors. ## Dry bandages and medicated dressings (including wet wrap therapy) Do not use occlusive medicated dressings and dry bandages to treat infected atopic eczema in children. Think about using localised medicated dressings or dry bandages with emollients as a treatment for areas of chronic lichenified (localised skin thickening) atopic eczema in children. Think about using localised medicated dressings or dry bandages with emollients and topical corticosteroids for short-term treatment of flares (7 to 14 days) or areas of chronic lichenified atopic eczema in children. Do not use whole-body (limbs and trunk) occlusive dressings (including wet wrap therapy) or whole-body dry bandages (including tubular bandages and garments) as first-line treatment for atopic eczema in children. If using these treatments, they should be started by a healthcare professional trained in their use. When combining whole-body (limbs and trunk) occlusive dressings (including wet wrap therapy) with topical corticosteroids for atopic eczema in children: use initially for 7 to 14 days seek specialist dermatological advice before continuing this combination for longer think about stopping the topical corticosteroids and continuing the dressings alongside emollients until the atopic eczema is controlled. ## Antihistamines Do not routinely use oral antihistamines to manage atopic eczema in children. For children with severe atopic eczema or children with mild or moderate atopic eczema who have severe itching or urticaria, offer a 1‑month trial of a non-sedating antihistamine. If treatment is successful, think about continuing it while symptoms persist, and review every 3 months. If sleep disturbance has a significant impact on the child or parents or carers, offer a 7‑ to 14‑day trial of an age-appropriate sedating antihistamine to children aged 6 months or over during an acute flare of atopic eczema. Think about repeating this during subsequent flares. ## Managing infections See also the section on managing secondary bacterial infections of eczema in the NICE guideline on treating secondary bacterial infection of eczema and other common skin conditions: antimicrobial prescribing. Offer children with atopic eczema and their parents or carers information on how to recognise the symptoms and signs of bacterial infection with staphylococcus and/or streptococcus: weeping pustules crusts eczema failing to respond to therapy rapidly worsening eczema fever malaise. Provide clear information on how to access treatment for infected atopic eczema. Explain to children with atopic eczema and their parents or carers that they should obtain new supplies of their topical atopic eczema medications after treatment for infected atopic eczema. This is because their medications can become contaminated and act as a source of infection. Consider herpes simplex (cold sore) infection if a child's infected atopic eczema fails to respond to treatment with antibiotics and an appropriate topical corticosteroid. If a child with atopic eczema has a lesion on the skin that is suspected to be herpes simplex, treat with oral aciclovir even if the infection is localised. If eczema herpeticum (widespread herpes simplex) is suspected in a child with atopic eczema, immediately start treatment with systemic aciclovir and refer the child for same-day specialist dermatological advice. If secondary bacterial infection is also suspected, start treatment with systemic antibiotics. If eczema herpeticum involves the skin around the eyes, treat with systemic aciclovir and refer the child for same-day ophthalmological and dermatological advice. Offer children with atopic eczema and their parents or carers information on how to recognise eczema herpeticum: areas of rapidly worsening, painful eczema clustered blisters that look like early-stage cold sores punched-out erosions (circular, depressed, ulcerated lesions), usually 1 mm to 3 mm, that are uniform in appearance (these may combine to form larger areas of erosion with crusting) possible fever, lethargy or distress. ## Phototherapy and systemic treatments Consider phototherapy or systemic treatments for severe atopic eczema in children when: -ther management options have failed or are inappropriate, and there is a significant negative impact on quality of life. Only use phototherapy and systemic treatments under specialist dermatological supervision by staff who are experienced in working with children. Only start phototherapy or systemic treatments in children with atopic eczema after assessment and documentation of severity of atopic eczema and quality of life (see recommendation 1.2.1.1). ## Complementary therapies Explain to children with atopic eczema and their parents or carers that the effectiveness and safety of the following therapies has not yet adequately been assessed in clinical trials: homeopathy herbal medicine massage food supplements. Explain to children with atopic eczema and their parents or carers that: they should be cautious about using herbal medicines in children, particularly for products that are not labelled in English or that do not come with information about safe usage (see the MHRA's using herbal medicines: advice to consumers) topical corticosteroids are deliberately added to some herbal products intended for use in children with atopic eczema liver toxicity has been associated with the use of some Chinese herbal medicines intended to treat atopic eczema. Ask children with atopic eczema and their parents or carers to tell their healthcare professionals if they are using or intend to use complementary therapies. Explain to children with atopic eczema and their parents or carers that if they plan to use complementary therapies, they should keep using emollients as well. Advise children with atopic eczema and their parents or carers that using regular massage along with emollients may improve the atopic eczema. # Education and adherence to therapy Provide education to children with atopic eczema and their parents or carers about atopic eczema and its treatment. Provide verbal and written information, with practical demonstrations, and cover: how much of the treatments to use how often to apply treatments when and how to step treatment up or down how to treat infected atopic eczema.Reinforce this at every consultation, addressing factors that affect adherence. When discussing treatment options with children with atopic eczema and their parents and carers, tailor information to suit the child's cultural practices relating to skin care (including oiling the skin) and the way they bathe. Explain to children with atopic eczema and their parents or carers that atopic eczema may temporarily cause the skin to become lighter or darker. # Indications for referral Immediately (same day) refer children for specialist dermatological advice if eczema herpeticum is suspected (see recommendations 1.5.1.42 and 1.5.1.43). Urgently (within 2 weeks) refer children for specialist dermatological advice if: their atopic eczema is severe and has not responded to optimal topical therapy after 1 week treatment of bacterially infected atopic eczema has failed. Refer children with atopic eczema for specialist dermatological advice if: the diagnosis is, or has become, uncertain management has not controlled the atopic eczema satisfactorily, based on a subjective assessment by the child, parent or carer (for example, the child is having 1 to 2 weeks of flares per month or is having adverse reactions to many emollients) atopic eczema on the face has not responded to treatment the child or their parents or carers may benefit from specialist advice on how to apply treatments (for example, bandaging techniques) contact allergic dermatitis is suspected (for example, persistent atopic eczema or facial, eyelid or hand atopic eczema) the atopic eczema is causing significant social or psychological problems for the child or their parents or carers (for example, sleep disturbance or poor school attendance) atopic eczema is associated with severe and recurrent infections, especially deep abscesses or pneumonia. If atopic eczema is responding to optimal management but the child's quality of life and psychosocial wellbeing has not improved, refer them for psychological advice. Refer children with moderate or severe atopic eczema and suspected food allergy for specialist investigation and management. Refer children with atopic eczema for specialist advice relating to growth if they are not growing at the expected growth trajectory (as reflected by UK growth charts). # Recommendations for research The 2007 guideline development group has made the following recommendations for research. # Infant feeding What is the optimal feeding regimen in the first year of life for children with established atopic eczema? ## Why this is important Dietary manipulation has the potential to decrease disease severity in children with proven food allergy. A study is needed to explore the potential benefits and harms of delaying the introduction of allergenic foods such as milk, egg and peanuts in babies with early signs of atopic eczema to assess the potential impact on atopic eczema severity and the subsequent development of food allergy, asthma and allergic rhinitis. # Prevention of flares Which are the best, most cost-effective treatment strategies for managing and preventing flares in children with atopic eczema? ## Why this is important Atopic eczema is usually an episodic disease of exacerbation (flares) and remissions, except for severe cases where it may be continuous (2% to 6% of cases). Flares may occur as frequently as 2 or 3 times per month and have a very negative effect on quality of life. They are time consuming and expensive to treat. There is limited evidence suggesting that strategies to prevent flares can reduce the number, frequency and severity of flares and the amount of treatment required. Identifying good strategies would improve patient care and quality of life, and free up NHS resources. Strategies that could be considered in this research include continuous versus intermittent topical treatments or combinations of products such as topical corticosteroids and topical calcineurin inhibitors. # Early intervention What effect does improving the control of atopic eczema in the first year of life have on the long-term control and severity of atopic eczema and the subsequent development and severity of food allergy, asthma and allergic rhinitis? ## Why this is important Uncontrolled atopic eczema in children may progress to chronic disease involving the production of auto-immune antibodies to the skin. Early intervention to restore the defective skin barrier might alter the course of atopic eczema by preventing allergen penetration. A systematic review is needed to evaluate the available evidence on these factors. The results should feed into the design of a large randomised controlled trial investigating the long-term effect of controlling atopic eczema in the first year of life. Early effective treatment to control atopic eczema and the development of other atopic conditions would be extremely cost effective, have a major impact on service provision and improve the quality of life of children with atopic eczema and their parents and carers. # Adverse effects of topical corticosteroids What are the long-term effects (when used for between 1 year and 3 years) of typical use of topical corticosteroids in children with atopic eczema? ## Why this is important Around 70% to 80% of parents and carers of children with atopic eczema are concerned about the side effects of topical corticosteroids, and this often prevents adherence to therapy (at least 25% of parents and carers report non-use because of anxiety). Despite the fact that topical corticosteroids have been in clinical use since 1962, there is limited data on their long-term effects (greater than a few weeks) on skin thickness, hypothalamic–pituitary–adrenal (HPA) axis suppression and other side effects. Clinical consensus suggests that long-term use, within clinically recommended dosages, appears to be safe; research confirming this would greatly improve adherence to therapy and clinical outcomes, and reduce parental anxiety. The research could include comparisons between children who use topical corticosteroids for shorter and longer periods, and with those who use other topical preparations such as emollients and topical calcineurin inhibitors. # Education and adherence to therapy How effective and cost effective are different models of educational programmes in the early management of atopic eczema in children, in terms of improving adherence to therapy and patient outcomes such as disease severity and quality of life? ## Why this is important Atopic eczema is a common childhood disease affecting 1 in 5 children in the UK. Effective therapy improves quality of life for children with atopic eczema and their parents and carers, and can be provided for over 80% of children with atopic eczema in a primary care setting. It is known that a lack of education about therapy leads to poor adherence, and consequently to treatment failure.# Rationale and impact This section briefly explains why the committee made the recommendations and how they might affect practice. # Emollient bath additives Recommendations 1.5.1.4, 1.5.1.10 and 1.5.1.11 ## Why the committee made the recommendations Evidence from the BATHE trial indicated that emollient bath additives are not clinically or cost effective when used in addition to standard care (which included applying leave-on emollients and washing with emollients or emollient soap substitutes). While evidence suggested that emollient bath additives are not harmful, prescribing a product with no additional benefit places unnecessary burdens on patients and carers, in terms of acquiring and using the product. Some children with sensory processing disorders are unable to tolerate leave-on emollients that are applied directly to the skin, and emollients applied during bathing or showering may be their only option. The committee discussed making a different recommendation on emollient bath additives for this group, but decided not to because: there was no evidence on the effectiveness of emollient bath additives compared with no emollient use they can wash with leave-on emollients or emollient soap substitutes, so there is already a way for them to benefit from emollients leave-on emollients can also be diluted in hot water and added to bath water, so there is an alternative option available. The committee recommended personalised advice on washing because children face a variety of issues in controlling their eczema: while some children with sensory processing disorders are unable to tolerate leave-on emollients, not all children in this group have the same needs for children who cannot tolerate leave-on emollients, and who are using emollient bath additives alone to control their eczema, they and their families would benefit from advice on how to wash with leave-on emollients or emollient soap substitutes families who buy emollient bath additives over the counter could save money if they knew they did not need to use these products. ## How the recommendations might affect practice NHS England advised that emollient bath additives should not be prescribed, in their 2019 guidance on items which should not routinely be prescribed in primary care. Despite this, prescribing of emollient bath additives has continued, and there has been geographical variation in prescribing. The new recommendation supports the NHS England guidance and should further reduce prescribing of emollient bath additives. This would save money for the NHS and reduce geographical variation. Return to recommendations# The algorithm The full guideline (pages 50 and 51) contains a care pathway for atopic eczema in children.# Context Atopic eczema (atopic dermatitis) is a chronic inflammatory itchy skin condition that develops in early childhood in the majority of cases. It is typically an episodic disease of exacerbation (flares, which may occur as frequently as 2 or 3 per month) and remissions. In some cases, it may be continuous. Atopic eczema often has a genetic component that leads to the breakdown of the skin barrier. This makes the skin susceptible to trigger factors, including irritants and allergens, which can make the eczema worse. Many cases of atopic eczema clear or improve during childhood, whereas others persist into adulthood. Some children who have atopic eczema will go on to develop asthma, allergic rhinitis or food allergy; this sequence of events is sometimes referred to as the 'atopic march'. Although atopic eczema is not always recognised by healthcare professionals as being a serious medical condition, it can have a significant negative impact on quality of life for children and their parents and carers. This guideline concerns the management of atopic eczema in children from birth up to the age of 12 years. It has been developed with the aim of providing guidance on: diagnosis and assessment of the impact of the condition management during and between flares information and education for children and their parents or carers about the condition.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosis\n\nTake clinical and drug histories of children with atopic eczema, including questions about:\n\ntime of onset, pattern and severity of the atopic eczema\n\nresponse to previous and current treatments\n\npossible trigger factors (irritant and allergic)\n\nthe impact of the atopic eczema on the child and their parents or carers\n\ndietary history, including any dietary manipulation\n\ngrowth and development\n\npersonal and family history of atopic conditions. \n\nDiagnose atopic eczema when a child has an itchy skin condition plus 3 or more of the following:\n\nvisible flexural dermatitis involving the skin creases, such as the bends of the elbows or behind the knees (or visible dermatitis on the cheeks and/or extensor areas in children aged 18\xa0months or under)\n\nprevious flexural dermatitis (or dermatitis on the cheeks and/or extensor areas in children aged 18\xa0months or under)\n\ndry skin in the last 12\xa0months\n\nasthma or allergic rhinitis (or history of atopic disease in a first-degree relative of children aged under 4\xa0years)\n\nonset of signs and symptoms under the age of 2\xa0years (do not use this criterion in children aged under 4\xa0years).Healthcare professionals should be aware that in Asian, Black Caribbean and Black African children, atopic eczema can affect the extensor surfaces rather than the flexures, and discoid (circular) or follicular (around hair follicles) patterns may be more common. \n\n# Assessing severity, psychological and psychosocial wellbeing and quality of life\n\nUse a holistic approach when assessing a child's atopic eczema at each consultation, taking into account:\n\nthe severity of the atopic eczema\n\nthe child's quality of life, including everyday activities, sleep, and psychosocial wellbeing (see table\xa01)\n\nthat there is not necessarily a direct relationship between the severity of the atopic eczema and the impact it has on quality of life. \n\nSkin and physical severity\n\nImpact on quality of life and psychosocial wellbeing\n\nClear: normal skin, no evidence of active atopic eczema\n\nNone: no impact on quality of life\n\nMild: areas of dry skin, infrequent itching (with or without small areas of redness)\n\nMild: little impact on everyday activities, sleep and psychosocial wellbeing\n\nModerate: areas of dry skin, frequent itching, redness (with or without excoriation and localised skin thickening)\n\nModerate: moderate impact on everyday activities and psychosocial wellbeing, frequently disturbed sleep\n\nSevere: widespread areas of dry skin, incessant itching, redness (with or without excoriation, extensive skin thickening, bleeding, oozing, cracking and alteration of pigmentation)\n\nSevere: severe limitation of everyday activities and psychosocial functioning, nightly loss of sleep\n\nExplain the physical severity category (see table\xa01) of the atopic eczema to the child and their parents or carers. \n\nAssess whether the child's atopic eczema is consistent in severity, or whether there are areas of differing severity. If there are areas of differing severity, treat each area independently. \n\nDuring an assessment of psychological and psychosocial wellbeing and quality of life, take into account the impact of atopic eczema on parents or carers as well as the child, and provide them with advice and support. \n\nWhen deciding treatment strategies, take into account that all categories of severity of atopic eczema can have a negative impact on psychological and psychosocial wellbeing and quality of life. \n\nConsider using the following additional tools to provide objective measures of the severity of atopic eczema, quality of life and response to treatment:\n\nvisual analogue scales (0 to 10) capturing the child's and/or parents' or carers' assessment of severity, itch and sleep loss over the previous 3\xa0days and nights\n\nvalidated tools:\n\n\n\nPatient-Oriented Eczema Measure (POEM) for severity\n\nChildren's Dermatology Life Quality Index (CDLQI), Infants' Dermatitis Quality of Life Index (IDQoL) or Dermatitis Family Impact (DFI) questionnaire for quality of life. \n\n\n\n# Discussing related conditions and how atopic eczema may change over time\n\nExplain to children with atopic eczema and their parents or carers that:\n\nthe condition often improves with time, but not all children will grow out of atopic eczema and it may get worse in teenage or adult life\n\nchildren with atopic eczema often develop asthma and/or allergic rhinitis\n\nsometimes food allergy is associated with atopic eczema, particularly in very young children. \n\n# Identifying and managing trigger factors\n\nWhen assessing children with atopic eczema, identify potential trigger factors, including:\n\nirritants, for example soaps and detergents (including shampoos, bubble baths, shower gels and washing-up liquids)\n\nskin infections\n\ncontact allergens\n\nfood allergens\n\ninhalant allergens. \n\nConsider a diagnosis of food allergy in:\n\nchildren with atopic eczema who have had immediate symptoms from eating a particular food\n\nbabies and young children with moderate or severe atopic eczema that has not been controlled by optimum management, particularly if associated with gut dysmotility (colic, vomiting, altered bowel habit) or failure to thrive. \n\nConsider a diagnosis of inhalant allergy in:\n\nchildren with seasonal flares of atopic eczema\n\nchildren with atopic eczema associated with asthma or allergic rhinitis\n\nchildren aged 3\xa0years or over with atopic eczema on the face, particularly around the eyes. \n\nConsider a diagnosis of allergic contact dermatitis in children with:\n\nan exacerbation of previously controlled atopic eczema, or\n\nreactions to topical treatments. \n\nReassure children with mild atopic eczema and their parents or carers that most children with mild atopic eczema do not need to have tests for allergies. \n\nAdvise children with atopic eczema and their parents or carers not to use high street or internet allergy tests, because there is no evidence of their value in managing atopic eczema. \n\nFor bottle-fed babies aged under 6\xa0months with moderate or severe atopic eczema that has not been controlled by optimal treatment with emollients and mild topical corticosteroids, offer a 6‑ to 8‑week trial of an extensively hydrolysed protein formula or amino acid formula in place of cow's milk formula. \n\nRefer children with atopic eczema for specialist dietary advice if they have followed a cow's milk-free diet for longer than 8\xa0weeks. \n\nDo not use diets based on unmodified proteins of other species' milk (for example, goat's milk or sheep's milk) or partially hydrolysed formulas to manage suspected cow's milk allergy in children with atopic eczema. \n\nOffer diets that include soya protein along with specialist dietary advice for children aged 6\xa0months or over. \n\nFor children who are being breast fed, explain that it is not known whether changing the mother's diet will reduce the severity of the atopic eczema. If food allergy is strongly suspected, consider a trial of an allergen-specific exclusion diet. \n\nExplain to children with atopic eczema and their parents or carers that:\n\nit is unclear what role factors such as stress, humidity or extremes of temperature have in causing flares of atopic eczema, and\n\nthey should avoid these factors when possible. \n\n# Treatment\n\n## Stepped approach to management\n\nUse the stepped approach in table\xa02 for managing atopic eczema in children.\n\nEmollients are the basis of management and should always be used, even when atopic eczema is clear.\n\nManagement can then be stepped up or down, according to the severity of symptoms, with the addition of the other treatments listed in table\xa02. \n\n\n\nMild atopic eczema\n\nemollients\n\nmild-potency topical corticosteroids.\n\nModerate atopic eczema\n\nemollients\n\nmoderate-potency topical corticosteroids\n\ntopical calcineurin inhibitors\n\nbandages.\n\nSevere atopic eczema\n\nemollients\n\npotent topical corticosteroids\n\ntopical calcineurin inhibitors\n\nbandages\n\nphototherapy\n\nsystemic therapy.\n\nOffer children with atopic eczema and their parents or carers information on how to recognise flares of atopic eczema (increased dryness, itching, redness, swelling and general irritability). Give clear instructions on how to manage flares according to the stepped-care plan, and prescribe treatments that allow children and their parents or carers to follow this plan. \n\nStart treatment for flares of atopic eczema as soon as signs and symptoms appear, and continue treatment for approximately 48\xa0hours after symptoms subside. \n\n## Emollients\n\nEmollient creams are vital in helping to manage dry skin conditions, but there are Medicines and Healthcare products Regulatory Agency (MHRA) warnings about fire hazards associated with build-up of emollient residue on clothing and bedding.\n\nOffer children with atopic eczema a choice of unperfumed emollients to use every day for moisturising. This may be a combination of products or one product for all purposes. Prescribe large quantities of leave-on emollients (250\xa0g to 500\xa0g weekly) that are easily available to use at nursery, pre-school or school. [2007, amended 2023]\n\nExplain to children with atopic eczema and their parents or carers that they should use emollients:\n\nin larger amounts and more often than other treatments\n\non their whole body, both when the atopic eczema is clear and while using all other treatments. \n\nShow children with atopic eczema and their parents or carers how to apply emollients, including how to smooth emollients onto the skin rather than rubbing them in. \n\nIf their current emollient causes irritation or is not acceptable, offer a different way to apply it or offer an alternative emollient. [2007, amended 2023]\n\nReview repeat prescriptions of individual products and combinations of products with children with atopic eczema and their parents or carers at least once a year. \n\nWhen children with atopic eczema are using emollients and other topical products at the same time of day, explain that:\n\nthey should apply one product at a time, and wait several minutes before applying the next product\n\nthey can choose which product to apply first. [2007, amended 2023]\n\nOffer personalised advice on washing with emollients or emollient soap substitutes, and explain to children with atopic eczema and their parents or carers that:\n\nthey should use leave-on emollients or emollient soap substitutes instead of soaps and detergent-based wash products\n\nleave-on emollients can be added to bath water\n\nchildren aged under 12\xa0months should use leave-on emollients or emollient soap substitutes instead of shampoos\n\nolder children using shampoo should use a brand that is unperfumed and ideally labelled as suitable for eczema, and they should avoid washing their hair in bath water. [2007, amended 2023]\n\nDo not offer emollient bath additives to children with atopic eczema. \n\nFor a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on emollient bath additives\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: adding bath emollients to the management of atopic eczema in children under 12 years.\n\nLoading. Please wait.\n\n## Topical corticosteroids\n\nRecommendations\xa01.5.1.14 and 1.5.1.15 are from NICE's technology appraisal guidance on frequency of application of topical corticosteroids for atopic eczema.\n\nDiscuss the benefits and harms of treatment with topical corticosteroids with children with atopic eczema and their parents or carers, emphasising that the benefits outweigh possible harms when they are applied correctly. \n\nTailor the potency of topical corticosteroids to the severity of the child's atopic eczema (which may vary according to body site):\n\nuse mild potency for mild atopic eczema\n\nuse moderate potency for moderate atopic eczema\n\nuse potent for severe atopic eczema\n\nuse mild potency for the face and neck, except for short-term (3 to 5\xa0days) use of moderate potency for severe flares\n\nuse moderate or potent preparations for short periods only (7 to 14\xa0days) for flares in vulnerable sites such as axillae and groin\n\ndo not use very potent preparations in children without specialist dermatological advice. \n\nIt is recommended that topical corticosteroids for atopic eczema should be prescribed for application only once or twice daily. \n\nIt is recommended that where more than one alternative topical corticosteroid is considered clinically appropriate within a potency class, the drug with the lowest acquisition cost should be prescribed, taking into account pack size and frequency of application. \n\nExplain to children with atopic eczema and their parents or carers that they should only apply topical corticosteroids to areas of active atopic eczema (or eczema that has been active within the past 48\xa0hours), which may include areas of broken skin. \n\nIf a mild or moderately potent topical corticosteroid has not controlled the atopic eczema within 7 to 14\xa0days:\n\nexclude secondary bacterial or viral infection\n\nfor children aged 12\xa0months or over, use potent topical corticosteroids for as short a time as possible (no longer than 14\xa0days, and not on the face or neck)\n\nif the atopic eczema is still uncontrolled, review the diagnosis and refer the child for specialist dermatological advice. \n\nDo not use potent topical corticosteroids in children aged under 12\xa0months without specialist dermatological supervision. \n\nWhen dispensing topical corticosteroids, apply labels stating the potency class to the container (for example, the tube), not the outer packaging. \n\nOnce the atopic eczema has been controlled, consider treating problem areas with topical corticosteroids for 2\xa0consecutive days per week to prevent flares in children with frequent flares (2 or 3\xa0per month). Review this strategy within 3 to 6\xa0months. \n\nConsider a different topical corticosteroid of the same potency as an alternative to stepping up treatment if tachyphylaxis to a topical corticosteroid is suspected in children with atopic eczema. \n\n## Topical calcineurin inhibitors\n\nRecommendations\xa01.5.1.22 to 1.5.1.26 are from NICE's technology appraisal guidance on tacrolimus and pimecrolimus for atopic eczema.\n\nDo not use topical tacrolimus and pimecrolimus for mild atopic eczema, or as first-line treatments for atopic eczema of any severity. \n\nTopical tacrolimus is recommended, within its licensed indications, as an option for the second-line treatment of moderate to severe atopic eczema in adults and children aged 2\xa0years and older that has not been controlled by topical corticosteroids (see recommendation\xa01.5.1.25), where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy. \n\nPimecrolimus is recommended, within its licensed indications, as an option for the second-line treatment of moderate atopic eczema on the face and neck in children aged 2\xa0years to 16\xa0years that has not been controlled by topical corticosteroids (see recommendation\xa01.5.1.25), where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy. \n\nFor the purposes of this guidance, atopic eczema that has not been controlled by topical corticosteroids refers to disease that has not shown a satisfactory clinical response to adequate use of the maximum strength and potency that is appropriate for the patient's age and the area being treated. \n\nIt is recommended that treatment with tacrolimus or pimecrolimus be initiated only by physicians (including general practitioners) with a special interest and experience in dermatology, and only after careful discussion with the patient about the potential risks and benefits of all appropriate second-line treatment options. \n\nExplain to children with atopic eczema and their parents or carers that they should only apply topical calcineurin inhibitors to areas of active atopic eczema, which may include areas of broken skin. \n\nDo not use topical calcineurin inhibitors under occlusion (bandages and dressings) for treating atopic eczema in children without specialist dermatological advice. \n\nFor facial atopic eczema in children that requires long-term or frequent use of mild topical corticosteroids, consider stepping up treatment to topical calcineurin inhibitors. \n\n## Dry bandages and medicated dressings (including wet wrap therapy)\n\nDo not use occlusive medicated dressings and dry bandages to treat infected atopic eczema in children. \n\nThink about using localised medicated dressings or dry bandages with emollients as a treatment for areas of chronic lichenified (localised skin thickening) atopic eczema in children. \n\nThink about using localised medicated dressings or dry bandages with emollients and topical corticosteroids for short-term treatment of flares (7 to 14\xa0days) or areas of chronic lichenified atopic eczema in children. \n\nDo not use whole-body (limbs and trunk) occlusive dressings (including wet wrap therapy) or whole-body dry bandages (including tubular bandages and garments) as first-line treatment for atopic eczema in children. If using these treatments, they should be started by a healthcare professional trained in their use. \n\nWhen combining whole-body (limbs and trunk) occlusive dressings (including wet wrap therapy) with topical corticosteroids for atopic eczema in children:\n\nuse initially for 7 to 14\xa0days\n\nseek specialist dermatological advice before continuing this combination for longer\n\nthink about stopping the topical corticosteroids and continuing the dressings alongside emollients until the atopic eczema is controlled. \n\n## Antihistamines\n\nDo not routinely use oral antihistamines to manage atopic eczema in children. \n\nFor children with severe atopic eczema or children with mild or moderate atopic eczema who have severe itching or urticaria, offer a 1‑month trial of a non-sedating antihistamine. If treatment is successful, think about continuing it while symptoms persist, and review every 3\xa0months. \n\nIf sleep disturbance has a significant impact on the child or parents or carers, offer a 7‑ to 14‑day trial of an age-appropriate sedating antihistamine to children aged 6\xa0months or over during an acute flare of atopic eczema. Think about repeating this during subsequent flares. \n\n## Managing infections\n\nSee also the section on managing secondary bacterial infections of eczema in the NICE guideline on treating secondary bacterial infection of eczema and other common skin conditions: antimicrobial prescribing.\n\nOffer children with atopic eczema and their parents or carers information on how to recognise the symptoms and signs of bacterial infection with staphylococcus and/or streptococcus:\n\nweeping\n\npustules\n\ncrusts\n\neczema failing to respond to therapy\n\nrapidly worsening eczema\n\nfever\n\nmalaise. Provide clear information on how to access treatment for infected atopic eczema. \n\nExplain to children with atopic eczema and their parents or carers that they should obtain new supplies of their topical atopic eczema medications after treatment for infected atopic eczema. This is because their medications can become contaminated and act as a source of infection. \n\nConsider herpes simplex (cold sore) infection if a child's infected atopic eczema fails to respond to treatment with antibiotics and an appropriate topical corticosteroid. \n\nIf a child with atopic eczema has a lesion on the skin that is suspected to be herpes simplex, treat with oral aciclovir even if the infection is localised. \n\nIf eczema herpeticum (widespread herpes simplex) is suspected in a child with atopic eczema, immediately start treatment with systemic aciclovir and refer the child for same-day specialist dermatological advice. If secondary bacterial infection is also suspected, start treatment with systemic antibiotics. \n\nIf eczema herpeticum involves the skin around the eyes, treat with systemic aciclovir and refer the child for same-day ophthalmological and dermatological advice. \n\nOffer children with atopic eczema and their parents or carers information on how to recognise eczema herpeticum:\n\nareas of rapidly worsening, painful eczema\n\nclustered blisters that look like early-stage cold sores\n\npunched-out erosions (circular, depressed, ulcerated lesions), usually 1\xa0mm to 3\xa0mm, that are uniform in appearance (these may combine to form larger areas of erosion with crusting)\n\npossible fever, lethargy or distress. \n\n## Phototherapy and systemic treatments\n\nConsider phototherapy or systemic treatments for severe atopic eczema in children when:\n\nother management options have failed or are inappropriate, and\n\nthere is a significant negative impact on quality of life. Only use phototherapy and systemic treatments under specialist dermatological supervision by staff who are experienced in working with children. \n\nOnly start phototherapy or systemic treatments in children with atopic eczema after assessment and documentation of severity of atopic eczema and quality of life (see recommendation\xa01.2.1.1). \n\n## Complementary therapies\n\nExplain to children with atopic eczema and their parents or carers that the effectiveness and safety of the following therapies has not yet adequately been assessed in clinical trials:\n\nhomeopathy\n\nherbal medicine\n\nmassage\n\nfood supplements. \n\nExplain to children with atopic eczema and their parents or carers that:\n\nthey should be cautious about using herbal medicines in children, particularly for products that are not labelled in English or that do not come with information about safe usage (see the MHRA's using herbal medicines: advice to consumers)\n\ntopical corticosteroids are deliberately added to some herbal products intended for use in children with atopic eczema\n\nliver toxicity has been associated with the use of some Chinese herbal medicines intended to treat atopic eczema. \n\nAsk children with atopic eczema and their parents or carers to tell their healthcare professionals if they are using or intend to use complementary therapies. \n\nExplain to children with atopic eczema and their parents or carers that if they plan to use complementary therapies, they should keep using emollients as well. \n\nAdvise children with atopic eczema and their parents or carers that using regular massage along with emollients may improve the atopic eczema. \n\n# Education and adherence to therapy\n\nProvide education to children with atopic eczema and their parents or carers about atopic eczema and its treatment. Provide verbal and written information, with practical demonstrations, and cover:\n\nhow much of the treatments to use\n\nhow often to apply treatments\n\nwhen and how to step treatment up or down\n\nhow to treat infected atopic eczema.Reinforce this at every consultation, addressing factors that affect adherence. \n\nWhen discussing treatment options with children with atopic eczema and their parents and carers, tailor information to suit the child's cultural practices relating to skin care (including oiling the skin) and the way they bathe. \n\nExplain to children with atopic eczema and their parents or carers that atopic eczema may temporarily cause the skin to become lighter or darker. \n\n# Indications for referral\n\nImmediately (same day) refer children for specialist dermatological advice if eczema herpeticum is suspected (see recommendations\xa01.5.1.42 and 1.5.1.43). \n\nUrgently (within 2\xa0weeks) refer children for specialist dermatological advice if:\n\ntheir atopic eczema is severe and has not responded to optimal topical therapy after 1\xa0week\n\ntreatment of bacterially infected atopic eczema has failed. \n\nRefer children with atopic eczema for specialist dermatological advice if:\n\nthe diagnosis is, or has become, uncertain\n\nmanagement has not controlled the atopic eczema satisfactorily, based on a subjective assessment by the child, parent or carer (for example, the child is having 1 to 2\xa0weeks of flares per month or is having adverse reactions to many emollients)\n\natopic eczema on the face has not responded to treatment\n\nthe child or their parents or carers may benefit from specialist advice on how to apply treatments (for example, bandaging techniques)\n\ncontact allergic dermatitis is suspected (for example, persistent atopic eczema or facial, eyelid or hand atopic eczema)\n\nthe atopic eczema is causing significant social or psychological problems for the child or their parents or carers (for example, sleep disturbance or poor school attendance)\n\natopic eczema is associated with severe and recurrent infections, especially deep abscesses or pneumonia. \n\nIf atopic eczema is responding to optimal management but the child's quality of life and psychosocial wellbeing has not improved, refer them for psychological advice. \n\nRefer children with moderate or severe atopic eczema and suspected food allergy for specialist investigation and management. \n\nRefer children with atopic eczema for specialist advice relating to growth if they are not growing at the expected growth trajectory (as reflected by UK growth charts). ", 'Recommendations for research': 'The 2007 guideline development group has made the following recommendations for research.\n\n# Infant feeding\n\nWhat is the optimal feeding regimen in the first year of life for children with established atopic eczema? \n\n## Why this is important\n\nDietary manipulation has the potential to decrease disease severity in children with proven food allergy. A study is needed to explore the potential benefits and harms of delaying the introduction of allergenic foods such as milk, egg and peanuts in babies with early signs of atopic eczema to assess the potential impact on atopic eczema severity and the subsequent development of food allergy, asthma and allergic rhinitis.\n\n# Prevention of flares\n\nWhich are the best, most cost-effective treatment strategies for managing and preventing flares in children with atopic eczema? \n\n## Why this is important\n\nAtopic eczema is usually an episodic disease of exacerbation (flares) and remissions, except for severe cases where it may be continuous (2% to 6% of cases). Flares may occur as frequently as 2 or 3 times per month and have a very negative effect on quality of life. They are time consuming and expensive to treat.\n\nThere is limited evidence suggesting that strategies to prevent flares can reduce the number, frequency and severity of flares and the amount of treatment required. Identifying good strategies would improve patient care and quality of life, and free up NHS resources.\n\nStrategies that could be considered in this research include continuous versus intermittent topical treatments or combinations of products such as topical corticosteroids and topical calcineurin inhibitors.\n\n# Early intervention\n\nWhat effect does improving the control of atopic eczema in the first year of life have on the long-term control and severity of atopic eczema and the subsequent development and severity of food allergy, asthma and allergic rhinitis? \n\n## Why this is important\n\nUncontrolled atopic eczema in children may progress to chronic disease involving the production of auto-immune antibodies to the skin. Early intervention to restore the defective skin barrier might alter the course of atopic eczema by preventing allergen penetration. A systematic review is needed to evaluate the available evidence on these factors. The results should feed into the design of a large randomised controlled trial investigating the long-term effect of controlling atopic eczema in the first year of life. Early effective treatment to control atopic eczema and the development of other atopic conditions would be extremely cost effective, have a major impact on service provision and improve the quality of life of children with atopic eczema and their parents and carers.\n\n# Adverse effects of topical corticosteroids\n\nWhat are the long-term effects (when used for between 1\xa0year and 3\xa0years) of typical use of topical corticosteroids in children with atopic eczema? \n\n## Why this is important\n\nAround 70% to 80% of parents and carers of children with atopic eczema are concerned about the side effects of topical corticosteroids, and this often prevents adherence to therapy (at least 25% of parents and carers report non-use because of anxiety). Despite the fact that topical corticosteroids have been in clinical use since 1962, there is limited data on their long-term effects (greater than a few weeks) on skin thickness, hypothalamic–pituitary–adrenal (HPA) axis suppression and other side effects.\n\nClinical consensus suggests that long-term use, within clinically recommended dosages, appears to be safe; research confirming this would greatly improve adherence to therapy and clinical outcomes, and reduce parental anxiety. The research could include comparisons between children who use topical corticosteroids for shorter and longer periods, and with those who use other topical preparations such as emollients and topical calcineurin inhibitors.\n\n# Education and adherence to therapy\n\nHow effective and cost effective are different models of educational programmes in the early management of atopic eczema in children, in terms of improving adherence to therapy and patient outcomes such as disease severity and quality of life? \n\n## Why this is important\n\nAtopic eczema is a common childhood disease affecting 1 in 5\xa0children in the UK. Effective therapy improves quality of life for children with atopic eczema and their parents and carers, and can be provided for over 80% of children with atopic eczema in a primary care setting. It is known that a lack of education about therapy leads to poor adherence, and consequently to treatment failure.', 'Rationale and impact': 'This section briefly explains why the committee made the recommendations and how they might affect practice.\n\n# Emollient bath additives\n\nRecommendations 1.5.1.4, 1.5.1.10 and 1.5.1.11\n\n## Why the committee made the recommendations\n\nEvidence from the BATHE trial indicated that emollient bath additives are not clinically or cost effective when used in addition to standard care (which included applying leave-on emollients and washing with emollients or emollient soap substitutes). While evidence suggested that emollient bath additives are not harmful, prescribing a product with no additional benefit places unnecessary burdens on patients and carers, in terms of acquiring and using the product.\n\nSome children with sensory processing disorders are unable to tolerate leave-on emollients that are applied directly to the skin, and emollients applied during bathing or showering may be their only option. The committee discussed making a different recommendation on emollient bath additives for this group, but decided not to because:\n\nthere was no evidence on the effectiveness of emollient bath additives compared with no emollient use\n\nthey can wash with leave-on emollients or emollient soap substitutes, so there is already a way for them to benefit from emollients\n\nleave-on emollients can also be diluted in hot water and added to bath water, so there is an alternative option available.\n\nThe committee recommended personalised advice on washing because children face a variety of issues in controlling their eczema:\n\nwhile some children with sensory processing disorders are unable to tolerate leave-on emollients, not all children in this group have the same needs\n\nfor children who cannot tolerate leave-on emollients, and who are using emollient bath additives alone to control their eczema, they and their families would benefit from advice on how to wash with leave-on emollients or emollient soap substitutes\n\nfamilies who buy emollient bath additives over the counter could save money if they knew they did not need to use these products.\n\n## How the recommendations might affect practice\n\nNHS England advised that emollient bath additives should not be prescribed, in their 2019 guidance on items which should not routinely be prescribed in primary care. Despite this, prescribing of emollient bath additives has continued, and there has been geographical variation in prescribing.\n\nThe new recommendation supports the NHS England guidance and should further reduce prescribing of emollient bath additives. This would save money for the NHS and reduce geographical variation.\n\nReturn to recommendations', 'The algorithm': 'The full guideline (pages 50 and 51) contains a care pathway for atopic eczema in children.', 'Context': "Atopic eczema (atopic dermatitis) is a chronic inflammatory itchy skin condition that develops in early childhood in the majority of cases. It is typically an episodic disease of exacerbation (flares, which may occur as frequently as 2 or 3\xa0per\xa0month) and remissions. In some cases, it may be continuous. Atopic eczema often has a genetic component that leads to the breakdown of the skin barrier. This makes the skin susceptible to trigger factors, including irritants and allergens, which can make the eczema worse.\n\nMany cases of atopic eczema clear or improve during childhood, whereas others persist into adulthood. Some children who have atopic eczema will go on to develop asthma, allergic rhinitis or food allergy; this sequence of events is sometimes referred to as the 'atopic march'. Although atopic eczema is not always recognised by healthcare professionals as being a serious medical condition, it can have a significant negative impact on quality of life for children and their parents and carers.\n\nThis guideline concerns the management of atopic eczema in children from birth up to the age of 12\xa0years. It has been developed with the aim of providing guidance on:\n\ndiagnosis and assessment of the impact of the condition\n\nmanagement during and between flares\n\ninformation and education for children and their parents or carers about the condition."}	https://www.nice.org.uk/guidance/cg57	This guideline covers diagnosing and managing atopic eczema in children under 12. It aims to improve care for children with atopic eczema by making detailed recommendations on treatment and specialist referral. The guideline also explains how healthcare professionals should assess the effect eczema has on quality of life, in addition to its physical severity.
c994420d98af0866b15d68c6421f53a8a0b84358	nice	FibroScan for assessing liver fibrosis and cirrhosis outside secondary and specialist care	FibroScan for assessing liver fibrosis and cirrhosis outside secondary and specialist care Evidence-based recommendations on FibroScan for assessing liver fibrosis and cirrhosis outside secondary and specialist care. # Recommendations This guidance does not evaluate use of FibroScan for wider use than what is currently recommended in national guidelines. For example, it does not evaluate use of FibroScan outside secondary and specialist care to allow widespread screening for early liver disease. The recommendation for its use outside secondary and specialist care does not affect who should have testing as recommended in national guidelines. FibroScan is recommended as an option for assessing liver fibrosis or cirrhosis outside secondary and specialist care if: each FibroScan device is expected to be used for at least 500 scans per year, typically requiring use in locations which cover larger populations, such as community diagnostic hubs this is likely to improve access to testing for underserved groups it is used in accordance with national guidelines (see sections 2.3 to 2.5) a clear care pathway with guidance for healthcare professionals doing the test on what to do based on a FibroScan result is established locally through collaboration between primary or community care and secondary or specialist care providers there is training for healthcare professionals on how to do the test, and the company provides supporting materials to make sure people using the test continue to use it correctly. Why the committee made these recommendations Using FibroScan to assess liver fibrosis and cirrhosis outside secondary and specialist care has the potential to detect liver disease earlier. Providing tests at locations that are closer to more people who need them may improve access and attendance at appointments. This may also reduce health inequalities for people from underserved groups (such as disabled people, people living in rural areas or people from lower socioeconomic backgrounds). This assessment did not assess wider use of FibroScan than what is currently recommended in national guidelines (see sections 2.3 to 2.5). It only considered changing the location of testing and therefore FibroScan is only recommended for use outside secondary and specialist care in line with national guidelines. To maintain test performance, testing should be done as part of a clear care pathway. Also, training on doing the test should be provided and trained operators should use the device frequently to maintain their expertise. There is some uncertainty about the overall long-term costs of using the test outside secondary and specialist care. But, it is likely that if each device is used frequently, the immediate costs of doing a test in the community will be lower than the cost of referring a person for testing in secondary or specialist care. So, FibroScan is recommended as an option for assessing liver fibrosis and cirrhosis outside secondary and specialist care.# The diagnostic test # Clinical need and practice Liver fibrosis happens when persistent inflammation of the liver causes excessive scar tissue to build up in the organ and nearby blood vessels. The presence of scar tissue can impair overall liver function and limit blood flow which may lead to the death of liver cells. Advanced liver fibrosis can develop into cirrhosis, liver failure, portal hypertension and possibly needing a liver transplant. Liver fibrosis is caused by hepatitis, non-alcoholic fatty liver disease and alcohol-related liver disease. Cirrhosis is a late-stage liver disease that happens when inflammation and fibrosis has spread throughout the liver and disrupts the shape and function of the liver. Cirrhosis usually develops silently after exposure to 1 or more risk factors such as alcohol misuse and hepatitis B or C which cause inflammation in the liver, or obesity. But, not everyone with inflammation of the liver will eventually develop cirrhosis. Untreated cirrhosis can cause liver failure, liver cancer or death. NICE's guideline on assessing and managing cirrhosis in over 16s recommends using transient elastography to diagnose cirrhosis in people with hepatitis C, high alcohol consumption, diagnosed alcohol-related liver disease, or non-alcoholic fatty liver disease advanced fibrosis. NICE's guideline on diagnosing and managing chronic hepatitis B recommends transient elastography as an initial test for liver disease in adults newly referred for assessment and for the annual reassessment of liver disease in adults who are not taking antiviral treatment. NICE's guideline on assessing and managing non-alcoholic fatty liver disease states that the enhanced liver fibrosis test should be considered for people with non-alcoholic fatty liver disease to test for advanced liver fibrosis. Clinical experts highlighted that this test is not available everywhere, and FibroScan is often used instead of, or alongside, the enhanced liver fibrosis test. This is consistent with the British Society of Gastroenterology's guidance on non-alcoholic fatty liver disease and guidance on diagnosing and monitoring non-alcoholic fatty liver disease published in the British Medical Journal. # The intervention ## FibroScan used outside secondary and specialist care FibroScan (Echosens) is a non-invasive medical device that assesses liver fibrosis and cirrhosis by measuring the degree of liver stiffness. It can distinguish normal liver or minimal fibrosis from cirrhotic livers. FibroScan uses proprietary vibration-controlled transient elastography to quantify liver stiffness, which is essentially a measure of the extent of liver scarring. There are multiple products in the FibroScan range with different features, but all measure liver stiffness using transient elastography. The full list of devices can be found in table 1 of the scope. Different sizes of probes (small, medium or extra-large) are available. The device comes with a medium probe. Small and extra-large probes are optional extras. The extra-large probe is designed to enhance signal penetration through deeper tissues, reducing device failure rates in people with obesity. In this assessment, the intervention is FibroScan used outside secondary and specialist care. The population tested included only those who would have FibroScan in line with current NHS practice. The assessment focused on where the test should be done, rather than who should have the test. Submissions provided by the company were based on the cost of the FibroScan 430 Mini+ at £48,000 both within and outside of secondary and specialist care settings. # The comparator ## FibroScan used in secondary or specialist care The comparator is FibroScan used in the same way as the intervention, but in secondary or specialist care.# Committee discussion The diagnostics advisory committee considered evidence on FibroScan for assessing liver fibrosis and cirrhosis from several sources, including an external assessment report and an overview of that report. Full details are in the project documents for this guidance. # Increased access to FibroScan may improve early detection of liver disease Liver disease is a significant and growing cause of mortality in the UK and is often asymptomatic in early stages. Clinical experts explained that bringing FibroScan testing closer to people who need it improves attendance at appointments which could help with earlier detection of liver disease. They highlighted that there is a need to enable early detection of liver disease to reduce the number of cases being identified late in the disease course, and that fibrosis is reversible at early stages. Clinical experts commented that people generally have a positive experience with FibroScan and could be motivated by the test results to make behavioural changes that can reverse the course of their liver disease if detected early. But, they clarified that there was no evidence showing long-term behavioural change after FibroScan use. ## There may be benefits to local testing Patient experts reported that people often travel long distances to access FibroScan, especially in rural areas. Easier access to the test could reduce time and costs associated with this. It could help people attend the test in a more familiar environment. It could also help people with disabilities that make it difficult to travel. Patient experts commented that needing to travel longer distances could be a particular barrier for people from lower socioeconomic groups, who may be at higher risk of liver disease and typically die from the condition much earlier. The committee commented that the benefits outlined may not be seen if multiple appointments are needed to first do the scan and then separately deliver lifestyle advice. Clinical experts responded that lifestyle interventions are often delivered by healthcare assistants or nurses, and that any advice needed based on a FibroScan result would be given in the same appointment as the scan was done (see section 3.12). Clinical experts further commented that the increasing prevalence of liver disease means that secondary care services risk being overwhelmed, and that moving some aspects of care like FibroScan testing to alternative settings could help manage the workload. The extent to which making FibroScan available outside of secondary and specialist care would improve access to testing depends on which locations testing is made available, and what transport links are available (compared with transport links to secondary or specialist care). # Clinical effectiveness ## There is no data comparing the performance of FibroScan when used in alternative settings with its use in secondary or specialist care There was no evidence comparing the performance of FibroScan for measuring liver fibrosis when it is used in alternative settings with when it is used in secondary or specialist care. At consultation on the draft guidance, the lack of published evidence was confirmed by the company. ## Performance of FibroScan may depend on the experience of the user Clinical experts explained that how well FibroScan works depends on the experience of the user. They stated that if FibroScan is used often enough to make sure it is being used correctly, performance between different care settings would be comparable. ## There is no evidence on how often FibroScan would need to be used to maintain competence The committee considered the level of use that would be needed for users to maintain competence with FibroScan. The company commented that it encouraged users to make sure that competency is validated in practice, but that it does not currently provide guidance on requirements for the level of use. Clinical experts highlighted that there is no independent accreditation scheme for users, and that this is also the case for tests done in secondary or specialist care. They explained that FibroScan users outside secondary or specialist care in their areas had close links with local hepatology departments which could provide support when needed. The company explained that pilot schemes in primary care networks typically saw 20 to 30 people a month. The committee noted that it is unclear how many FibroScan tests are currently done in the NHS (see section 3.11). Clinical experts highlighted that there is no clear evidence to define a number or frequency of tests that need to be done to achieve and maintain expertise. The committee considered that sufficient levels of use may not be achieved if the test was available in individual GP practice populations, but use in services that cover larger populations, such as community diagnostic hubs or across a primary care network, would likely mean the users do enough tests to be sure it is being used correctly. The committee concluded that if used outside secondary or specialist care, it would be important to make sure that operators used FibroScan often enough to be able to accurately use the test, and for centres to consider having an accreditation framework in place. ## FibroScan can be done by any healthcare professional if they are suitably trained Clinical experts commented that FibroScan is relatively simple to use, that it indicates if the test has not worked, and that all grades of staff can use the technology if appropriately trained. At consultation, the company proposed several measures they could introduce to make sure that user competency is maintained after the initial training. These included developing a competency checklist and framework for annual assessment, offering on-site assessment, developing online competency assessments, or getting continuing professional development accreditation for FibroScan training. The committee agreed these would be valuable and would build confidence in test results. The committee concluded that if these measures were put in place, it would give reassurance that FibroScan assessment done outside secondary or specialist care would be done effectively. ## With appropriate training and quality assurance, and frequent use, FibroScan can be done effectively outside secondary or specialist care The committee recalled that there was no data directly comparing the performance of FibroScan tests done in, or outside, secondary or specialist care (see section 3.3). But, if the test was done in an alternative setting where appropriately trained operators do enough scans to maintain their expertise (see section 3.5), the committee concluded that it was likely that test performance could be maintained outside of secondary or specialist care, if there are ongoing measures to ensure quality such as those proposed by the company (see section 3.6). ## There was concern that greater availability of FibroScan outside secondary and specialist care could lead to wider use The committee recalled that the population in this assessment was restricted to those who would have FibroScan as in current NHS practice (see section 2.10). The test was only assessed for use in people it is already recommended for. It noted that performance of the test would depend on the population being tested, and that the value of testing would depend on the availability and effectiveness of interventions for the population tested, based on test results. Some consultation comments mentioned a potential benefit of FibroScan outside secondary or specialist care may be that it allows for wider screening for early liver disease. The committee noted that such use had not been assessed in this guidance and expressed concern that using FibroScan outside secondary or specialist care could lead to its use in a wider population than assessed, which could in turn affect its performance. It concluded that if recommended, the test should only be used as recommended in national guidelines (see sections 2.3 to 2.5). ## FibroScan should be used as part of a clear care pathway Clinical experts and committee members emphasised that clear guidance on what to do with the results of FibroScan is vital, particularly if testing is done outside a specialist setting. FibroScan done in alternative settings could reduce the number of unnecessary referrals to hepatology services. But, if there is uncertainty about what to do based on a result, a referral to specialist services, or contact with these services to ask advice, may still be made. Clinical experts highlighted that this could happen often if multiple conflicting test results (including FibroScan) were available. Liver pathways should be designed in agreement with primary and secondary care centres, and incorporate all tests used for detection and characterisation of liver disease, not just FibroScan. The committee concluded that establishing clear care pathways, with guidance for healthcare professionals on what to do based on a FibroScan result based on existing national guidelines, would be essential to ensure appropriate clinical management of liver disease in people who have FibroScan tests done outside secondary and specialist care settings. # Cost modelling ## The long-term effects of testing outside secondary and specialist care on costs are uncertain In the base-case analysis provided by the company, the economic model used a 1‑year time horizon. The committee commented that this omits potential costs or cost savings that would only appear many years after testing, such as the costs of treating previously undetected liver disease. The committee noted that increased attendance at FibroScan appointments in primary or community care increased costs in the model, because more people were referred for follow-up appointments in hepatology. But, any potential cost savings or health benefits of greater detection of liver disease were not considered (see section 3.1). At consultation on the draft guidance, the company submitted a scenario analysis with a 5‑year time horizon, which estimated lower long-term costs of about £30 less per person if testing was done in primary or community care. The external assessment group (EAG) explained that the lower cost was because there were fewer people with missed liver disease if testing was done in primary or community care, because more people attended scans. The committee considered it was unclear what assumptions were made in the modelling to base this on. Company representatives were not able to provide further clarity in the committee meeting. The company's model did not allow people's liver disease to progress in the 5‑year time period modelled. Clinical experts commented that this may not be appropriate for people with alcohol-related liver disease, whose condition can progress at a faster rate. The committee noted that the effect of lifestyle advice may differ depending on who provides it, for example a GP compared with a liver specialist, but experts said that there was no evidence on this. Clinical experts commented that referrals to hepatology services may increase after adopting FibroScan outside secondary and specialist care, but this may mean that more people who would benefit from specialist care are able to access it. Clinical experts also commented there was uncertainty about the long-term effect of using the test outside secondary or specialist care, for example, on levels of hospitalisation. The committee considered it plausible that testing in alternative settings could lead to longer term cost savings but thought that the company analysis did not allow this to be assessed. In advance of the third committee meeting, the company provided a revised model, and accompanying description, of the long-term implications of missing liver disease. This included allowing liver disease to progress within the modelled time period. This led to lower costs if FibroScan was done in primary or community care because increased attendance at scans was assumed to increase detection of liver disease and reduce progression to more severe stages. The EAG questioned the long-term costs used in the model because they came from a study of antiviral treatment for people with chronic hepatitis C (Wright et al. 2006). It suggested a study in which costs were related to managing non-alcoholic fatty liver disease (Tanajewski et al. 2017) as an alternative source. Some of the results from the updated model provided by the company for the third committee meeting, and further analyses run by the EAG using this model, did indicate that testing in primary or community care reduced long-term costs. Clinical experts said that earlier detection of liver disease could plausibly lead to cost savings. But, the committee also considered that costs could be higher in the long term (although potentially with accompanying improvements in health-related quality of life), particularly if a time frame longer than the 5 years modelled was used. The committee concluded that there is considerable uncertainty about the long-term effect of FibroScan testing outside secondary or specialist care on costs. ## There is uncertainty about the cost per scan in secondary care but the model likely underestimates this cost The committee discussed the costs used in the original model submitted by the company, and the revised costs used by the EAG. The EAG removed a cost from the company's model for staff time to do and evaluate FibroScan in secondary or specialist care because this time was already incorporated within an existing cost used in the model. This meant that, using the figure proposed by the company for testing in this setting, the cost of doing FibroScan was greater per scan when done in primary or community care. Experts agreed that the staff costs of doing the scan would be included in the Health Resource Group (HRG) cost used by the company. The company used HRG bundled costs for ultrasound elastography to estimate the cost of FibroScan in secondary or specialist care, at £43.93 in the base case. This cost was also used by the EAG. The company highlighted that a scenario analysis done by the EAG in which a higher cost per use in secondary or specialist care (£61.98) was used, based on a weighted average of 2 different costs attributed to the HRG code, and suggested that this might be more appropriate. The EAG commented that the results of this scenario still indicated that using FibroScan outside secondary or specialist care was cost incurring. In their report, the EAG highlighted difficulties in evaluating the costs of doing FibroScan in the different settings that were a consequence of comparing a bundled HRG cost from secondary care with a cost obtained by micro-costing in a non-hospital setting, where a HRG code does not currently exist. The committee noted that the HRG code for ultrasound elastography was used only 3,561 times for outpatients in 2019 to 2020, which likely underestimated the number of FibroScan tests done in the NHS. Further scans may be done during outpatient appointments and recorded using other HRG codes, potentially at higher cost. At consultation, the company provided further analyses. Its base-case analysis kept the higher cost of testing in secondary care, including additional costs for staff time to do the test as well as the HRG code. Analyses using alternative costs were not cost neutral or cost saving for testing done in primary or community care. The company did not provide any further support for their choice of cost used in the base case or rationale for the most appropriate choice of cost for the test in secondary care. The committee also questioned whether the full costs of a referral for testing in secondary or specialist care had been incorporated. Missed appointments were included as a separate cost in the model. A clinical expert commented that the cost of missed appointments was likely to already be captured in the cost of doing scans used in the company's model. If so, including an additional cost for missed appointments was not appropriate. Clinical experts noted that if a person misses an appointment in secondary care, they may need to restart the referral pathway to access FibroScan, incurring further cost. The committee concluded that there was still considerable uncertainty about the costs of testing in secondary care, and suggested further analysis to address this. In advance of the third committee meeting, the company provided further analyses. This included a micro-costing-based estimate of £40.61 for doing FibroScan in secondary care. The number of scans (610) used to determine this was from a survey of 4 NHS trusts. The EAG noted some limitations in the company's micro-costing approach but stated this was its preferred method for assessing costs. Clinical experts noticed that the company's micro-costing only included costs of doing FibroScan but not the costs of a referral for a hepatologist outpatient appointment that would happen in practice if a GP decided that the scan was needed. The EAG noted that the NHS reference cost for this appointment is £268 (cost in individual trusts may vary). The committee concluded that while there is uncertainty about the exact cost of testing, it is likely that the model underestimates the cost of doing FibroScan in secondary care. ## The extent of use of FibroScan outside secondary or specialist care will affect cost per use The committee noted that the cost the company has provided for FibroScan in primary or community care in their original submission is higher (£58.00 per scan, plus £10.50 for staff time to do the test and evaluate FibroScan result) than the HRG code cost used in the EAG's base case and scenario analysis for FibroScan in secondary or specialist care (see section 3.11). This was based on a fixed cost being charged by the company per scan, with no upfront cost for the machine. At consultation, the company submitted an alternative costing model in which the FibroScan device was purchased outright, which included a maintenance contract over the assumed 7‑year lifespan of the device. The average cost per scan, calculated assuming 500 scans per year being done based on Southampton clinical commissioning group use, was £34.29 plus staff time to do the test. The EAG did a threshold analysis and found that the device would have to be used at least 300 times a year for this model to be cheaper than the pay-per-scan model originally suggested. The company stated that their intended use of the tests outside secondary or specialist care is in hubs and diagnostic centres, rather than single GP practices, where use would be expected to be higher. The committee agreed that this usage may be achieved if the device was used in primary care networks or community diagnostic hubs (see section 3.7). But, it noted that only a single estimate of expected use in primary or community care had been provided by the company. The committee recalled that moving FibroScan testing outside secondary and specialist care would potentially move workload to other settings for activities that happen based on test results, such as lifestyle advice, and questioned whether the time taken by healthcare professionals to do this has been adequately captured in costs of doing the test outside secondary and specialist care. They further highlighted that even if a person is not referred to a specialist service after a test done outside this setting, advice from staff in these services may be sought. A clinical expert emphasised that community and primary care staff such as nurses and healthcare assistants are experienced in providing lifestyle and diet advice (see section 3.2) and that any advice could be given in the same appointment as the FibroScan test was done. The committee concluded that there was uncertainty about whether the costs of doing FibroScan outside secondary and community care used in the company's model were an accurate reflection of the true cost of testing. It further noted that if buying the FibroScan device outright, the cost per use would depend on the extent of use, and asked for further information to support estimates of expected use. In advance of the third committee meeting, the company provided further analysis. Using local real-world data and national data sources, the company estimated that 1 FibroScan device shared between 5 primary care networks would be used for 2,500 to 5,000 scans per year. The EAG considered the estimates based on real-world data more robust but stated that using 6 sources of information provided by the company, the EAG found only 1 example where FibroScan was used in as many as 500 to 1,000 people per year per primary care network. But of the 8 clinical experts consulted by the EAG, 5 said sharing 1 device between 5 primary care networks was plausible in some scenarios and all thought a single network would be able to do 500 scans per year. The clinical experts attending the committee meeting supported this view. The committee noted that in its updated submissions, the company had provided the cost per FibroScan done in primary care based on buying the device outright and at least 500 scans per device being done per year (£44.79), rather than the cost per scan based on a pay-per-scan charging model as in its original submission (£58.00 per scan, plus £10.50 for staff time). ## Using FibroScan in alternative settings is likely to cost less than doing the test in secondary care There is still uncertainty about the true cost of doing a test both in secondary and specialist care (see section 3.11) or outside these settings (see section 3.12). The committee recalled that it is likely that the model underestimated the cost of testing in secondary care (see section 3.11). Higher cost of testing in this setting would make testing outside of secondary and specialist care more likely to be cost saving. The committee concluded that, based on buying FibroScan 430 Mini+ outright (see section 2.11) and an expected use of at least 500 scans per year per device as modelled by the company, the immediate costs related to a FibroScan test were likely to be lower outside of secondary and specialist care. The committee also recalled that making sure FibroScan was used enough outside secondary and specialist care was important to make sure operators do enough scans to maintain their expertise (see section 3.7).The committee further recalled that there is considerable uncertainty about the long-term effect on costs of using the test outside secondary and specialist care (see section 3.10). On balance, the committee concluded that there was enough certainty that the immediate costs of using FibroScan for assessing liver fibrosis and cirrhosis outside secondary and specialist care are likely to be lower than the cost of referring people for testing in secondary or specialist care to allow it to recommend use in this setting. ## It would be beneficial to monitor the effect of FibroScan outside secondary and specialist care to make sure that the expected benefits are seen The committee commented that it would be beneficial to monitor the effect of greater availability of FibroScan outside secondary and specialist care on relevant costs and outcomes to make sure that the proposed benefits are being achieved in practice in the NHS.	{'Recommendations': 'This guidance does not evaluate use of FibroScan for wider use than what is currently recommended in national guidelines. For example, it does not evaluate use of FibroScan outside secondary and specialist care to allow widespread screening for early liver disease. The recommendation for its use outside secondary and specialist care does not affect who should have testing as recommended in national guidelines.\n\nFibroScan is recommended as an option for assessing liver fibrosis or cirrhosis outside secondary and specialist care if:\n\neach FibroScan device is expected to be used for at least 500\xa0scans per year, typically requiring use in locations which cover larger populations, such as community diagnostic hubs\n\nthis is likely to improve access to testing for underserved groups\n\nit is used in accordance with national guidelines (see sections\xa02.3 to 2.5)\n\na clear care pathway with guidance for healthcare professionals doing the test on what to do based on a FibroScan result is established locally through collaboration between primary or community care and secondary or specialist care providers\n\nthere is training for healthcare professionals on how to do the test, and\n\nthe company provides supporting materials to make sure people using the test continue to use it correctly.\n\nWhy the committee made these recommendations\n\nUsing FibroScan to assess liver fibrosis and cirrhosis outside secondary and specialist care has the potential to detect liver disease earlier. Providing tests at locations that are closer to more people who need them may improve access and attendance at appointments. This may also reduce health inequalities for people from underserved groups (such as disabled people, people living in rural areas or people from lower socioeconomic backgrounds).\n\nThis assessment did not assess wider use of FibroScan than what is currently recommended in national guidelines (see sections\xa02.3 to\xa02.5). It only considered changing the location of testing and therefore FibroScan is only recommended for use outside secondary and specialist care in line with national guidelines. To maintain test performance, testing should be done as part of a clear care pathway. Also, training on doing the test should be provided and trained operators should use the device frequently to maintain their expertise.\n\nThere is some uncertainty about the overall long-term costs of using the test outside secondary and specialist care. But, it is likely that if each device is used frequently, the immediate costs of doing a test in the community will be lower than the cost of referring a person for testing in secondary or specialist care. So, FibroScan is recommended as an option for assessing liver fibrosis and cirrhosis outside secondary and specialist care.', 'The diagnostic test': "# Clinical need and practice\n\nLiver fibrosis happens when persistent inflammation of the liver causes excessive scar tissue to build up in the organ and nearby blood vessels. The presence of scar tissue can impair overall liver function and limit blood flow which may lead to the death of liver cells. Advanced liver fibrosis can develop into cirrhosis, liver failure, portal hypertension and possibly needing a liver transplant. Liver fibrosis is caused by hepatitis, non-alcoholic fatty liver disease and alcohol-related liver disease.\n\nCirrhosis is a late-stage liver disease that happens when inflammation and fibrosis has spread throughout the liver and disrupts the shape and function of the liver. Cirrhosis usually develops silently after exposure to 1\xa0or more risk factors such as alcohol misuse and hepatitis\xa0B or C which cause inflammation in the liver, or obesity. But, not everyone with inflammation of the liver will eventually develop cirrhosis. Untreated cirrhosis can cause liver failure, liver cancer or death.\n\nNICE's guideline on assessing and managing cirrhosis in over 16s recommends using transient elastography to diagnose cirrhosis in people with hepatitis\xa0C, high alcohol consumption, diagnosed alcohol-related liver disease, or non-alcoholic fatty liver disease advanced fibrosis.\n\nNICE's guideline on diagnosing and managing chronic hepatitis\xa0B recommends transient elastography as an initial test for liver disease in adults newly referred for assessment and for the annual reassessment of liver disease in adults who are not taking antiviral treatment.\n\nNICE's guideline on assessing and managing non-alcoholic fatty liver disease states that the enhanced liver fibrosis test should be considered for people with non-alcoholic fatty liver disease to test for advanced liver fibrosis. Clinical experts highlighted that this test is not available everywhere, and FibroScan is often used instead of, or alongside, the enhanced liver fibrosis test. This is consistent with the British Society of Gastroenterology's guidance on non-alcoholic fatty liver disease and guidance on diagnosing and monitoring non-alcoholic fatty liver disease published in the British Medical Journal.\n\n# The intervention\n\n## FibroScan used outside secondary and specialist care\n\nFibroScan (Echosens) is a non-invasive medical device that assesses liver fibrosis and cirrhosis by measuring the degree of liver stiffness. It can distinguish normal liver or minimal fibrosis from cirrhotic livers.\n\nFibroScan uses proprietary vibration-controlled transient elastography to quantify liver stiffness, which is essentially a measure of the extent of liver scarring.\n\nThere are multiple products in the FibroScan range with different features, but all measure liver stiffness using transient elastography. The full list of devices can be found in table 1 of the scope.\n\nDifferent sizes of probes (small, medium or extra-large) are available. The device comes with a medium probe. Small and extra-large probes are optional extras. The extra-large probe is designed to enhance signal penetration through deeper tissues, reducing device failure rates in people with obesity.\n\nIn this assessment, the intervention is FibroScan used outside secondary and specialist care. The population tested included only those who would have FibroScan in line with current NHS practice. The assessment focused on where the test should be done, rather than who should have the test.\n\nSubmissions provided by the company were based on the cost of the FibroScan\xa0430\xa0Mini+ at £48,000 both within and outside of secondary and specialist care settings.\n\n# The comparator\n\n## FibroScan used in secondary or specialist care\n\nThe comparator is FibroScan used in the same way as the intervention, but in secondary or specialist care.", 'Committee discussion': "The diagnostics advisory committee considered evidence on FibroScan for assessing liver fibrosis and cirrhosis from several sources, including an external assessment report and an overview of that report. Full details are in the project documents for this guidance.\n\n# Increased access to FibroScan may improve early detection of liver disease\n\nLiver disease is a significant and growing cause of mortality in the UK and is often asymptomatic in early stages. Clinical experts explained that bringing FibroScan testing closer to people who need it improves attendance at appointments which could help with earlier detection of liver disease. They highlighted that there is a need to enable early detection of liver disease to reduce the number of cases being identified late in the disease course, and that fibrosis is reversible at early stages. Clinical experts commented that people generally have a positive experience with FibroScan and could be motivated by the test results to make behavioural changes that can reverse the course of their liver disease if detected early. But, they clarified that there was no evidence showing long-term behavioural change after FibroScan use.\n\n## There may be benefits to local testing\n\nPatient experts reported that people often travel long distances to access FibroScan, especially in rural areas. Easier access to the test could reduce time and costs associated with this. It could help people attend the test in a more familiar environment. It could also help people with disabilities that make it difficult to travel. Patient experts commented that needing to travel longer distances could be a particular barrier for people from lower socioeconomic groups, who may be at higher risk of liver disease and typically die from the condition much earlier. The committee commented that the benefits outlined may not be seen if multiple appointments are needed to first do the scan and then separately deliver lifestyle advice. Clinical experts responded that lifestyle interventions are often delivered by healthcare assistants or nurses, and that any advice needed based on a FibroScan result would be given in the same appointment as the scan was done (see section\xa03.12). Clinical experts further commented that the increasing prevalence of liver disease means that secondary care services risk being overwhelmed, and that moving some aspects of care like FibroScan testing to alternative settings could help manage the workload. The extent to which making FibroScan available outside of secondary and specialist care would improve access to testing depends on which locations testing is made available, and what transport links are available (compared with transport links to secondary or specialist care).\n\n# Clinical effectiveness\n\n## There is no data comparing the performance of FibroScan when used in alternative settings with its use in secondary or specialist care\n\nThere was no evidence comparing the performance of FibroScan for measuring liver fibrosis when it is used in alternative settings with when it is used in secondary or specialist care. At consultation on the draft guidance, the lack of published evidence was confirmed by the company.\n\n## Performance of FibroScan may depend on the experience of the user\n\nClinical experts explained that how well FibroScan works depends on the experience of the user. They stated that if FibroScan is used often enough to make sure it is being used correctly, performance between different care settings would be comparable.\n\n## There is no evidence on how often FibroScan would need to be used to maintain competence\n\nThe committee considered the level of use that would be needed for users to maintain competence with FibroScan. The company commented that it encouraged users to make sure that competency is validated in practice, but that it does not currently provide guidance on requirements for the level of use. Clinical experts highlighted that there is no independent accreditation scheme for users, and that this is also the case for tests done in secondary or specialist care. They explained that FibroScan users outside secondary or specialist care in their areas had close links with local hepatology departments which could provide support when needed. The company explained that pilot schemes in primary care networks typically saw 20 to 30\xa0people a month. The committee noted that it is unclear how many FibroScan tests are currently done in the NHS (see section\xa03.11). Clinical experts highlighted that there is no clear evidence to define a number or frequency of tests that need to be done to achieve and maintain expertise. The committee considered that sufficient levels of use may not be achieved if the test was available in individual GP practice populations, but use in services that cover larger populations, such as community diagnostic hubs or across a primary care network, would likely mean the users do enough tests to be sure it is being used correctly. The committee concluded that if used outside secondary or specialist care, it would be important to make sure that operators used FibroScan often enough to be able to accurately use the test, and for centres to consider having an accreditation framework in place.\n\n## FibroScan can be done by any healthcare professional if they are suitably trained\n\nClinical experts commented that FibroScan is relatively simple to use, that it indicates if the test has not worked, and that all grades of staff can use the technology if appropriately trained. At consultation, the company proposed several measures they could introduce to make sure that user competency is maintained after the initial training. These included developing a competency checklist and framework for annual assessment, offering on-site assessment, developing online competency assessments, or getting continuing professional development accreditation for FibroScan training. The committee agreed these would be valuable and would build confidence in test results. The committee concluded that if these measures were put in place, it would give reassurance that FibroScan assessment done outside secondary or specialist care would be done effectively.\n\n## With appropriate training and quality assurance, and frequent use, FibroScan can be done effectively outside secondary or specialist care\n\nThe committee recalled that there was no data directly comparing the performance of FibroScan tests done in, or outside, secondary or specialist care (see section\xa03.3). But, if the test was done in an alternative setting where appropriately trained operators do enough scans to maintain their expertise (see section\xa03.5), the committee concluded that it was likely that test performance could be maintained outside of secondary or specialist care, if there are ongoing measures to ensure quality such as those proposed by the company (see section\xa03.6).\n\n## There was concern that greater availability of FibroScan outside secondary and specialist care could lead to wider use\n\nThe committee recalled that the population in this assessment was restricted to those who would have FibroScan as in current NHS practice (see section\xa02.10). The test was only assessed for use in people it is already recommended for. It noted that performance of the test would depend on the population being tested, and that the value of testing would depend on the availability and effectiveness of interventions for the population tested, based on test results. Some consultation comments mentioned a potential benefit of FibroScan outside secondary or specialist care may be that it allows for wider screening for early liver disease. The committee noted that such use had not been assessed in this guidance and expressed concern that using FibroScan outside secondary or specialist care could lead to its use in a wider population than assessed, which could in turn affect its performance. It concluded that if recommended, the test should only be used as recommended in national guidelines (see sections\xa02.3 to 2.5).\n\n## FibroScan should be used as part of a clear care pathway\n\nClinical experts and committee members emphasised that clear guidance on what to do with the results of FibroScan is vital, particularly if testing is done outside a specialist setting. FibroScan done in alternative settings could reduce the number of unnecessary referrals to hepatology services. But, if there is uncertainty about what to do based on a result, a referral to specialist services, or contact with these services to ask advice, may still be made. Clinical experts highlighted that this could happen often if multiple conflicting test results (including FibroScan) were available. Liver pathways should be designed in agreement with primary and secondary care centres, and incorporate all tests used for detection and characterisation of liver disease, not just FibroScan. The committee concluded that establishing clear care pathways, with guidance for healthcare professionals on what to do based on a FibroScan result based on existing national guidelines, would be essential to ensure appropriate clinical management of liver disease in people who have FibroScan tests done outside secondary and specialist care settings.\n\n# Cost modelling\n\n## The long-term effects of testing outside secondary and specialist care on costs are uncertain\n\nIn the base-case analysis provided by the company, the economic model used a 1‑year time horizon. The committee commented that this omits potential costs or cost savings that would only appear many years after testing, such as the costs of treating previously undetected liver disease. The committee noted that increased attendance at FibroScan appointments in primary or community care increased costs in the model, because more people were referred for follow-up appointments in hepatology. But, any potential cost savings or health benefits of greater detection of liver disease were not considered (see section\xa03.1). At consultation on the draft guidance, the company submitted a scenario analysis with a 5‑year time horizon, which estimated lower long-term costs of about £30 less per person if testing was done in primary or community care. The external assessment group (EAG) explained that the lower cost was because there were fewer people with missed liver disease if testing was done in primary or community care, because more people attended scans. The committee considered it was unclear what assumptions were made in the modelling to base this on. Company representatives were not able to provide further clarity in the committee meeting. The company's model did not allow people's liver disease to progress in the 5‑year time period modelled. Clinical experts commented that this may not be appropriate for people with alcohol-related liver disease, whose condition can progress at a faster rate. The committee noted that the effect of lifestyle advice may differ depending on who provides it, for example a GP compared with a liver specialist, but experts said that there was no evidence on this. Clinical experts commented that referrals to hepatology services may increase after adopting FibroScan outside secondary and specialist care, but this may mean that more people who would benefit from specialist care are able to access it. Clinical experts also commented there was uncertainty about the long-term effect of using the test outside secondary or specialist care, for example, on levels of hospitalisation. The committee considered it plausible that testing in alternative settings could lead to longer term cost savings but thought that the company analysis did not allow this to be assessed. In advance of the third committee meeting, the company provided a revised model, and accompanying description, of the long-term implications of missing liver disease. This included allowing liver disease to progress within the modelled time period. This led to lower costs if FibroScan was done in primary or community care because increased attendance at scans was assumed to increase detection of liver disease and reduce progression to more severe stages. The EAG questioned the long-term costs used in the model because they came from a study of antiviral treatment for people with chronic hepatitis\xa0C (Wright et al. 2006). It suggested a study in which costs were related to managing non-alcoholic fatty liver disease (Tanajewski et al. 2017) as an alternative source. Some of the results from the updated model provided by the company for the third committee meeting, and further analyses run by the EAG using this model, did indicate that testing in primary or community care reduced long-term costs. Clinical experts said that earlier detection of liver disease could plausibly lead to cost savings. But, the committee also considered that costs could be higher in the long term (although potentially with accompanying improvements in health-related quality of life), particularly if a time frame longer than the 5\xa0years modelled was used. The committee concluded that there is considerable uncertainty about the long-term effect of FibroScan testing outside secondary or specialist care on costs.\n\n## There is uncertainty about the cost per scan in secondary care but the model likely underestimates this cost\n\nThe committee discussed the costs used in the original model submitted by the company, and the revised costs used by the EAG. The EAG removed a cost from the company's model for staff time to do and evaluate FibroScan in secondary or specialist care because this time was already incorporated within an existing cost used in the model. This meant that, using the figure proposed by the company for testing in this setting, the cost of doing FibroScan was greater per scan when done in primary or community care. Experts agreed that the staff costs of doing the scan would be included in the Health Resource Group (HRG) cost used by the company. The company used HRG bundled costs for ultrasound elastography to estimate the cost of FibroScan in secondary or specialist care, at £43.93 in the base case. This cost was also used by the EAG. The company highlighted that a scenario analysis done by the EAG in which a higher cost per use in secondary or specialist care (£61.98) was used, based on a weighted average of 2 different costs attributed to the HRG code, and suggested that this might be more appropriate. The EAG commented that the results of this scenario still indicated that using FibroScan outside secondary or specialist care was cost incurring. In their report, the EAG highlighted difficulties in evaluating the costs of doing FibroScan in the different settings that were a consequence of comparing a bundled HRG cost from secondary care with a cost obtained by micro-costing in a non-hospital setting, where a HRG code does not currently exist. The committee noted that the HRG code for ultrasound elastography was used only 3,561\xa0times for outpatients in 2019 to 2020, which likely underestimated the number of FibroScan tests done in the NHS. Further scans may be done during outpatient appointments and recorded using other HRG codes, potentially at higher cost. At consultation, the company provided further analyses. Its base-case analysis kept the higher cost of testing in secondary care, including additional costs for staff time to do the test as well as the HRG code. Analyses using alternative costs were not cost neutral or cost saving for testing done in primary or community care. The company did not provide any further support for their choice of cost used in the base case or rationale for the most appropriate choice of cost for the test in secondary care. The committee also questioned whether the full costs of a referral for testing in secondary or specialist care had been incorporated. Missed appointments were included as a separate cost in the model. A clinical expert commented that the cost of missed appointments was likely to already be captured in the cost of doing scans used in the company's model. If so, including an additional cost for missed appointments was not appropriate. Clinical experts noted that if a person misses an appointment in secondary care, they may need to restart the referral pathway to access FibroScan, incurring further cost. The committee concluded that there was still considerable uncertainty about the costs of testing in secondary care, and suggested further analysis to address this. In advance of the third committee meeting, the company provided further analyses. This included a micro-costing-based estimate of £40.61 for doing FibroScan in secondary care. The number of scans (610) used to determine this was from a survey of 4\xa0NHS trusts. The EAG noted some limitations in the company's micro-costing approach but stated this was its preferred method for assessing costs. Clinical experts noticed that the company's micro-costing only included costs of doing FibroScan but not the costs of a referral for a hepatologist outpatient appointment that would happen in practice if a GP decided that the scan was needed. The EAG noted that the NHS reference cost for this appointment is £268 (cost in individual trusts may vary). The committee concluded that while there is uncertainty about the exact cost of testing, it is likely that the model underestimates the cost of doing FibroScan in secondary care.\n\n## The extent of use of FibroScan outside secondary or specialist care will affect cost per use\n\nThe committee noted that the cost the company has provided for FibroScan in primary or community care in their original submission is higher (£58.00 per scan, plus £10.50 for staff time to do the test and evaluate FibroScan result) than the HRG code cost used in the EAG's base case and scenario analysis for FibroScan in secondary or specialist care (see section\xa03.11). This was based on a fixed cost being charged by the company per scan, with no upfront cost for the machine. At consultation, the company submitted an alternative costing model in which the FibroScan device was purchased outright, which included a maintenance contract over the assumed 7‑year lifespan of the device. The average cost per scan, calculated assuming 500\xa0scans per year being done based on Southampton clinical commissioning group use, was £34.29 plus staff time to do the test. The EAG did a threshold analysis and found that the device would have to be used at least 300\xa0times a year for this model to be cheaper than the pay-per-scan model originally suggested. The company stated that their intended use of the tests outside secondary or specialist care is in hubs and diagnostic centres, rather than single GP practices, where use would be expected to be higher. The committee agreed that this usage may be achieved if the device was used in primary care networks or community diagnostic hubs (see section\xa03.7). But, it noted that only a single estimate of expected use in primary or community care had been provided by the company. The committee recalled that moving FibroScan testing outside secondary and specialist care would potentially move workload to other settings for activities that happen based on test results, such as lifestyle advice, and questioned whether the time taken by healthcare professionals to do this has been adequately captured in costs of doing the test outside secondary and specialist care. They further highlighted that even if a person is not referred to a specialist service after a test done outside this setting, advice from staff in these services may be sought. A clinical expert emphasised that community and primary care staff such as nurses and healthcare assistants are experienced in providing lifestyle and diet advice (see section\xa03.2) and that any advice could be given in the same appointment as the FibroScan test was done. The committee concluded that there was uncertainty about whether the costs of doing FibroScan outside secondary and community care used in the company's model were an accurate reflection of the true cost of testing. It further noted that if buying the FibroScan device outright, the cost per use would depend on the extent of use, and asked for further information to support estimates of expected use. In advance of the third committee meeting, the company provided further analysis. Using local real-world data and national data sources, the company estimated that 1\xa0FibroScan device shared between 5\xa0primary care networks would be used for 2,500 to 5,000\xa0scans per year. The EAG considered the estimates based on real-world data more robust but stated that using 6\xa0sources of information provided by the company, the EAG found only 1\xa0example where FibroScan was used in as many as 500 to 1,000\xa0people per year per primary care network. But of the 8\xa0clinical experts consulted by the EAG, 5 said sharing 1\xa0device between 5\xa0primary care networks was plausible in some scenarios and all thought a single network would be able to do 500\xa0scans per year. The clinical experts attending the committee meeting supported this view. The committee noted that in its updated submissions, the company had provided the cost per FibroScan done in primary care based on buying the device outright and at least 500\xa0scans per device being done per year (£44.79), rather than the cost per scan based on a pay-per-scan charging model as in its original submission (£58.00 per scan, plus £10.50 for staff time).\n\n## Using FibroScan in alternative settings is likely to cost less than doing the test in secondary care\n\nThere is still uncertainty about the true cost of doing a test both in secondary and specialist care (see section\xa03.11) or outside these settings (see section\xa03.12). The committee recalled that it is likely that the model underestimated the cost of testing in secondary care (see section\xa03.11). Higher cost of testing in this setting would make testing outside of secondary and specialist care more likely to be cost saving. The committee concluded that, based on buying FibroScan\xa0430\xa0Mini+ outright (see section\xa02.11) and an expected use of at least 500\xa0scans per year per device as modelled by the company, the immediate costs related to a FibroScan test were likely to be lower outside of secondary and specialist care. The committee also recalled that making sure FibroScan was used enough outside secondary and specialist care was important to make sure operators do enough scans to maintain their expertise (see section\xa03.7).The committee further recalled that there is considerable uncertainty about the long-term effect on costs of using the test outside secondary and specialist care (see section\xa03.10). On balance, the committee concluded that there was enough certainty that the immediate costs of using FibroScan for assessing liver fibrosis and cirrhosis outside secondary and specialist care are likely to be lower than the cost of referring people for testing in secondary or specialist care to allow it to recommend use in this setting.\n\n## It would be beneficial to monitor the effect of FibroScan outside secondary and specialist care to make sure that the expected benefits are seen\n\nThe committee commented that it would be beneficial to monitor the effect of greater availability of FibroScan outside secondary and specialist care on relevant costs and outcomes to make sure that the proposed benefits are being achieved in practice in the NHS."}	https://www.nice.org.uk/guidance/dg48	Evidence-based recommendations on FibroScan for assessing liver fibrosis and cirrhosis outside secondary and specialist care.
8697a4babbf901f5ab6d4dd340ab4f1d543b2b45	nice	Daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma	Daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma Evidence-based recommendations on daratumumab (Darzalex) with bortezomib and dexamethasone for previously treated multiple myeloma in adults. # Recommendations Daratumumab with bortezomib and dexamethasone is recommended as an option for treating multiple myeloma in adults, only if they have had just 1 previous line of treatment and: it included lenalidomide or lenalidomide is unsuitable as a second-line treatment and the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with daratumumab with bortezomib and dexamethasone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations This evaluation reviews the evidence for daratumumab with bortezomib and dexamethasone from NICE technology appraisal guidance 573. It also reviews new data collected as part of the managed access agreement. The company proposed daratumumab with bortezomib and dexamethasone as a second-line treatment, which is narrower than its marketing authorisation. Second‑line treatments for multiple myeloma include: bortezomib with dexamethasone carfilzomib with dexamethasone lenalidomide with dexamethasone carfilzomib with lenalidomide and dexamethasone. Clinical trial evidence shows that daratumumab with bortezomib and dexamethasone decreases the risk of dying and the chance of myeloma returning or getting worse compared with bortezomib with dexamethasone. There is no direct evidence comparing it with carfilzomib with dexamethasone. An indirect comparison suggests that it decreases the risk of the myeloma returning or getting worse compared with carfilzomib with dexamethasone. No evidence was provided for a comparison with the lenalidomide treatments. The most likely cost-effectiveness estimates for daratumumab with bortezomib and dexamethasone are below what NICE considers an acceptable use of NHS resources. Because no comparison was done with lenalidomide treatments, daratumumab with bortezomib and dexamethasone is only recommended for people who cannot have lenalidomide as a second treatment. This includes people who had lenalidomide as their first treatment, or when lenalidomide is unsuitable as a second‑line treatment.# Information about daratumumab with bortezomib and dexamethasone # Marketing authorisation indication Daratumumab (Darzalex, Janssen) is indicated 'in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for daratumumab. # Price The list prices for daratumumab (excluding VAT; BNF online, accessed February 2023) are: £4,320 per 1,800 mg/15 ml solution for injection vial £360 per 100 mg/5 ml concentrate for solution for infusion vial £1,440 per 400 mg/20 ml concentrate for solution for infusion vial. The company has a commercial arrangement. This makes daratumumab with bortezomib and dexamethasone available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Janssen, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Treatment pathway ## Daratumumab plus bortezomib and dexamethasone This evaluation reviews the evidence for daratumumab plus bortezomib and dexamethasone for relapsed multiple myeloma, which was approved for use in the Cancer Drugs Fund in NICE technology appraisal guidance 573. It also reviews new data collected as part of the managed access agreement. The company presented evidence for daratumumab plus bortezomib and dexamethasone as a second-line treatment only, in line with the original company submission and recommendation in technology appraisal guidance 573. The committee recognised that limiting this treatment to second line was narrower than its marketing authorisation. But concluded that it would appraise daratumumab plus bortezomib and dexamethasone after only 1 previous treatment, having been presented only with evidence for its use as a second-line treatment. ## Evolving treatment pathway Multiple myeloma is a chronic condition that affects how long people live and their quality of life. A clinical expert described it as a relapsing and remitting disease with a complex and evolving pathway. The Cancer Drugs Fund clinical lead explained that each appraisal is a snapshot in time. They explained that since daratumumab plus bortezomib and dexamethasone was available through the Cancer Drugs Fund several new multiple myeloma drugs have been recommended for routine commissioning in the NHS. This has changed what would be offered to people with a new diagnosis, and what subsequent treatment is offered to those who could have daratumumab plus bortezomib and dexamethasone. The committee acknowledged that this makes interpreting clinical trial evidence for this appraisal challenging, because the trial (see section 3.5) started several years ago and may not reflect the current multiple myeloma pathway. The committee noted that the company submission also included new data collected as part of the managed access agreement. It was aware that this data may have limitations because the managed access period mostly took place during the COVID‑19 pandemic. The pandemic may have affected the data collected in 2 ways. First, by affecting the care pathway, because some other treatment options were made available for an interim period. Second, because there may be excess mortality associated with COVID‑19 in people who had daratumumab plus bortezomib and dexamethasone. The committee agreed that it would consider these limitations in its decision making. ## New treatment option Patient experts stated that in their experience, daratumumab plus bortezomib and dexamethasone had very few side effects. This was echoed in a patient survey done by Myeloma UK, which said that 95% of respondents would recommend the treatment, despite some people having side effects. One patient expert noted that having daratumumab plus bortezomib and dexamethasone had dramatically increased their quality of life. They said it helped with maintaining day to day routines, and meant that they were likely to be well enough for more options later in the treatment pathway. They explained that this was important because the condition becomes more resistant to treatment with each relapse. The committee recognised the need for effective, well-tolerated treatment options for people with multiple myeloma who have had a previous treatment. ## Comparators Treatment options for people with newly diagnosed multiple myeloma depend on if a stem cell transplant is a suitable treatment option. Once the disease progresses, treatment options depend on what treatments people have had before, response to these treatments, and patient preference. The committee noted that progression through the pathway is slow, and each remission and progression may span several years. It noted that treatment choice at each line may differ in clinical practice depending on when a person entered the treatment pathway, and what treatments have been available to them before. For someone who has had 1 previous line of treatment, currently available options at second line are: bortezomib (see NICE's technology appraisal guidance on bortezomib monotherapy for relapsed multiple myeloma) carfilzomib plus dexamethasone (see NICE's technology appraisal guidance on carfilzomib for previously treated multiple myeloma) lenalidomide plus dexamethasone (see NICE's technology appraisal guidance on lenalidomide with dexamethasone for multiple myeloma after 1 treatment with bortezomib) carfilzomib plus lenalidomide and dexamethasone (see NICE's technology appraisal guidance on carfilzomib with dexamethasone and lenalidomide for previously treated multiple myeloma).The committee considered the available treatment options and if these were appropriately included in the evidence presented. The company submission focused on second-line treatment options, including bortezomib plus dexamethasone and carfilzomib plus dexamethasone, which aligned with the comparators included in the NICE scope. The clinical expert explained that most people for whom a transplant is suitable would now have lenalidomide at first line, so would have bortezomib or carfilzomib combination treatments at second line. But they explained that some people would not progress through the transplant pathway to lenalidomide maintenance at first line, so would be able to have lenalidomide at a later line. They also noted that for those who cannot have a transplant, lenalidomide plus dexamethasone is the most widely used first-line treatment option in clinical practice, and accounts for 70% to 80% of treatments used. Anyone whose disease relapsed following lenalidomide would have bortezomib or carfilzomib as a second-line treatment. But the clinical expert explained that lenalidomide combinations were also used as second-line treatment options. For 20% to 30% of people who cannot have a transplant, bortezomib combination treatments would be the preferred first-choice treatment. They explained this would be used if a finite period of treatment is preferred or if a rapid response is needed. The Cancer Drugs Fund clinical lead confirmed that all these treatments are used in NHS practice. But they explained that second-line lenalidomide use may currently be higher than estimated by the clinical expert, but that this reflected the slow evolution of the multiple myeloma pathway. That is, in the past, people may have had thalidomide or bortezomib as first-line treatment if lenalidomide had not been available at first line, so these people would be able to have lenalidomide at second line, though this proportion was likely to reduce over time. The committee noted that it is complicated to determine the relevant comparators because of the evolving treatment pathway. It concluded that bortezomib plus dexamethasone and carfilzomib plus dexamethasone were the main comparators for this appraisal. The committee was aware the lenalidomide combination treatments had not been included in the scope, but understood that some people would have lenalidomide combination treatments at second line in the NHS. The committee agreed it could not make a recommendation for this population because it had seen no evidence for it. # Clinical evidence ## Data sources Clinical evidence for daratumumab plus bortezomib and dexamethasone compared with bortezomib plus dexamethasone came from the CASTOR trial. CASTOR is an ongoing, randomised, open-label, multicentre, phase 3 trial. The population included adults with relapsed or refractory multiple myeloma. Because the company chose to focus on daratumumab plus bortezomib and dexamethasone as a second-line treatment (see section 3.1), it presented data from the trial for people who had only had 1 previous treatment. In the original submission for technology appraisal guidance 573, the CASTOR trial had a median follow up of 26.9 months. After the period of managed access, this was 50.2 months for progression-free survival and 72.6 months for overall survival. The trial evidence showed that daratumumab plus bortezomib and dexamethasone reduced the risk of disease progression or death by 79% (hazard ratio 0.21, 95% confidence interval 0.15 to 0.31) compared with bortezomib plus dexamethasone. Daratumumab plus bortezomib and dexamethasone also reduced the risk of death by 44% (HR 0.56, 95% CI 0.39 to 0.80) compared with bortezomib plus dexamethasone. The committee questioned if previous treatment with bortezomib or daratumumab (both available at first line) would affect the results in the NHS. The clinical expert and Cancer Drugs Fund clinical lead explained that having bortezomib or daratumumab before is not expected to affect the effectiveness of daratumumab plus bortezomib and dexamethasone, if these treatments are used for a finite time rather than until disease progression. They noted that there are often several years between remissions. The committee concluded that the CASTOR trial showed that daratumumab plus bortezomib and dexamethasone is clinically effective compared with bortezomib plus dexamethasone. It further concluded that CASTOR was the most suitable source for establishing the relative effect of these 2 treatments. ## Adjusting for subsequent treatments The CASTOR trial was a global trial, which meant not all subsequent treatments used in the trial (at third line and beyond) are available in the NHS. Because alternative treatments may affect survival results, the company presented an inverse probability of censoring weights (IPCW) analysis to adjust the survival estimates. The adjusted HR showed a small but important difference in the clinical trial results. In the CASTOR trial some people had daratumumab as a subsequent treatment, but not at fourth line (where it is recommended in the NHS, see NICE's technology appraisal guidance on daratumumab monotherapy). If a person has daratumumab at an earlier line, they would not have fourth-line daratumumab monotherapy. At the committee meeting the company explained that the adjusted analyses from the trial estimated that only a proportion of people who had second-line bortezomib plus dexamethasone would have had had fourth-line daratumumab monotherapy (the exact figure is academic in confidence). The clinical expert noted that in the NHS most people who have not had a CD38 targeted therapy previously (for example, daratumamab or isatuximab) would have fourth-line daratumumab monotherapy. The committee agreed it is appropriate to adjust the analyses for subsequent treatments not available in the NHS, but that the company's adjusted analyses did not reflect current practice. It agreed that most people progressing to fourth-line treatment who had not had a CD38 targeted therapy before would have fourth-line daratumumab monotherapy. This is because no other CD38 targeted therapies were routinely commissioned at the time of the first committee meeting. The committee was aware that daratumumab monotherapy was expected to have a survival benefit at fourth line. The committee noted that the benefit appeared to have been underestimated in the adjusted analysis for people who had bortezomib plus dexamethasone. So, the hazard ratio estimated by the IPCW analysis is likely to be biased in favour of daratumumab plus bortezomib and dexamethasone. The committee concluded that the adjusted and unadjusted HRs were associated with uncertainty and reflected the higher and lower bounds of clinical effectiveness. The true effect of daratumumab plus bortezomib and dexamethasone compared with bortezomib plus dexamethasone was likely to lie between the adjusted and unadjusted HRs. ## Indirect comparison There was no trial directly comparing daratumumab plus bortezomib and dexamethasone with carfilzomib plus dexamethasone. So, the company did a network meta-analysis using data from the second-line subgroup of CASTOR and ENDEAVOR (which compared carfilzomib plus dexamethasone with bortezomib plus dexamethasone). Evidence from the network meta-analysis showed that daratumumab plus bortezomib and dexamethasone improves overall survival and progression-free survival compared with carfilzomib plus dexamethasone. The committee concluded that the network meta-analysis was appropriate for decision making. ## SACT dataset The CASTOR trial took place across 16 countries, with no study centres in England. Interpreting the available evidence is difficult because the clinical trial happened several years ago and the current multiple myeloma pathway in England is significantly different to when the trial started (see section 3.6). The systemic anti-cancer therapy (SACT) dataset provides real world evidence for people having daratumumab plus bortezomib and dexamethasone in the NHS in England, starting in March 2019. During the managed access period data was collected on overall survival and median treatment duration. A naive comparison shows that overall survival reported in the SACT dataset is lower than that reported in the CASTOR trial. The population in the SACT dataset was on average older than in CASTOR, but limited data was available on comorbidities and any increased risk of mortality. To address the differences in patient population between CASTOR and the SACT data, the company did a matching-adjusted indirect comparison. This adjusted for differences in various baseline characteristics, including age. But the results showed that the prognostic factors explored did not explain the differences between the datasets. The committee agreed that the SACT dataset is more likely to reflect the true experience of people having daratumumab plus bortezomib and dexamethasone in England, but that it has several limitations. It mostly took place during the COVID‑19 pandemic, had a shorter follow-up time than the CASTOR trial and data was missing for key prognostic variables (such as ECOG performance status and international staging system). The committee noted that SACT data might include excess mortality because of COVID‑19. The committee would have liked to have seen the survival outcomes for people who entered the SACT dataset before March 2020 to see if this projected a different survival curve than the complete managed access period. The patient experts explained that many people with multiple myeloma shielded through the pandemic, which reduced the risk of being infected. But they noted that people who had daratumumab plus bortezomib and dexamethasone were still attending hospital appointments at least once a month. One patient expert explained that if people with multiple myeloma were infected with SARS‑CoV‑2 (the virus that causes COVID‑19) they were likely to have poorer outcomes than the general population in England. The clinical expert explained that the pandemic is also likely to have changed treatment decisions, because oral ixazomib with lenalidomide and dexamethasone was made available at second line. This aimed to reduce frequent visits to hospital for treatment injections. The Cancer Drugs Fund clinical lead said that the use of ixazomib with lenalidomide and dexamethasone peaked at 15% of second-line treatments. Because of the availability of alternative treatment options at second-line, some people had daratumumab plus bortezomib and dexamethasone at third line. But it was clarified that this proportion was very small and would be unlikely to affect the results. The committee was aware of the limitations of the SACT data but noted that it included a larger sample size than the CASTOR trial. The committee concluded that the SACT data appeared to be a better source to estimate absolute (baseline) event rates for overall survival. This is because it better represented the population in NHS clinical practice than the CASTOR trial. But it further concluded that the impact of COVID‑19 on survival outcomes from the SACT data was uncertain. The committee considered this during decision making. ## Real-world evidence for bortezomib plus dexamethasone Although the SACT data provided evidence for people having daratumumab plus bortezomib and dexamethasone in the NHS, there was no data for comparator treatments. The company used data from 3 real-world cohorts of people who did not have daratumumab plus bortezomib and dexamethasone, to compare overall survival with SACT data in a naive comparison. The committee noted that the comparisons were likely to be at high risk of bias because the populations included in the studies differed. The company also presented a scenario analysis where it simulated a bortezomib plus dexamethasone survival curve using the absolute (baseline) event rates from the SACT data and applying the relative treatment effect observed in CASTOR. The real-world cohorts were then used to validate this comparison. The EAG noted that although the naive comparison has limitations, the cohorts show a similar survival trajectory to the simulated bortezomib plus dexamethasone curve. The committee concluded the scenarios were associated with uncertainty but suggest that the relative effects seen in CASTOR would hold in clinical practice. # Economic model ## Company's model The company chose a partitioned survival model to estimate the cost effectiveness of daratumumab plus bortezomib and dexamethasone. The model included 3 health states: progression-free, progressed disease and death. The probability of being in a given health state was calculated using the overall survival and progression-free survival curves. The model time horizon was 30 years. The model had the same structure as the original appraisal but included data from CASTOR and the indirect comparison in the network meta-analysis. Also, baseline characteristics for age and gender were updated to reflect those seen in the SACT dataset. The company explained that this increased the age-related mortality in the model because the starting age was higher. The committee concluded that the model structure is acceptable. ## Modelling survival The company's base case used updated data from CASTOR to simulate time to stopping treatment, progression-free survival, and overall survival. The company fitted parametric curves to the trial data for daratumumab plus bortezomib and dexamethasone and bortezomib plus dexamethasone to extrapolate the observed data beyond the period of follow up. After technical engagement, the company changed the parametric function used to extrapolate the data for the bortezomib plus dexamethasone arm. It selected the Weibull curve based on it having good visual and statistical fit, and clinical plausibility, estimating a small proportion of people would be alive at 10 years. To simulate the survival path of people who have carfilzomib plus dexamethasone, the company applied the HRs from the network meta-analysis to the daratumumab plus bortezomib and dexamethasone arm. The committee recalled it was appropriate to use the SACT data for estimating survival for people who had daratumumab plus bortezomib and dexamethasone. NICE's technical support document 13 recommends using registry data to estimate absolute baseline event rates, and that randomised evidence should be used to quantify relative differences. The committee also agreed that the company's approach for the comparison of daratumumab plus bortezomib and dexamethasone with bortezomib plus dexamethasone allowed the 2 curves to diverge over time. This may overestimate the benefit of daratumumab plus bortezomib and dexamethasone. ## SACT scenarios The company presented 2 exploratory scenario analyses using the SACT data. In both cases, the model estimated overall survival with daratumumab plus bortezomib and dexamethasone using a Weibull curve fitted to the SACT data to extrapolate to the time horizon of the model. The company then simulated a bortezomib plus dexamethasone arm by applying the either the adjusted or unadjusted HRs for overall survival from CASTOR (that is, the relative effect between treatments estimated from the randomised data) to the extrapolated daratumumab plus bortezomib and dexamethasone data from SACT. The company made several assumptions to estimate progression-free survival in this analysis. These included using time to treatment stopping data from the SACT dataset and applying an HR from CASTOR to account for people stopping treatment for reasons other than disease progression. The committee noted this was a reasonable approximation because progression-free survival data was not captured in the SACT dataset. The company then applied the progression-free survival relative treatment effect HR from CASTOR (either adjusted or unadjusted) to estimate progression-free survival with bortezomib plus dexamethasone. Analyses that used the additional follow-up data available in CASTOR could have been useful to reduce some of the uncertainty. The committee noted that this could be done in several ways. For example, by applying the appropriate shape and scale parameters (using a Weibull distribution) to the CASTOR data and adjusting them so that they match the survival in the SACT data. Or, the CASTOR data could be used to extrapolate beyond the SACT follow-up period but with appropriate survival constraints. The committee concluded that although these additional scenarios would be informative, they would need additional assumptions. So the simulations based on SACT data extrapolations using the relative treatment effect from the trial were preferred to model survival for daratumumab plus bortezomib and dexamethasone, and bortezomib plus dexamethasone. The committee noted that using the fixed HR from the trial and applying it to the SACT data reduced the risk of overestimating the benefit of daratumumab plus bortezomib and dexamethasone. It agreed that both the adjusted and unadjusted hazard ratio should be considered for decision making because the IPCW analysis did not accurately reflect subsequent treatment use in the NHS (see sections 3.4 and 3.5, and section 3.13). The committee agreed that the scenarios were associated with uncertainty because of the unknown impact of COVID‑19 on the survival estimates, but that it would consider this in its decision making. ## Subsequent treatment costs The company modelled the costs of subsequent treatments using a basket approach, applying one-off costs based on the CASTOR trial. The committee recalled that the trial happened several years ago and subsequent treatments did not reflect current NHS practice. The model only included 1 subsequent line of treatment applied for the proportion of people still alive at the point of disease progression. But in practice people who have multiple myeloma are likely to have several subsequent treatments. The committee agreed this simplification prevented full exploration of subsequent treatments and their effects on the cost-effectiveness modelling. It noted that lenalidomide plus dexamethasone as a subsequent line of treatment is likely to have been overestimated and was inconsistent with the assumption that most people have lenalidomide at first line (see section 3.3). The committee agreed that it would have preferred to see estimates where the proportion was close to zero for those who have daratumumab plus bortezomib and dexamethasone at second line. This is because this would reflect the current treatment pathway. The committee also noted that the costs and clinical estimates for subsequent daratumumab treatment were not aligned in the modelling. It noted that a higher proportion of people who had bortezomib plus dexamethasone had costs for fourth-line daratumumab monotherapy than the company stated had been included in the clinical estimates using the adjusted effectiveness data. This would bias the company's cost-effectiveness estimates in favour of daratumumab plus bortezomib and dexamethasone. The committee agreed that the basket costs applied for subsequent treatments are not likely to reflect current practice. It noted that this was likely to reflect the evolving treatment pathway and the simplistic application in the model, but the impact of subsequent treatments on the cost-effectiveness results is uncertain. ## Utilities The company used utility values in the model based on EQ-5D data collected in the ENDEAVOR trial, which was preferred during the original evaluation of daratumumab plus bortezomib and dexamethasone. Disutilities were applied based on the rate of grade 3 and 4 adverse events in CASTOR trial. The clinical and patient experts explained that grade 1 or 2 adverse events would not lead to people stopping treatment but would likely affect quality of life. One patient expert explained the positive experience they had had while having daratumumab, with limited side effects. The committee noted that grade 1 and 2 events were not included in the modelling but noted that these were more frequent in the bortezomib plus dexamethasone arm of the trial. It concluded that there is likely a small underestimate on how daratumumab plus bortezomib and dexamethasone affects quality of life. # Cost-effectiveness estimates ## Acceptable ICER NICE's manual on health technology evaluation notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the evidence presented but will also take into account other aspects including uncaptured health benefits. The committee agreed that CASTOR trial showed that daratumumab plus bortezomib and dexamethasone is a clinically effective treatment. It noted that the benefit was likely to remain long term and the relative effect is likely to hold when used outside the clinical trial setting. It also heard from patient and clinical experts about the relative ease and lack of side effects associated with taking this treatment, and the importance of having the most effective treatments possible available at second line. The committee recognised that there was uncaptured health benefit from not including low-level side effects of treatment, and the ease of administration (including using subcutaneous administration instead of intravenous). It agreed that it would accept an ICER at the upper end of the acceptable range if this was based on more conservative modelling assumptions. This is because it would allow the committee to have more confidence that residual uncertainties would not result in the cost effectiveness estimates being above what NICE considers an acceptable use of NHS resources. ## Company and EAG cost-effectiveness estimates Because of confidential commercial arrangements for daratumumab, bortezomib and post-progression treatments, the cost-effectiveness results are confidential and cannot be reported here. After technical engagement the company and EAG had the same base case, which used updated data from CASTOR to simulate time to stopping treatment, progression-free survival, and overall survival (see section 3.11). The committee agreed that its preferred scenarios for the comparison with bortezomib plus dexamethasone used the extrapolated daratumumab plus bortezomib and dexamethasone data from SACT, and applied the relative treatment effect from CASTOR to estimate outcomes in the bortezomib plus dexamethasone arm (see section 3.11). The preferred scenarios for the comparison with carfilzomib plus dexamethasone applied the relative treatment effect from the network meta-analysis to the same analysis. The committee agreed that uncertainty remained in 3 areas of the cost-effectiveness estimates: The effect of COVID-19 on the outcomes in the SACT dataset (see section 3.8). Adjusting the relative treatment effect from CASTOR to account for use of subsequent treatments not available in the NHS. The adjusted and unadjusted HRs reflected the higher and lower bounds of clinical effectiveness (see section 3.5). Modelling the costs of subsequent treatments (see section 3.13).The committee recalled that although bortezomib plus dexamethasone and carfilzomib plus dexamethasone were the main comparators for this appraisal, a small proportion of people would have second-line lenalidomide combination treatments. Lenalidomide combination treatments were not included as comparators in the scope of this appraisal. The committee was not able to evaluate the comparisons to lenalidomide because no evidence was submitted. So the committee was not able to make a recommendation for people for whom lenalidomide may be considered at second line. # Conclusion The most likely cost-effectiveness estimates for daratumumab plus bortezomib and dexamethasone are within what NICE considers an acceptable use of NHS resources. The committee concluded that daratumumab plus bortezomib and dexamethasone is recommended for treating multiple myeloma in adults who have had just 1 previous line of treatment and: it included lenalidomide or lenalidomide is unsuitable as a second-line treatment.	{'Recommendations': 'Daratumumab with bortezomib and dexamethasone is recommended as an option for treating multiple myeloma in adults, only if they have had just 1 previous line of treatment and:\n\nit included lenalidomide or\n\nlenalidomide is unsuitable as a second-line treatment and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with daratumumab with bortezomib and dexamethasone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThis evaluation reviews the evidence for daratumumab with bortezomib and dexamethasone from NICE technology appraisal guidance 573. It also reviews new data collected as part of the managed access agreement.\n\nThe company proposed daratumumab with bortezomib and dexamethasone as a second-line treatment, which is narrower than its marketing authorisation. Second‑line treatments for multiple myeloma include:\n\nbortezomib with dexamethasone\n\ncarfilzomib with dexamethasone\n\nlenalidomide with dexamethasone\n\ncarfilzomib with lenalidomide and dexamethasone.\n\nClinical trial evidence shows that daratumumab with bortezomib and dexamethasone decreases the risk of dying and the chance of myeloma returning or getting worse compared with bortezomib with dexamethasone. There is no direct evidence comparing it with carfilzomib with dexamethasone. An indirect comparison suggests that it decreases the risk of the myeloma returning or getting worse compared with carfilzomib with dexamethasone. No evidence was provided for a comparison with the lenalidomide treatments.\n\nThe most likely cost-effectiveness estimates for daratumumab with bortezomib and dexamethasone are below what NICE considers an acceptable use of NHS resources. Because no comparison was done with lenalidomide treatments, daratumumab with bortezomib and dexamethasone is only recommended for people who cannot have lenalidomide as a second treatment. This includes people who had lenalidomide as their first treatment, or when lenalidomide is unsuitable as a second‑line treatment.', 'Information about daratumumab with bortezomib and dexamethasone': "# Marketing authorisation indication\n\nDaratumumab (Darzalex, Janssen) is indicated 'in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for daratumumab.\n\n# Price\n\nThe list prices for daratumumab (excluding VAT; BNF online, accessed February\xa02023) are:\n\n£4,320 per 1,800\xa0mg/15\xa0ml solution for injection vial\n\n£360 per 100\xa0mg/5\xa0ml concentrate for solution for infusion vial\n\n£1,440 per 400\xa0mg/20\xa0ml concentrate for solution for infusion vial.\n\nThe company has a commercial arrangement. This makes daratumumab with bortezomib and dexamethasone available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Janssen, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Daratumumab plus bortezomib and dexamethasone\n\nThis evaluation reviews the evidence for daratumumab plus bortezomib and dexamethasone for relapsed multiple myeloma, which was approved for use in the Cancer Drugs Fund in NICE technology appraisal guidance\xa0573. It also reviews new data collected as part of the managed access agreement. The company presented evidence for daratumumab plus bortezomib and dexamethasone as a second-line treatment only, in line with the original company submission and recommendation in technology appraisal guidance 573. The committee recognised that limiting this treatment to second line was narrower than its marketing authorisation. But concluded that it would appraise daratumumab plus bortezomib and dexamethasone after only 1\xa0previous treatment, having been presented only with evidence for its use as a second-line treatment.\n\n## Evolving treatment pathway\n\nMultiple myeloma is a chronic condition that affects how long people live and their quality of life. A clinical expert described it as a relapsing and remitting disease with a complex and evolving pathway. The Cancer Drugs Fund clinical lead explained that each appraisal is a snapshot in time. They explained that since daratumumab plus bortezomib and dexamethasone was available through the Cancer Drugs Fund several new multiple myeloma drugs have been recommended for routine commissioning in the NHS. This has changed what would be offered to people with a new diagnosis, and what subsequent treatment is offered to those who could have daratumumab plus bortezomib and dexamethasone. The committee acknowledged that this makes interpreting clinical trial evidence for this appraisal challenging, because the trial (see section\xa03.5) started several years ago and may not reflect the current multiple myeloma pathway. The committee noted that the company submission also included new data collected as part of the managed access agreement. It was aware that this data may have limitations because the managed access period mostly took place during the COVID‑19 pandemic. The pandemic may have affected the data collected in 2 ways. First, by affecting the care pathway, because some other treatment options were made available for an interim period. Second, because there may be excess mortality associated with COVID‑19 in people who had daratumumab plus bortezomib and dexamethasone. The committee agreed that it would consider these limitations in its decision making.\n\n## New treatment option\n\nPatient experts stated that in their experience, daratumumab plus bortezomib and dexamethasone had very few side effects. This was echoed in a patient survey done by Myeloma UK, which said that 95% of respondents would recommend the treatment, despite some people having side effects. One patient expert noted that having daratumumab plus bortezomib and dexamethasone had dramatically increased their quality of life. They said it helped with maintaining day to day routines, and meant that they were likely to be well enough for more options later in the treatment pathway. They explained that this was important because the condition becomes more resistant to treatment with each relapse. The committee recognised the need for effective, well-tolerated treatment options for people with multiple myeloma who have had a previous treatment.\n\n## Comparators\n\nTreatment options for people with newly diagnosed multiple myeloma depend on if a stem cell transplant is a suitable treatment option. Once the disease progresses, treatment options depend on what treatments people have had before, response to these treatments, and patient preference. The committee noted that progression through the pathway is slow, and each remission and progression may span several years. It noted that treatment choice at each line may differ in clinical practice depending on when a person entered the treatment pathway, and what treatments have been available to them before. For someone who has had 1 previous line of treatment, currently available options at second line are:\n\nbortezomib (see NICE's technology appraisal guidance on bortezomib monotherapy for relapsed multiple myeloma)\n\ncarfilzomib plus dexamethasone (see NICE's technology appraisal guidance on carfilzomib for previously treated multiple myeloma)\n\nlenalidomide plus dexamethasone (see NICE's technology appraisal guidance on lenalidomide with dexamethasone for multiple myeloma after 1 treatment with bortezomib)\n\ncarfilzomib plus lenalidomide and dexamethasone (see NICE's technology appraisal guidance on carfilzomib with dexamethasone and lenalidomide for previously treated multiple myeloma).The committee considered the available treatment options and if these were appropriately included in the evidence presented. The company submission focused on second-line treatment options, including bortezomib plus dexamethasone and carfilzomib plus dexamethasone, which aligned with the comparators included in the NICE scope. The clinical expert explained that most people for whom a transplant is suitable would now have lenalidomide at first line, so would have bortezomib or carfilzomib combination treatments at second line. But they explained that some people would not progress through the transplant pathway to lenalidomide maintenance at first line, so would be able to have lenalidomide at a later line. They also noted that for those who cannot have a transplant, lenalidomide plus dexamethasone is the most widely used first-line treatment option in clinical practice, and accounts for 70% to 80% of treatments used. Anyone whose disease relapsed following lenalidomide would have bortezomib or carfilzomib as a second-line treatment. But the clinical expert explained that lenalidomide combinations were also used as second-line treatment options. For 20% to 30% of people who cannot have a transplant, bortezomib combination treatments would be the preferred first-choice treatment. They explained this would be used if a finite period of treatment is preferred or if a rapid response is needed. The Cancer Drugs Fund clinical lead confirmed that all these treatments are used in NHS practice. But they explained that second-line lenalidomide use may currently be higher than estimated by the clinical expert, but that this reflected the slow evolution of the multiple myeloma pathway. That is, in the past, people may have had thalidomide or bortezomib as first-line treatment if lenalidomide had not been available at first line, so these people would be able to have lenalidomide at second line, though this proportion was likely to reduce over time. The committee noted that it is complicated to determine the relevant comparators because of the evolving treatment pathway. It concluded that bortezomib plus dexamethasone and carfilzomib plus dexamethasone were the main comparators for this appraisal. The committee was aware the lenalidomide combination treatments had not been included in the scope, but understood that some people would have lenalidomide combination treatments at second line in the NHS. The committee agreed it could not make a recommendation for this population because it had seen no evidence for it.\n\n# Clinical evidence\n\n## Data sources\n\nClinical evidence for daratumumab plus bortezomib and dexamethasone compared with bortezomib plus dexamethasone came from the CASTOR trial. CASTOR is an ongoing, randomised, open-label, multicentre, phase\xa03 trial. The population included adults with relapsed or refractory multiple myeloma. Because the company chose to focus on daratumumab plus bortezomib and dexamethasone as a second-line treatment (see section\xa03.1), it presented data from the trial for people who had only had 1\xa0previous treatment. In the original submission for technology appraisal guidance 573, the CASTOR trial had a median follow up of 26.9\xa0months. After the period of managed access, this was 50.2\xa0months for progression-free survival and 72.6\xa0months for overall survival. The trial evidence showed that daratumumab plus bortezomib and dexamethasone reduced the risk of disease progression or death by 79% (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.15 to 0.31) compared with bortezomib plus dexamethasone. Daratumumab plus bortezomib and dexamethasone also reduced the risk of death by 44% (HR 0.56, 95%\xa0CI\xa00.39 to 0.80) compared with bortezomib plus dexamethasone. The committee questioned if previous treatment with bortezomib or daratumumab (both available at first line) would affect the results in the NHS. The clinical expert and Cancer Drugs Fund clinical lead explained that having bortezomib or daratumumab before is not expected to affect the effectiveness of daratumumab plus bortezomib and dexamethasone, if these treatments are used for a finite time rather than until disease progression. They noted that there are often several years between remissions. The committee concluded that the CASTOR trial showed that daratumumab plus bortezomib and dexamethasone is clinically effective compared with bortezomib plus dexamethasone. It further concluded that CASTOR was the most suitable source for establishing the relative effect of these 2\xa0treatments.\n\n## Adjusting for subsequent treatments\n\nThe CASTOR trial was a global trial, which meant not all subsequent treatments used in the trial (at third line and beyond) are available in the NHS. Because alternative treatments may affect survival results, the company presented an inverse probability of censoring weights (IPCW) analysis to adjust the survival estimates. The adjusted HR showed a small but important difference in the clinical trial results. In the CASTOR trial some people had daratumumab as a subsequent treatment, but not at fourth line (where it is recommended in the NHS, see NICE's technology appraisal guidance on daratumumab monotherapy). If a person has daratumumab at an earlier line, they would not have fourth-line daratumumab monotherapy. At the committee meeting the company explained that the adjusted analyses from the trial estimated that only a proportion of people who had second-line bortezomib plus dexamethasone would have had had fourth-line daratumumab monotherapy (the exact figure is academic in confidence). The clinical expert noted that in the NHS most people who have not had a CD38 targeted therapy previously (for example, daratumamab or isatuximab) would have fourth-line daratumumab monotherapy. The committee agreed it is appropriate to adjust the analyses for subsequent treatments not available in the NHS, but that the company's adjusted analyses did not reflect current practice. It agreed that most people progressing to fourth-line treatment who had not had a CD38 targeted therapy before would have fourth-line daratumumab monotherapy. This is because no other CD38 targeted therapies were routinely commissioned at the time of the first committee meeting. The committee was aware that daratumumab monotherapy was expected to have a survival benefit at fourth line. The committee noted that the benefit appeared to have been underestimated in the adjusted analysis for people who had bortezomib plus dexamethasone. So, the hazard ratio estimated by the IPCW analysis is likely to be biased in favour of daratumumab plus bortezomib and dexamethasone. The committee concluded that the adjusted and unadjusted HRs were associated with uncertainty and reflected the higher and lower bounds of clinical effectiveness. The true effect of daratumumab plus bortezomib and dexamethasone compared with bortezomib plus dexamethasone was likely to lie between the adjusted and unadjusted HRs.\n\n## Indirect comparison\n\nThere was no trial directly comparing daratumumab plus bortezomib and dexamethasone with carfilzomib plus dexamethasone. So, the company did a network meta-analysis using data from the second-line subgroup of CASTOR and ENDEAVOR (which compared carfilzomib plus dexamethasone with bortezomib plus dexamethasone). Evidence from the network meta-analysis showed that daratumumab plus bortezomib and dexamethasone improves overall survival and progression-free survival compared with carfilzomib plus dexamethasone. The committee concluded that the network meta-analysis was appropriate for decision making.\n\n## SACT dataset\n\nThe CASTOR trial took place across 16 countries, with no study centres in England. Interpreting the available evidence is difficult because the clinical trial happened several years ago and the current multiple myeloma pathway in England is significantly different to when the trial started (see section\xa03.6). The systemic anti-cancer therapy (SACT) dataset provides real world evidence for people having daratumumab plus bortezomib and dexamethasone in the NHS in England, starting in March\xa02019. During the managed access period data was collected on overall survival and median treatment duration. A naive comparison shows that overall survival reported in the SACT dataset is lower than that reported in the CASTOR trial. The population in the SACT dataset was on average older than in CASTOR, but limited data was available on comorbidities and any increased risk of mortality. To address the differences in patient population between CASTOR and the SACT data, the company did a matching-adjusted indirect comparison. This adjusted for differences in various baseline characteristics, including age. But the results showed that the prognostic factors explored did not explain the differences between the datasets. The committee agreed that the SACT dataset is more likely to reflect the true experience of people having daratumumab plus bortezomib and dexamethasone in England, but that it has several limitations. It mostly took place during the COVID‑19 pandemic, had a shorter follow-up time than the CASTOR trial and data was missing for key prognostic variables (such as ECOG performance status and international staging system). The committee noted that SACT data might include excess mortality because of COVID‑19. The committee would have liked to have seen the survival outcomes for people who entered the SACT dataset before March 2020 to see if this projected a different survival curve than the complete managed access period. The patient experts explained that many people with multiple myeloma shielded through the pandemic, which reduced the risk of being infected. But they noted that people who had daratumumab plus bortezomib and dexamethasone were still attending hospital appointments at least once a month. One patient expert explained that if people with multiple myeloma were infected with SARS‑CoV‑2 (the virus that causes COVID‑19) they were likely to have poorer outcomes than the general population in England. The clinical expert explained that the pandemic is also likely to have changed treatment decisions, because oral ixazomib with lenalidomide and dexamethasone was made available at second line. This aimed to reduce frequent visits to hospital for treatment injections. The Cancer Drugs Fund clinical lead said that the use of ixazomib with lenalidomide and dexamethasone peaked at 15% of second-line treatments. Because of the availability of alternative treatment options at second-line, some people had daratumumab plus bortezomib and dexamethasone at third line. But it was clarified that this proportion was very small and would be unlikely to affect the results. The committee was aware of the limitations of the SACT data but noted that it included a larger sample size than the CASTOR trial. The committee concluded that the SACT data appeared to be a better source to estimate absolute (baseline) event rates for overall survival. This is because it better represented the population in NHS clinical practice than the CASTOR trial. But it further concluded that the impact of COVID‑19 on survival outcomes from the SACT data was uncertain. The committee considered this during decision making.\n\n## Real-world evidence for bortezomib plus dexamethasone\n\nAlthough the SACT data provided evidence for people having daratumumab plus bortezomib and dexamethasone in the NHS, there was no data for comparator treatments. The company used data from 3 real-world cohorts of people who did not have daratumumab plus bortezomib and dexamethasone, to compare overall survival with SACT data in a naive comparison. The committee noted that the comparisons were likely to be at high risk of bias because the populations included in the studies differed. The company also presented a scenario analysis where it simulated a bortezomib plus dexamethasone survival curve using the absolute (baseline) event rates from the SACT data and applying the relative treatment effect observed in CASTOR. The real-world cohorts were then used to validate this comparison. The EAG noted that although the naive comparison has limitations, the cohorts show a similar survival trajectory to the simulated bortezomib plus dexamethasone curve. The committee concluded the scenarios were associated with uncertainty but suggest that the relative effects seen in CASTOR would hold in clinical practice.\n\n# Economic model\n\n## Company's model\n\nThe company chose a partitioned survival model to estimate the cost effectiveness of daratumumab plus bortezomib and dexamethasone. The model included 3\xa0health states: progression-free, progressed disease and death. The probability of being in a given health state was calculated using the overall survival and progression-free survival curves. The model time horizon was 30\xa0years. The model had the same structure as the original appraisal but included data from CASTOR and the indirect comparison in the network meta-analysis. Also, baseline characteristics for age and gender were updated to reflect those seen in the SACT dataset. The company explained that this increased the age-related mortality in the model because the starting age was higher. The committee concluded that the model structure is acceptable.\n\n## Modelling survival\n\nThe company's base case used updated data from CASTOR to simulate time to stopping treatment, progression-free survival, and overall survival. The company fitted parametric curves to the trial data for daratumumab plus bortezomib and dexamethasone and bortezomib plus dexamethasone to extrapolate the observed data beyond the period of follow up. After technical engagement, the company changed the parametric function used to extrapolate the data for the bortezomib plus dexamethasone arm. It selected the Weibull curve based on it having good visual and statistical fit, and clinical plausibility, estimating a small proportion of people would be alive at 10\xa0years. To simulate the survival path of people who have carfilzomib plus dexamethasone, the company applied the HRs from the network meta-analysis to the daratumumab plus bortezomib and dexamethasone arm. The committee recalled it was appropriate to use the SACT data for estimating survival for people who had daratumumab plus bortezomib and dexamethasone. NICE's technical support document\xa013 recommends using registry data to estimate absolute baseline event rates, and that randomised evidence should be used to quantify relative differences. The committee also agreed that the company's approach for the comparison of daratumumab plus bortezomib and dexamethasone with bortezomib plus dexamethasone allowed the 2\xa0curves to diverge over time. This may overestimate the benefit of daratumumab plus bortezomib and dexamethasone.\n\n## SACT scenarios\n\nThe company presented 2\xa0exploratory scenario analyses using the SACT data. In both cases, the model estimated overall survival with daratumumab plus bortezomib and dexamethasone using a Weibull curve fitted to the SACT data to extrapolate to the time horizon of the model. The company then simulated a bortezomib plus dexamethasone arm by applying the either the adjusted or unadjusted HRs for overall survival from CASTOR (that is, the relative effect between treatments estimated from the randomised data) to the extrapolated daratumumab plus bortezomib and dexamethasone data from SACT. The company made several assumptions to estimate progression-free survival in this analysis. These included using time to treatment stopping data from the SACT dataset and applying an HR from CASTOR to account for people stopping treatment for reasons other than disease progression. The committee noted this was a reasonable approximation because progression-free survival data was not captured in the SACT dataset. The company then applied the progression-free survival relative treatment effect HR from CASTOR (either adjusted or unadjusted) to estimate progression-free survival with bortezomib plus dexamethasone. Analyses that used the additional follow-up data available in CASTOR could have been useful to reduce some of the uncertainty. The committee noted that this could be done in several ways. For example, by applying the appropriate shape and scale parameters (using a Weibull distribution) to the CASTOR data and adjusting them so that they match the survival in the SACT data. Or, the CASTOR data could be used to extrapolate beyond the SACT follow-up period but with appropriate survival constraints. The committee concluded that although these additional scenarios would be informative, they would need additional assumptions. So the simulations based on SACT data extrapolations using the relative treatment effect from the trial were preferred to model survival for daratumumab plus bortezomib and dexamethasone, and bortezomib plus dexamethasone. The committee noted that using the fixed HR from the trial and applying it to the SACT data reduced the risk of overestimating the benefit of daratumumab plus bortezomib and dexamethasone. It agreed that both the adjusted and unadjusted hazard ratio should be considered for decision making because the IPCW analysis did not accurately reflect subsequent treatment use in the NHS (see sections\xa03.4 and\xa03.5, and section\xa03.13). The committee agreed that the scenarios were associated with uncertainty because of the unknown impact of COVID‑19 on the survival estimates, but that it would consider this in its decision making.\n\n## Subsequent treatment costs\n\nThe company modelled the costs of subsequent treatments using a basket approach, applying one-off costs based on the CASTOR trial. The committee recalled that the trial happened several years ago and subsequent treatments did not reflect current NHS practice. The model only included 1 subsequent line of treatment applied for the proportion of people still alive at the point of disease progression. But in practice people who have multiple myeloma are likely to have several subsequent treatments. The committee agreed this simplification prevented full exploration of subsequent treatments and their effects on the cost-effectiveness modelling. It noted that lenalidomide plus dexamethasone as a subsequent line of treatment is likely to have been overestimated and was inconsistent with the assumption that most people have lenalidomide at first line (see section\xa03.3). The committee agreed that it would have preferred to see estimates where the proportion was close to zero for those who have daratumumab plus bortezomib and dexamethasone at second line. This is because this would reflect the current treatment pathway. The committee also noted that the costs and clinical estimates for subsequent daratumumab treatment were not aligned in the modelling. It noted that a higher proportion of people who had bortezomib plus dexamethasone had costs for fourth-line daratumumab monotherapy than the company stated had been included in the clinical estimates using the adjusted effectiveness data. This would bias the company's cost-effectiveness estimates in favour of daratumumab plus bortezomib and dexamethasone. The committee agreed that the basket costs applied for subsequent treatments are not likely to reflect current practice. It noted that this was likely to reflect the evolving treatment pathway and the simplistic application in the model, but the impact of subsequent treatments on the cost-effectiveness results is uncertain.\n\n## Utilities\n\nThe company used utility values in the model based on EQ-5D data collected in the ENDEAVOR trial, which was preferred during the original evaluation of daratumumab plus bortezomib and dexamethasone. Disutilities were applied based on the rate of grade\xa03 and\xa04 adverse events in CASTOR trial. The clinical and patient experts explained that grade\xa01 or 2 adverse events would not lead to people stopping treatment but would likely affect quality of life. One patient expert explained the positive experience they had had while having daratumumab, with limited side effects. The committee noted that grade\xa01 and 2 events were not included in the modelling but noted that these were more frequent in the bortezomib plus dexamethasone arm of the trial. It concluded that there is likely a small underestimate on how daratumumab plus bortezomib and dexamethasone affects quality of life.\n\n# Cost-effectiveness estimates\n\n## Acceptable ICER\n\nNICE's manual on health technology evaluation notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the evidence presented but will also take into account other aspects including uncaptured health benefits. The committee agreed that CASTOR trial showed that daratumumab plus bortezomib and dexamethasone is a clinically effective treatment. It noted that the benefit was likely to remain long term and the relative effect is likely to hold when used outside the clinical trial setting. It also heard from patient and clinical experts about the relative ease and lack of side effects associated with taking this treatment, and the importance of having the most effective treatments possible available at second line. The committee recognised that there was uncaptured health benefit from not including low-level side effects of treatment, and the ease of administration (including using subcutaneous administration instead of intravenous). It agreed that it would accept an ICER at the upper end of the acceptable range if this was based on more conservative modelling assumptions. This is because it would allow the committee to have more confidence that residual uncertainties would not result in the cost effectiveness estimates being above what NICE considers an acceptable use of NHS resources.\n\n## Company and EAG cost-effectiveness estimates\n\nBecause of confidential commercial arrangements for daratumumab, bortezomib and post-progression treatments, the cost-effectiveness results are confidential and cannot be reported here. After technical engagement the company and EAG had the same base case, which used updated data from CASTOR to simulate time to stopping treatment, progression-free survival, and overall survival (see section\xa03.11). The committee agreed that its preferred scenarios for the comparison with bortezomib plus dexamethasone used the extrapolated daratumumab plus bortezomib and dexamethasone data from SACT, and applied the relative treatment effect from CASTOR to estimate outcomes in the bortezomib plus dexamethasone arm (see section 3.11). The preferred scenarios for the comparison with carfilzomib plus dexamethasone applied the relative treatment effect from the network meta-analysis to the same analysis. The committee agreed that uncertainty remained in 3 areas of the cost-effectiveness estimates:\n\nThe effect of COVID-19 on the outcomes in the SACT dataset (see section\xa03.8).\n\nAdjusting the relative treatment effect from CASTOR to account for use of subsequent treatments not available in the NHS. The adjusted and unadjusted HRs reflected the higher and lower bounds of clinical effectiveness (see section\xa03.5).\n\nModelling the costs of subsequent treatments (see section\xa03.13).The committee recalled that although bortezomib plus dexamethasone and carfilzomib plus dexamethasone were the main comparators for this appraisal, a small proportion of people would have second-line lenalidomide combination treatments. Lenalidomide combination treatments were not included as comparators in the scope of this appraisal. The committee was not able to evaluate the comparisons to lenalidomide because no evidence was submitted. So the committee was not able to make a recommendation for people for whom lenalidomide may be considered at second line.\n\n# Conclusion\n\nThe most likely cost-effectiveness estimates for daratumumab plus bortezomib and dexamethasone are within what NICE considers an acceptable use of NHS resources. The committee concluded that daratumumab plus bortezomib and dexamethasone is recommended for treating multiple myeloma in adults who have had just 1 previous line of treatment and:\n\nit included lenalidomide or\n\nlenalidomide is unsuitable as a second-line treatment."}	https://www.nice.org.uk/guidance/ta897	Evidence-based recommendations on daratumumab (Darzalex) with bortezomib and dexamethasone for previously treated multiple myeloma in adults.
9caf8ceb6f67e85b88dc0c885513da97325135c9	nice	Intraoperative electron beam radiotherapy for locally advanced and locally recurrent colorectal cancer	Intraoperative electron beam radiotherapy for locally advanced and locally recurrent colorectal cancer Evidence-based recommendations on intraoperative electron beam radiotherapy for locally advanced and locally recurrent colorectal cancer. This involves delivering electron beam radiation directly to the tumour during surgery. The aim is to stop the cancer from coming back and spreading further. # Recommendations Evidence on the safety of intraoperative electron beam radiotherapy for locally advanced and locally recurrent colorectal cancer is adequate. Evidence on efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Further research should preferably be in the form of suitably powered randomised controlled trials and should report details of patient selection (including tumour type and staging), the technique of radiotherapy and the extent of surgery undertaken, and key outcomes (as detailed in sections 3.2 and 3.3). Patient selection and the procedure should only be done in specialist centres by a multidisciplinary team experienced in managing colorectal cancer. The multidisciplinary team should include a colorectal surgeon, a clinical oncologist, a medical physicist, a radiographer and an anaesthetist with specialist training in the procedure.# The condition, current treatments and procedure # The condition Colorectal cancer is a common cancer. It typically occurs in people older than 50, with the risk increasing with age. About 5% to 20% of people with colorectal cancer have locally advanced disease, in which the cancer has invaded nearby tissues. After primary resection to remove the tumour, it returns in the same place in about 5% to 20% of people. # Current treatments There are various treatments for colorectal cancer, including resection, chemotherapy and radiotherapy. Treatment choice depends on the type of cancer, location and staging. The radicality of resection is the most important prognostic factor for survival. Resection is referred to as: R0, when there are clear margins around the tumour; R1, when there are microscopically involved margins; and R2, when there are macroscopically involved margins or gross residual disease. # The procedure The procedure is done during surgery for locally advanced or locally recurrent colorectal cancer. Once the tumour is resected, the patient is positioned to receive a megavoltage electron dose from a linear accelerator. This can happen in the operating theatre if it's equipped with a stationary linear accelerator. Otherwise, the person is transferred to a dedicated room, or a mobile linear accelerator is brought into the theatre. Radiation-sensitive organs surrounding the tumour site can be displaced or shielded from the intraoperative electron beam radiotherapy (IOERT) field. A single large fraction of radiation (typically 10 Gy to 20 Gy) is then delivered by an applicator directly to the tumour bed. The aim is to improve local control and increase survival rates. There are several techniques for delivering intraoperative radiotherapy, including IOERT, high dose rate brachytherapy, and orthovoltage. This guidance relates to IOERT only, not high dose rate brachytherapy or orthovoltage techniques.	{'Recommendations': 'Evidence on the safety of intraoperative electron beam radiotherapy for locally advanced and locally recurrent colorectal cancer is adequate. Evidence on efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should preferably be in the form of suitably powered randomised controlled trials and should report details of patient selection (including tumour type and staging), the technique of radiotherapy and the extent of surgery undertaken, and key outcomes (as detailed in sections\xa03.2 and 3.3).\n\nPatient selection and the procedure should only be done in specialist centres by a multidisciplinary team experienced in managing colorectal cancer. The multidisciplinary team should include a colorectal surgeon, a clinical oncologist, a medical physicist, a radiographer and an anaesthetist with specialist training in the procedure.', 'The condition, current treatments and procedure': "# The condition\n\nColorectal cancer is a common cancer. It typically occurs in people older than 50, with the risk increasing with age. About 5% to 20% of people with colorectal cancer have locally advanced disease, in which the cancer has invaded nearby tissues. After primary resection to remove the tumour, it returns in the same place in about 5% to 20% of people.\n\n# Current treatments\n\nThere are various treatments for colorectal cancer, including resection, chemotherapy and radiotherapy. Treatment choice depends on the type of cancer, location and staging. The radicality of resection is the most important prognostic factor for survival. Resection is referred to as: R0, when there are clear margins around the tumour; R1, when there are microscopically involved margins; and R2, when there are macroscopically involved margins or gross residual disease.\n\n# The procedure\n\nThe procedure is done during surgery for locally advanced or locally recurrent colorectal cancer. Once the tumour is resected, the patient is positioned to receive a megavoltage electron dose from a linear accelerator. This can happen in the operating theatre if it's equipped with a stationary linear accelerator. Otherwise, the person is transferred to a dedicated room, or a mobile linear accelerator is brought into the theatre. Radiation-sensitive organs surrounding the tumour site can be displaced or shielded from the intraoperative electron beam radiotherapy (IOERT) field. A single large fraction of radiation (typically 10\xa0Gy to 20\xa0Gy) is then delivered by an applicator directly to the tumour bed. The aim is to improve local control and increase survival rates.\n\nThere are several techniques for delivering intraoperative radiotherapy, including IOERT, high dose rate brachytherapy, and orthovoltage. This guidance relates to IOERT only, not high dose rate brachytherapy or orthovoltage techniques."}	https://www.nice.org.uk/guidance/ipg763	Evidence-based recommendations on intraoperative electron beam radiotherapy for locally advanced and locally recurrent colorectal cancer. This involves delivering electron beam radiation directly to the tumour during surgery. The aim is to stop the cancer from coming back and spreading further.
8ce6e7445e59b6996dcc68436f3e1e37c399e444	nice	Transperineal biopsy for diagnosing prostate cancer	Transperineal biopsy for diagnosing prostate cancer Evidence-based recommendations on transperineal biopsy for diagnosing prostate cancer. # Recommendations Local anaesthetic transperineal (LATP) prostate biopsy using the freehand needle positioning device PrecisionPoint is recommended as an option for diagnosing prostate cancer. Although there is considerably less evidence and therefore greater uncertainty of clinical benefit for them, the following freehand needle positioning devices are expected to have similar cancer detection rates and adverse events to those of PrecisionPoint: EZU‑PA3U device Trinity Perine Grid UA1232 puncture attachment.There are technical differences between them, but they all work in a similar way using the same biopsy technique. So, these devices are recommended as options for diagnosing prostate cancer. Centres are encouraged to take part in research and data collection, including the randomised controlled trial of transrectal biopsy compared with LATP biopsy (the TRANSLATE trial; see section 3.8) to help refine clinical practice. There is not enough evidence to recommend double freehand LATP prostate biopsy using the CamPROBE device. Further research is recommended to understand its clinical effectiveness. Why the committee made these recommendations Standard prostate biopsy uses local anaesthetic transrectal ultrasound (LA‑TRUS). This involves taking samples of prostate tissue by inserting a biopsy needle through the rectal wall via the anus. An alternative is LATP prostate biopsy, which involves inserting the needle through the perineum, the skin area between the anus and the scrotum. Techniques for LATP biopsy vary. It can be done using a freehand needle positioning device, a grid and stepping device, or using a coaxial needle only (double freehand). The evidence suggests no significant difference in cancer detection rates between LATP biopsy and LA‑TRUS biopsy, but it suggests lower rates of infection and sepsis after LATP biopsies. More evidence on their differences will come from the ongoing TRANSLATE trial, which may help refine clinical practice. Most of the clinical evidence for freehand needle positioning devices is on the PrecisionPoint device. There is no comparative evidence for the EZU‑PA3U, UA1232, or Trinity Perine Grid devices, but experts suggest that cancer detection rates and adverse events are expected to be similar for the different freehand devices. This is because they all function in a similar way, in that they attach to the ultrasound probe and keep the needle in line with it. The biopsy technique is the same. The most likely cost-effectiveness estimates for freehand needle positioning devices are within what NICE considers an acceptable use of NHS resources. So, LATP biopsy using a freehand needle positioning device is recommended. There is no comparative evidence on the CamPROBE device, which uses a double freehand technique. Experts said that because the double freehand technique is different to using the freehand needle positioning devices, more research is needed to understand the cancer detection rates, adverse events and cost effectiveness.# The diagnostic tests # Clinical need and practice Prostate cancer is the most commonly diagnosed cancer in men in the UK. It mainly affects people over 50 and the risk is higher for people of African family background and people with a family history of prostate cancer. Prostate cancer can be slow or quickly growing. If it is growing quickly, it is more likely to spread and may require treatment, which includes radiotherapy, chemotherapy, surgery or a combination of these. The section on assessment and diagnosis in NICE's guideline on prostate cancer recommends that after someone is referred to secondary care with suspected clinically localised prostate cancer, they should be offered a multiparametric MRI (mpMRI) test. The results of this MRI should be reported using a 5‑point Likert scale. People with a Likert score of 3 or more should be offered an mpMRI-influenced prostate biopsy. Prostate biopsies can be targeted using MRI to identify lesions to take a small number of tissue samples or cores from. Or they can be systematic, taking multiple samples from different regions of the left and right side of the prostate. The current standard prostate biopsy is mpMRI-influenced local anaesthetic transrectal ultrasound (LA‑TRUS) biopsy or mpMRI-influenced local anaesthetic transperineal (LATP) biopsy. Both routes use a transrectal ultrasound probe inserted into the anus to image the prostate. Both approaches are done in an outpatient setting. In a TRUS prostate biopsy, samples of prostate tissue are collected using a biopsy needle inserted through the rectal wall via the anus. The disadvantage of this method is that some people get serious infections, including sepsis, requiring hospital admission and antibiotics. In LATP biopsy, the needle enters the body through the perineum, the skin area between the anus and the scrotum. This could greatly reduce the risk of biopsy-related sepsis compared with a TRUS biopsy, and therefore may reduce hospital admissions and the need for preventative antibiotics. # The interventions ## CamPROBE The CamPROBE (JEB Technologies) is a cannulated transperineal access system designed specifically for prostate biopsies. It consists of a coaxial cannula with an integrated needle. This needle can be attached to a standard syringe, allowing the device to be inserted and local anaesthetic to be injected at the same time under ultrasound guidance. This removes the need for separate punctures, nerve blocks or sedation. Once the cannula is in position, the integrated needle is removed and standard 18‑gauge core-needle biopsies can be taken through the retained cannula. CamPROBE is a disposable, single-use device that provides a transperineal biopsy route with only 2 puncture sites. The CamPROBE device does not attach to the ultrasound probe, so it requires a double freehand technique to manually keep the needle in line with the ultrasound probe. It costs £35, and 2 devices per procedure are required. At the time of writing this guidance, CamPROBE has a CE mark and is available on the UK market for clinical use. ## EZU-PA3U device The FUJIFILM EZU‑PA3U is a reusable dedicated freehand needle positioning device. It can be attached to either the FUJIFILM CC41R or the C41L47RP biplane transducer. The needle holder can be positioned on the vertical plane by sliding up or down before securing it into the required position. The needle holder is compatible with 14‑gauge or 18‑gauge needles. The company says that a coaxial needle can be used with the device. Needle targeting in the transverse plane is achieved by rotating the probe left or right until the needle trajectory is aligned with the lesion or area of interest. It costs £2,000 and is reusable. ## PrecisionPoint The PrecisionPoint transperineal access system (BXTAccelyon) is a freehand needle positioning device that enables freehand LATP prostate biopsies in an outpatient setting. It uses the Perineologic 15‑gauge, 7 cm access needle, which is securely attached to the transrectal ultrasound probe via the PrecisionPoint needle guide. The guide comprises a clip and moving carriage with 5 vertical holes. The integral access needle is aligned with the ultrasound probe, so when the needle is inserted into the perineum it can be seen on the ultrasound image. The access needle typically requires only 2 entry points: 1 on the left and 1 on the right side of the anal verge. The biopsy needle can then be guided and directed to the relevant regions. The company says that the device is compatible with any biplane TRUS or transperineal probe from any ultrasound manufacturer. It costs £200 and is a single-use device. ## SureFire SureFire (Delta Surgical) is a disposable freehand needle positioning device. It is designed to be used freehand without a stepper or stabilising device. It consists of a vertical needle guide with separate puncture channels at 9 different height settings, and an ultrasound probe clamp. The vertical needle guide can be rotated to reach different areas of the left and right side of the prostate, using the different height puncture channels. It costs £120. At the time of writing this guidance, SureFire was not available on the UK market and therefore was not considered by the committee in decision making. ## Trinity Perine Grid Trinity Perine (KOELIS/Kebomed) is a reusable freehand needle positioning device grid that attaches to an ultrasound probe for freehand transperineal biopsies under local anaesthetic. It consists of a vertical needle guide with 20 different height settings at 3 mm intervals, and an ultrasound probe clamp. There are 2 Perine Grids (18G and 14G). Each has a different needle gauge range. The 18G is compatible with 17‑gauge to 20‑gauge needles and the 14G is compatible with 14‑gauge to 16‑gauge needles. The company says that the Perine Grid can be used with a coaxial needle such as the BARD TruGuide disposable coaxial needle or equivalent. The device is compatible with the KOELIS Sidefire Ultrasound probe. It costs £754.40 and can be reprocessed 100 times. ## UA1232 puncture attachment The UA1232 metal puncture attachment (BK Medical) is designed for transperineal puncture and biopsy. It consists of a freehand needle positioning device and a mounting ring with a lock screw. The needle guide comprises 9 parallel guide channels, spaced 5 mm apart, each with an internal diameter of 2.1 mm suitable for a 14‑gauge needle. The company says that the choice of needle should be made by the clinician and the needle gauge should be compatible with the guide channel diameter. All parts of the puncture attachment can be sterilised by autoclave or disinfected by immersion in a suitable solution. The device is indicated for use with BK Medical ultrasound probes. It costs £1,400 and is reusable. # The comparators The comparators are: LA‑TRUS prostate biopsy LATP prostate biopsy using a grid and stepping device general anaesthetic transperineal (GATP) prostate biopsy using a grid and stepping device.Grid and stepping device-based biopsy approaches require the needle to pass through the perineum multiple times as the needle is passed through different holes in the grid to access different regions of the prostate. The grid is mounted on the stepping device, which is also used to hold and position the ultrasound probe.# Committee discussion The diagnostics advisory committee considered evidence on local anaesthetic transperineal (LATP) prostate biopsy, with or without the following freehand needle positioning devices: EZU‑PA3U (FUJIFILM) PrecisionPoint (BXTAccelyon) SureFire (Delta Surgical) Trinity Perine Grid (KOELIS/Kebomed) UA1232 (BK Medical). The diagnostics advisory committee also considered evidence on LATP prostate biopsy with the CamPROBE device (JEB Technologies), which is used with a double freehand technique. Evidence was considered from several sources, including a diagnostics assessment report and an overview of that report. Full details are in the project documents for this guidance. # Risk of infection, possible side effects, pain and embarrassment are important patient concerns about prostate biopsy Patient experts explained the main issues and concerns around prostate biopsy from a patient perspective. These included the importance of getting clear and accurate information about the procedure and possible side effects. They highlighted risk of infection as a major concern for patients. Patients were also worried about the severity and duration of side effects such as urinary retention and haematuria. A patient expert explained the importance of getting early results to reduce the anxiety of waiting for a biopsy result. The committee heard that prostate biopsies using any method can be undignified and embarrassing for patients. Alongside pain, this may be a factor in some patients preferring to have a general anaesthetic. This may be more of an issue for LATP biopsies because patients need to be in a lithotomy position. Patient experts said that unpleasant prostate biopsy experiences can stop people going to any more biopsy appointments. # Clinical effectiveness ## The evidence on cancer detection rates is limited and suggests no significant difference between different biopsy methods The evidence on cancer detection rates of the different prostate biopsy approaches was limited. The clinical-effectiveness review included 23 studies and the strength of evidence was mixed. Six studies were randomised controlled trials (RCTs), but most were observational. Six studies were only available as conference abstracts and 1 (Bojin 2019) was an unpublished slide set. The external assessment group (EAG) said that there was a high risk of reporting bias in these studies because of the limited information that they included. Most studies did not report whether a prebiopsy multiparametric MRI (mpMRI) had been done and some did not report the number of biopsy cores taken. In studies that did report the number of cores, these varied from around 12 to 24 cores. The committee noted that studies that used an mpMRI image to take targeted biopsy samples and those that took more cores may result in higher cancer detection rates regardless of the biopsy technique used. Eight of the studies used the PrecisionPoint device, 4 used a coaxial needle and 1 used a grid and stepper (for LATP compared with general anaesthetic transperineal biopsy). There were 4 single-arm studies (1 on CamPROBE and 3 on the UA1232 device). The rest did not report what device was used. There was no comparative evidence on the CamPROBE, EZU‑PA3U, UA1232 or Trinity Perine Grid devices. The committee noted that of the 23 included studies, a single RCT available as a conference abstract was the only study used in the network meta-analysis of cancer detection rates for LATP using a freehand needle positioning device. The committee said that there was limited evidence on cancer detection rates and that caution should be used when interpreting the results. It also noted that the ongoing RCT of transrectal compared with LATP biopsy (TRANSLATE; see section 3.8) will provide further evidence on detection rates of clinically significant prostate cancer. The committee concluded that, because there was generally no significant difference between LATP using any method, LATP using a freehand needle positioning device, local anaesthetic transrectal ultrasound (LA‑TRUS) or GATP, it could not say if one technique was better than the others. ## The freehand needle positioning devices all work in a similar way using the same biopsy technique Clinical experts said that the EZU‑PA3U, PrecisionPoint, Trinity Perine Grid and UA1232 freehand needle positioning devices are mechanical devices that, despite some technical differences, all work in a similar way for the user. They attach to the ultrasound probe and align the needle with the probe axis, keeping them in line during the procedure. So, the biopsy technique used with them is considered to be the same. The needles the devices use are indicated for taking biopsy samples through the skin. A clinical expert said that when they moved to using the PrecisionPoint device, there was no difference in the biopsy sample quality. Although the PrecisionPoint device comes with a specific non-coring access needle as part of the kit, the companies for EZU‑PA3U, Trinity Perine Grid and UA1232 said that their devices could be used with needles bought separately provided they are compatible with the guide channel diameter. Use of an access needle or a coaxial needle means that generally 4 or fewer punctures of the skin are needed. Other differences between the devices are that: PrecisionPoint is a single-use disposable device, whereas the other devices are reusable and need to be sterilised between uses. PrecisionPoint can be used with third party ultrasound probes, whereas other devices need to be used with specific ultrasound probes.The EAG confirmed that the costs associated with sterilisation were included in the economic modelling. ## Cancer detection rates and adverse events are likely to be similar between the different freehand needle positioning devices All the comparative clinical evidence for freehand needle positioning devices was on the PrecisionPoint device. However, a clinical expert explained that the different freehand devices all work in a similar way with the same biopsy technique (see section 3.3). The clinical experts said they would not expect significant differences in cancer detection rates and adverse event rates between the devices. No studies directly compared the individual devices, so there was no evidence that one performs better than any other. The committee concluded that the clinical effectiveness in terms of cancer detection and adverse events was likely to be similar for all the freehand needle positioning devices, although this was uncertain. ## The evidence is not generalisable to double freehand prostate biopsy using the CamPROBE device A clinical expert explained that double freehand prostate biopsy approaches should be considered separately to the freehand approach that uses a needle positioning guide. They noted that for double freehand, a needle is used without a positioning guide, so 1 hand guides the ultrasound probe while the other guides the needle, and they need to be kept in line manually. CamPROBE is a double freehand device, so it is not attached to the ultrasound probe. There was no evidence comparing CamPROBE with any of the freehand needle positioning devices. The committee concluded that, because of these differences and the lack of evidence, it was uncertain if CamPROBE would have the same clinical effectiveness in terms of cancer detection and adverse events as the freehand needle positioning devices. Comparative studies of the CamPROBE biopsy device are needed to assess its clinical effectiveness (see section 4.1). ## Rates of infection and sepsis are higher for TRUS biopsies than transperineal biopsies Clinical experts said that sepsis can happen after a prostate biopsy. It is rare but serious, and can result in death. In the EAG's clinical-effectiveness review, relatively few studies reported post-biopsy sepsis. In the studies that did report sepsis, it only occurred after LA‑TRUS biopsy and not after transperineal biopsy. An analysis of recent hospital episode statistics data (from 2017 to 2019) by Tamhankar et al. (2020) showed that there was a difference in rates of infection and sepsis between TRUS biopsies and transperineal biopsies. Rates of infection were 1.50% in people who had a TRUS biopsy and 0.67% for a transperineal biopsy. Similarly, rates of sepsis were higher for TRUS biopsies (1.12%) than for transperineal biopsies (0.42%). The committee concluded that LATP biopsies may reduce the risk of infection and sepsis compared with TRUS biopsies. ## There are some differences between LATP and TRUS biopsy approaches Clinical experts explained the key differences between LA‑TRUS and LATP biopsy approaches. An LA‑TRUS biopsy tends to take fewer cores (usually 12), whereas centres that use the Ginsburg protocol for LATP may take 24 cores or more (2 LATP protocols are used in the UK: RAPID and Ginsburg). However, some centres may also take 12 cores for LATP plus additional targeted cores based on mpMRI results. A clinical expert said that mpMRI may identify anterior lesions of the prostate and these can be more difficult to reach using LA‑TRUS biopsy than LATP. However, the committee heard that there was no evidence to assess the clinical effectiveness of the different biopsy approaches in people with anterior lesions. Clinical experts said that LATP may be less tolerable because of the lithotomy position, and if numerous skin punctures were needed, when using a grid and stepper for example. LATP biopsies also take slightly longer than TRUS biopsies, particularly when clinicians are training or first start using the technique. However, a clinical expert said that when practitioners are trained equally in the techniques, the difference is minimal. Less experienced clinicians may find it easier to use a grid and stepper. Clinical experts explained that, in a minority of cases, LATP might be contraindicated, such as in people who have had gender reassignment. There are also some patient groups with a higher risk of infection (for example, immunocompromised people) who would prefer LATP because of the lower risk of sepsis with LATP than LA‑TRUS. Clinical experts explained that there is a move towards using LATP nationally and that some centres no longer do TRUS prostate biopsies. ## Participation in the ongoing TRANSLATE RCT is encouraged to generate further evidence to help refine clinical practice The ongoing TRANSLATE RCT will provide further comparative evidence on LA‑TRUS biopsy and LATP biopsy using a freehand needle positioning device. The trial aims to recruit 1,042 people with a prostate over 15 months from 9 NHS hospitals in the UK. The protocol says that an average of around 12 systematic biopsy cores will be taken, depending on prostate size, with an additional 4 target biopsy cores for each significant lesion seen on prebiopsy MRI. The primary outcome is detection rates of clinically significant prostate cancer. Secondary outcomes include rates of infection, health-related quality of life, patient-reported tolerability of the procedure, patient-reported biopsy-related complications, number of subsequent prostate biopsy procedures, cost effectiveness, and histological parameters. The trial will last for 31 months and is expected to end in October 2023. The committee concluded that centres should be encouraged to participate in research and data collection, including the TRANSLATE RCT, to generate more evidence to help understand the effects of differences between the LATP and LA‑TRUS biopsy approaches and refine clinical practice. # Cost effectiveness ## The committee prefers the new assumptions used in the EAG's revised analysis The committee considered the original and revised base-case analyses and noted that in the revised analysis, the key differences with the largest effect on the incremental cost-effectiveness ratios (ICERs) were that: studies that used spinal anaesthesia were excluded -vernight hospitalisation data from the Berry et al. (2020) study was excluded.A clinical expert said that studies that used spinal anaesthesia were more closely aligned with general anaesthetic approaches, so they could not be used to assess LATP. A clinical expert explained that the Berry et al. (2020) study used older data from when transperineal biopsy was frequently done under general anaesthetic and more cores were taken. Overnight stays after this type of biopsy were more common, but this does not reflect current clinical practice. Clinical experts agreed that excluding the spinal anaesthesia studies and the Berry et al. overnight stay data was appropriate, and the committee concluded that it preferred the EAG's revised base case. ## There is not enough evidence to determine whether LATP using CamPROBE is a cost-effective use of NHS resources In the analysis in which most studies did LATP prostate biopsy using a double freehand coaxial needle (LATP-other), this group was dominated by LA‑TRUS in most analyses. ICERs for PrecisionPoint compared with LA‑TRUS were generally cost effective at below £30,000 per quality-adjusted life year (QALY) gained. This was driven by cancer detection rates. The clinical experts noted that the relative risks for cancer detection used in the revised base-case model were lower for LATP‑other (coaxial needle studies) than for PrecisionPoint and for LA‑TRUS. However, confidence intervals were wide and overlapped, so it is uncertain whether one technique is better than another. The committee concluded that it was uncertain if LATP prostate biopsy using a double freehand coaxial needle approach is cost effective. It also recalled that there was no comparative evidence on the CamPROBE double freehand device (section 3.5). The committee therefore concluded that there was not enough evidence to understand the cost effectiveness of LATP using CamPROBE, and more evidence was needed. ## Using the cost of the PrecisionPoint device in a scenario analysis increases the ICERs The EAG did a scenario analysis using the PrecisionPoint device cost instead of an average cost of all the freehand devices. In this scenario, the ICER for LATP using PrecisionPoint compared with LA‑TRUS remained below £20,000 per QALY gained for people having a first biopsy, but was higher than £30,000 per QALY gained in people having a repeat biopsy. However, clinical experts explained that the proportion of people having a first biopsy is much greater than the proportion of people having a repeat biopsy. The EAG did not model alternative scenarios using the costs of the other freehand devices, but the committee noted that the PrecisionPoint device was the most expensive. The committee concluded therefore that all the freehand needle positioning devices, including PrecisionPoint, had the potential to be cost effective in first and repeat biopsies. ## Histopathology costs may be overestimated in the revised model The EAG's model results were very sensitive to changes in the number of cores taken during the biopsy. It said that this was because of the histopathology cost per core. In the revised base case, a higher histopathology cost was used, increasing from £107.50 for 12 cores in the original model to £438.96 for 12 cores in the revised model. The EAG explained that this had little effect on the base-case ICERs because the histopathology costs cancel each other out when it is assumed that 12 cores are taken for each biopsy approach. However, if the number of cores differs between biopsy approaches, then there is a bigger effect on the results. The committee noted that the incremental QALYs were very small, which made the ICERs sensitive to changes in cost. Increasing the number of cores from 12 to 24 for LATP biopsy resulted in a very large increase in the ICERs, taking the results above what is generally considered to be cost effective by NICE. A clinical expert said that the average number of cores taken by a centre depended on which LATP biopsy protocol it used. Two LATP protocols are used in the UK: RAPID and Ginsburg. Centres using the RAPID protocol take around 12 to 15 cores, whereas centres using the Ginsburg protocol take 24 or more. A clinical expert explained that the model may have overestimated the likely increase in histopathology costs in the 24‑core scenario, because increasing from 12 to 24 cores increases histopathology costs only minimally. Histopathology costs only increase substantially if more than 24 cores needed analysing. The committee concluded that the histopathology costs are likely to be overestimated in the revised base case, and that moving from 12 to 24 cores is unlikely to have a substantial effect on the ICERs. ## The freehand needle positioning devices have the potential to be cost effective and are recommended as an option for LATP biopsy The committee noted that in most analyses, freehand needle positioning devices were cost effective, with ICERs well below £20,000 per QALY gained. Although there was some uncertainty in the model results around cancer detection rates and biopsy costs (see section 3.2), there was no evidence to suggest that LATP biopsy using a freehand needle positioning device was any less effective than LA‑TRUS biopsy. The ongoing TRANSLATE study will provide comparative data that may help reduce this uncertainty. The reduced rates of infection and sepsis were an important benefit of LATP biopsy (see section 3.6). Cost-effectiveness modelling suggests that using a freehand needle positioning device for transperineal biopsy has the potential to be cost effective (see section 3.11). The committee therefore concluded that the freehand needle positioning devices should be recommended as an option for LATP biopsy.# Recommendations for further research Further comparative clinical-effectiveness evidence on the CamPROBE biopsy device is recommended to understand how double freehand prostate biopsy approaches compare with transrectal ultrasound biopsy or transperineal biopsy using freehand needle positioning devices (see section 3.5). A patient experience study is recommended to better understand tolerability of local anaesthetic prostate biopsy, what aspects of the procedure may cause patients embarrassment, and how this could be reduced to increase uptake. Further research is recommended to understand how the number of biopsy cores taken during local anaesthetic transperineal (LATP) prostate biopsy varies across centres and how this affects prostate biopsy histopathology costs.	{'Recommendations': 'Local anaesthetic transperineal (LATP) prostate biopsy using the freehand needle positioning device PrecisionPoint is recommended as an option for diagnosing prostate cancer.\n\nAlthough there is considerably less evidence and therefore greater uncertainty of clinical benefit for them, the following freehand needle positioning devices are expected to have similar cancer detection rates and adverse events to those of PrecisionPoint:\n\nEZU‑PA3U device\n\nTrinity Perine Grid\n\nUA1232 puncture attachment.There are technical differences between them, but they all work in a similar way using the same biopsy technique. So, these devices are recommended as options for diagnosing prostate cancer.\n\nCentres are encouraged to take part in research and data collection, including the randomised controlled trial of transrectal biopsy compared with LATP biopsy (the TRANSLATE trial; see section\xa03.8) to help refine clinical practice.\n\nThere is not enough evidence to recommend double freehand LATP prostate biopsy using the CamPROBE device. Further research is recommended to understand its clinical effectiveness.\n\nWhy the committee made these recommendations\n\nStandard prostate biopsy uses local anaesthetic transrectal ultrasound (LA‑TRUS). This involves taking samples of prostate tissue by inserting a biopsy needle through the rectal wall via the anus. An alternative is LATP prostate biopsy, which involves inserting the needle through the perineum, the skin area between the anus and the scrotum.\n\nTechniques for LATP biopsy vary. It can be done using a freehand needle positioning device, a grid and stepping device, or using a coaxial needle only (double freehand).\n\nThe evidence suggests no significant difference in cancer detection rates between LATP biopsy and LA‑TRUS biopsy, but it suggests lower rates of infection and sepsis after LATP biopsies. More evidence on their differences will come from the ongoing TRANSLATE trial, which may help refine clinical practice.\n\nMost of the clinical evidence for freehand needle positioning devices is on the PrecisionPoint device. There is no comparative evidence for the EZU‑PA3U, UA1232, or Trinity Perine Grid devices, but experts suggest that cancer detection rates and adverse events are expected to be similar for the different freehand devices. This is because they all function in a similar way, in that they attach to the ultrasound probe and keep the needle in line with it. The biopsy technique is the same.\n\nThe most likely cost-effectiveness estimates for freehand needle positioning devices are within what NICE considers an acceptable use of NHS resources. So, LATP biopsy using a freehand needle positioning device is recommended.\n\nThere is no comparative evidence on the CamPROBE device, which uses a double freehand technique. Experts said that because the double freehand technique is different to using the freehand needle positioning devices, more research is needed to understand the cancer detection rates, adverse events and cost effectiveness.', 'The diagnostic tests': "# Clinical need and practice\n\nProstate cancer is the most commonly diagnosed cancer in men in the UK. It mainly affects people over 50 and the risk is higher for people of African family background and people with a family history of prostate cancer.\n\nProstate cancer can be slow or quickly growing. If it is growing quickly, it is more likely to spread and may require treatment, which includes radiotherapy, chemotherapy, surgery or a combination of these.\n\nThe section on assessment and diagnosis in NICE's guideline on prostate cancer recommends that after someone is referred to secondary care with suspected clinically localised prostate cancer, they should be offered a multiparametric MRI (mpMRI) test. The results of this MRI should be reported using a 5‑point Likert scale. People with a Likert score of 3 or more should be offered an mpMRI-influenced prostate biopsy.\n\nProstate biopsies can be targeted using MRI to identify lesions to take a small number of tissue samples or cores from. Or they can be systematic, taking multiple samples from different regions of the left and right side of the prostate.\n\nThe current standard prostate biopsy is mpMRI-influenced local anaesthetic transrectal ultrasound (LA‑TRUS) biopsy or mpMRI-influenced local anaesthetic transperineal (LATP) biopsy. Both routes use a transrectal ultrasound probe inserted into the anus to image the prostate. Both approaches are done in an outpatient setting.\n\nIn a TRUS prostate biopsy, samples of prostate tissue are collected using a biopsy needle inserted through the rectal wall via the anus. The disadvantage of this method is that some people get serious infections, including sepsis, requiring hospital admission and antibiotics. In LATP biopsy, the needle enters the body through the perineum, the skin area between the anus and the scrotum. This could greatly reduce the risk of biopsy-related sepsis compared with a TRUS biopsy, and therefore may reduce hospital admissions and the need for preventative antibiotics.\n\n# The interventions\n\n## CamPROBE\n\nThe CamPROBE (JEB Technologies) is a cannulated transperineal access system designed specifically for prostate biopsies. It consists of a coaxial cannula with an integrated needle. This needle can be attached to a standard syringe, allowing the device to be inserted and local anaesthetic to be injected at the same time under ultrasound guidance. This removes the need for separate punctures, nerve blocks or sedation. Once the cannula is in position, the integrated needle is removed and standard 18‑gauge core-needle biopsies can be taken through the retained cannula. CamPROBE is a disposable, single-use device that provides a transperineal biopsy route with only 2 puncture sites. The CamPROBE device does not attach to the ultrasound probe, so it requires a double freehand technique to manually keep the needle in line with the ultrasound probe. It costs £35, and 2 devices per procedure are required. At the time of writing this guidance, CamPROBE has a CE mark and is available on the UK market for clinical use.\n\n## EZU-PA3U device\n\nThe FUJIFILM EZU‑PA3U is a reusable dedicated freehand needle positioning device. It can be attached to either the FUJIFILM CC41R or the C41L47RP biplane transducer. The needle holder can be positioned on the vertical plane by sliding up or down before securing it into the required position. The needle holder is compatible with 14‑gauge or 18‑gauge needles. The company says that a coaxial needle can be used with the device. Needle targeting in the transverse plane is achieved by rotating the probe left or right until the needle trajectory is aligned with the lesion or area of interest. It costs £2,000 and is reusable.\n\n## PrecisionPoint\n\nThe PrecisionPoint transperineal access system (BXTAccelyon) is a freehand needle positioning device that enables freehand LATP prostate biopsies in an outpatient setting. It uses the Perineologic 15‑gauge, 7\xa0cm access needle, which is securely attached to the transrectal ultrasound probe via the PrecisionPoint needle guide. The guide comprises a clip and moving carriage with 5 vertical holes. The integral access needle is aligned with the ultrasound probe, so when the needle is inserted into the perineum it can be seen on the ultrasound image. The access needle typically requires only 2 entry points: 1 on the left and 1 on the right side of the anal verge. The biopsy needle can then be guided and directed to the relevant regions. The company says that the device is compatible with any biplane TRUS or transperineal probe from any ultrasound manufacturer. It costs £200 and is a single-use device.\n\n## SureFire\n\nSureFire (Delta Surgical) is a disposable freehand needle positioning device. It is designed to be used freehand without a stepper or stabilising device. It consists of a vertical needle guide with separate puncture channels at 9 different height settings, and an ultrasound probe clamp. The vertical needle guide can be rotated to reach different areas of the left and right side of the prostate, using the different height puncture channels. It costs £120. At the time of writing this guidance, SureFire was not available on the UK market and therefore was not considered by the committee in decision making.\n\n## Trinity Perine Grid\n\nTrinity Perine (KOELIS/Kebomed) is a reusable freehand needle positioning device grid that attaches to an ultrasound probe for freehand transperineal biopsies under local anaesthetic. It consists of a vertical needle guide with 20 different height settings at 3\xa0mm intervals, and an ultrasound probe clamp. There are 2 Perine Grids (18G and 14G). Each has a different needle gauge range. The 18G is compatible with 17‑gauge to 20‑gauge needles and the 14G is compatible with 14‑gauge to 16‑gauge needles. The company says that the Perine Grid can be used with a coaxial needle such as the BARD TruGuide disposable coaxial needle or equivalent. The device is compatible with the KOELIS Sidefire Ultrasound probe. It costs £754.40 and can be reprocessed 100 times.\n\n## UA1232 puncture attachment\n\nThe UA1232 metal puncture attachment (BK Medical) is designed for transperineal puncture and biopsy. It consists of a freehand needle positioning device and a mounting ring with a lock screw. The needle guide comprises 9 parallel guide channels, spaced 5\xa0mm apart, each with an internal diameter of 2.1\xa0mm suitable for a 14‑gauge needle. The company says that the choice of needle should be made by the clinician and the needle gauge should be compatible with the guide channel diameter. All parts of the puncture attachment can be sterilised by autoclave or disinfected by immersion in a suitable solution. The device is indicated for use with BK Medical ultrasound probes. It costs £1,400 and is reusable.\n\n# The comparators\n\nThe comparators are:\n\nLA‑TRUS prostate biopsy\n\nLATP prostate biopsy using a grid and stepping device\n\ngeneral anaesthetic transperineal (GATP) prostate biopsy using a grid and stepping device.Grid and stepping device-based biopsy approaches require the needle to pass through the perineum multiple times as the needle is passed through different holes in the grid to access different regions of the prostate. The grid is mounted on the stepping device, which is also used to hold and position the ultrasound probe.", 'Committee discussion': "The diagnostics advisory committee considered evidence on local anaesthetic transperineal (LATP) prostate biopsy, with or without the following freehand needle positioning devices:\n\nEZU‑PA3U (FUJIFILM)\n\nPrecisionPoint (BXTAccelyon)\n\nSureFire (Delta Surgical)\n\nTrinity Perine Grid (KOELIS/Kebomed)\n\nUA1232 (BK Medical).\n\nThe diagnostics advisory committee also considered evidence on LATP prostate biopsy with the CamPROBE device (JEB Technologies), which is used with a double freehand technique.\n\nEvidence was considered from several sources, including a diagnostics assessment report and an overview of that report. Full details are in the project documents for this guidance.\n\n# Risk of infection, possible side effects, pain and embarrassment are important patient concerns about prostate biopsy\n\nPatient experts explained the main issues and concerns around prostate biopsy from a patient perspective. These included the importance of getting clear and accurate information about the procedure and possible side effects. They highlighted risk of infection as a major concern for patients. Patients were also worried about the severity and duration of side effects such as urinary retention and haematuria. A patient expert explained the importance of getting early results to reduce the anxiety of waiting for a biopsy result. The committee heard that prostate biopsies using any method can be undignified and embarrassing for patients. Alongside pain, this may be a factor in some patients preferring to have a general anaesthetic. This may be more of an issue for LATP biopsies because patients need to be in a lithotomy position. Patient experts said that unpleasant prostate biopsy experiences can stop people going to any more biopsy appointments.\n\n# Clinical effectiveness\n\n## The evidence on cancer detection rates is limited and suggests no significant difference between different biopsy methods\n\nThe evidence on cancer detection rates of the different prostate biopsy approaches was limited. The clinical-effectiveness review included 23 studies and the strength of evidence was mixed. Six studies were randomised controlled trials (RCTs), but most were observational. Six studies were only available as conference abstracts and 1 (Bojin 2019) was an unpublished slide set. The external assessment group (EAG) said that there was a high risk of reporting bias in these studies because of the limited information that they included. Most studies did not report whether a prebiopsy multiparametric MRI (mpMRI) had been done and some did not report the number of biopsy cores taken. In studies that did report the number of cores, these varied from around 12 to 24 cores. The committee noted that studies that used an mpMRI image to take targeted biopsy samples and those that took more cores may result in higher cancer detection rates regardless of the biopsy technique used. Eight of the studies used the PrecisionPoint device, 4 used a coaxial needle and 1 used a grid and stepper (for LATP compared with general anaesthetic transperineal [GATP] biopsy). There were 4 single-arm studies (1 on CamPROBE and 3 on the UA1232 device). The rest did not report what device was used. There was no comparative evidence on the CamPROBE, EZU‑PA3U, UA1232 or Trinity Perine Grid devices. The committee noted that of the 23 included studies, a single RCT available as a conference abstract was the only study used in the network meta-analysis of cancer detection rates for LATP using a freehand needle positioning device. The committee said that there was limited evidence on cancer detection rates and that caution should be used when interpreting the results. It also noted that the ongoing RCT of transrectal compared with LATP biopsy (TRANSLATE; see section\xa03.8) will provide further evidence on detection rates of clinically significant prostate cancer. The committee concluded that, because there was generally no significant difference between LATP using any method, LATP using a freehand needle positioning device, local anaesthetic transrectal ultrasound (LA‑TRUS) or GATP, it could not say if one technique was better than the others.\n\n## The freehand needle positioning devices all work in a similar way using the same biopsy technique\n\nClinical experts said that the EZU‑PA3U, PrecisionPoint, Trinity Perine Grid and UA1232 freehand needle positioning devices are mechanical devices that, despite some technical differences, all work in a similar way for the user. They attach to the ultrasound probe and align the needle with the probe axis, keeping them in line during the procedure. So, the biopsy technique used with them is considered to be the same. The needles the devices use are indicated for taking biopsy samples through the skin. A clinical expert said that when they moved to using the PrecisionPoint device, there was no difference in the biopsy sample quality. Although the PrecisionPoint device comes with a specific non-coring access needle as part of the kit, the companies for EZU‑PA3U, Trinity Perine Grid and UA1232 said that their devices could be used with needles bought separately provided they are compatible with the guide channel diameter. Use of an access needle or a coaxial needle means that generally 4 or fewer punctures of the skin are needed. Other differences between the devices are that:\n\nPrecisionPoint is a single-use disposable device, whereas the other devices are reusable and need to be sterilised between uses.\n\nPrecisionPoint can be used with third party ultrasound probes, whereas other devices need to be used with specific ultrasound probes.The EAG confirmed that the costs associated with sterilisation were included in the economic modelling.\n\n## Cancer detection rates and adverse events are likely to be similar between the different freehand needle positioning devices\n\nAll the comparative clinical evidence for freehand needle positioning devices was on the PrecisionPoint device. However, a clinical expert explained that the different freehand devices all work in a similar way with the same biopsy technique (see section\xa03.3). The clinical experts said they would not expect significant differences in cancer detection rates and adverse event rates between the devices. No studies directly compared the individual devices, so there was no evidence that one performs better than any other. The committee concluded that the clinical effectiveness in terms of cancer detection and adverse events was likely to be similar for all the freehand needle positioning devices, although this was uncertain.\n\n## The evidence is not generalisable to double freehand prostate biopsy using the CamPROBE device\n\nA clinical expert explained that double freehand prostate biopsy approaches should be considered separately to the freehand approach that uses a needle positioning guide. They noted that for double freehand, a needle is used without a positioning guide, so 1 hand guides the ultrasound probe while the other guides the needle, and they need to be kept in line manually. CamPROBE is a double freehand device, so it is not attached to the ultrasound probe. There was no evidence comparing CamPROBE with any of the freehand needle positioning devices. The committee concluded that, because of these differences and the lack of evidence, it was uncertain if CamPROBE would have the same clinical effectiveness in terms of cancer detection and adverse events as the freehand needle positioning devices. Comparative studies of the CamPROBE biopsy device are needed to assess its clinical effectiveness (see section\xa04.1).\n\n## Rates of infection and sepsis are higher for TRUS biopsies than transperineal biopsies\n\nClinical experts said that sepsis can happen after a prostate biopsy. It is rare but serious, and can result in death. In the EAG's clinical-effectiveness review, relatively few studies reported post-biopsy sepsis. In the studies that did report sepsis, it only occurred after LA‑TRUS biopsy and not after transperineal biopsy. An analysis of recent hospital episode statistics data (from 2017 to 2019) by Tamhankar et al. (2020) showed that there was a difference in rates of infection and sepsis between TRUS biopsies and transperineal biopsies. Rates of infection were 1.50% in people who had a TRUS biopsy and 0.67% for a transperineal biopsy. Similarly, rates of sepsis were higher for TRUS biopsies (1.12%) than for transperineal biopsies (0.42%). The committee concluded that LATP biopsies may reduce the risk of infection and sepsis compared with TRUS biopsies.\n\n## There are some differences between LATP and TRUS biopsy approaches\n\nClinical experts explained the key differences between LA‑TRUS and LATP biopsy approaches. An LA‑TRUS biopsy tends to take fewer cores (usually 12), whereas centres that use the Ginsburg protocol for LATP may take 24 cores or more (2 LATP protocols are used in the UK: RAPID and Ginsburg). However, some centres may also take 12 cores for LATP plus additional targeted cores based on mpMRI results. A clinical expert said that mpMRI may identify anterior lesions of the prostate and these can be more difficult to reach using LA‑TRUS biopsy than LATP. However, the committee heard that there was no evidence to assess the clinical effectiveness of the different biopsy approaches in people with anterior lesions. Clinical experts said that LATP may be less tolerable because of the lithotomy position, and if numerous skin punctures were needed, when using a grid and stepper for example. LATP biopsies also take slightly longer than TRUS biopsies, particularly when clinicians are training or first start using the technique. However, a clinical expert said that when practitioners are trained equally in the techniques, the difference is minimal. Less experienced clinicians may find it easier to use a grid and stepper. Clinical experts explained that, in a minority of cases, LATP might be contraindicated, such as in people who have had gender reassignment. There are also some patient groups with a higher risk of infection (for example, immunocompromised people) who would prefer LATP because of the lower risk of sepsis with LATP than LA‑TRUS. Clinical experts explained that there is a move towards using LATP nationally and that some centres no longer do TRUS prostate biopsies.\n\n## Participation in the ongoing TRANSLATE RCT is encouraged to generate further evidence to help refine clinical practice\n\nThe ongoing TRANSLATE RCT will provide further comparative evidence on LA‑TRUS biopsy and LATP biopsy using a freehand needle positioning device. The trial aims to recruit 1,042 people with a prostate over 15\xa0months from 9 NHS hospitals in the UK. The protocol says that an average of around 12 systematic biopsy cores will be taken, depending on prostate size, with an additional 4 target biopsy cores for each significant lesion seen on prebiopsy MRI. The primary outcome is detection rates of clinically significant prostate cancer. Secondary outcomes include rates of infection, health-related quality of life, patient-reported tolerability of the procedure, patient-reported biopsy-related complications, number of subsequent prostate biopsy procedures, cost effectiveness, and histological parameters. The trial will last for 31\xa0months and is expected to end in October 2023. The committee concluded that centres should be encouraged to participate in research and data collection, including the TRANSLATE RCT, to generate more evidence to help understand the effects of differences between the LATP and LA‑TRUS biopsy approaches and refine clinical practice.\n\n# Cost effectiveness\n\n## The committee prefers the new assumptions used in the EAG's revised analysis\n\nThe committee considered the original and revised base-case analyses and noted that in the revised analysis, the key differences with the largest effect on the incremental cost-effectiveness ratios (ICERs) were that:\n\nstudies that used spinal anaesthesia were excluded\n\novernight hospitalisation data from the Berry et al. (2020) study was excluded.A clinical expert said that studies that used spinal anaesthesia were more closely aligned with general anaesthetic approaches, so they could not be used to assess LATP. A clinical expert explained that the Berry et al. (2020) study used older data from when transperineal biopsy was frequently done under general anaesthetic and more cores were taken. Overnight stays after this type of biopsy were more common, but this does not reflect current clinical practice. Clinical experts agreed that excluding the spinal anaesthesia studies and the Berry et al. overnight stay data was appropriate, and the committee concluded that it preferred the EAG's revised base case.\n\n## There is not enough evidence to determine whether LATP using CamPROBE is a cost-effective use of NHS resources\n\nIn the analysis in which most studies did LATP prostate biopsy using a double freehand coaxial needle (LATP-other), this group was dominated by LA‑TRUS in most analyses. ICERs for PrecisionPoint compared with LA‑TRUS were generally cost effective at below £30,000 per quality-adjusted life year (QALY) gained. This was driven by cancer detection rates. The clinical experts noted that the relative risks for cancer detection used in the revised base-case model were lower for LATP‑other (coaxial needle studies) than for PrecisionPoint and for LA‑TRUS. However, confidence intervals were wide and overlapped, so it is uncertain whether one technique is better than another. The committee concluded that it was uncertain if LATP prostate biopsy using a double freehand coaxial needle approach is cost effective. It also recalled that there was no comparative evidence on the CamPROBE double freehand device (section\xa03.5). The committee therefore concluded that there was not enough evidence to understand the cost effectiveness of LATP using CamPROBE, and more evidence was needed.\n\n## Using the cost of the PrecisionPoint device in a scenario analysis increases the ICERs\n\nThe EAG did a scenario analysis using the PrecisionPoint device cost instead of an average cost of all the freehand devices. In this scenario, the ICER for LATP using PrecisionPoint compared with LA‑TRUS remained below £20,000 per QALY gained for people having a first biopsy, but was higher than £30,000 per QALY gained in people having a repeat biopsy. However, clinical experts explained that the proportion of people having a first biopsy is much greater than the proportion of people having a repeat biopsy. The EAG did not model alternative scenarios using the costs of the other freehand devices, but the committee noted that the PrecisionPoint device was the most expensive. The committee concluded therefore that all the freehand needle positioning devices, including PrecisionPoint, had the potential to be cost effective in first and repeat biopsies.\n\n## Histopathology costs may be overestimated in the revised model\n\nThe EAG's model results were very sensitive to changes in the number of cores taken during the biopsy. It said that this was because of the histopathology cost per core. In the revised base case, a higher histopathology cost was used, increasing from £107.50 for 12 cores in the original model to £438.96 for 12 cores in the revised model. The EAG explained that this had little effect on the base-case ICERs because the histopathology costs cancel each other out when it is assumed that 12 cores are taken for each biopsy approach. However, if the number of cores differs between biopsy approaches, then there is a bigger effect on the results. The committee noted that the incremental QALYs were very small, which made the ICERs sensitive to changes in cost. Increasing the number of cores from 12 to 24 for LATP biopsy resulted in a very large increase in the ICERs, taking the results above what is generally considered to be cost effective by NICE. A clinical expert said that the average number of cores taken by a centre depended on which LATP biopsy protocol it used. Two LATP protocols are used in the UK: RAPID and Ginsburg. Centres using the RAPID protocol take around 12 to 15 cores, whereas centres using the Ginsburg protocol take 24 or more. A clinical expert explained that the model may have overestimated the likely increase in histopathology costs in the 24‑core scenario, because increasing from 12 to 24 cores increases histopathology costs only minimally. Histopathology costs only increase substantially if more than 24 cores needed analysing. The committee concluded that the histopathology costs are likely to be overestimated in the revised base case, and that moving from 12 to 24 cores is unlikely to have a substantial effect on the ICERs.\n\n## The freehand needle positioning devices have the potential to be cost effective and are recommended as an option for LATP biopsy\n\nThe committee noted that in most analyses, freehand needle positioning devices were cost effective, with ICERs well below £20,000 per QALY gained. Although there was some uncertainty in the model results around cancer detection rates and biopsy costs (see section\xa03.2), there was no evidence to suggest that LATP biopsy using a freehand needle positioning device was any less effective than LA‑TRUS biopsy. The ongoing TRANSLATE study will provide comparative data that may help reduce this uncertainty. The reduced rates of infection and sepsis were an important benefit of LATP biopsy (see section\xa03.6). Cost-effectiveness modelling suggests that using a freehand needle positioning device for transperineal biopsy has the potential to be cost effective (see section\xa03.11). The committee therefore concluded that the freehand needle positioning devices should be recommended as an option for LATP biopsy.", 'Recommendations for further research': 'Further comparative clinical-effectiveness evidence on the CamPROBE biopsy device is recommended to understand how double freehand prostate biopsy approaches compare with transrectal ultrasound biopsy or transperineal biopsy using freehand needle positioning devices (see section\xa03.5).\n\nA patient experience study is recommended to better understand tolerability of local anaesthetic prostate biopsy, what aspects of the procedure may cause patients embarrassment, and how this could be reduced to increase uptake.\n\nFurther research is recommended to understand how the number of biopsy cores taken during local anaesthetic transperineal (LATP) prostate biopsy varies across centres and how this affects prostate biopsy histopathology costs.'}	https://www.nice.org.uk/guidance/dg54	Evidence-based recommendations on transperineal biopsy for diagnosing prostate cancer.
2ec843871f676b7154e8285b434b0a2138ce3bbf	nice	Ibrutinib with venetoclax for untreated chronic lymphocytic leukaemia	Ibrutinib with venetoclax for untreated chronic lymphocytic leukaemia Evidence-based recommendations on ibrutinib (Imbruvica) with venetoclax (Venclyxto) for untreated chronic lymphocytic leukaemia in adults. # Recommendations Ibrutinib plus venetoclax is recommended, within its marketing authorisation, as an option for untreated chronic lymphocytic leukaemia (CLL) in adults. This is only if the companies provide both drugs according to the commercial arrangements. Why the committee made this recommendation Treatments for untreated CLL include acalabrutinib, fludarabine plus cyclophosphamide and rituximab (FCR), ibrutinib alone, obinutuzumab plus chlorambucil, and venetoclax plus obinutuzumab. FCR is rarely used in clinical practice. Clinical evidence shows that CLL takes longer to get worse, and people live longer, when they have ibrutinib plus venetoclax compared with obinutuzumab plus chlorambucil. An indirect comparison with acalabrutinib, FCR, ibrutinib alone, and venetoclax plus obinutuzumab suggests that CLL takes longer to get worse when treated with ibrutinib plus venetoclax. The cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources, so ibrutinib plus venetoclax is recommended.# Information about ibrutinib with venetoclax # Marketing authorisation indication Ibrutinib (Imbruvica, Janssen-Cilag) with venetoclax (Venclyxto, AbbVie) is indicated for 'the treatment of adult patients with previously untreated chronic lymphocytic leukaemia'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for ibrutinib. # Price A 28‑pack of 140‑mg ibrutinib tablets costs £1,430.80 (excluding VAT; BNF online accessed February 2022). The company has a commercial arrangement. This makes ibrutinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount. A 112‑pack of 100‑mg venetoclax tablets costs £4,789.47 (excluding VAT; BNF online accessed February 2022). AbbVie has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is AbbVie's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Janssen-Cilag, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition Chronic lymphocytic leukaemia (CLL) is a malignant disorder of white blood cells and is the most common type of leukaemia in England. The patient experts explained that the physical and psychological effects of CLL have a debilitating effect on their daily lives. The risk of CLL increases with age. CLL progression and poor prognosis is commonly caused by a deletion of chromosome 17p (17p deletion) or mutation of the tumour protein p53 (TP53 mutation). The committee concluded that CLL substantially affects physical and psychological quality of life. # Clinical management and comparators The clinical and patient experts said that the population of people with untreated CLL is heterogeneous. They have different mutation statuses and comorbidities, and this affects their treatment options. The patient experts also highlighted that current treatments for CLL, such as intensive chemotherapy, have short and long-term side effects. ## FCR or BR suitable population The company said that, if people do not have a 17p deletion or TP53 mutation and can take chemo-immunotherapies, they may be offered fludarabine plus cyclophosphamide and rituximab (FCR). It said that bendamustine plus rituximab (BR) is rarely used. People with CLL who can have FCR or BR are referred to as 'FCR or BR suitable' from here onwards. The company did not present evidence comparing ibrutinib plus venetoclax with BR. The clinical experts and the NHS England representative noted that FCR is sometimes used by smaller centres that are unable to offer other treatment options. They confirmed that BR is rarely used in clinical practice in England. They highlighted that it is challenging to split diagnosis and treatment options by FCR or BR suitability because they are hardly used. The NHS England representative explained that venetoclax plus obinutuzumab is the most common treatment for this population, but it is only available through the Cancer Drugs Fund. So, it is not in scope as a comparator according to section 2.2.15 of the NICE health technology evaluation manual. The committee concluded that the FCR or BR suitable population cannot be accurately defined in clinical practice in England, and that implementing this criterion is challenging for clinicians. ## FCR or BR unsuitable and the high-risk population The company said that people without a 17p deletion or TP53 mutation, who have comorbidities that make FCR and BR unsuitable (this population is referred to as 'FCR or BR unsuitable' from here onwards), are offered: acalabrutinib monotherapy -binutuzumab plus chlorambucil or venetoclax plus obinutuzumab. People with a 17p deletion or TP53 mutation (this population is referred to as the 'high-risk group' from here onwards) are offered: acalabrutinib monotherapy ibrutinib monotherapy idelalisib plus rituximab or venetoclax plus obinutuzumab. The company did not present evidence comparing ibrutinib plus venetoclax with idelalisib plus rituximab. The clinical experts explained that idelalisib plus rituximab is rarely used in clinical practice because it has an intensive dosing regimen and is associated with an increased infection risk. The NHS England representative said that acalabrutinib monotherapy is the main treatment used for the high-risk group. They reiterated that FCR or BR suitability is not assessed in clinical practice (see section 3.3). Instead, for people without a 17p deletion or TP53 mutation (this population is referred to as the 'non-high-risk group' from here onwards), acalabrutinib monotherapy or venetoclax plus obinutuzumab are the main treatment options. The committee concluded that all relevant comparators were included by the company and restated that FCR or BR suitability is not typically assessed in clinical practice. The patient and clinical experts explained that ibrutinib plus venetoclax generally causes fewer side effects than current treatments and that people with CLL value the fixed treatment duration. The committee concluded that ibrutinib plus venetoclax would be welcomed as a new treatment option for people with untreated CLL for both the high-risk and non-high-risk groups. # Clinical effectiveness ## Data sources For the company's FCR or BR suitable group, the main evidence came from the fixed duration cohort of the CAPTIVATE study. CAPTIVATE was a phase 2 open-label study with a single arm (ibrutinib plus venetoclax, n=159). The study enrolled people with untreated CLL aged between 18 and 70. Of the 159 enrolled participants, 136 did not have a 17p deletion. For the FCR or BR unsuitable group, the company submitted results from the GLOW trial. GLOW was an open-label, phase 3 randomised clinical trial comparing ibrutinib plus venetoclax (n=106) with obinutuzumab plus chlorambucil (n=105). It enrolled people with untreated CLL without a 17p deletion or known TP53 mutation. They had to be either 65 or older, or between 18 and 64 with a Cumulative Illness Rating Scale score over 6 or a creatinine clearance of less than 70 ml/min, or both. Low creatinine clearance levels indicate serious kidney damage. The EAG considered that the fixed duration cohort of the CAPTIVATE study and the GLOW trial were high-quality studies. This is despite open-label study limitations applying to both studies and non-randomised study limitations applying to the CAPTIVATE study. The committee was satisfied that the clinical effectiveness evidence was largely relevant to the decision problem and the studies recruited participants that are reflective of people who would be offered ibrutinib plus venetoclax in NHS clinical practice. ## Clinical study results In the CAPTIVATE fixed duration group, median progression-free survival and overall survival were not reached for ibrutinib plus venetoclax at 38.7 months or with longer follow-up data from the updated data cut. After a median follow up of 46 months in the GLOW trial, there was a statistically significant improvement in progression-free survival and overall survival (hazard ratio 0.487, 95% confidence interval 0.262 to 0.907, p=0.0205) for ibrutinib plus venetoclax compared with obinutuzumab plus chlorambucil. The progression-free survival hazard ratio was available but is considered confidential by the company and cannot be reported here. Median progression-free survival in the GLOW trial was not reached for ibrutinib plus venetoclax but was reached for obinutuzumab plus chlorambucil. Median overall survival was not reached in either treatment arm. The committee concluded that updated data cuts for the CAPTIVATE and GLOW studies showed clinically meaningful and consistent results for ibrutinib plus venetoclax. However, it noted that there was no evidence directly comparing ibrutinib plus venetoclax with commonly used NHS treatments such as acalabrutinib monotherapy and venetoclax plus obinutuzumab (see sections 3.3 and 3.4). ## Clinical data immaturity The EAG said the clinical study results for ibrutinib plus venetoclax were immature because median progression-free survival was not reached in either study (see section 3.6). The company said that not reaching median survival times shows a lack of events during follow up, which indicates that treatment with ibrutinib plus venetoclax is efficacious. It also noted that median progression-free survival was not reached in the venetoclax plus obinutuzumab or acalabrutinib arms in their pivotal trials. Nonetheless this uncertainty was accepted and both treatments were recommended in NICE's technology appraisal guidance on venetoclax with obinutuzumab for untreated CLL and on acalabrutinib for treating CLL. The EAG said that lack of events can be because of small sample sizes in the analyses, and the duration of follow up from the direct evidence for this appraisal cannot be considered long term for first-line treatments for CLL. The clinical experts explained that long-term outcomes and adverse events for ibrutinib plus venetoclax were needed but additional trial data was not available. The committee concluded that, in the absence of more mature data at the time of evaluation, the CAPTIVATE and GLOW studies were the most relevant clinical evidence for ibrutinib plus venetoclax. ## Indirect treatment comparison methods and results Direct evidence was only available for the comparison of ibrutinib plus venetoclax with obinutuzumab plus chlorambucil from the GLOW trial. Indirect treatment comparisons were needed for the other comparators. Only the progression-free survival hazard ratio was used from this comparison in the model. Mortality rates were instead taken from clinical trials with longer follow-up data (see section 3.12 and the company submission in the committee papers). The following indirect treatment comparison methods were applied: For the FCR or BR suitable group: the company applied inverse probability for treatment weighting to adjust for prognostic factors and baseline characteristics for ibrutinib plus venetoclax from CAPTIVATE and FCR from the E1912 trial (Shanafelt et al. 2022). The clinical experts said that all the important prognostic factors were considered by the company in its indirect comparisons. For the base case, the company applied the probability weighting to the FCR control arm using the average treatment effect in the control arm (ATC) approach. It also explored other methods, including estimation of the average treatment effect in the ibrutinib plus venetoclax arm (ATT). It considered the ATC approach most appropriate because the FCR arm was the reference curve estimating CLL progression in the model. The ATC approach suggested a statistically significant improvement in progression-free survival for ibrutinib plus venetoclax compared with FCR. The exact hazard ratios and statistical values are considered confidential by the company and cannot be reported here. For the FCR or BR unsuitable group: the company did an anchored matching adjusted indirect comparison (MAIC) and used data from the acalabrutinib arm of the ELEVATE-TN trial (Sharman et al. 2022) and the venetoclax plus obinutuzumab arm of the CLL14 trial (Al-Sawaf et al. 2020). First, the participants who would have been excluded from CLL14 were identified from GLOW and excluded from the analysis. Because of data limitations this step was not done with ELEVATE-TN and participants with a 17p deletion could not be removed from the analysis. Next, to adjust for treatment effect modifiers, 4 characteristics were matched (age, European Cooperative Oncology Group status, Cumulative Illness Rating Scale score, and TP53 status). Proportional hazards were assumed to estimate a constant hazard ratio for inclusion in the economic model. The progression-free survival hazard ratios favoured ibrutinib plus venetoclax but were not statistically significant. The exact hazard ratios and statistical values are considered confidential by the company and cannot be reported here. ## Indirect treatment comparison limitations The EAG had several concerns with the company's indirect comparisons: For the FCR or BR suitable group: the EAG questioned the use of the ATC hazard ratios over the ATT approach (see section 3.8) because the ATT progression-free survival hazard ratio was not statistically significant. The company explained that the FCR trial (E1912) had longer follow up and more events than ibrutinib plus venetoclax in CAPTIVATE, providing a clear justification for using the FCR reference curve and therefore the ATC hazard ratios (see the clarification responses in the committee papers). On the EAG's request, the company provided a scenario in which ibrutinib plus venetoclax from CAPTIVATE was the reference curve and the ATT hazard ratio was applied. This did not make a substantial difference to the overall outcomes. The committee concluded that the ATC approach was suitable for decision making. But it noted that the indirect treatment comparison was associated with uncertainty because of the inconsistency between the ATT and ATC results. For the FCR or BR unsuitable group: the EAG said that the rate at which progression-free survival events (hazards) occurred was not proportional between ibrutinib plus venetoclax and the comparator arms. It remained cautious about applying the estimated hazard ratios from the GLOW trial follow-up duration to the entire model time horizon of 30 to 40 years. The company presented a scenario analysis using hazard ratios that varied over time and explained that this did not substantially affect the final outcomes. The committee acknowledged that substantial uncertainties were associated with the anchored MAICs. But it concluded that, in the absence of direct evidence and more mature data, the company's anchored MAICs with acalabrutinib and venetoclax plus obinutuzumab were acceptable for decision making. ## High-risk CLL group The company assumed that the results from the FCR or BR unsuitable indirect comparisons (see section 3.8) could apply to the high-risk CLL population, and that acalabrutinib was clinically equivalent to ibrutinib. The company said that there was no additional evidence for the high-risk group. It pointed out that the ibrutinib efficacy assumption was previously accepted in NICE's technology appraisal guidance on acalabrutinib for treating CLL. The committee remained cautious about this assumption and noted that ELEVATE‑TN (the acalabrutinib trial) included the high-risk group but it was excluded from the GLOW trial. The clinical experts explained that poorer clinical outcomes are expected for high-risk CLL compared with non-high-risk CLL. The clinical efficacy outcomes for high-risk CLL were therefore optimistic, but there was no alternative clinical evidence for this population. The committee noted that there was no direct evidence presented for this population. Although there was uncertainty, it concluded that clinical equivalence between acalabrutinib and ibrutinib was plausible in the high-risk CLL population, and this was acceptable for decision making. ## Long-term treatment effects The company assumed in its model that the treatment effect of ibrutinib plus venetoclax compared with obinutuzumab plus chlorambucil and the other comparators is maintained for a lifetime horizon (30 to 40 years) in the model (see sections 3.8 and 3.9). The EAG said that assuming a continued treatment effect was an issue because it considered the ibrutinib plus venetoclax clinical study data to be immature (see section 3.7). The proportional hazards and comparative efficacy assumptions as discussed in section 3.9 also relied on this immature clinical data, further increasing uncertainty in the model outcomes. At the clarification stage and on the EAG's request, the company provided treatment effect waning scenarios in which ibrutinib plus venetoclax's treatment effect declined after 5 or 10 years. The committee acknowledged these scenarios and considered that assuming treatment effect waning after 5 years of stopping treatment was a conservative assumption, but considered all treatment effect waning scenarios in its decision making. # Economic model ## The company's modelling approach The company submitted a semi-Markov model with 4 health states: progression-free on first-line treatment, progression-free on second-line treatment, disease progression, and death. For the FCR or BR suitable group, the company informed the transitions from the progression-free first-line state to the second-line and progressed states using E1912, and the efficacy of FCR compared with ibrutinib plus venetoclax. For the FCR or BR unsuitable group the equivalent transitions were informed by GLOW and the efficacy estimates of ibrutinib plus venetoclax compared with acalabrutinib and venetoclax plus obinutuzumab (see section 3.8). The ibrutinib arm of the RESONATE trial (Byrd et al. 2014) was used to inform the transitions from the second-line progression-free state to the progressed and death health states for both groups because it had a longer follow up (65 months) than other CLL trials. The EAG considered the model structure appropriate for modelling untreated CLL. The committee noted that the company's model structure can only apply exponential distributions with a constant rate for transitions out of the second-line progression-free and post-progression states. The company described the model as a semi-Markov model and included tunnel states in its structure. But these were used only to track costs rather than to determine health state occupancy over time. The company noted that the exponential distribution gave a good fit to the data from the RESONATE trial, but the committee remained concerned that the limitations of the model structure meant that no other survival distributions could be explored. Despite these concerns, the committee considered the model structure to be adequate for decision making. ## Model outcomes The company estimated the rate of transition from the progression-free first-line state to progression-free second-line or progressed health states by subtracting the hazards (rate at which events occur) of general population mortality from the hazards of progression. The EAG said that this method led to inconsistencies in model outcomes. The risk of progression was 0% in the FCR or BR unsuitable group after a number of years, implying that a proportion of the ibrutinib plus venetoclax and acalabrutinib arm were cured of CLL. This same estimation was not made for the FCR or BR suitable group, for whom the risk of CLL progression in the model reached 0% much later. This is because background mortality was lower for the FCR or BR suitable group compared with the FCR or BR unsuitable group. The company said that the age at which progression-free survival was capped by general population mortality was consistent (around 85 years) and the risk of progression reached zero at a similar time in both groups. Clinical experts noted that the data did not suggest a different risk of progression between these 2 groups. They also pointed out that CLL is not usually considered to be curable, and treatments aim to maintain deep remissions instead. At technical engagement the company provided a scenario in which the transition probability of progression in the FCR or BR unsuitable group did not fall below the FCR or BR suitable group. This scenario did not substantially change the final outcomes. The EAG said that the scenario helped reduce uncertainties but the model's limitations remained. The committee concluded that the model structure and its outcomes remained appropriate for decision making despite the limitations of the data used to inform its parameters. # Utility values ## Progression-free utility The company mapped the EQ‑5D‑5L values from the GLOW trial to EQ‑5D‑3L to estimate the progression-free first-line utility value. It applied the same utility value to both the FCR or BR suitable and unsuitable groups. The EAG noted that the progression-free first-line utility value was higher than UK population age-sex matched utility and therefore an overestimate. The company said the value was consistent with the CLL14 and ELEVATE‑TN trials but ran a scenario capping the value by UK population utilities. The final outcomes did not substantially change as a result of this scenario. The clinical experts explained that the quality of life of people after CLL treatment is lower than the UK general population and even lower for people having chemo-immunotherapy. The committee agreed with the clinical experts and preferred the capped UK utility values. ## Quality of life in second-line treatment The company used a utility value of 0.6 from Holzner et al. (2004) for the progression-free second-line and progressed states. The study collected quality of life data from people with CLL over 1 year. The company age-adjusted the Holzner utility value to the E1912 trial population for the FCR or BR suitable group and to the GLOW trial population for the FCR or BR unsuitable group. The EAG only agreed with using 0.6 for the progressed state and not for the progression-free second-line state. Because Holzner was an older source, the quality of life benefits of second-line treatments are not captured and therefore underestimated. The EAG preferred to apply a utility multiplier to the age-adjusted progression-free first-line value (see section 3.14) to estimate the second-line value. The utility multiplier was calculated by dividing the EQ‑5D values for progressed disease by the progression-free first-line values from the GLOW trial. The clinical experts said it was reasonable to assume a lower utility value for people in the progressed state because of their more advanced disease compared with people on second-line treatment. The committee agreed that 0.6 was an underestimate but highlighted that the EAG's utility multiplier may be an overestimate. It also acknowledged that these utility values had limited impact on the final outcomes. The committee agreed with the clinical experts and concluded that the EAG's approach was appropriate to use in the model. # Adverse effects ## Tolerability profile The CAPTIVATE and GLOW study results showed that ibrutinib plus venetoclax had an acceptable tolerability profile. The patient experts highlighted that ibrutinib plus venetoclax was associated with fewer adverse effects, which were generally well tolerated. The fixed treatment duration also meant the adverse effects were for a limited time. The clinical experts said the common adverse effects of treatments like ibrutinib include hypertension and heart problems. In rare cases continuous use may increase the risk of skin cancer. They said that people with CLL have a high burden of tumour cells. Venetoclax breaks down these tumour cells and the breakdown (lysis) of these cells leads to adverse effects called 'tumour lysis syndrome'. Venetoclax's gradual ramp-up dose is therefore essential to minimise tumour lysis syndrome. For the ibrutinib plus venetoclax combination, the clinical experts noted that the lead-in ibrutinib treatment reduces the tumour burden upfront, which reduces the risk of tumour lysis syndrome once venetoclax is introduced after the third cycle of treatment. The patient and clinical experts said that the fixed duration reduces the cumulative risk of adverse effects, and that the associated quality of life benefits should be considered by the committee. The committee agreed that ibrutinib plus venetoclax was likely to be generally well tolerated and that its fixed duration was an additional advantage compared with current treatments. ## Risk of drug resistance The committee noted that ibrutinib and venetoclax are recommended treatment options for previously treated CLL. The committee questioned whether using these 2 efficacious second-line CLL treatments together as a first-line treatment might limit the remaining treatment options for relapsed or refractory CLL. The clinical experts explained that the fixed duration of ibrutinib plus venetoclax reduces the chances of CLL becoming resistant to them, unlike what might happen for 'treat to progression' monotherapies like ibrutinib and acalabrutinib. The NHS England representative said that retreatment with ibrutinib, venetoclax or other first-line options should be allowed if the CLL has responded well to these first-line treatments, subject to marketing authorisations in Great Britain. The committee acknowledged this and agreed that ibrutinib plus venetoclax as a first-line option was unlikely to significantly limit treatment options for relapsed or refractory CLL. # Cost-effectiveness estimates ## FCR or BR suitable population The company's probabilistic base-case incremental cost-effectiveness ratio (ICER) for ibrutinib plus venetoclax compared with FCR for untreated CLL when FCR or BR is suitable was below £20,000 per quality-adjusted life year (QALY) gained. Incorporating the EAG's preferred assumptions on applying cost and utility decrement from cycle zero in the model, including oral treatment wastage costs and updated utility values (see sections 3.14 and 3.15), increased the ICER but it remained below £20,000 per QALY gained. The committee used the EAG's base case for decision making. It also considered the following scenarios: ibrutinib plus venetoclax's treatment effect declining over 5 and 10 years efficacy of ibrutinib plus venetoclax compared with FCR using the ATT indirect treatment comparison approach.In all the scenarios the committee considered, the ICER remained below £30,000 per QALY gained. ## FCR or BR unsuitable and high-risk population In the company's and EAG's probabilistic base case, ibrutinib plus venetoclax was more effective and less costly and therefore the dominant treatment option compared with obinutuzumab plus chlorambucil and venetoclax plus obinutuzumab. Ibrutinib plus venetoclax resulted in cost savings and a small QALY loss compared with acalabrutinib and ibrutinib, producing ICERs that reflected 'savings per QALY lost'. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the typical decision rule of accepting ICERs below a given threshold is reversed. So the higher the ICER, the more cost effective a treatment becomes. The committee used the EAG's base case for decision making. It also considered the following scenarios: ibrutinib plus venetoclax's treatment effect declining over 5 and 10 years the probability of CLL progression in the FCR or BR unsuitable group capped by the FCR or BR suitable group equal efficacy (a progression-free survival hazard ratio of 1) assumed for acalabrutinib and ibrutinib plus venetoclax.In all the scenarios the committee considered, the direction of the ICERs remained consistent with the EAG's probabilistic base case. The ICERs were either dominant or significantly above £30,000 savings per QALY lost. ## High-risk and non-high-risk groups In sections 3.3 and 3.4 the committee previously concluded that implementing the 'FCR or BR suitability' criterion would be challenging for clinicians in the NHS in England. The committee therefore considered the totality of the cost-effectiveness results across all 3 groups in sections 3.18 and 3.19 to make its recommendations. The committee placed greater weight on the FCR or BR unsuitable and high-risk group results because the comparators were more relevant for the NHS in England than FCR (see section 3.4). The committee recalled that there was substantial uncertainty in the company's indirect treatment comparison and long-term treatment effect assumptions (see section 3.9 and section 3.11) and said ICERs closer to £20,000 per QALY gained would be more appropriate. The decision-making ICERs used by the committee took account of all available confidential discounts, including those for comparators and follow-up treatments, so exact ICERs cannot be reported here. The ICERs remained an acceptable use of NHS resources. So, the committee concluded that ibrutinib plus venetoclax is cost effective for anyone with untreated chronic lymphocytic leukaemia. # Other factors ## Equality issues No equality or social value judgement issues were identified. ## Severity NICE's advice about conditions with a high degree of severity did not apply. ## Innovation The committee considered if ibrutinib plus venetoclax was innovative. It did not identify additional benefits of ibrutinib plus venetoclax not captured in the economic modelling. So, the committee concluded that all benefits of ibrutinib plus venetoclax had already been taken into account. # Conclusion ## Recommendation The committee considered inputs from clinical and patient experts which suggested there were limited treatment options for both the high-risk and non-high-risk groups. Also, ibrutinib plus venetoclax's fixed treatment duration and better toxicity profile than current treatments made it a highly valued treatment option. The committee concluded that ibrutinib plus venetoclax gives clinicians an additional valuable treatment option. It also considered ibrutinib plus venetoclax to represent a cost-effective use of NHS resources. So, ibrutinib plus venetoclax is recommended for routine commissioning for anyone with untreated chronic lymphocytic leukaemia.	{'Recommendations': 'Ibrutinib plus venetoclax is recommended, within its marketing authorisation, as an option for untreated chronic lymphocytic leukaemia (CLL) in adults. This is only if the companies provide both drugs according to the commercial arrangements.\n\nWhy the committee made this recommendation\n\nTreatments for untreated CLL include acalabrutinib, fludarabine plus cyclophosphamide and rituximab (FCR), ibrutinib alone, obinutuzumab plus chlorambucil, and venetoclax plus obinutuzumab. FCR is rarely used in clinical practice.\n\nClinical evidence shows that CLL takes longer to get worse, and people live longer, when they have ibrutinib plus venetoclax compared with obinutuzumab plus chlorambucil. An indirect comparison with acalabrutinib, FCR, ibrutinib alone, and venetoclax plus obinutuzumab suggests that CLL takes longer to get worse when treated with ibrutinib plus venetoclax.\n\nThe cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources, so ibrutinib plus venetoclax is recommended.', 'Information about ibrutinib with venetoclax': "# Marketing authorisation indication\n\nIbrutinib (Imbruvica, Janssen-Cilag) with venetoclax (Venclyxto, AbbVie) is indicated for 'the treatment of adult patients with previously untreated chronic lymphocytic leukaemia'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for ibrutinib.\n\n# Price\n\nA 28‑pack of 140‑mg ibrutinib tablets costs £1,430.80 (excluding VAT; BNF online accessed February 2022). The company has a commercial arrangement. This makes ibrutinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\nA 112‑pack of 100‑mg venetoclax tablets costs £4,789.47 (excluding VAT; BNF online accessed February 2022). AbbVie has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is AbbVie's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Janssen-Cilag, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\nChronic lymphocytic leukaemia (CLL) is a malignant disorder of white blood cells and is the most common type of leukaemia in England. The patient experts explained that the physical and psychological effects of CLL have a debilitating effect on their daily lives. The risk of CLL increases with age. CLL progression and poor prognosis is commonly caused by a deletion of chromosome 17p (17p\xa0deletion) or mutation of the tumour protein\xa0p53 (TP53\xa0mutation). The committee concluded that CLL substantially affects physical and psychological quality of life.\n\n# Clinical management and comparators\n\nThe clinical and patient experts said that the population of people with untreated CLL is heterogeneous. They have different mutation statuses and comorbidities, and this affects their treatment options. The patient experts also highlighted that current treatments for CLL, such as intensive chemotherapy, have short and long-term side effects.\n\n## FCR or BR suitable population\n\nThe company said that, if people do not have a 17p\xa0deletion or TP53\xa0mutation and can take chemo-immunotherapies, they may be offered fludarabine plus cyclophosphamide and rituximab (FCR). It said that bendamustine plus rituximab (BR) is rarely used. People with CLL who can have FCR or BR are referred to as 'FCR or BR suitable' from here onwards. The company did not present evidence comparing ibrutinib plus venetoclax with BR. The clinical experts and the NHS England representative noted that FCR is sometimes used by smaller centres that are unable to offer other treatment options. They confirmed that BR is rarely used in clinical practice in England. They highlighted that it is challenging to split diagnosis and treatment options by FCR or BR suitability because they are hardly used. The NHS England representative explained that venetoclax plus obinutuzumab is the most common treatment for this population, but it is only available through the Cancer Drugs Fund. So, it is not in scope as a comparator according to section\xa02.2.15 of the NICE health technology evaluation manual. The committee concluded that the FCR or BR suitable population cannot be accurately defined in clinical practice in England, and that implementing this criterion is challenging for clinicians.\n\n## FCR or BR unsuitable and the high-risk population\n\nThe company said that people without a 17p\xa0deletion or TP53\xa0mutation, who have comorbidities that make FCR and BR unsuitable (this population is referred to as 'FCR or BR unsuitable' from here onwards), are offered:\n\nacalabrutinib monotherapy\n\nobinutuzumab plus chlorambucil or\n\nvenetoclax plus obinutuzumab. People with a 17p\xa0deletion or TP53\xa0mutation (this population is referred to as the 'high-risk group' from here onwards) are offered:\n\nacalabrutinib monotherapy\n\nibrutinib monotherapy\n\nidelalisib plus rituximab or\n\nvenetoclax plus obinutuzumab. The company did not present evidence comparing ibrutinib plus venetoclax with idelalisib plus rituximab. The clinical experts explained that idelalisib plus rituximab is rarely used in clinical practice because it has an intensive dosing regimen and is associated with an increased infection risk. The NHS England representative said that acalabrutinib monotherapy is the main treatment used for the high-risk group. They reiterated that FCR or BR suitability is not assessed in clinical practice (see section\xa03.3). Instead, for people without a 17p\xa0deletion or TP53\xa0mutation (this population is referred to as the 'non-high-risk group' from here onwards), acalabrutinib monotherapy or venetoclax plus obinutuzumab are the main treatment options. The committee concluded that all relevant comparators were included by the company and restated that FCR or BR suitability is not typically assessed in clinical practice. The patient and clinical experts explained that ibrutinib plus venetoclax generally causes fewer side effects than current treatments and that people with CLL value the fixed treatment duration. The committee concluded that ibrutinib plus venetoclax would be welcomed as a new treatment option for people with untreated CLL for both the high-risk and non-high-risk groups.\n\n# Clinical effectiveness\n\n## Data sources\n\nFor the company's FCR or BR suitable group, the main evidence came from the fixed duration cohort of the CAPTIVATE study. CAPTIVATE was a phase\xa02 open-label study with a single arm (ibrutinib plus venetoclax, n=159). The study enrolled people with untreated CLL aged between 18 and 70. Of the 159 enrolled participants, 136 did not have a 17p\xa0deletion. For the FCR or BR unsuitable group, the company submitted results from the GLOW trial. GLOW was an open-label, phase\xa03 randomised clinical trial comparing ibrutinib plus venetoclax (n=106) with obinutuzumab plus chlorambucil (n=105). It enrolled people with untreated CLL without a 17p\xa0deletion or known TP53\xa0mutation. They had to be either 65 or older, or between 18 and 64 with a Cumulative Illness Rating Scale score over 6 or a creatinine clearance of less than 70\xa0ml/min, or both. Low creatinine clearance levels indicate serious kidney damage. The EAG considered that the fixed duration cohort of the CAPTIVATE study and the GLOW trial were high-quality studies. This is despite open-label study limitations applying to both studies and non-randomised study limitations applying to the CAPTIVATE study. The committee was satisfied that the clinical effectiveness evidence was largely relevant to the decision problem and the studies recruited participants that are reflective of people who would be offered ibrutinib plus venetoclax in NHS clinical practice.\n\n## Clinical study results\n\nIn the CAPTIVATE fixed duration group, median progression-free survival and overall survival were not reached for ibrutinib plus venetoclax at 38.7\xa0months or with longer follow-up data from the updated data cut. After a median follow up of 46\xa0months in the GLOW trial, there was a statistically significant improvement in progression-free survival and overall survival (hazard ratio 0.487, 95% confidence interval 0.262 to 0.907, p=0.0205) for ibrutinib plus venetoclax compared with obinutuzumab plus chlorambucil. The progression-free survival hazard ratio was available but is considered confidential by the company and cannot be reported here. Median progression-free survival in the GLOW trial was not reached for ibrutinib plus venetoclax but was reached for obinutuzumab plus chlorambucil. Median overall survival was not reached in either treatment arm. The committee concluded that updated data cuts for the CAPTIVATE and GLOW studies showed clinically meaningful and consistent results for ibrutinib plus venetoclax. However, it noted that there was no evidence directly comparing ibrutinib plus venetoclax with commonly used NHS treatments such as acalabrutinib monotherapy and venetoclax plus obinutuzumab (see sections\xa03.3 and 3.4).\n\n## Clinical data immaturity\n\nThe EAG said the clinical study results for ibrutinib plus venetoclax were immature because median progression-free survival was not reached in either study (see section\xa03.6). The company said that not reaching median survival times shows a lack of events during follow up, which indicates that treatment with ibrutinib plus venetoclax is efficacious. It also noted that median progression-free survival was not reached in the venetoclax plus obinutuzumab or acalabrutinib arms in their pivotal trials. Nonetheless this uncertainty was accepted and both treatments were recommended in NICE's technology appraisal guidance on venetoclax with obinutuzumab for untreated CLL and on acalabrutinib for treating CLL. The EAG said that lack of events can be because of small sample sizes in the analyses, and the duration of follow up from the direct evidence for this appraisal cannot be considered long term for first-line treatments for CLL. The clinical experts explained that long-term outcomes and adverse events for ibrutinib plus venetoclax were needed but additional trial data was not available. The committee concluded that, in the absence of more mature data at the time of evaluation, the CAPTIVATE and GLOW studies were the most relevant clinical evidence for ibrutinib plus venetoclax.\n\n## Indirect treatment comparison methods and results\n\nDirect evidence was only available for the comparison of ibrutinib plus venetoclax with obinutuzumab plus chlorambucil from the GLOW trial. Indirect treatment comparisons were needed for the other comparators. Only the progression-free survival hazard ratio was used from this comparison in the model. Mortality rates were instead taken from clinical trials with longer follow-up data (see section\xa03.12 and the company submission in the committee papers). The following indirect treatment comparison methods were applied:\n\nFor the FCR or BR suitable group: the company applied inverse probability for treatment weighting to adjust for prognostic factors and baseline characteristics for ibrutinib plus venetoclax from CAPTIVATE and FCR from the E1912 trial (Shanafelt et al. 2022). The clinical experts said that all the important prognostic factors were considered by the company in its indirect comparisons. For the base case, the company applied the probability weighting to the FCR control arm using the average treatment effect in the control arm (ATC) approach. It also explored other methods, including estimation of the average treatment effect in the ibrutinib plus venetoclax arm (ATT). It considered the ATC approach most appropriate because the FCR arm was the reference curve estimating CLL progression in the model. The ATC approach suggested a statistically significant improvement in progression-free survival for ibrutinib plus venetoclax compared with FCR. The exact hazard ratios and statistical values are considered confidential by the company and cannot be reported here.\n\nFor the FCR or BR unsuitable group: the company did an anchored matching adjusted indirect comparison (MAIC) and used data from the acalabrutinib arm of the ELEVATE-TN trial (Sharman et al. 2022) and the venetoclax plus obinutuzumab arm of the CLL14 trial (Al-Sawaf et al. 2020). First, the participants who would have been excluded from CLL14 were identified from GLOW and excluded from the analysis. Because of data limitations this step was not done with ELEVATE-TN and participants with a 17p\xa0deletion could not be removed from the analysis. Next, to adjust for treatment effect modifiers, 4\xa0characteristics were matched (age, European Cooperative Oncology Group [ECOG] status, Cumulative Illness Rating Scale score, and TP53 status). Proportional hazards were assumed to estimate a constant hazard ratio for inclusion in the economic model. The progression-free survival hazard ratios favoured ibrutinib plus venetoclax but were not statistically significant. The exact hazard ratios and statistical values are considered confidential by the company and cannot be reported here.\n\n## Indirect treatment comparison limitations\n\nThe EAG had several concerns with the company's indirect comparisons:\n\nFor the FCR or BR suitable group: the EAG questioned the use of the ATC hazard ratios over the ATT approach (see section\xa03.8) because the ATT progression-free survival hazard ratio was not statistically significant. The company explained that the FCR trial (E1912) had longer follow up and more events than ibrutinib plus venetoclax in CAPTIVATE, providing a clear justification for using the FCR reference curve and therefore the ATC hazard ratios (see the clarification responses in the committee papers). On the EAG's request, the company provided a scenario in which ibrutinib plus venetoclax from CAPTIVATE was the reference curve and the ATT hazard ratio was applied. This did not make a substantial difference to the overall outcomes. The committee concluded that the ATC approach was suitable for decision making. But it noted that the indirect treatment comparison was associated with uncertainty because of the inconsistency between the ATT and ATC results.\n\nFor the FCR or BR unsuitable group: the EAG said that the rate at which progression-free survival events (hazards) occurred was not proportional between ibrutinib plus venetoclax and the comparator arms. It remained cautious about applying the estimated hazard ratios from the GLOW trial follow-up duration to the entire model time horizon of 30 to 40\xa0years. The company presented a scenario analysis using hazard ratios that varied over time and explained that this did not substantially affect the final outcomes. The committee acknowledged that substantial uncertainties were associated with the anchored MAICs. But it concluded that, in the absence of direct evidence and more mature data, the company's anchored MAICs with acalabrutinib and venetoclax plus obinutuzumab were acceptable for decision making.\n\n## High-risk CLL group\n\nThe company assumed that the results from the FCR or BR unsuitable indirect comparisons (see section\xa03.8) could apply to the high-risk CLL population, and that acalabrutinib was clinically equivalent to ibrutinib. The company said that there was no additional evidence for the high-risk group. It pointed out that the ibrutinib efficacy assumption was previously accepted in NICE's technology appraisal guidance on acalabrutinib for treating CLL. The committee remained cautious about this assumption and noted that ELEVATE‑TN (the acalabrutinib trial) included the high-risk group but it was excluded from the GLOW trial. The clinical experts explained that poorer clinical outcomes are expected for high-risk CLL compared with non-high-risk CLL. The clinical efficacy outcomes for high-risk CLL were therefore optimistic, but there was no alternative clinical evidence for this population. The committee noted that there was no direct evidence presented for this population. Although there was uncertainty, it concluded that clinical equivalence between acalabrutinib and ibrutinib was plausible in the high-risk CLL population, and this was acceptable for decision making.\n\n## Long-term treatment effects\n\nThe company assumed in its model that the treatment effect of ibrutinib plus venetoclax compared with obinutuzumab plus chlorambucil and the other comparators is maintained for a lifetime horizon (30 to 40\xa0years) in the model (see sections\xa03.8 and 3.9). The EAG said that assuming a continued treatment effect was an issue because it considered the ibrutinib plus venetoclax clinical study data to be immature (see section\xa03.7). The proportional hazards and comparative efficacy assumptions as discussed in section 3.9 also relied on this immature clinical data, further increasing uncertainty in the model outcomes. At the clarification stage and on the EAG's request, the company provided treatment effect waning scenarios in which ibrutinib plus venetoclax's treatment effect declined after 5 or 10\xa0years. The committee acknowledged these scenarios and considered that assuming treatment effect waning after 5\xa0years of stopping treatment was a conservative assumption, but considered all treatment effect waning scenarios in its decision making.\n\n# Economic model\n\n## The company's modelling approach\n\nThe company submitted a semi-Markov model with 4\xa0health states: progression-free on first-line treatment, progression-free on second-line treatment, disease progression, and death. For the FCR or BR suitable group, the company informed the transitions from the progression-free first-line state to the second-line and progressed states using E1912, and the efficacy of FCR compared with ibrutinib plus venetoclax. For the FCR or BR unsuitable group the equivalent transitions were informed by GLOW and the efficacy estimates of ibrutinib plus venetoclax compared with acalabrutinib and venetoclax plus obinutuzumab (see section\xa03.8). The ibrutinib arm of the RESONATE trial (Byrd et al. 2014) was used to inform the transitions from the second-line progression-free state to the progressed and death health states for both groups because it had a longer follow up (65\xa0months) than other CLL trials. The EAG considered the model structure appropriate for modelling untreated CLL. The committee noted that the company's model structure can only apply exponential distributions with a constant rate for transitions out of the second-line progression-free and post-progression states. The company described the model as a semi-Markov model and included tunnel states in its structure. But these were used only to track costs rather than to determine health state occupancy over time. The company noted that the exponential distribution gave a good fit to the data from\xa0the RESONATE trial, but the committee remained concerned that the limitations of the model structure meant that no other survival distributions could be explored. Despite these concerns, the committee considered the model structure to be adequate for decision making.\n\n## Model outcomes\n\nThe company estimated the rate of transition from the progression-free first-line state to progression-free second-line or progressed health states by subtracting the hazards (rate at which events occur) of general population mortality from the hazards of progression. The EAG said that this method led to inconsistencies in model outcomes. The risk of progression was 0% in the FCR or BR unsuitable group after a number of years, implying that a proportion of the ibrutinib plus venetoclax and acalabrutinib arm were cured of CLL. This same estimation was not made for the FCR or BR suitable group, for whom the risk of CLL progression in the model reached 0% much later. This is because background mortality was lower for the FCR or BR suitable group compared with the FCR or BR unsuitable group. The company said that the age at which progression-free survival was capped by general population mortality was consistent (around 85\xa0years) and the risk of progression reached zero at a similar time in both groups. Clinical experts noted that the data did not suggest a different risk of progression between these 2\xa0groups. They also pointed out that CLL is not usually considered to be curable, and treatments aim to maintain deep remissions instead. At technical engagement the company provided a scenario in which the transition probability of progression in the FCR or BR unsuitable group did not fall below the FCR or BR suitable group. This scenario did not substantially change the final outcomes. The EAG said that the scenario helped reduce uncertainties but the model's limitations remained. The committee concluded that the model structure and its outcomes remained appropriate for decision making despite the limitations of the data used to inform its parameters.\n\n# Utility values\n\n## Progression-free utility\n\nThe company mapped the EQ‑5D‑5L values from the GLOW trial to EQ‑5D‑3L to estimate the progression-free first-line utility value. It applied the same utility value to both the FCR or BR suitable and unsuitable groups. The EAG noted that the progression-free first-line utility value was higher than UK population age-sex matched utility and therefore an overestimate. The company said the value was consistent with the CLL14 and ELEVATE‑TN trials but ran a scenario capping the value by UK population utilities. The final outcomes did not substantially change as a result of this scenario. The clinical experts explained that the quality of life of people after CLL treatment is lower than the UK general population and even lower for people having chemo-immunotherapy. The committee agreed with the clinical experts and preferred the capped UK utility values.\n\n## Quality of life in second-line treatment\n\nThe company used a utility value of 0.6 from Holzner et al. (2004) for the progression-free second-line and progressed states. The study collected quality of life data from people with CLL over 1\xa0year. The company age-adjusted the Holzner utility value to the E1912 trial population for the FCR or BR suitable group and to the GLOW trial population for the FCR or BR unsuitable group. The EAG only agreed with using 0.6 for the progressed state and not for the progression-free second-line state. Because Holzner was an older source, the quality of life benefits of second-line treatments are not captured and therefore underestimated. The EAG preferred to apply a utility multiplier to the age-adjusted progression-free first-line value (see section\xa03.14) to estimate the second-line value. The utility multiplier was calculated by dividing the EQ‑5D values for progressed disease by the progression-free first-line values from the GLOW trial. The clinical experts said it was reasonable to assume a lower utility value for people in the progressed state because of their more advanced disease compared with people on second-line treatment. The committee agreed that 0.6 was an underestimate but highlighted that the EAG's utility multiplier may be an overestimate. It also acknowledged that these utility values had limited impact on the final outcomes. The committee agreed with the clinical experts and concluded that the EAG's approach was appropriate to use in the model.\n\n# Adverse effects\n\n## Tolerability profile\n\nThe CAPTIVATE and GLOW study results showed that ibrutinib plus venetoclax had an acceptable tolerability profile. The patient experts highlighted that ibrutinib plus venetoclax was associated with fewer adverse effects, which were generally well tolerated. The fixed treatment duration also meant the adverse effects were for a limited time. The clinical experts said the common adverse effects of treatments like ibrutinib include hypertension and heart problems. In rare cases continuous use may increase the risk of skin cancer. They said that people with CLL have a high burden of tumour cells. Venetoclax breaks down these tumour cells and the breakdown (lysis) of these cells leads to adverse effects called 'tumour lysis syndrome'. Venetoclax's gradual ramp-up dose is therefore essential to minimise tumour lysis syndrome. For the ibrutinib plus venetoclax combination, the clinical experts noted that the lead-in ibrutinib treatment reduces the tumour burden upfront, which reduces the risk of tumour lysis syndrome once venetoclax is introduced after the third cycle of treatment. The patient and clinical experts said that the fixed duration reduces the cumulative risk of adverse effects, and that the associated quality of life benefits should be considered by the committee. The committee agreed that ibrutinib plus venetoclax was likely to be generally well tolerated and that its fixed duration was an additional advantage compared with current treatments.\n\n## Risk of drug resistance\n\nThe committee noted that ibrutinib and venetoclax are recommended treatment options for previously treated CLL. The committee questioned whether using these 2\xa0efficacious second-line CLL treatments together as a first-line treatment might limit the remaining treatment options for relapsed or refractory CLL. The clinical experts explained that the fixed duration of ibrutinib plus venetoclax reduces the chances of CLL becoming resistant to them, unlike what might happen for 'treat to progression' monotherapies like ibrutinib and acalabrutinib. The NHS England representative said that retreatment with ibrutinib, venetoclax or other first-line options should be allowed if the CLL has responded well to these first-line treatments, subject to marketing authorisations in Great Britain. The committee acknowledged this and agreed that ibrutinib plus venetoclax as a first-line option was unlikely to significantly limit treatment options for relapsed or refractory CLL.\n\n# Cost-effectiveness estimates\n\n## FCR or BR suitable population\n\nThe company's probabilistic base-case incremental cost-effectiveness ratio (ICER) for ibrutinib plus venetoclax compared with FCR for untreated CLL when FCR or BR is suitable was below £20,000 per quality-adjusted life year (QALY) gained. Incorporating the EAG's preferred assumptions on applying cost and utility decrement from cycle zero in the model, including oral treatment wastage costs and updated utility values (see sections\xa03.14 and 3.15), increased the ICER but it remained below £20,000 per QALY gained. The committee used the EAG's base case for decision making. It also considered the following scenarios:\n\nibrutinib plus venetoclax's treatment effect declining over 5 and 10\xa0years\n\nefficacy of ibrutinib plus venetoclax compared with FCR using the ATT indirect treatment comparison approach.In all the scenarios the committee considered, the ICER remained below £30,000 per QALY gained.\n\n## FCR or BR unsuitable and high-risk population\n\nIn the company's and EAG's probabilistic base case, ibrutinib plus venetoclax was more effective and less costly and therefore the dominant treatment option compared with obinutuzumab plus chlorambucil and venetoclax plus obinutuzumab. Ibrutinib plus venetoclax resulted in cost savings and a small QALY loss compared with acalabrutinib and ibrutinib, producing ICERs that reflected 'savings per QALY lost'. The committee noted that, in situations in which an ICER is derived from a technology that is less effective and less costly than its comparator, the typical decision rule of accepting ICERs below a given threshold is reversed. So the higher the ICER, the more cost effective a treatment becomes. The committee used the EAG's base case for decision making. It also considered the following scenarios:\n\nibrutinib plus venetoclax's treatment effect declining over 5 and 10\xa0years\n\nthe probability of CLL progression in the FCR or BR unsuitable group capped by the FCR or BR suitable group\n\nequal efficacy (a progression-free survival hazard ratio of 1) assumed for acalabrutinib and ibrutinib plus venetoclax.In all the scenarios the committee considered, the direction of the ICERs remained consistent with the EAG's probabilistic base case. The ICERs were either dominant or significantly above £30,000 savings per QALY lost.\n\n## High-risk and non-high-risk groups\n\nIn sections\xa03.3 and 3.4 the committee previously concluded that implementing the 'FCR or BR suitability' criterion would be challenging for clinicians in the NHS in England. The committee therefore considered the totality of the cost-effectiveness results across all 3 groups in sections\xa03.18 and 3.19 to make its recommendations. The committee placed greater weight on the FCR or BR unsuitable and high-risk group results because the comparators were more relevant for the NHS in England than FCR (see section\xa03.4). The committee recalled that there was substantial uncertainty in the company's indirect treatment comparison and long-term treatment effect assumptions (see section\xa03.9 and section\xa03.11) and said ICERs closer to £20,000 per QALY gained would be more appropriate. The decision-making ICERs used by the committee took account of all available confidential discounts, including those for comparators and follow-up treatments, so exact ICERs cannot be reported here. The ICERs remained an acceptable use of NHS resources. So, the committee concluded that ibrutinib plus venetoclax is cost effective for anyone with untreated chronic lymphocytic leukaemia.\n\n# Other factors\n\n## Equality issues\n\nNo equality or social value judgement issues were identified.\n\n## Severity\n\nNICE's advice about conditions with a high degree of severity did not apply.\n\n## Innovation\n\nThe committee considered if ibrutinib plus venetoclax was innovative. It did not identify additional benefits of ibrutinib plus venetoclax not captured in the economic modelling. So, the committee concluded that all benefits of ibrutinib plus venetoclax had already been taken into account.\n\n# Conclusion\n\n## Recommendation\n\nThe committee considered inputs from clinical and patient experts which suggested there were limited treatment options for both the high-risk and non-high-risk groups. Also, ibrutinib plus venetoclax's fixed treatment duration and better toxicity profile than current treatments made it a highly valued treatment option. The committee concluded that ibrutinib plus venetoclax gives clinicians an additional valuable treatment option. It also considered ibrutinib plus venetoclax to represent a cost-effective use of NHS resources. So, ibrutinib plus venetoclax is recommended for routine commissioning for anyone with untreated chronic lymphocytic leukaemia."}	https://www.nice.org.uk/guidance/ta891	Evidence-based recommendations on ibrutinib (Imbruvica) with venetoclax (Venclyxto) for untreated chronic lymphocytic leukaemia in adults.
15384793c426d7e6b573a812797f095b54d7ea9f	nice	Mosunetuzumab for treating relapsed or refractory follicular lymphoma	Mosunetuzumab for treating relapsed or refractory follicular lymphoma Evidence-based recommendations on mosunetuzumab (Lunsumio) for relapsed or refractory follicular lymphoma in adults. # Recommendations Mosunetuzumab is not recommended, within its marketing authorisation, for treating relapsed or refractory follicular lymphoma in adults who have had 2 or more systemic therapies. This recommendation is not intended to affect treatment with mosunetuzumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Treatment options for relapsed or refractory follicular lymphoma are limited and there is no standard care. After 2 previous therapies, treatment may include rituximab plus lenalidomide or rituximab plus chemotherapy. Clinical evidence suggests that follicular lymphoma responds to treatment with mosunetuzumab, so the cancer may not get worse as quickly. But these results are from a trial that did not compare mosunetuzumab with placebo or any other treatment options. Indirect comparisons of mosunetuzumab with other treatment options are very uncertain with inconsistent results. The cost-effectiveness estimates for mosunetuzumab are highly uncertain and do not represent a cost-effective use of NHS resources. So, mosunetuzumab is not recommended for routine use in the NHS. Mosunetuzumab cannot be recommended with managed access. This is because mosunetuzumab is not likely to be cost effective. Also, more data collected in the Cancer Drugs Fund would not resolve the high level of uncertainty.# Information about mosunetuzumab # Marketing authorisation indication Mosunetuzumab (Lunsumio, Roche) is indicated for 'the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for mosunetuzumab. # Price Mosunetuzumab costs £220 per 1 mg/1 ml concentrate for solution for infusion vial and £6,600 per 30 mg/30 ml concentrate for solution for infusion vial (excluding VAT; company submission). The cost per course of treatment is £66,660 for 8 cycles and £126,600 for 17 cycles. The company has a commercial arrangement, which would have applied if mosunetuzumab had been recommended.# Committee discussion The evaluation committee considered evidence submitted by Roche, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition and current treatment ## Unmet need Follicular lymphoma is a type of indolent, low-grade non-Hodgkin lymphoma. The patient expert noted that it is an incurable cancer that will return and people with the condition will need subsequent treatment for life. They explained that there is always the fear of relapse when living with the disease. Clinical experts noted that survival and remission duration worsen with each successive relapse. They explained that there is no current standard care and a lack of treatment options. This creates difficult treatment choices from a mixed basket of options for relapsed or refractory follicular lymphoma. The clinical experts explained that when selecting treatment, factors such as a person's age, frailty and wishes are considered. The patient expert noted that people value alternatives to chemotherapy. Stakeholders commented on the draft guidance that mosunetuzumab could provide an extra line of treatment. The committee concluded that new treatment options would be welcomed by patients and clinicians. ## Current treatment Clinical experts noted that in previously treated follicular lymphoma, treatment options include: lenalidomide with rituximab (see NICE technology appraisal guidance on lenalidomide with rituximab for previously treated follicular lymphoma) -binutuzumab with bendamustine (see NICE technology appraisal guidance on obinutuzumab with bendamustine for treating follicular lymphoma after rituximab) and rituximab plus chemotherapy followed by rituximab maintenance therapy. They explained that for rituximab plus chemotherapy, people are likely to have rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP), rituximab plus cyclophosphamide, vincristine and prednisolone (R‑CVP) or rituximab plus bendamustine. Clinical experts noted that after first-line treatment, R‑CHOP and R‑CVP may be favoured over rituximab plus bendamustine. This is because rituximab plus bendamustine can be associated with greater toxicity. They noted that people aged over 70 do not tolerate bendamustine well. The committee noted that older people in mutual carer relationships would benefit from a non-chemotherapy treatment. Clinical experts explained that because of the long natural history of follicular lymphoma, some people have had potentially less effective treatments such as rituximab plus chemotherapy at second line. Others have had newer options such as rituximab plus lenalidomide or obinutuzumab plus bendamustine. So, the treatment landscape is complicated and changing. The experts noted that at third line and beyond, treatment choice will be influenced by previous therapy. This means people will have either rituximab plus lenalidomide if they have not had it before, or rituximab plus chemotherapy if they previously had rituximab plus lenalidomide. Rituximab plus chemotherapy may include rituximab plus bendamustine if a person is well enough and has not already had it. The NHS England Cancer Drugs Fund clinical lead noted that across second- and third-line treatment, more people currently have rituximab plus bendamustine than rituximab plus lenalidomide in NHS practice. The committee noted that obinutuzumab plus bendamustine is rarely used third line, so it is not a relevant comparator for this appraisal. The committee concluded that treatments used at third line or later are rituximab plus lenalidomide and rituximab plus chemotherapy, which may include rituximab plus bendamustine. # Clinical evidence ## Study population and generalisability GO29781 was a phase 2, multicentre, single-arm, non-comparative study in people with relapsed or refractory haematologic malignancies expected to express the CD20 antigen. Clinical evidence for mosunetuzumab is from a pivotal cohort of 90 people with relapsed or refractory follicular lymphoma who have had at least 2 previous therapies that included both an anti‑CD20 inhibitor and an alkylating agent. Patients had a median age of 60. The company noted that its clinical advisers considered the study population broadly representative of people who have had 2 or more previous treatments for follicular lymphoma in UK clinical practice, in terms of age (UK median age around 66), daily functioning, disease stage and prognosis. The EAG noted that only 2% of people in the study were from the UK and most were from the US (44%). Clinical experts confirmed that the study population broadly reflects UK clinical practice. They noted that the study population had a higher proportion of people with factors known to be associated with poorer outcomes for follicular lymphoma that is treated at third line or later. More than 50% of people in the study had cancer that was refractory to both an anti‑CD20 inhibitor and an alkylating agent. Also, more than 50% had disease progression within 24 months after the first systemic therapy. The committee concluded that the study population included people with a poor prognosis and was broadly generalisable to UK clinical practice. ## Outcomes and results The primary efficacy endpoint in the GO29781 pivotal cohort was complete response as assessed by an independent review facility. In the primary analysis (March 2021), 58% of people who had mosunetuzumab had a complete response. This was statistically significantly higher than a historical control complete response rate of 14% in a similar patient population. After a median follow up of 18 months (August 2021), 60% of people who had mosunetuzumab had a complete tumour response. Median progression-free survival with mosunetuzumab was 17.9 months. Median overall survival was not reached. Clinical experts stated that the complete response rate seen with mosunetuzumab was very encouraging. The committee noted that it would have liked to have seen results from a phase 3 trial of mosunetuzumab compared with standard care treatments. The lack of any comparative data makes it difficult to interpret the trial results. The company explained that a phase 3 trial was planned with idelalisib as the comparator, but this did not go ahead because of emerging safety findings for the comparator drug class. The committee noted that the most common adverse event in the single-arm study of mosunetuzumab was cytokine release syndrome, which was seen in more than 40% of people. However, more than 95% of people with cytokine release syndrome had less severe events (grade 1 or 2). The company noted that cytokine release syndrome usually happened in the first treatment cycle on day 15 when the dose level was being increased. They added that it could be effectively managed with good clinical awareness and preventative treatment when starting mosunetuzumab. Clinical experts noted that mosunetuzumab was well tolerated after 1 month. It was not associated with lingering effects that would be seen with chemotherapy, and the need for treatment every 3 weeks after the first cycle of mosunetuzumab was manageable. The experts explained that mosunetuzumab could be administered in non-specialist centres if staff are trained to identify and manage cytokine release syndrome. The committee concluded that mosunetuzumab was potentially a promising new treatment option in relapsed or refractory follicular lymphoma. # Indirect treatment comparisons ## Comparators Because of the lack of direct comparative evidence for mosunetuzumab, the company did indirect treatment comparisons for the outcomes of overall survival, progression-free survival, tumour response and stopping treatment because of adverse events. Stakeholders commented on the draft guidance that real-world datasets could potentially have been incorporated into the indirect treatment comparisons. The committee noted some of these included people in the UK. The company noted that these datasets were not used because they included people who had treatment at an earlier line of therapy or included a mixed histology (not all follicular lymphoma). The company used rituximab plus lenalidomide and rituximab plus bendamustine in its indirect comparisons with mosunetuzumab. Rituximab plus lenalidomide and rituximab plus chemotherapy, which may include rituximab plus bendamustine, are used at third line or later in follicular lymphoma (see section 3.2). The company acknowledged that in practice, people may have other types of chemotherapy with rituximab (such as R‑CHOP and R‑CVP). It explained that an indirect comparison with R‑CHOP was attempted but was not feasible because of several limitations. The EAG agreed that an indirect comparison with R‑CHOP could not be done reliably. The committee noted that in the company's approach, the comparator rituximab plus bendamustine would also be used to represent other types of rituximab plus chemotherapy in the indirect comparison. Clinical experts suggested that it is not plausible for rituximab plus bendamustine to represent rituximab used in combination with other types of chemotherapy. However, there is limited data to challenge whether rituximab plus bendamustine is representative of rituximab plus chemotherapy had by people at third line or later. The clinical experts added that if rituximab plus bendamustine is representative, it sets the bar high for the indirect treatment comparison because people having treatment will be younger and fitter. They noted that differences seen between rituximab plus bendamustine and other rituximab plus chemotherapy combinations at first line may be less evident at third line, but it is not clear if this is the case. The committee concluded that rituximab plus lenalidomide is a suitable comparator for mosunetuzumab in an indirect treatment comparison. It also concluded that rituximab plus bendamustine is a reasonable comparator, but whether it is representative of other types of rituximab plus chemotherapy is highly uncertain. ## Comparison with rituximab plus lenalidomide For the comparison of mosunetuzumab with rituximab plus lenalidomide, the company used the AUGMENT study of rituximab plus lenalidomide, for which it did not have access to individual patient data. Therefore, a matching-adjusted indirect comparison (MAIC) was done. In this, the GO29781 study cohort was matched and statistically adjusted to resemble that of the AUGMENT study population, to predict treatment effects as if mosunetuzumab had been evaluated in the AUGMENT study population. The EAG noted that some important prognostic factors and effect modifiers were not included in the MAIC. These were: number of previous therapies, refractory status to previous anti‑CD20 inhibitor, previous stem cell transplant and size of the largest lymph node lesion. The company explained that it was not possible to match for these variables because data was not available from AUGMENT. The EAG also noted that the variable 'low haemoglobin' should have been excluded from the MAIC because it was taken from the full GO29781 study population, not the relevant study cohort. Clinical experts noted that 'number of previous therapies' was an important prognostic variable missing from the MAIC. They also stated that stem cell transplant is increasingly uncommon in this population so is less relevant. The EAG noted that having several unmatched variables in the MAIC leads to high uncertainty in the results and the potential for bias, with the amount and direction of bias unclear. It added that the selection of covariates in the analysis had failed to maximise the effective sample size available to represent the efficacy of mosunetuzumab. The committee concluded that the indirect comparison of mosunetuzumab with rituximab plus lenalidomide was not matched for some important variables, making it highly uncertain with a potential for bias. ## Comparison with rituximab plus bendamustine For the comparison of mosunetuzumab with rituximab plus bendamustine, the company used the CONTRALTO and GO29365 studies of rituximab plus bendamustine, which had individual patient data. Therefore, propensity score analyses were done. In these, an estimate of treatment effect is calculated after accounting for differences in covariates believed to be prognostic factors or treatment-effect modifiers across the treatment groups. The company explored several approaches and after technical engagement selected an inverse probability of treatment weighting method. In this, subjects are weighted by the inverse probability of treatment. This is done to balance the baseline characteristics between individuals in 2 separate studies and remove confounding. The company explained that the selection of variables in the analysis was based on improving the overall balance of these. The EAG noted that generally the important prognostic factors and effect modifiers were included in the analysis. It suggested that it was unclear whether double-refractory status should have been included in the analysis because it had wide standard errors making it unreliable. It noted that when the interaction of double-refractory status with treatment arm was included, there was an impact in the mosunetuzumab arm but a neutral effect in the rituximab plus bendamustine arm. The clinical plausibility of this is unclear. The committee concluded that there was some uncertainty associated with the indirect comparison of mosunetuzumab with rituximab plus bendamustine. ## Results of indirect treatment comparisons The company considers the results of the indirect treatment comparisons to be confidential so they cannot be described here. The EAG noted that there were inconsistent results within the 2 indirect comparisons, making them highly uncertain. That is, the results favoured mosunetuzumab for some endpoints but the comparator for others. Differences in the results across the 2 indirect comparisons also made them difficult to interpret. The company noted that in both indirect comparisons there were differences between the mosunetuzumab and comparator study populations that may lead to bias against mosunetuzumab. In the AUGMENT study used in the MAIC, less than 50% of people having rituximab plus lenalidomide had treatment at third line or later and none had follicular lymphoma that was refractory to rituximab. The committee noted that the mosunetuzumab study cohort had more relapses and greater treatment refractoriness than people in AUGMENT (see section 3.3). The company noted that in the propensity score analysis, there were also important differences between the study populations. This suggests that people who had treatment with mosunetuzumab had a poorer prognosis than those in the pooled studies of rituximab plus bendamustine. Clinical experts had said that people having treatment with rituximab plus bendamustine would typically be younger and fitter than people having other types of rituximab plus chemotherapy (see section 3.5). The committee concluded that the results of the indirect treatment comparisons were highly uncertain. It also concluded that the inconsistencies within them made them very unreliable. # Economic model ## Company's modelling approach The company used a partitioned survival model to represent progression-free and overall survival for mosunetuzumab compared with rituximab plus lenalidomide and rituximab plus bendamustine. It had 3 health states: progression-free, post-progression, and dead. The model had a lifetime time horizon (40 years). Each model cycle lasted 1 week. The company and EAG agreed that a half-cycle correction should be applied. The committee considered that a partitioned survival model is a standard approach to estimate the cost effectiveness of many cancer drugs. But it noted that a response-based modelling approach could be more suitable for comparing mosunetuzumab with rituximab plus lenalidomide. This may have avoided some of the problems seen with the survival modelling of mosunetuzumab compared with rituximab plus lenalidomide (see section 3.8 and section 3.12) and more fully captured the benefits of complete response. However, a response-based model would have its own uncertainty because of the limitations in the data available to model outcomes in people having different response levels. The committee suggested that external data would also be needed for estimating overall survival. The committee concluded that the company's economic model used a standard approach, but this was not reliable for the comparison of mosunetuzumab with rituximab plus lenalidomide. It also concluded that an alternative approach could help inform decision making in the comparison of mosunetuzumab with rituximab plus lenalidomide. ## Survival distributions selected For the comparison of mosunetuzumab with rituximab plus lenalidomide, both the company and EAG selected a log normal distribution to model progression-free survival in the rituximab plus lenalidomide arm. The company used the Weibull distribution for the mosunetuzumab arm. The EAG preferred to use a log normal distribution for the mosunetuzumab arm using available data and switched to the log normal distribution used for rituximab plus lenalidomide when observed data was not available. Both the company and EAG selected a Weibull function to model overall survival in the mosunetuzumab and rituximab plus lenalidomide arms. For the comparison of mosunetuzumab with rituximab plus bendamustine, the company and EAG took the same approach to model progression-free survival. In this comparison, the company considered rituximab plus bendamustine to also be representative of other types of rituximab plus chemotherapy (see section 3.5). The company and EAG selected a log normal distribution for both the mosunetuzumab and rituximab plus bendamustine arms. The company and EAG agreed on using an exponential distribution to model overall survival in the mosunetuzumab and rituximab plus bendamustine arms. The committee concluded that the company and EAG agreed on most survival distributions and all would be considered. ## Overall survival modelling For both comparisons, the company modelled the mosunetuzumab and comparator arms separately. The EAG preferred to pool the mosunetuzumab and comparator arms, which removed the treatment difference for overall survival from both comparisons. The EAG noted that the overall survival data from the single-arm mosunetuzumab study was very immature. It preferred to pool the intervention and comparator arms because there was no clear overall survival benefit. The committee noted that the EAG's pooling of overall survival data for the 2 arms changed the cost-effectiveness estimate from that of the company's base case for mosunetuzumab compared with rituximab plus lenalidomide. It also noted that pooling overall survival data had a substantial impact on the cost-effectiveness estimate for mosunetuzumab compared with rituximab plus bendamustine. The committee noted that the EAG's approach assumed that both treatments have the same overall survival, whereas the clinical experts expected people to live longer with mosunetuzumab. The company and EAG took different approaches to model survival for the 2 comparisons, and the EAG preferred to pool overall survival. The committee concluded that it would consider both approaches. ## Plausibility of the company's survival modelling The company acknowledged that because of data sparsity and immaturity, there was some uncertainty in the efficacy estimates included in the model. It added that data from further follow up of people in the clinical study could reduce some of this uncertainty. Clinical experts suggested that the company's modelled progression-free survival curves appeared reasonable. The committee noted that the lower life-years gained by people in the company's model with mosunetuzumab compared with rituximab plus lenalidomide did not reflect the potential benefit of mosunetuzumab on tumour response suggested by the single-arm study data. The findings of the indirect treatment comparison cannot be reported. The committee recalled that the EAG preferred to use pooled overall survival data for the extrapolations (see section 3.11). It noted that this preference to pool overall survival data meant that life-years gained were the same for mosunetuzumab and its comparator in the EAG's model, for both comparisons. The company suggested that its own modelling may underestimate any survival benefit of mosunetuzumab because of limitations of the indirect treatment comparison (see section 3.8). It considered the EAG's preference to pool overall survival data to be overly conservative. The company noted that pooling overall survival data is inconsistent with the complete response rate seen in the mosunetuzumab study (see section 3.4). The findings of the indirect treatment comparison cannot be reported. Clinical experts noted that in follicular lymphoma, if you can achieve a durable complete response then you tend to see good progression-free survival. They added that in this cancer type, progression-free survival may not impact overall survival. But, it is unlikely that improved progression-free survival leads to a loss of overall survival. Stakeholders commented on the draft guidance that the model may place too much emphasis on overall survival. They explained that a progression-free survival benefit may not translate into improved overall survival in follicular lymphoma because of the long natural history of the condition and a heterogenous population having a range of treatments (see section 3.2). The committee concluded that the survival modelling was highly uncertain for both comparisons. It concluded that in the comparison with rituximab plus lenalidomide, the company's modelling of mosunetuzumab overall survival was unlikely to be plausible. It also concluded that the EAG scenarios could be plausible even though they are conservative. ## Utility values In its original base case presented at the first committee meeting, the company's utility values for the health states of progression-free survival and post-progression survival were based on the GO29781 study cohort. The company noted that this data was collected beyond the end of treatment during study follow up. In total, 63 observations in post-progression survival were included. Of these, 19 were made after 1 year. The EAG noted that because the company used study data as the source of utility values, for anyone in the study in early post-progression the corresponding utility value is then extrapolated forwards for many years in the model. At the first meeting, the committee agreed that the company's approach was acceptable even though it was associated with some uncertainty. During the consultation the company changed its source of utility values, preferring to use those from the literature (Wild et al. 2006) in its updated base case. The company stated that this addressed the uncertainties because the values were elicited from 222 UK patients and were previously used in NICE's technology appraisal guidance on idelalisib for treating refractory follicular lymphoma. In the present evaluation, the EAG noted that Wild et al. was published as an abstract only and the utility values cannot be validated. The committee noted that in the GO29781 study cohort, the utility value for post-progression represented people on subsequent treatment. It also noted that it was not known whether the utility value for post-progression from the Wild et al. abstract represented people on subsequent treatment or not. The EAG noted that Wild et al. data has a much larger difference in utility value between the progression-free and post-progression states than the GO29781 study cohort. It noted that both potential sources have limitations. So, the EAG preferred not to change the utility values in its base case, which are from the GO29781 study cohort. The committee considered that the company and EAG took different approaches and both were associated with some uncertainty. It concluded that it preferred the GO29781 study cohort values because they were from a clinical study of people having mosunetuzumab, while Wild et al. may not be a robust source and could not be validated. ## Subsequent therapy assumptions The company's model applied subsequent treatment costs from the point of disease progression for all treatment arms. The EAG noted that this reflected what might happen in clinical practice. It added that this approach produced a bias towards lower costs in favour of mosunetuzumab. This is because progression-free survival and time on treatment is assumed to be equal for the comparators, but not for mosunetuzumab. After the first committee meeting, the company and EAG agreed on the distribution of subsequent treatments. These included rituximab plus lenalidomide (35%), rituximab plus chemotherapy (25%) and other non-rituximab-based chemotherapy (10%) for the mosunetuzumab and rituximab plus bedamustine treatment arms. In the rituximab plus lenalidomide arm it was assumed that people would not have rituximab plus lenalidomide as their subsequent therapy. So, in this arm subsequent treatment types included rituximab plus chemotherapy (50%) and other non-rituximab-based chemotherapy (20%). The committee noted that the subsequent therapy assumptions were informed by clinical advice. The EAG noted that it was possible that some people would have previous treatment with rituximab plus lenalidomide but not have it as their most recent previous therapy. This was not accounted for in the EAG's and company's updated base cases. The committee concluded that the company's subsequent treatment assumptions are likely to reflect clinical practice. # Cost-effectiveness estimates ## Company and EAG cost-effectiveness estimates The company submitted incremental cost-effectiveness ratios (ICERs) for mosunetuzumab compared with rituximab plus lenalidomide and rituximab plus bendamustine incorporating a patient access scheme discount. The deterministic and probabilistic ICERs were broadly similar. The ICERs cannot be presented because they include confidential discounted prices for lenalidomide and rituximab. For the comparison with rituximab plus lenalidomide, mosunetuzumab was more costly and less effective in the company's updated base case. Also, mosunetuzumab was more costly and marginally less effective than rituximab plus lenalidomide in the EAG's preferred base case. The committee noted that in the company's model, people had lower life-years gained with mosunetuzumab compared with rituximab plus lenalidomide (see section 3.12). It also noted that in the EAG's preferred model, life-years gained were the same for mosunetuzumab and rituximab plus lenalidomide. For the comparison with rituximab plus bendamustine, the mosunetuzumab ICER was above £30,000 per quality-adjusted life year (QALY) gained in the company's updated base case and substantially higher than £30,000 per QALY gained in the EAG base case. In a scenario analysis, the EAG explored the impact on its preferred base case of changing the utility values (see section 3.13) for the comparison of mosunetuzumab and rituximab plus bendamustine. The committee noted that using the utility values from Wild et al. reduced the cost-effectiveness estimate of the EAG's preferred base case by a large amount, but the ICER remained substantially above £30,000 per QALY gained. The committee noted that for both comparisons the ICERs for the EAG base cases do not include any potential overall survival benefit for mosunetuzumab, which may be plausible but conservative (see section 3.12). The committee concluded that, based on the ICERs presented, mosunetuzumab does not represent a cost-effective use of NHS resources. ## Cost-effective estimates are highly uncertain NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will specifically consider the degree of certainty and uncertainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty in the cost-effectiveness estimate caused by: a single-arm trial being the primary source of clinical evidence for mosunetuzumab (see sections 3.3 and 3.4) issues with the indirect treatment comparisons including the comparators and the representativeness of rituximab plus bendamustine for other types of rituximab plus chemotherapy (see section 3.5), variables included (see sections 3.6 and 3.7), differences between the study populations included and the reliability and plausibility of the results (see section 3.8) immaturity and sparsity of efficacy estimates included in the model (see section 3.12) limitations in the data used to inform the utility values (see section 3.13).The committee concluded that the cost-effectiveness estimates are highly uncertain. ## Mosunetuzumab is not cost effective The committee noted that in the company's updated and EAG's base cases for the comparison with rituximab plus lenalidomide, mosunetuzumab was more expensive and less effective (see section 3.15). For the comparison with rituximab plus bendamustine, mosunetuzumab was not plausibly cost effective because both the company's updated and EAG's base cases were greater than £30,000 per QALY gained (see section 3.15). The estimates are also associated with considerable uncertainty. The committee concluded that mosunetuzumab did not represent a cost-effective use of NHS resources so could not be recommended for routine commissioning. # Managed access ## Criteria for managed access not met Having concluded that mosunetuzumab could not be recommended for routine use, the committee then considered if it could be recommended with managed access for treating relapsed or refractory follicular lymphoma after 2 or more systemic therapies. The committee discussed the criteria for a managed access recommendation by NICE (see NICE's webpage on managed access). It noted that the company had submitted a proposal for managed access. The company considered that additional data collection could resolve some of the uncertainties associated with its cost-effectiveness modelling. It noted that this would include further data collection from the GO29781 study cohort, which would continue until at least June 2024. It also proposed that if recommended with managed access, the company would do a prospective study collecting real-world evidence on mosunetuzumab. This would include progression-free survival data. The committee noted that longer-term data from the GO29781 study cohort would be helpful to inform the survival modelling and post-progression utilities. But, this would depend on how much data can be collected to resolve some uncertainties. Also, the timeframe for data collection with managed access may not be long enough to show an overall survival benefit, which is one of the key uncertainties (see section 3.12). The committee noted that the Systemic Anti-Cancer Dataset (SACT) would provide useful UK-based data to explore the generalisability of the GO29781 study cohort to patients in the UK. It noted that it was unlikely SACT data would sufficiently resolve the high uncertainty associated with the indirect treatment comparisons. It added that SACT would not provide any information on previous treatment lines. It would also be unlikely to provide any overall survival data with a long enough duration to reduce uncertainty by very much. The committee noted that additional data collection would not resolve any uncertainty about whether rituximab plus bendamustine is representative of other types of rituximab plus chemotherapy (R‑CHOP, R‑CVP). The company proposed a potential new source of evidence on comparator treatments. It considers all details related to this confidential so it cannot be described here. It suggested that this would allow more robust indirect treatment comparisons. Stakeholders commented on the draft guidance that clinical studies completing during 2023 to 2026 may provide additional data on standard care. The committee noted these may provide useful information on comparators, but any comparison with mosunetuzumab would still be unanchored. Also, when adjusting for prognostic factors and effective modifiers the effective sample size may be small. It also noted that comparator studies cannot form part of a managed access agreement. The company confirmed that there are no ongoing comparative trials to provide more robust, controlled evidence on mosunetuzumab monotherapy at third line or later for relapsed or refractory follicular lymphoma. The committee highlighted that, because the indirect treatment comparisons were highly uncertain, a trial comparing mosunetuzumab with standard care comparators is needed. The committee appreciated that managed access is designed to resolve uncertainties, but it did not think that it would sufficiently resolve the high level of uncertainty in this submission (see section 3.14). Also, it had not seen evidence that mosunetuzumab had plausible potential to be cost effective, because the company and EAG base cases were both greater than £30,000 per QALY gained (see section 3.15). The committee concluded that mosunetuzumab did not meet the criteria to be considered for a recommendation with managed access. # Other factors ## Potential equality issue Stakeholders commented on the draft guidance that not recommending mosunetuzumab may disadvantage older or frailer people with follicular lymphoma because they do not have access to the full range of immunochemotherapy treatment options. They also noted that these people have an even greater need for novel therapies earlier in the disease course. The committee acknowledged that some people have a greater unmet need for new treatment options. It also noted that its recommendation applies to all people within the marketing authorisation indication for mosunetuzumab (see section 2.1). The committee concluded that this is not an equality issue. NICE's advice about conditions with a high degree of severity did not apply. ## Innovation The committee noted that mosunetuzumab is the first of a new class of drugs in this setting with a unique mode of action. New treatment options would be welcomed by patients and clinicians (see section 3.1) in an area where there is no current standard care (see section 3.2). Clinical experts advised that mosunetuzumab can be used after multiple previous treatments and in chemotherapy-resistant relapsed or refractory follicular lymphoma. The committee considered whether mosunetuzumab was innovative. It recalled that the economic modelling of mosunetuzumab was highly uncertain. Because of this, it was possible that there were some benefits of mosunetuzumab not captured in the modelling. So, it concluded that mosunetuzumab may be innovative but there is a high level of uncertainty in the evidence presented. It would like to consider innovation together with the exploration of other uncertainties in the model, along with evidence of any uncaptured benefits. # Conclusion Mosunetuzumab is not recommended for treating relapsed or refractory follicular lymphoma after 2 or more systemic therapies.	{'Recommendations': 'Mosunetuzumab is not recommended, within its marketing authorisation, for treating relapsed or refractory follicular lymphoma in adults who have had 2 or more systemic therapies.\n\nThis recommendation is not intended to affect treatment with mosunetuzumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment options for relapsed or refractory follicular lymphoma are limited and there is no standard care. After 2 previous therapies, treatment may include rituximab plus lenalidomide or rituximab plus chemotherapy.\n\nClinical evidence suggests that follicular lymphoma responds to treatment with mosunetuzumab, so the cancer may not get worse as quickly. But these results are from a trial that did not compare mosunetuzumab with placebo or any other treatment options. Indirect comparisons of mosunetuzumab with other treatment options are very uncertain with inconsistent results.\n\nThe cost-effectiveness estimates for mosunetuzumab are highly uncertain and do not represent a cost-effective use of NHS resources. So, mosunetuzumab is not recommended for routine use in the NHS.\n\nMosunetuzumab cannot be recommended with managed access. This is because mosunetuzumab is not likely to be cost effective. Also, more data collected in the Cancer Drugs Fund would not resolve the high level of uncertainty.', 'Information about mosunetuzumab': "# Marketing authorisation indication\n\nMosunetuzumab (Lunsumio, Roche) is indicated for 'the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for mosunetuzumab.\n\n# Price\n\nMosunetuzumab costs £220 per 1\xa0mg/1\xa0ml concentrate for solution for infusion vial and £6,600 per 30\xa0mg/30\xa0ml concentrate for solution for infusion vial (excluding VAT; company submission). The cost per course of treatment is £66,660 for 8\xa0cycles and £126,600 for 17\xa0cycles.\n\nThe company has a commercial arrangement, which would have applied if mosunetuzumab had been recommended.", 'Committee discussion': "The evaluation committee considered evidence submitted by Roche, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition and current treatment\n\n## Unmet need\n\nFollicular lymphoma is a type of indolent, low-grade non-Hodgkin lymphoma. The patient expert noted that it is an incurable cancer that will return and people with the condition will need subsequent treatment for life. They explained that there is always the fear of relapse when living with the disease. Clinical experts noted that survival and remission duration worsen with each successive relapse. They explained that there is no current standard care and a lack of treatment options. This creates difficult treatment choices from a mixed basket of options for relapsed or refractory follicular lymphoma. The clinical experts explained that when selecting treatment, factors such as a person's age, frailty and wishes are considered. The patient expert noted that people value alternatives to chemotherapy. Stakeholders commented on the draft guidance that mosunetuzumab could provide an extra line of treatment. The committee concluded that new treatment options would be welcomed by patients and clinicians.\n\n## Current treatment\n\nClinical experts noted that in previously treated follicular lymphoma, treatment options include:\n\nlenalidomide with rituximab (see NICE technology appraisal guidance on lenalidomide with rituximab for previously treated follicular lymphoma)\n\nobinutuzumab with bendamustine (see NICE technology appraisal guidance on obinutuzumab with bendamustine for treating follicular lymphoma after rituximab) and\n\nrituximab plus chemotherapy followed by rituximab maintenance therapy. They explained that for rituximab plus chemotherapy, people are likely to have rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP), rituximab plus cyclophosphamide, vincristine and prednisolone (R‑CVP) or rituximab plus bendamustine. Clinical experts noted that after first-line treatment, R‑CHOP and R‑CVP may be favoured over rituximab plus bendamustine. This is because rituximab plus bendamustine can be associated with greater toxicity. They noted that people aged over\xa070 do not tolerate bendamustine well. The committee noted that older people in mutual carer relationships would benefit from a non-chemotherapy treatment. Clinical experts explained that because of the long natural history of follicular lymphoma, some people have had potentially less effective treatments such as rituximab plus chemotherapy at second line. Others have had newer options such as rituximab plus lenalidomide or obinutuzumab plus bendamustine. So, the treatment landscape is complicated and changing. The experts noted that at third line and beyond, treatment choice will be influenced by previous therapy. This means people will have either rituximab plus lenalidomide if they have not had it before, or rituximab plus chemotherapy if they previously had rituximab plus lenalidomide. Rituximab plus chemotherapy may include rituximab plus bendamustine if a person is well enough and has not already had it. The NHS England Cancer Drugs Fund clinical lead noted that across second- and third-line treatment, more people currently have rituximab plus bendamustine than rituximab plus lenalidomide in NHS practice. The committee noted that obinutuzumab plus bendamustine is rarely used third line, so it is not a relevant comparator for this appraisal. The committee concluded that treatments used at third line or later are rituximab plus lenalidomide and rituximab plus chemotherapy, which may include rituximab plus bendamustine.\n\n# Clinical evidence\n\n## Study population and generalisability\n\nGO29781 was a phase\xa02, multicentre, single-arm, non-comparative study in people with relapsed or refractory haematologic malignancies expected to express the CD20 antigen. Clinical evidence for mosunetuzumab is from a pivotal cohort of 90\xa0people with relapsed or refractory follicular lymphoma who have had at least 2 previous therapies that included both an anti‑CD20 inhibitor and an alkylating agent. Patients had a median age of\xa060. The company noted that its clinical advisers considered the study population broadly representative of people who have had 2 or more previous treatments for follicular lymphoma in UK clinical practice, in terms of age (UK median age around 66), daily functioning, disease stage and prognosis. The EAG noted that only 2% of people in the study were from the UK and most were from the US (44%). Clinical experts confirmed that the study population broadly reflects UK clinical practice. They noted that the study population had a higher proportion of people with factors known to be associated with poorer outcomes for follicular lymphoma that is treated at third line or later. More than 50% of people in the study had cancer that was refractory to both an anti‑CD20 inhibitor and an alkylating agent. Also, more than 50% had disease progression within 24\xa0months after the first systemic therapy. The committee concluded that the study population included people with a poor prognosis and was broadly generalisable to UK clinical practice.\n\n## Outcomes and results\n\nThe primary efficacy endpoint in the GO29781 pivotal cohort was complete response as assessed by an independent review facility. In the primary analysis (March 2021), 58% of people who had mosunetuzumab had a complete response. This was statistically significantly higher than a historical control complete response rate of 14% in a similar patient population. After a median follow up of 18\xa0months (August 2021), 60% of people who had mosunetuzumab had a complete tumour response. Median progression-free survival with mosunetuzumab was 17.9\xa0months. Median overall survival was not reached. Clinical experts stated that the complete response rate seen with mosunetuzumab was very encouraging. The committee noted that it would have liked to have seen results from a phase\xa03 trial of mosunetuzumab compared with standard care treatments. The lack of any comparative data makes it difficult to interpret the trial results. The company explained that a phase\xa03 trial was planned with idelalisib as the comparator, but this did not go ahead because of emerging safety findings for the comparator drug class. The committee noted that the most common adverse event in the single-arm study of mosunetuzumab was cytokine release syndrome, which was seen in more than 40% of people. However, more than 95% of people with cytokine release syndrome had less severe events (grade\xa01 or\xa02). The company noted that cytokine release syndrome usually happened in the first treatment cycle on day\xa015 when the dose level was being increased. They added that it could be effectively managed with good clinical awareness and preventative treatment when starting mosunetuzumab. Clinical experts noted that mosunetuzumab was well tolerated after 1\xa0month. It was not associated with lingering effects that would be seen with chemotherapy, and the need for treatment every 3\xa0weeks after the first cycle of mosunetuzumab was manageable. The experts explained that mosunetuzumab could be administered in non-specialist centres if staff are trained to identify and manage cytokine release syndrome. The committee concluded that mosunetuzumab was potentially a promising new treatment option in relapsed or refractory follicular lymphoma.\n\n# Indirect treatment comparisons\n\n## Comparators\n\nBecause of the lack of direct comparative evidence for mosunetuzumab, the company did indirect treatment comparisons for the outcomes of overall survival, progression-free survival, tumour response and stopping treatment because of adverse events. Stakeholders commented on the draft guidance that real-world datasets could potentially have been incorporated into the indirect treatment comparisons. The committee noted some of these included people in the UK. The company noted that these datasets were not used because they included people who had treatment at an earlier line of therapy or included a mixed histology (not all follicular lymphoma). The company used rituximab plus lenalidomide and rituximab plus bendamustine in its indirect comparisons with mosunetuzumab. Rituximab plus lenalidomide and rituximab plus chemotherapy, which may include rituximab plus bendamustine, are used at third line or later in follicular lymphoma (see section\xa03.2). The company acknowledged that in practice, people may have other types of chemotherapy with rituximab (such as R‑CHOP and R‑CVP). It explained that an indirect comparison with R‑CHOP was attempted but was not feasible because of several limitations. The EAG agreed that an indirect comparison with R‑CHOP could not be done reliably. The committee noted that in the company's approach, the comparator rituximab plus bendamustine would also be used to represent other types of rituximab plus chemotherapy in the indirect comparison. Clinical experts suggested that it is not plausible for rituximab plus bendamustine to represent rituximab used in combination with other types of chemotherapy. However, there is limited data to challenge whether rituximab plus bendamustine is representative of rituximab plus chemotherapy had by people at third line or later. The clinical experts added that if rituximab plus bendamustine is representative, it sets the bar high for the indirect treatment comparison because people having treatment will be younger and fitter. They noted that differences seen between rituximab plus bendamustine and other rituximab plus chemotherapy combinations at first line may be less evident at third line, but it is not clear if this is the case. The committee concluded that rituximab plus lenalidomide is a suitable comparator for mosunetuzumab in an indirect treatment comparison. It also concluded that rituximab plus bendamustine is a reasonable comparator, but whether it is representative of other types of rituximab plus chemotherapy is highly uncertain.\n\n## Comparison with rituximab plus lenalidomide\n\nFor the comparison of mosunetuzumab with rituximab plus lenalidomide, the company used the AUGMENT study of rituximab plus lenalidomide, for which it did not have access to individual patient data. Therefore, a matching-adjusted indirect comparison (MAIC) was done. In this, the GO29781 study cohort was matched and statistically adjusted to resemble that of the AUGMENT study population, to predict treatment effects as if mosunetuzumab had been evaluated in the AUGMENT study population. The EAG noted that some important prognostic factors and effect modifiers were not included in the MAIC. These were: number of previous therapies, refractory status to previous anti‑CD20 inhibitor, previous stem cell transplant and size of the largest lymph node lesion. The company explained that it was not possible to match for these variables because data was not available from AUGMENT. The EAG also noted that the variable 'low haemoglobin' should have been excluded from the MAIC because it was taken from the full GO29781 study population, not the relevant study cohort. Clinical experts noted that 'number of previous therapies' was an important prognostic variable missing from the MAIC. They also stated that stem cell transplant is increasingly uncommon in this population so is less relevant. The EAG noted that having several unmatched variables in the MAIC leads to high uncertainty in the results and the potential for bias, with the amount and direction of bias unclear. It added that the selection of covariates in the analysis had failed to maximise the effective sample size available to represent the efficacy of mosunetuzumab. The committee concluded that the indirect comparison of mosunetuzumab with rituximab plus lenalidomide was not matched for some important variables, making it highly uncertain with a potential for bias.\n\n## Comparison with rituximab plus bendamustine\n\nFor the comparison of mosunetuzumab with rituximab plus bendamustine, the company used the CONTRALTO and GO29365 studies of rituximab plus bendamustine, which had individual patient data. Therefore, propensity score analyses were done. In these, an estimate of treatment effect is calculated after accounting for differences in covariates believed to be prognostic factors or treatment-effect modifiers across the treatment groups. The company explored several approaches and after technical engagement selected an inverse probability of treatment weighting method. In this, subjects are weighted by the inverse probability of treatment. This is done to balance the baseline characteristics between individuals in 2 separate studies and remove confounding. The company explained that the selection of variables in the analysis was based on improving the overall balance of these. The EAG noted that generally the important prognostic factors and effect modifiers were included in the analysis. It suggested that it was unclear whether double-refractory status should have been included in the analysis because it had wide standard errors making it unreliable. It noted that when the interaction of double-refractory status with treatment arm was included, there was an impact in the mosunetuzumab arm but a neutral effect in the rituximab plus bendamustine arm. The clinical plausibility of this is unclear. The committee concluded that there was some uncertainty associated with the indirect comparison of mosunetuzumab with rituximab plus bendamustine.\n\n## Results of indirect treatment comparisons\n\nThe company considers the results of the indirect treatment comparisons to be confidential so they cannot be described here. The EAG noted that there were inconsistent results within the 2 indirect comparisons, making them highly uncertain. That is, the results favoured mosunetuzumab for some endpoints but the comparator for others. Differences in the results across the 2 indirect comparisons also made them difficult to interpret. The company noted that in both indirect comparisons there were differences between the mosunetuzumab and comparator study populations that may lead to bias against mosunetuzumab. In the AUGMENT study used in the MAIC, less than 50% of people having rituximab plus lenalidomide had treatment at third line or later and none had follicular lymphoma that was refractory to rituximab. The committee noted that the mosunetuzumab study cohort had more relapses and greater treatment refractoriness than people in AUGMENT (see section\xa03.3). The company noted that in the propensity score analysis, there were also important differences between the study populations. This suggests that people who had treatment with mosunetuzumab had a poorer prognosis than those in the pooled studies of rituximab plus bendamustine. Clinical experts had said that people having treatment with rituximab plus bendamustine would typically be younger and fitter than people having other types of rituximab plus chemotherapy (see section\xa03.5). The committee concluded that the results of the indirect treatment comparisons were highly uncertain. It also concluded that the inconsistencies within them made them very unreliable.\n\n# Economic model\n\n## Company's modelling approach\n\nThe company used a partitioned survival model to represent progression-free and overall survival for mosunetuzumab compared with rituximab plus lenalidomide and rituximab plus bendamustine. It had 3 health states: progression-free, post-progression, and dead. The model had a lifetime time horizon (40\xa0years). Each model cycle lasted 1\xa0week. The company and EAG agreed that a half-cycle correction should be applied. The committee considered that a partitioned survival model is a standard approach to estimate the cost effectiveness of many cancer drugs. But it noted that a response-based modelling approach could be more suitable for comparing mosunetuzumab with rituximab plus lenalidomide. This may have avoided some of the problems seen with the survival modelling of mosunetuzumab compared with rituximab plus lenalidomide (see section\xa03.8 and section 3.12) and more fully captured the benefits of complete response. However, a response-based model would have its own uncertainty because of the limitations in the data available to model outcomes in people having different response levels. The committee suggested that external data would also be needed for estimating overall survival. The committee concluded that the company's economic model used a standard approach, but this was not reliable for the comparison of mosunetuzumab with rituximab plus lenalidomide. It also concluded that an alternative approach could help inform decision making in the comparison of mosunetuzumab with rituximab plus lenalidomide.\n\n## Survival distributions selected\n\nFor the comparison of mosunetuzumab with rituximab plus lenalidomide, both the company and EAG selected a log normal distribution to model progression-free survival in the rituximab plus lenalidomide arm. The company used the Weibull distribution for the mosunetuzumab arm. The EAG preferred to use a log normal distribution for the mosunetuzumab arm using available data and switched to the log normal distribution used for rituximab plus lenalidomide when observed data was not available. Both the company and EAG selected a Weibull function to model overall survival in the mosunetuzumab and rituximab plus lenalidomide arms. For the comparison of mosunetuzumab with rituximab plus bendamustine, the company and EAG took the same approach to model progression-free survival. In this comparison, the company considered rituximab plus bendamustine to also be representative of other types of rituximab plus chemotherapy (see section\xa03.5). The company and EAG selected a log normal distribution for both the mosunetuzumab and rituximab plus bendamustine arms. The company and EAG agreed on using an exponential distribution to model overall survival in the mosunetuzumab and rituximab plus bendamustine arms. The committee concluded that the company and EAG agreed on most survival distributions and all would be considered.\n\n## Overall survival modelling\n\nFor both comparisons, the company modelled the mosunetuzumab and comparator arms separately. The EAG preferred to pool the mosunetuzumab and comparator arms, which removed the treatment difference for overall survival from both comparisons. The EAG noted that the overall survival data from the single-arm mosunetuzumab study was very immature. It preferred to pool the intervention and comparator arms because there was no clear overall survival benefit. The committee noted that the EAG's pooling of overall survival data for the 2 arms changed the cost-effectiveness estimate from that of the company's base case for mosunetuzumab compared with rituximab plus lenalidomide. It also noted that pooling overall survival data had a substantial impact on the cost-effectiveness estimate for mosunetuzumab compared with rituximab plus bendamustine. The committee noted that the EAG's approach assumed that both treatments have the same overall survival, whereas the clinical experts expected people to live longer with mosunetuzumab. The company and EAG took different approaches to model survival for the 2 comparisons, and the EAG preferred to pool overall survival. The committee concluded that it would consider both approaches.\n\n## Plausibility of the company's survival modelling\n\nThe company acknowledged that because of data sparsity and immaturity, there was some uncertainty in the efficacy estimates included in the model. It added that data from further follow up of people in the clinical study could reduce some of this uncertainty. Clinical experts suggested that the company's modelled progression-free survival curves appeared reasonable. The committee noted that the lower life-years gained by people in the company's model with mosunetuzumab compared with rituximab plus lenalidomide did not reflect the potential benefit of mosunetuzumab on tumour response suggested by the single-arm study data. The findings of the indirect treatment comparison cannot be reported. The committee recalled that the EAG preferred to use pooled overall survival data for the extrapolations (see section\xa03.11). It noted that this preference to pool overall survival data meant that life-years gained were the same for mosunetuzumab and its comparator in the EAG's model, for both comparisons. The company suggested that its own modelling may underestimate any survival benefit of mosunetuzumab because of limitations of the indirect treatment comparison (see section\xa03.8). It considered the EAG's preference to pool overall survival data to be overly conservative. The company noted that pooling overall survival data is inconsistent with the complete response rate seen in the mosunetuzumab study (see section\xa03.4). The findings of the indirect treatment comparison cannot be reported. Clinical experts noted that in follicular lymphoma, if you can achieve a durable complete response then you tend to see good progression-free survival. They added that in this cancer type, progression-free survival may not impact overall survival. But, it is unlikely that improved progression-free survival leads to a loss of overall survival. Stakeholders commented on the draft guidance that the model may place too much emphasis on overall survival. They explained that a progression-free survival benefit may not translate into improved overall survival in follicular lymphoma because of the long natural history of the condition and a heterogenous population having a range of treatments (see section\xa03.2). The committee concluded that the survival modelling was highly uncertain for both comparisons. It concluded that in the comparison with rituximab plus lenalidomide, the company's modelling of mosunetuzumab overall survival was unlikely to be plausible. It also concluded that the EAG scenarios could be plausible even though they are conservative.\n\n## Utility values\n\nIn its original base case presented at the first committee meeting, the company's utility values for the health states of progression-free survival and post-progression survival were based on the GO29781 study cohort. The company noted that this data was collected beyond the end of treatment during study follow up. In total, 63 observations in post-progression survival were included. Of these, 19 were made after 1\xa0year. The EAG noted that because the company used study data as the source of utility values, for anyone in the study in early post-progression the corresponding utility value is then extrapolated forwards for many years in the model. At the first meeting, the committee agreed that the company's approach was acceptable even though it was associated with some uncertainty. During the consultation the company changed its source of utility values, preferring to use those from the literature (Wild et al. 2006) in its updated base case. The company stated that this addressed the uncertainties because the values were elicited from 222 UK patients and were previously used in NICE's technology appraisal guidance on idelalisib for treating refractory follicular lymphoma. In the present evaluation, the EAG noted that Wild et al. was published as an abstract only and the utility values cannot be validated. The committee noted that in the GO29781 study cohort, the utility value for post-progression represented people on subsequent treatment. It also noted that it was not known whether the utility value for post-progression from the Wild et al. abstract represented people on subsequent treatment or not. The EAG noted that Wild et al. data has a much larger difference in utility value between the progression-free and post-progression states than the GO29781 study cohort. It noted that both potential sources have limitations. So, the EAG preferred not to change the utility values in its base case, which are from the GO29781 study cohort. The committee considered that the company and EAG took different approaches and both were associated with some uncertainty. It concluded that it preferred the GO29781 study cohort values because they were from a clinical study of people having mosunetuzumab, while Wild et al. may not be a robust source and could not be validated.\n\n## Subsequent therapy assumptions\n\nThe company's model applied subsequent treatment costs from the point of disease progression for all treatment arms. The EAG noted that this reflected what might happen in clinical practice. It added that this approach produced a bias towards lower costs in favour of mosunetuzumab. This is because progression-free survival and time on treatment is assumed to be equal for the comparators, but not for mosunetuzumab. After the first committee meeting, the company and EAG agreed on the distribution of subsequent treatments. These included rituximab plus lenalidomide (35%), rituximab plus chemotherapy (25%) and other non-rituximab-based chemotherapy (10%) for the mosunetuzumab and rituximab plus bedamustine treatment arms. In the rituximab plus lenalidomide arm it was assumed that people would not have rituximab plus lenalidomide as their subsequent therapy. So, in this arm subsequent treatment types included rituximab plus chemotherapy (50%) and other non-rituximab-based chemotherapy (20%). The committee noted that the subsequent therapy assumptions were informed by clinical advice. The EAG noted that it was possible that some people would have previous treatment with rituximab plus lenalidomide but not have it as their most recent previous therapy. This was not accounted for in the EAG's and company's updated base cases. The committee concluded that the company's subsequent treatment assumptions are likely to reflect clinical practice.\n\n# Cost-effectiveness estimates\n\n## Company and EAG cost-effectiveness estimates\n\nThe company submitted incremental cost-effectiveness ratios (ICERs) for mosunetuzumab compared with rituximab plus lenalidomide and rituximab plus bendamustine incorporating a patient access scheme discount. The deterministic and probabilistic ICERs were broadly similar. The ICERs cannot be presented because they include confidential discounted prices for lenalidomide and rituximab. For the comparison with rituximab plus lenalidomide, mosunetuzumab was more costly and less effective in the company's updated base case. Also, mosunetuzumab was more costly and marginally less effective than rituximab plus lenalidomide in the EAG's preferred base case. The committee noted that in the company's model, people had lower life-years gained with mosunetuzumab compared with rituximab plus lenalidomide (see section\xa03.12). It also noted that in the EAG's preferred model, life-years gained were the same for mosunetuzumab and rituximab plus lenalidomide. For the comparison with rituximab plus bendamustine, the mosunetuzumab ICER was above £30,000 per quality-adjusted life year (QALY) gained in the company's updated base case and substantially higher than £30,000 per QALY gained in the EAG base case. In a scenario analysis, the EAG explored the impact on its preferred base case of changing the utility values (see section\xa03.13) for the comparison of mosunetuzumab and rituximab plus bendamustine. The committee noted that using the utility values from Wild et al. reduced the cost-effectiveness estimate of the EAG's preferred base case by a large amount, but the ICER remained substantially above £30,000 per QALY gained. The committee noted that for both comparisons the ICERs for the EAG base cases do not include any potential overall survival benefit for mosunetuzumab, which may be plausible but conservative (see section\xa03.12). The committee concluded that, based on the ICERs presented, mosunetuzumab does not represent a cost-effective use of NHS resources.\n\n## Cost-effective estimates are highly uncertain\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will specifically consider the degree of certainty and uncertainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty in the cost-effectiveness estimate caused by:\n\na single-arm trial being the primary source of clinical evidence for mosunetuzumab (see sections\xa03.3 and\xa03.4)\n\nissues with the indirect treatment comparisons including the comparators and the representativeness of rituximab plus bendamustine for other types of rituximab plus chemotherapy (see section\xa03.5), variables included (see sections\xa03.6 and\xa03.7), differences between the study populations included and the reliability and plausibility of the results (see section\xa03.8)\n\nimmaturity and sparsity of efficacy estimates included in the model (see section\xa03.12)\n\nlimitations in the data used to inform the utility values (see section\xa03.13).The committee concluded that the cost-effectiveness estimates are highly uncertain.\n\n## Mosunetuzumab is not cost effective\n\nThe committee noted that in the company's updated and EAG's base cases for the comparison with rituximab plus lenalidomide, mosunetuzumab was more expensive and less effective (see section\xa03.15). For the comparison with rituximab plus bendamustine, mosunetuzumab was not plausibly cost effective because both the company's updated and EAG's base cases were greater than £30,000 per QALY gained (see section\xa03.15). The estimates are also associated with considerable uncertainty. The committee concluded that mosunetuzumab did not represent a cost-effective use of NHS resources so could not be recommended for routine commissioning.\n\n# Managed access\n\n## Criteria for managed access not met\n\nHaving concluded that mosunetuzumab could not be recommended for routine use, the committee then considered if it could be recommended with managed access for treating relapsed or refractory follicular lymphoma after 2 or more systemic therapies. The committee discussed the criteria for a managed access recommendation by NICE (see NICE's webpage on managed access). It noted that the company had submitted a proposal for managed access. The company considered that additional data collection could resolve some of the uncertainties associated with its cost-effectiveness modelling. It noted that this would include further data collection from the GO29781 study cohort, which would continue until at least June 2024. It also proposed that if recommended with managed access, the company would do a prospective study collecting real-world evidence on mosunetuzumab. This would include progression-free survival data. The committee noted that longer-term data from the GO29781 study cohort would be helpful to inform the survival modelling and post-progression utilities. But, this would depend on how much data can be collected to resolve some uncertainties. Also, the timeframe for data collection with managed access may not be long enough to show an overall survival benefit, which is one of the key uncertainties (see section\xa03.12). The committee noted that the Systemic Anti-Cancer Dataset (SACT) would provide useful UK-based data to explore the generalisability of the GO29781 study cohort to patients in the UK. It noted that it was unlikely SACT data would sufficiently resolve the high uncertainty associated with the indirect treatment comparisons. It added that SACT would not provide any information on previous treatment lines. It would also be unlikely to provide any overall survival data with a long enough duration to reduce uncertainty by very much. The committee noted that additional data collection would not resolve any uncertainty about whether rituximab plus bendamustine is representative of other types of rituximab plus chemotherapy (R‑CHOP, R‑CVP). The company proposed a potential new source of evidence on comparator treatments. It considers all details related to this confidential so it cannot be described here. It suggested that this would allow more robust indirect treatment comparisons. Stakeholders commented on the draft guidance that clinical studies completing during 2023 to 2026 may provide additional data on standard care. The committee noted these may provide useful information on comparators, but any comparison with mosunetuzumab would still be unanchored. Also, when adjusting for prognostic factors and effective modifiers the effective sample size may be small. It also noted that comparator studies cannot form part of a managed access agreement. The company confirmed that there are no ongoing comparative trials to provide more robust, controlled evidence on mosunetuzumab monotherapy at third line or later for relapsed or refractory follicular lymphoma. The committee highlighted that, because the indirect treatment comparisons were highly uncertain, a trial comparing mosunetuzumab with standard care comparators is needed. The committee appreciated that managed access is designed to resolve uncertainties, but it did not think that it would sufficiently resolve the high level of uncertainty in this submission (see section\xa03.14). Also, it had not seen evidence that mosunetuzumab had plausible potential to be cost effective, because the company and EAG base cases were both greater than £30,000 per QALY gained (see section\xa03.15). The committee concluded that mosunetuzumab did not meet the criteria to be considered for a recommendation with managed access.\n\n# Other factors\n\n## Potential equality issue\n\nStakeholders commented on the draft guidance that not recommending mosunetuzumab may disadvantage older or frailer people with follicular lymphoma because they do not have access to the full range of immunochemotherapy treatment options. They also noted that these people have an even greater need for novel therapies earlier in the disease course. The committee acknowledged that some people have a greater unmet need for new treatment options. It also noted that its recommendation applies to all people within the marketing authorisation indication for mosunetuzumab (see section\xa02.1). The committee concluded that this is not an equality issue.\n\nNICE's advice about conditions with a high degree of severity did not apply.\n\n## Innovation\n\nThe committee noted that mosunetuzumab is the first of a new class of drugs in this setting with a unique mode of action. New treatment options would be welcomed by patients and clinicians (see section\xa03.1) in an area where there is no current standard care (see section\xa03.2). Clinical experts advised that mosunetuzumab can be used after multiple previous treatments and in chemotherapy-resistant relapsed or refractory follicular lymphoma. The committee considered whether mosunetuzumab was innovative. It recalled that the economic modelling of mosunetuzumab was highly uncertain. Because of this, it was possible that there were some benefits of mosunetuzumab not captured in the modelling. So, it concluded that mosunetuzumab may be innovative but there is a high level of uncertainty in the evidence presented. It would like to consider innovation together with the exploration of other uncertainties in the model, along with evidence of any uncaptured benefits.\n\n# Conclusion\n\nMosunetuzumab is not recommended for treating relapsed or refractory follicular lymphoma after 2 or more systemic therapies."}	https://www.nice.org.uk/guidance/ta892	Evidence-based recommendations on mosunetuzumab (Lunsumio) for relapsed or refractory follicular lymphoma in adults.
a34673264fe4f7f5dc98d8abf685bd2fd4222095	nice	Cardiovascular disease: risk assessment and reduction, including lipid modification	Cardiovascular disease: risk assessment and reduction, including lipid modification This guideline covers the assessment and care of adults who are at risk of or who have cardiovascular disease (CVD), such as heart disease and stroke. It aims to help healthcare professionals identify people who are at risk of cardiovascular problems including people with type 1 or type 2 diabetes, or chronic kidney disease. It describes the lifestyle changes people can make and how statins can be used to reduce their risk. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Identifying and assessing cardiovascular disease risk for people without established cardiovascular disease ## Identifying people for full formal risk assessment For the primary prevention of cardiovascular disease (CVD) in primary care, use a systematic strategy to identify people who are likely to be at high risk of CVD. Prioritise people based on an estimate of their CVD risk before doing a full formal risk assessment. Estimate their CVD risk using CVD risk factors already recorded in primary care electronic medical records. Review estimates of CVD risk on an ongoing basis for people over 40. Prioritise people for a full formal risk assessment if their estimated 10‑year risk of CVD is 10% or more. Discuss the process of risk assessment with the person identified as being at risk, including the option of declining any formal risk assessment. Do not use opportunistic assessment as the main strategy in primary care to identify CVD risk in unselected people. ## Full formal risk assessment Use the QRISK3 tool to calculate the estimated CVD risk within the next 10 years for people aged between 25 and 84 without CVD. Use the QRISK3 tool for people with type 2 diabetes aged between 25 and 84. Until electronic clinical systems in which QRISK2 is embedded are updated with QRISK3, it may be necessary to use QRISK2. When assessing risk for people taking corticosteroids or atypical antipsychotics or people with systemic lupus erythematosus, migraine, severe mental illness or erectile dysfunction, use QRISK3 (the online version of QRISK3, if necessary) because QRISK2 does not take these risk factors into account and so may underestimate the 10‑year CVD risk in these populations. Do not use a risk assessment tool for people who are at high risk of CVD, including people with: type 1 diabetes (see the section on primary prevention of CVD for people with type 1 diabetes) an estimated glomerular filtration rate less than 60 ml/min/1.73 m2 and/or albuminuria (see the section on primary and secondary prevention of CVD for people with chronic kidney disease) familial hypercholesterolaemia (see NICE's guideline on familial hypercholesterolaemia) or other inherited disorders of lipid metabolism. Recognise that CVD risk tools may underestimate risk in certain groups of people, including but not limited to: people treated for HIV people already taking medicines to treat CVD risk factors people who have recently stopped smoking people taking medicines that can cause dyslipidaemia such as immunosuppressant drugs people with severe mental illness people with autoimmune disorders, and other systemic inflammatory disorders. Consider people aged 85 or older to be at increased risk of CVD because of age alone, particularly people who smoke or have raised blood pressure. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on full formal risk assessment . Full details of the evidence and the committee's discussion are in evidence review A: CVD risk assessment tools: primary prevention. Loading. Please wait. ## Communication about risk assessment, lifestyle changes and treatment Follow the recommendations on communication in NICE's guidelines on patient experience in adult NHS services and shared decision making. Set aside adequate time during the consultation to provide information on risk assessment and to answer any questions. Arrange for further consultation if needed. Document the discussion relating to the consultation on risk assessment and the person's decision. Offer people information about their absolute risk of CVD and the absolute benefits and harms of any intervention over a 10‑year period. Consider using a lifetime risk tool such as QRISK3-lifetime to inform discussions on CVD risk and to motivate lifestyle changes, particularly for people with a 10‑year QRISK3 score less than 10%, and people under 40 who have CVD risk factors. To encourage the person to participate in reducing their CVD risk: find out what, if anything, the person has already been told about their CVD risk and how they feel about it explore the person's beliefs about what determines future health (this may affect their attitude to changing risk) assess their readiness to make changes to their lifestyle (diet, physical activity, smoking and alcohol consumption), to undergo investigations and to take long-term medication assess their confidence to make changes to their lifestyle, undergo investigations and take medication inform them of potential future management options based on current evidence and best practice involve them in developing a shared management plan check that they have understood what has been discussed. If the person's CVD risk is at a level where treatment is recommended but they decline the offer of treatment, advise them that their CVD risk should be reassessed in the future. Record their choice in their medical records. For a short explanation of why the committee made the 2023 recommendation and how it might affect practice, see the rationale and impact section on communication about risk assessment, lifestyle changes and treatment . Full details of the evidence and the committee's discussion are in evidence review A: CVD risk assessment tools: primary prevention. Loading. Please wait. # Aspirin for primary prevention of cardiovascular disease Do not routinely offer aspirin for primary prevention of CVD. For guidance on using aspirin to prevent venous thromboembolism in over 16s in hospital, see NICE's guideline on venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NICE's surveillance team reviewed the evidence about aspirin for the primary prevention of CVD. Based on the review, NICE decided to add a do not routinely offer recommendation about this. For full details see the January 2023 exceptional surveillance report. # Lifestyle changes for the primary and secondary prevention of cardiovascular disease ## Behaviour change Advise and support people at high risk of or with CVD to achieve a healthy lifestyle in line with NICE's guideline on behaviour change: general approaches. ## Healthy eating For advice on healthy eating, see the NHS eat well guide. ## Cardioprotective diet Advise people at high risk of or with CVD to eat a diet in which total fat intake is 30% or less of total energy intake, saturated fats are 7% or less of total energy intake, and where possible saturated fats are replaced by mono‑unsaturated and polyunsaturated fats. Advise people at high risk of or with CVD to: reduce their saturated fat intake increase their mono-unsaturated fat intake with olive oil, rapeseed oil or spreads based on these oils and to use them in food preparation. Take account of a person's individual circumstances – for example, drug therapy, comorbidities and other lifestyle changes when giving dietary advice. For a short explanation of why the committee made the 2023 recommendation and how it might affect practice, see the rationale and impact section on cardioprotective diet . Full details of the evidence and the committee's discussion are in evidence review B: dietary cholesterol strategies. Loading. Please wait. ## Physical activity Advise people at high risk of or with CVD to do aerobic and muscle-strengthening activities in line with the UK Chief Medical Officers' physical activity guidelines. Encourage people who are unable to perform moderate intensity physical activity because of comorbidity, medical conditions or personal circumstances to exercise at their maximum safe capacity. Advice about physical activity should take into account the person's needs, preferences and circumstances. Agree goals and provide the person with written information about the benefits of activity and local opportunities to be active, in line with recommendation 2 of NICE's guideline on physical activity: brief advice for adults. Follow recommendation 8 of NICE's guideline on walking and cycling, and recommendation 2 of NICE's guideline on exercise referral schemes. ## Weight management Offer people at high risk of or with CVD who are overweight or obese appropriate interventions in line with NICE's guideline on obesity: identification, assessment and management. ## Alcohol consumption For advice on how to keep the health risks from drinking alcohol to a low level, see the UK Chief Medical Officer's alcohol consumption guidelines. ## Smoking cessation Advise and support all people who smoke to stop, in line with the recommendations on treating tobacco dependence in NICE's guideline on tobacco. ## Plant stanols and sterols Do not advise any of the following to take plant stanols or sterols to prevent CVD: people being treated for primary prevention people being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. # Lipid modification therapy for the primary and secondary prevention of cardiovascular disease Be aware that when deciding on lipid modification therapy to prevent CVD, drugs are preferred for which there is evidence in clinical trials of a beneficial effect on CVD morbidity and mortality. ## Initial lipid measurement and referral for specialist review Measure both total blood cholesterol and high-density lipoprotein (HDL) cholesterol to achieve the best estimate of CVD risk. Before starting lipid modification therapy for the primary prevention of CVD, take at least 1 blood sample to provide a full lipid profile. Measure total cholesterol, HDL cholesterol, non-HDL cholesterol and triglyceride concentrations. A fasting sample is not needed. Use the clinical findings, lipid profile and family history to judge the likelihood of a familial lipid disorder, rather than using strict lipid cut off values alone. Exclude possible common secondary causes of dyslipidaemia (such as excess alcohol intake, uncontrolled diabetes, hypothyroidism, liver disease and nephrotic syndrome) before referring for specialist review. Use the recommendations in NICE's guideline on familial hypercholesterolaemia to determine whether to suspect, and how to treat, familial hypercholesterolaemia. Arrange for specialist assessment of people with a total blood cholesterol concentration over 9.0 mmol/litre or a non-HDL cholesterol concentration over 7.5 mmol/litre even in the absence of a first-degree family history of premature coronary heart disease. Refer for urgent specialist review if a person has a triglyceride concentration over 20 mmol/litre that is not a result of excess alcohol intake or poor glycaemic control. In people with a triglyceride concentration between 10 and 20 mmol/litre: repeat the triglyceride measurement with a fasting test (after an interval of 5 days, but within 2 weeks) and review for potential secondary causes of hyperlipidaemia and seek specialist advice if the triglyceride concentration remains over 10 mmol/litre. In people with a triglyceride concentration between 4.5 and 9.9 mmol/litre: be aware that the CVD risk may be underestimated by risk assessment tools and -ptimise the management of other CVD risk factors present and seek specialist advice if non-HDL cholesterol concentration is over 7.5 mmol/litre. ## Statins for preventing cardiovascular disease There is a NICE patient decision aid to support discussions about statin therapy to reduce the risk of heart disease and stroke. Decide whether to start statin therapy after an informed discussion between the clinician and the person about the risks and benefits of statin treatment, taking into account additional factors such as potential benefits from lifestyle changes, informed patient preference, comorbidities, polypharmacy, general frailty and life expectancy. (See also NICE's guideline on multimorbidity.) Before starting statin treatment perform baseline blood tests and clinical assessment, and treat comorbidities and secondary causes of dyslipidaemia. Include all of the following in the assessment: smoking status alcohol consumption blood pressure (see NICE's guideline on hypertension) BMI or other measure of obesity (see NICE's guideline on obesity: identification, assessment and management) total cholesterol, non‑HDL cholesterol, HDL cholesterol and triglycerides diabetes status renal function transaminase level (alanine aminotransferase or aspartate aminotransferase) thyroid‑stimulating hormone in people with symptoms of underactive or overactive thyroid. Before offering statin treatment for primary prevention, discuss the benefits of lifestyle changes and optimise the management of all other modifiable CVD risk factors if possible. Recognise that people may need support to change their lifestyle. To help them do this, refer them to programmes such as exercise referral schemes or weight management services. (See NICE's guidelines on behaviour change: individual approaches, physical activity: exercise referral schemes and weight management: lifestyle services for overweight or obese adults.) Offer people the opportunity to have their risk of CVD assessed again after they have tried to change their lifestyle. If lifestyle change is ineffective or inappropriate offer statin treatment. Offer atorvastatin 20 mg for the primary prevention of CVD to people who have a 10‑year QRISK3 score of 10% or more. Do not rule out treatment with atorvastatin 20 mg for the primary prevention of CVD just because the person's 10‑year QRISK3 score is less than 10% if they have an informed preference for taking a statin or there is concern that risk may be underestimated. For people aged 85 and older consider treatment with atorvastatin 20 mg. Be aware of factors that may make treatment inappropriate (see recommendation 1.4.11). See also the section on follow-up of people started on statin treatment. Consider statin treatment for the primary prevention of CVD for adults with type 1 diabetes. Offer statin treatment for the primary prevention of CVD to adults with type 1 diabetes who: are older than 40 years or have had diabetes for more than 10 years or have established nephropathy or have other CVD risk factors. When starting treatment with a statin for adults with type 1 diabetes, use atorvastatin 20 mg. See also the section on follow-up of people started on statin treatment. Start statin treatment in people with CVD with atorvastatin 80 mg. Use a lower dose of atorvastatin if any of the following apply: potential drug interactions high risk of adverse effects patient preference. In May 2023, this was an off-label use of atorvastatin. See NICE's information on prescribing medicines. Do not delay statin treatment for secondary prevention of CVD but consider lifestyle changes at the same time if appropriate. If a person has acute coronary syndrome do not delay statin treatment. Take a lipid sample on admission and about 3 months after the start of treatment. See also the section on follow-up of people started on statin treatment. Offer atorvastatin 20 mg for the primary or secondary prevention of CVD to people with CKD. Increase the dose if a greater than 40% reduction in non‑HDL cholesterol is not achieved (see recommendation 1.4.28) and eGFR is 30 ml/min/1.73 m2 or more. Agree the use of higher doses with a renal specialist if eGFR is less than 30 ml/min/1.73 m2. See also the section on follow-up of people started on statin treatment.See NICE's guideline on chronic kidney disease for CKD classification. People on renal replacement therapy are outside the scope of this guideline. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on statins for preventing CVD . Full details of the evidence and the committee's discussion are in evidence review C: statins: efficacy and adverse effects. Loading. Please wait. ## Follow-up of people started on statin treatment Measure total cholesterol, HDL cholesterol and non‑HDL cholesterol in all people who have been started on high-intensity statin treatment (both primary and secondary prevention, including atorvastatin 20 mg for primary prevention) at 3 months of treatment. Aim for a greater than 40% reduction in non‑HDL cholesterol. If a greater than 40% reduction in non‑HDL cholesterol is not achieved: discuss adherence and timing of dose -ptimise adherence to diet and lifestyle measures consider increasing the dose if started on less than atorvastatin 80 mg and the person is judged to be at higher risk because of comorbidities, risk score or using clinical judgement. A partial update of this guideline to identify a specific treatment target for secondary prevention of CVD is in progress. Further information can be found on the NICE webpage for the next update of this guideline. Provide annual medication reviews for people taking statins. Use these reviews to discuss medicines adherence and lifestyle changes and address CVD risk factors. Consider an annual non‑fasting blood test for non‑HDL cholesterol to inform the discussion. Discuss with people who are stable on a low‑ or medium‑intensity statin the likely benefits and potential risks of changing to a high-intensity statin when they have a medication review and agree with the person whether a change is needed. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up of people started on statin treatment . Full details of the evidence and the committee's discussion are in evidence review C: statins: efficacy and adverse effects. Loading. Please wait. ## Advice and monitoring for adverse effects Advise people who are being treated with a statin: that other drugs, some foods (for example, grapefruit juice) and some supplements may interfere with statins and to always consult the patient information leaflet, a pharmacist or prescriber for advice when starting other drugs or thinking about taking supplements. Remind the person to restart the statin if they stopped taking it because of drug interactions or to treat intercurrent illnesses. Before offering a statin, ask the person if they have had persistent generalised unexplained muscle symptoms (pain, tenderness or weakness), whether associated or not with previous lipid‑lowering therapy. If they have, measure creatine kinase levels. If creatine kinase levels are: more than 5 times the upper limit of normal, re‑measure creatine kinase after 7 days; if creatine kinase levels are still 5 times the upper limit of normal, do not start statin treatment (see the section on intolerance of statins, and for other treatment options, see the NICE technology appraisal guidance on our topic page on lipid disorders) raised but less than 5 times the upper limit of normal, start statin treatment at a lower dose. Advise people who are being offered a statin that the risk of muscle pain, tenderness or weakness associated with statin use is small and the rate of severe muscle adverse effects (rhabdomyolysis) because of statins is extremely low. Advise people who are being treated with a statin to seek medical advice if they develop unexplained muscle symptoms (pain, tenderness or weakness). If this occurs, measure creatine kinase. If people report muscle pain, tenderness or weakness while taking a statin and have a creatine kinase level less than 5 times the upper limit of normal, reassure them that their symptoms are unlikely to be due to the statin and explore other possible causes. Do not measure creatine kinase levels in asymptomatic people who are being treated with a statin. Measure liver transaminase within 3 months of starting treatment (as well as at baseline, see recommendation 1.4.12) and at 12 months, but not again unless clinically indicated. Do not routinely exclude from statin therapy people who have liver transaminase levels that are raised but are less than 3 times the upper limit of normal. Do not stop statins because of an increase in blood glucose level or HbA1c. (See the recommendations on assessing for risk of diabetes mellitus in NICE's guideline on preventing type 2 diabetes.) Be aware that statins are contraindicated in pregnancy because of the risk to the unborn child of exposure to statins. Explain that: statins should be stopped if pregnancy is a possibility statins should be stopped 3 months before attempting to conceive statins should not be restarted until breastfeeding is finished. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on advice and monitoring for adverse effects . Full details of the evidence and the committee's discussion are in evidence review C: statins: efficacy and adverse effects. Loading. Please wait. ## Intolerance of statins If a person is not able to tolerate a high-intensity statin aim to treat with the maximum tolerated dose. Tell the person that any statin at any dose reduces CVD risk. If someone reports adverse effects when taking a high-intensity statin discuss the following possible strategies with them: stopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin changing to a different statin in the same intensity group (rosuvastatin if already receiving atorvastatin) reducing the dose within the same intensity group changing the statin to a lower intensity group. Seek specialist advice about options for treating people at high risk of CVD such as those with CKD, type 1 diabetes, type 2 diabetes or genetic dyslipidaemias, and those with CVD who are intolerant to 3 different statins. Seek advice by telephone, virtual clinic or referral. ## Adherence to statin therapy Do not offer coenzyme Q10 or vitamin D to increase adherence to statin treatment. ## Fibrates for preventing cardiovascular disease Do not routinely offer fibrates to prevent CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. For people with familial hypercholesterolaemia, follow the recommendations on drug treatment in NICE's guideline on familial hypercholesterolaemia. ## Nicotinic acid for preventing cardiovascular disease Do not offer nicotinic acid (niacin) to prevent CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. ## Bile acid sequestrants (anion exchange resins) for preventing cardiovascular disease Do not offer a bile acid sequestrant (anion exchange resin) to prevent CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. For people with familial hypercholesterolaemia, follow the recommendations on drug treatment in NICE's guideline on familial hypercholesterolaemia. ## Omega 3 fatty acid compounds for preventing cardiovascular disease Do not offer omega 3 fatty acid compounds to prevent CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes.Icosapent ethyl is an exception to this if used as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides. Tell people that there is no evidence that omega 3 fatty acid compounds help to prevent CVD, except use of icosapent ethyl as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy. ## Combination therapy for preventing cardiovascular disease To prevent CVD, do not offer the combination of a statin with: a bile acid sequestrant (anion exchange resin), a fibrate or nicotinic acid, or an omega 3 fatty acid compound, except icosapent ethyl as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy. For people with familial hypercholesterolaemia, follow the recommendations on drug treatment in NICE's guideline on familial hypercholesterolaemia. ## Other treatment options For other treatment options, see the NICE technology appraisal guidance on our topic page on lipid disorders. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## High-intensity statin The following doses for statins are high intensity, based on the percentage reduction in low-density lipoprotein (LDL) cholesterol they can produce: atorvastatin: 20 mg to 80 mg rosuvastatin: 10 mg to 40 mg ## Severe mental illness A diagnosis of schizophrenia, bipolar disorder or other psychoses. (In line with the criteria for severe mental health conditions used in the NHS annual health check for people with severe mental health conditions.)# Recommendations for research The guideline committee has made the following key recommendations for research. # Simplifying risk assessment What is the effectiveness of age alone and other routinely available risk factors compared with the formal structured multifactorial risk assessment to identify people at high risk of developing CVD? # Statin therapy for older people What is the effectiveness of statin therapy in older people? For a short explanation of why the committee made this recommendation for research, see the rationale section on statins for preventing CVD . Full details of the evidence and the committee's discussion are in evidence review C: statins: efficacy and adverse effects. Loading. Please wait. # Lipid modification therapy for people with type 1 diabetes What is the effectiveness of statins and/or other low-density lipoprotein (LDL) cholesterol‑lowering treatment in people with type 1 diabetes? For a short explanation of why the committee made this recommendation for research, see the rationale section on statins for preventing CVD . Full details of the evidence and the committee's discussion are in evidence review C: statins: efficacy and adverse effects. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Full formal risk assessment Recommendations 1.1.7 to 1.1.11 ## Why the committee made the recommendations The committee agreed that the evidence suggested QRISK3 performed best among tools evaluated in a UK population to assess the risk of a person without established CVD having a CVD event within the next 10 years. They agreed that no tool is very good at accurately discriminating between who will and who will not have a CVD event, but that tools are useful for guiding decisions about interventions to prevent CVD based on estimated risk. A small amount of evidence suggested that the additional fields included in QRISK3 (such as severe mental illness, regular corticosteroid use and atypical antipsychotic use) enabled the tool to perform better than QRISK2 at predicting CVD events for people with these risk factors. Use of QRISK3 should, therefore, result in more people within these groups being appropriately considered for risk reduction approaches including statin treatment. It was noted that the group of people with severe mental illness used to develop and validate QRISK3 included a high proportion of people with severe and moderate depression. This is reflected in the definition of severe mental illness in QRISK3 but does not reflect the definition used in electronic clinical systems in primary care. The committee agreed, informed by their clinical experience and expert opinion, that people with moderate to severe depression are not considered to have as great an increased risk of CVD as people with schizophrenia, bipolar disorder and other psychoses. By using data that grouped these conditions together, QRISK3 may underestimate CVD risk for people with schizophrenia, bipolar disorder and other psychoses. Despite this the committee agreed to recommend use of the tool for people with severe mental illness (however defined), but clinical judgement should inform interpretation. The committee was aware that the NHS Health Check best practice guidance states that gender should be recorded as reported by the individual. If the individual discloses gender reassignment, they should be provided with CVD risk calculations based on both genders and advised to discuss with their GP which calculation is most appropriate for them as an individual. They agreed that healthcare professionals are expected to follow this guidance when undertaking formal risk assessments. An age range is given for QRISK3 because it is only intended for people aged between 25 and 84 years (inclusive). The committee agreed that the use of a risk tool remains appropriate in people with type 2 diabetes to support shared decision making. They agreed, based on the evidence, that QRISK3 performed better than QRISK2 for the population as whole and so should be used for people with type 2 diabetes. The committee agreed to remove a 2014 recommendation to complete as many fields of the risk assessment tool as possible because QRISK3 explains that the tool can overestimate risk if fields are left blank. They also noted that BMI, ethnicity and family history of CVD should be recorded in people's medical records, so the committee agreed that the 2014 recommendation on recording this information was no longer needed. Evidence on the performance of QRISK3 was not considered sufficient to suggest changing the 2014 recommendations against using a CVD risk tool in people with type 1 diabetes or CKD as it had not been validated in a separate population from that in which the tool was developed. The committee agreed these groups should be considered high risk, as should people with familial hypercholesterolaemia. Based on their clinical experience, the committee identified a list of factors for which all CVD risk tools underestimate risk. They highlighted the importance of using clinical judgement to interpret risk scores. As risk scores are used to guide decisions about interventions to prevent CVD, the committee agreed it was particularly important to ensure people are not incorrectly considered to be at low risk. The 2014 recommendation to consider people aged 85 and older to be at increased risk of CVD was retained as the committee agreed with this statement and there are still no tools for this age group. The committee highlighted it is important that this group be considered for interventions to prevent CVD even though a formal risk assessment would not be carried out. The evidence for lifetime risk tools was not considered sufficient to recommend their use instead of 10‑year risk tools. However, the committee agreed they can have value in communication of risk. See the rationale for communication about risk assessment, lifestyle changes and treatment . Loading. Please wait. ## How the recommendations might affect practice QRISK2 is currently integrated into electronic clinical systems so 10‑year CVD risk assessments can be generated using data already available in a person's electronic records. At the time of development, the committee was aware of ongoing discussions about continuation of the inclusion of QRISK in electronic clinical systems. Using QRISK3 instead of QRISK2 will require clinical systems to be updated by software developers for the impact on practice to be minimised. Public Health England issued guidance in August 2021 on using QRISK3 in NHS health checks and how to deal with the transition period (responsibility for the NHS Health Check programme has transferred to the Office for Health Improvement and Disparities, but the guidance produced by PHE remains current). QRISK3 requires some additional clinical information that was not required for QRISK2. However, if integrated into electronic clinical systems, QRISK3 is not likely to require additional resources over QRISK2. There may be some implementation costs as healthcare professionals become familiar with the additional information included in QRISK3 and in managing the transition period. Return to recommendations # Communication about risk assessment, lifestyle changes and treatment Recommendation 1.1.16 ## Why the committee made the recommendation The committee agreed that the evidence did not support using lifetime CVD risk assessment tools to guide decisions on the need for statin treatment, because their accuracy could not be reliably assessed. However, the committee noted that the usefulness of lifetime risk tools is primarily in communicating risk. They agreed by consensus that lifetime risk tools should be considered to help inform discussions about risk and motivate lifestyle changes. The committee highlighted that these tools may underestimate the ongoing benefit of lipid lowering treatments as they do not predict risk reduction from taking medicines, and noted this should be considered when interpreting the results. They agreed lifetime risk calculation would not be necessary for everyone, but it may be particularly useful for people with a QRISK3 score less than 10% or under 40s who have CVD risk factors. ## How the recommendation might affect practice Lifetime risk tools are not routinely used in current clinical practice. The committee noted that there may be resource implications for calculating lifetime risk score estimates because lifetime risk tools are not currently embedded into electronic clinical systems and so scores are not automatically generated. There may also be implementation costs related to educating healthcare professionals about lifetime risk calculators. It is not clear if use of lifetime risk tools will result in longer consultations. The committee agreed that the online calculators for lifetime risk tools such as QRISK-lifetime were easy to complete and provided some interpretation of the risk scores to aid discussions, but acknowledged that lifetime risk assessment would not be done for everyone. The committee believe that using lifetime risk tools may have a long-term benefit in encouraging people to participate in lifestyle changes or engage in treatment, if appropriate. Given this, any additional time costs were considered likely to improve management of CVD risk and so reduce future CVD events. Return to recommendation # Aspirin for primary prevention of cardiovascular disease Recommendation 1.2.1 ## Why NICE made the recommendation NICE's surveillance team reviewed the evidence about aspirin for the primary prevention of CVD. Based on the review, NICE decided to add a do not routinely offer recommendation about this. For full details see the January 2023 exceptional surveillance report. Return to recommendation # Cardioprotective diet Recommendation 1.3.2 ## Why the committee made the recommendation There was no available evidence comparing the effectiveness of dietary cholesterol strategies with normal diets for adults with and without CVD, so the committee updated the 2014 recommendation based on their clinical experience and expert opinion. They removed the reference to restricting dietary cholesterol intake. Only evidence on dietary cholesterol was in scope for review and therefore the guidance on total fat intake and proportion of saturated fat versus unsaturated fat was not changed. ## How the recommendation might affect practice The committee agreed healthcare professionals already better understand the lack of a relationship between dietary cholesterol and CVD risk, so the new recommendation reflects current practice. The committee agreed there should be no change in practice or resource impact to the NHS because of this updated recommendation. Return to recommendation # Statins for preventing cardiovascular disease Recommendations 1.4.11 to 1.4.28 ## Why the committee made the recommendations Evidence on both the effectiveness and adverse effects of statins showed high-intensity statins are clinically effective and cost-effective compared to no statins, low-intensity statins, or medium-intensity statins for preventing CVD in people with or without CVD. Most of the 2014 recommendations were retained, including recommendations on: how to discuss statin therapy with people and decide to start treatment the tests and assessments that should happen before treatment starts discussing lifestyle changes secondary prevention. The recommendations state which high-intensity statin should be used initially, so the committee agreed that the recommendation to choose a high-intensity statin of low acquisition cost is no longer needed. The definition of high intensity statins was updated to remove simvastatin 80 mg. This is no longer used in current practice because of the risk of myopathy and muscle symptoms. Evidence showed that statins are cost effective for people with 10‑year CVD risk scores less than 10%. The committee agreed that if more people took statins there would be a greater reduction in CVD events. However, they also recognised that practical considerations needed to be taken into account. They agreed that risk scores are an important aid to shared decision making on statins. National audit data suggests that 56% of people with a QRISK score of 20% or more take statins, compared with less than 50% for people with scores between 10% and 20%. Therefore, the committee consensus was that an even smaller proportion of people with scores less than 10% may choose to take statins. The committee agreed that focusing on increasing uptake among people with the most potential to benefit would have more impact than lowering the statin treatment threshold. The 10% 10‑year QRISK score was therefore retained as the threshold for offering statins. Although QRISK3 is specified in the recommendations, it is acknowledged that QRISK2 may be used in some circumstances until QRISK3 is embedded in electronic clinical systems (see the panel below recommendation 1.1.8 for details). The 10% threshold applies whether QRISK2 or 3 is used. Despite this, the committee agreed that a more person-centred approach should be adopted and recommended atorvastatin 20 mg as an option for people who want to take statins, irrespective of their QRISK3 score, or where clinical judgement suggests the person may be at high risk of CVD (for example, if the person has CVD risk factors not covered by QRISK3). The committee agreed to retain 20 mg as the recommended starting dose for all people starting atorvastatin for primary prevention of CVD. Although there was committee consensus that higher doses have a greater effect, they agreed that starting at the lowest effective dose was likely to be preferable to patients, but that up-titration of the dose should be considered as appropriate, following recommendations in the section on follow-up of people started on statin treatment. The committee agreed to retain the following recommendations for research because there is still a lack of direct evidence in these areas: statin therapy for older people lipid modification therapy for people with type 1 diabetes. ## How the recommendations might affect practice Most recommendations about statin treatment have been retained from the 2014 update of the guideline and so should not require a change in practice. National audit data suggests that less than half of people with a QRISK score of 10% or more are on lipid-lowering therapy. It is unclear if people are not being offered statins or if they are declining or stopping treatment. Increased uptake of statins would result in higher medication and monitoring costs to the NHS. It would also contribute to workload burden in primary care GP practices and pharmacies and laboratories processing monitoring tests. The committee agreed this increase was necessary for downstream improvements in population health, and would be offset by savings due to a reduction in CVD events. The recommendation to consider starting atorvastatin 20 mg for people with QRISK3 scores less than 10% is a change in practice. The impact on medication and monitoring costs and workload will depend on the level of uptake. This will be offset by savings due to a reduction in CVD events and improvements in population health. Return to recommendations # Follow-up of people started on statin treatment Recommendations 1.4.29 to 1.4.33 ## Why the committee made the recommendations The committee reviewed the 2014 consensus recommendations on follow-up and agreed they were still valid and should be retained. ## How the recommendations might affect practice Although these recommendations remain unchanged from 2014 so should reflect current practice, the committee acknowledged that any increase in statin use would result in an increase in follow-up activity, including cholesterol testing at 3 months of treatment, and in the number of annual medication reviews. This was considered when amending the recommendations on statins. For further details see the impact section for the recommendations on statins . Return to recommendations Loading. Please wait. # Advice and monitoring for adverse effects Recommendations 1.4.34 to 1.4.45 ## Why the committee made the recommendations New evidence on adverse effects while on statins supported the 2014 recommendations. Evidence on the risk of muscle pain and rhabdomyolysis with statin use demonstrated a real effect, but the large body of evidence showed this was a very small increased risk when compared with similar populations not on statins; that is, when using high-intensity statins approximately 16% of people reported experiencing muscle pain, but of these cases only around 1 in 12 were likely to be due to the statin. The committee agreed to strengthen the recommendation to reassure people that the risk of these adverse effects occurring is low. The evidence supported the other 2014 recommendations on advice and monitoring for adverse effects and so they were retained. ## How the recommendations might affect practice The recommendations have been strengthened to emphasise the low risk of experiencing severe muscle adverse effects because of statin treatment. They are not expected to have an impact on resource use as discussions on adverse effects are already an important part of current practice in prescribing and monitoring statins. Return to recommendations# Context Cardiovascular disease (CVD) is the leading cause of death worldwide, accounting for almost 18 million deaths each year (over 30% of all global deaths). Around 7 million people in the UK have CVD. Over 70 million prescriptions for statins are dispensed in England each year, costing the NHS around £100 million. The total healthcare cost of CVD in England is estimated to be £7.4 billion. Despite the weight of conclusive research and consistent national and international guidelines, many people at significant risk of CVD do not receive lipid-lowering therapies, or they receive inadequate treatment. Anxieties about the safety of statins may mean healthcare professionals are reticent about offering them, and people are reluctant to start or continue statin treatment. Depending on statin intensity, 30% to 50% of people stop taking statins within 6 years. Over the past 5 years, more evidence has become available on the benefits and adverse effects of statins. Ways to estimate and explain CVD risk have also improved, and healthcare professionals now have more varied and accurate approaches available for individualised risk assessment. This can empower patients and professionals to discuss interventions to reduce short- and long-term CVD risk. Understanding of the relationship between dietary cholesterol and lipid levels has also evolved suggesting recommendations in the 2014 guideline required updating. Increasing awareness of elevated lipids (including cholesterol) as a risk factor for CVD, so that appropriate intervention can be provided, is critical to the delivery of the NHS Long Term Plan. By 2029, the ambition in England is for at least 45% of people aged 40 to 74 who are at significant risk of developing CVD to be on appropriate lipid-lowering therapy. Local achievement of this ambition can be monitored using the CVDPREVENT audit.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Identifying and assessing cardiovascular disease risk for people without established cardiovascular disease\n\n## Identifying people for full formal risk assessment\n\nFor the primary prevention of cardiovascular disease (CVD) in primary care, use a systematic strategy to identify people who are likely to be at high risk of CVD. [2008, amended 2014]\n\nPrioritise people based on an estimate of their CVD risk before doing a full formal risk assessment. Estimate their CVD risk using CVD risk factors already recorded in primary care electronic medical records. \n\nReview estimates of CVD risk on an ongoing basis for people over 40. \n\nPrioritise people for a full formal risk assessment if their estimated 10‑year risk of CVD is 10% or more. [2008, amended 2014]\n\nDiscuss the process of risk assessment with the person identified as being at risk, including the option of declining any formal risk assessment. \n\nDo not use opportunistic assessment as the main strategy in primary care to identify CVD risk in unselected people. \n\n## Full formal risk assessment\n\nUse the QRISK3 tool to calculate the estimated CVD risk within the next 10\xa0years for people aged between 25 and 84 without CVD. \n\nUse the QRISK3 tool for people with type 2 diabetes aged between 25 and 84. \n\nUntil electronic clinical systems in which QRISK2 is embedded are updated with QRISK3, it may be necessary to use QRISK2. When assessing risk for people taking corticosteroids or atypical antipsychotics or people with systemic lupus erythematosus, migraine, severe mental illness or erectile dysfunction, use QRISK3 (the online version of QRISK3, if necessary) because QRISK2 does not take these risk factors into account and so may underestimate the 10‑year CVD risk in these populations.\n\nDo not use a risk assessment tool for people who are at high risk of CVD, including people with:\n\ntype 1 diabetes (see the section on primary prevention of CVD for people with type 1 diabetes)\n\nan estimated glomerular filtration rate less than 60 ml/min/1.73 m2 and/or albuminuria (see the section on primary and secondary prevention of CVD for people with chronic kidney disease)\n\nfamilial hypercholesterolaemia (see NICE's guideline on familial hypercholesterolaemia) or other inherited disorders of lipid metabolism. \n\nRecognise that CVD risk tools may underestimate risk in certain groups of people, including but not limited to:\n\npeople treated for HIV\n\npeople already taking medicines to treat CVD risk factors\n\npeople who have recently stopped smoking\n\npeople taking medicines that can cause dyslipidaemia such as immunosuppressant drugs\n\npeople with severe mental illness\n\npeople with autoimmune disorders, and other systemic inflammatory disorders. \n\nConsider people aged 85 or older to be at increased risk of CVD because of age alone, particularly people who smoke or have raised blood pressure. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on full formal risk assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: CVD risk assessment tools: primary prevention.\n\nLoading. Please wait.\n\n## Communication about risk assessment, lifestyle changes and treatment\n\nFollow the recommendations on communication in NICE's guidelines on patient experience in adult NHS services and shared decision making. \n\nSet aside adequate time during the consultation to provide information on risk assessment and to answer any questions. Arrange for further consultation if needed. [2008, amended 2023]\n\nDocument the discussion relating to the consultation on risk assessment and the person's decision. \n\nOffer people information about their absolute risk of CVD and the absolute benefits and harms of any intervention over a 10‑year period. \n\nConsider using a lifetime risk tool such as QRISK3-lifetime to inform discussions on CVD risk and to motivate lifestyle changes, particularly for people with a 10‑year QRISK3 score less than 10%, and people under 40 who have CVD risk factors. \n\nTo encourage the person to participate in reducing their CVD risk:\n\nfind out what, if anything, the person has already been told about their CVD risk and how they feel about it\n\nexplore the person's beliefs about what determines future health (this may affect their attitude to changing risk)\n\nassess their readiness to make changes to their lifestyle (diet, physical activity, smoking and alcohol consumption), to undergo investigations and to take long-term medication\n\nassess their confidence to make changes to their lifestyle, undergo investigations and take medication\n\ninform them of potential future management options based on current evidence and best practice\n\ninvolve them in developing a shared management plan\n\ncheck that they have understood what has been discussed. [2008, amended 2014]\n\nIf the person's CVD risk is at a level where treatment is recommended but they decline the offer of treatment, advise them that their CVD risk should be reassessed in the future. Record their choice in their medical records. [2008, amended 2014]\n\nFor a short explanation of why the committee made the 2023 recommendation and how it might affect practice, see the rationale and impact section on communication about risk assessment, lifestyle changes and treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: CVD risk assessment tools: primary prevention.\n\nLoading. Please wait.\n\n# Aspirin for primary prevention of cardiovascular disease\n\nDo not routinely offer aspirin for primary prevention of CVD. \n\nFor guidance on using aspirin to prevent venous thromboembolism in over 16s in hospital, see NICE's guideline on venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism.\n\nNICE's surveillance team reviewed the evidence about aspirin for the primary prevention of CVD. Based on the review, NICE decided to add a do not routinely offer recommendation about this. For full details see the January 2023 exceptional surveillance report.\n\n# Lifestyle changes for the primary and secondary prevention of cardiovascular disease\n\n## Behaviour change\n\nAdvise and support people at high risk of or with CVD to achieve a healthy lifestyle in line with NICE's guideline on behaviour change: general approaches. [2014, amended 2023]\n\n## Healthy eating\n\nFor advice on healthy eating, see the NHS eat well guide.\n\n## Cardioprotective diet\n\nAdvise people at high risk of or with CVD to eat a diet in which total fat intake is 30% or less of total energy intake, saturated fats are 7% or less of total energy intake, and where possible saturated fats are replaced by mono‑unsaturated and polyunsaturated fats. \n\nAdvise people at high risk of or with CVD to:\n\nreduce their saturated fat intake\n\nincrease their mono-unsaturated fat intake with olive oil, rapeseed oil or spreads based on these oils and to use them in food preparation. \n\nTake account of a person's individual circumstances – for example, drug therapy, comorbidities and other lifestyle changes when giving dietary advice. \n\nFor a short explanation of why the committee made the 2023 recommendation and how it might affect practice, see the rationale and impact section on cardioprotective diet\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: dietary cholesterol strategies.\n\nLoading. Please wait.\n\n## Physical activity\n\nAdvise people at high risk of or with CVD to do aerobic and muscle-strengthening activities in line with the UK Chief Medical Officers' physical activity guidelines. [2008, amended 2014]\n\nEncourage people who are unable to perform moderate intensity physical activity because of comorbidity, medical conditions or personal circumstances to exercise at their maximum safe capacity. [2008, amended 2014]\n\nAdvice about physical activity should take into account the person's needs, preferences and circumstances. Agree goals and provide the person with written information about the benefits of activity and local opportunities to be active, in line with recommendation 2 of NICE's guideline on physical activity: brief advice for adults. \n\nFollow recommendation 8 of NICE's guideline on walking and cycling, and recommendation 2 of NICE's guideline on exercise referral schemes. \n\n## Weight management\n\nOffer people at high risk of or with CVD who are overweight or obese appropriate interventions in line with NICE's guideline on obesity: identification, assessment and management. \n\n## Alcohol consumption\n\nFor advice on how to keep the health risks from drinking alcohol to a low level, see the UK Chief Medical Officer's alcohol consumption guidelines. \n\n## Smoking cessation\n\nAdvise and support all people who smoke to stop, in line with the recommendations on treating tobacco dependence in NICE's guideline on tobacco. \n\n## Plant stanols and sterols\n\nDo not advise any of the following to take plant stanols or sterols to prevent CVD:\n\npeople being treated for primary prevention\n\npeople being treated for secondary prevention\n\npeople with CKD\n\npeople with type 1 diabetes\n\npeople with type 2 diabetes. \n\n# Lipid modification therapy for the primary and secondary prevention of cardiovascular disease\n\nBe aware that when deciding on lipid modification therapy to prevent CVD, drugs are preferred for which there is evidence in clinical trials of a beneficial effect on CVD morbidity and mortality. \n\n## Initial lipid measurement and referral for specialist review\n\nMeasure both total blood cholesterol and high-density lipoprotein (HDL) cholesterol to achieve the best estimate of CVD risk. \n\nBefore starting lipid modification therapy for the primary prevention of CVD, take at least 1 blood sample to provide a full lipid profile. Measure total cholesterol, HDL cholesterol, non-HDL cholesterol and triglyceride concentrations. A fasting sample is not needed. \n\nUse the clinical findings, lipid profile and family history to judge the likelihood of a familial lipid disorder, rather than using strict lipid cut off values alone. \n\nExclude possible common secondary causes of dyslipidaemia (such as excess alcohol intake, uncontrolled diabetes, hypothyroidism, liver disease and nephrotic syndrome) before referring for specialist review. \n\nUse the recommendations in NICE's guideline on familial hypercholesterolaemia to determine whether to suspect, and how to treat, familial hypercholesterolaemia. [2014, amended 2023]\n\nArrange for specialist assessment of people with a total blood cholesterol concentration over 9.0\xa0mmol/litre or a non-HDL cholesterol concentration over 7.5\xa0mmol/litre even in the absence of a first-degree family history of premature coronary heart disease. \n\nRefer for urgent specialist review if a person has a triglyceride concentration over 20\xa0mmol/litre that is not a result of excess alcohol intake or poor glycaemic control. \n\nIn people with a triglyceride concentration between 10 and 20\xa0mmol/litre:\n\nrepeat the triglyceride measurement with a fasting test (after an interval of 5 days, but within 2 weeks) and\n\nreview for potential secondary causes of hyperlipidaemia and\n\nseek specialist advice if the triglyceride concentration remains over 10\xa0mmol/litre. \n\nIn people with a triglyceride concentration between 4.5 and 9.9\xa0mmol/litre:\n\nbe aware that the CVD risk may be underestimated by risk assessment tools and\n\noptimise the management of other CVD risk factors present and\n\nseek specialist advice if non-HDL cholesterol concentration is over 7.5\xa0mmol/litre. \n\n## Statins for preventing cardiovascular disease\n\nThere is a NICE patient decision aid to support discussions about statin therapy to reduce the risk of heart disease and stroke.\n\nDecide whether to start statin therapy after an informed discussion between the clinician and the person about the risks and benefits of statin treatment, taking into account additional factors such as potential benefits from lifestyle changes, informed patient preference, comorbidities, polypharmacy, general frailty and life expectancy. (See also NICE's guideline on multimorbidity.) \n\nBefore starting statin treatment perform baseline blood tests and clinical assessment, and treat comorbidities and secondary causes of dyslipidaemia. Include all of the following in the assessment:\n\nsmoking status\n\nalcohol consumption\n\nblood pressure (see NICE's guideline on hypertension)\n\nBMI or other measure of obesity (see NICE's guideline on obesity: identification, assessment and management)\n\ntotal cholesterol, non‑HDL cholesterol, HDL cholesterol and triglycerides\n\ndiabetes status\n\nrenal function\n\ntransaminase level (alanine aminotransferase or aspartate aminotransferase)\n\nthyroid‑stimulating hormone in people with symptoms of underactive or overactive thyroid. \n\nBefore offering statin treatment for primary prevention, discuss the benefits of lifestyle changes and optimise the management of all other modifiable CVD risk factors if possible. \n\nRecognise that people may need support to change their lifestyle. To help them do this, refer them to programmes such as exercise referral schemes or weight management services. (See NICE's guidelines on behaviour change: individual approaches, physical activity: exercise referral schemes and weight management: lifestyle services for overweight or obese adults.) \n\nOffer people the opportunity to have their risk of CVD assessed again after they have tried to change their lifestyle. \n\nIf lifestyle change is ineffective or inappropriate offer statin treatment. \n\nOffer atorvastatin 20\xa0mg for the primary prevention of CVD to people who have a 10‑year QRISK3 score of 10% or more. \n\nDo not rule out treatment with atorvastatin 20\xa0mg for the primary prevention of CVD just because the person's 10‑year QRISK3 score is less than 10% if they have an informed preference for taking a statin or there is concern that risk may be underestimated. \n\nFor people aged 85\xa0and older consider treatment with atorvastatin 20\xa0mg. Be aware of factors that may make treatment inappropriate (see\xa0recommendation 1.4.11).\xa0See also the section on follow-up of people started on statin treatment.\n\nConsider statin treatment for the primary prevention of CVD for adults with type 1 diabetes. \n\nOffer statin treatment for the primary prevention of CVD to adults with type 1 diabetes who:\n\nare older than 40\xa0years or\n\nhave had diabetes for more than 10\xa0years or\n\nhave established nephropathy or\n\nhave other CVD risk factors. \n\nWhen starting treatment with a statin for adults with type 1 diabetes, use atorvastatin 20\xa0mg. See also the section on follow-up of people started on statin treatment.\n\nStart statin treatment in people with CVD with atorvastatin 80\xa0mg. Use a lower dose of atorvastatin if any of the following apply:\n\npotential drug interactions\n\nhigh risk of adverse effects\n\npatient preference. In May 2023, this was an off-label use of atorvastatin. See NICE's information on prescribing medicines.\n\nDo not delay statin treatment for secondary prevention of CVD but consider lifestyle changes at the same time if appropriate. \n\nIf a person has acute coronary syndrome do not delay statin treatment. Take a lipid sample on admission and about 3\xa0months after the start of treatment. See also the section on follow-up of people started on statin treatment.\n\nOffer atorvastatin 20\xa0mg for the primary or secondary prevention of CVD to people with CKD. \n\nIncrease the dose if a greater than 40% reduction in non‑HDL cholesterol is not achieved (see recommendation 1.4.28) and eGFR is 30\xa0ml/min/1.73\xa0m2 or more. \n\nAgree the use of higher doses with a renal specialist if eGFR is less than 30\xa0ml/min/1.73\xa0m2. See also the section on follow-up of people started on statin treatment.See NICE's guideline on chronic kidney disease for CKD classification. People on renal replacement therapy are outside the scope of this guideline.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on statins for preventing CVD\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: statins: efficacy and adverse effects.\n\nLoading. Please wait.\n\n## Follow-up of people started on statin treatment\n\nMeasure total cholesterol, HDL cholesterol and non‑HDL cholesterol in all people who have been started on high-intensity statin treatment (both primary and secondary prevention, including atorvastatin 20\xa0mg for primary prevention) at 3\xa0months of treatment. \n\nAim for a greater than 40% reduction in non‑HDL cholesterol. \n\nIf a greater than 40% reduction in non‑HDL cholesterol is not achieved:\n\ndiscuss adherence and timing of dose\n\noptimise adherence to diet and lifestyle measures\n\nconsider increasing the dose if started on less than atorvastatin 80\xa0mg and the person is judged to be at higher risk because of comorbidities, risk score or using clinical judgement. \n\nA partial update of this guideline to identify a specific treatment target for secondary prevention of CVD is in progress. Further information can be found on the NICE webpage for the next update of this guideline.\n\nProvide annual medication reviews for people taking statins.\n\nUse these reviews to discuss medicines adherence and lifestyle changes and address CVD risk factors.\n\nConsider an annual non‑fasting blood test for non‑HDL cholesterol to inform the discussion. \n\nDiscuss with people who are stable on a low‑ or medium‑intensity statin the likely benefits and potential risks of changing to a high-intensity statin when they have a medication review and agree with the person whether a change is needed. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up of people started on statin treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: statins: efficacy and adverse effects.\n\nLoading. Please wait.\n\n## Advice and monitoring for adverse effects\n\nAdvise people who are being treated with a statin:\n\nthat other drugs, some foods (for example, grapefruit juice) and some supplements may interfere with statins and\n\nto always consult the patient information leaflet, a pharmacist or prescriber for advice when starting other drugs or thinking about taking supplements. \n\nRemind the person to restart the statin if they stopped taking it because of drug interactions or to treat intercurrent illnesses. \n\nBefore offering a statin, ask the person if they have had persistent generalised unexplained muscle symptoms (pain, tenderness or weakness), whether associated or not with previous lipid‑lowering therapy. If they have, measure creatine kinase levels. If creatine kinase levels are:\n\nmore than 5 times the upper limit of normal, re‑measure creatine kinase after 7 days; if creatine kinase levels are still 5 times the upper limit of normal, do not start statin treatment (see the section on intolerance of statins, and for other treatment options, see the NICE technology appraisal guidance on our topic page on lipid disorders)\n\nraised but less than 5 times the upper limit of normal, start statin treatment at a lower dose. \n\nAdvise people who are being offered a statin that the risk of muscle pain, tenderness or weakness associated with statin use is small and the rate of severe muscle adverse effects (rhabdomyolysis) because of statins is extremely low. \n\nAdvise people who are being treated with a statin to seek medical advice if they develop unexplained muscle symptoms (pain, tenderness or weakness). If this occurs, measure creatine kinase. \n\nIf people report muscle pain, tenderness or weakness while taking a statin and have a creatine kinase level less than 5 times the upper limit of normal, reassure them that their symptoms are unlikely to be due to the statin and explore other possible causes. \n\nDo not measure creatine kinase levels in asymptomatic people who are being treated with a statin. \n\nMeasure liver transaminase within 3\xa0months of starting treatment (as well as at baseline, see recommendation 1.4.12) and at 12\xa0months, but not again unless clinically indicated. \n\nDo not routinely exclude from statin therapy people who have liver transaminase levels that are raised but are less than 3 times the upper limit of normal. \n\nDo not stop statins because of an increase in blood glucose level or HbA1c. (See the recommendations on assessing for risk of diabetes mellitus in NICE's guideline on preventing type 2 diabetes.) \n\nBe aware that statins are contraindicated in pregnancy because of the risk to the unborn child of exposure to statins. [2014, amended 2023]\n\nExplain that:\n\nstatins should be stopped if pregnancy is a possibility\n\nstatins should be stopped 3\xa0months before attempting to conceive\n\nstatins should not be restarted until breastfeeding is finished. [2014, amended 2023]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on advice and monitoring for adverse effects\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: statins: efficacy and adverse effects.\n\nLoading. Please wait.\n\n## Intolerance of statins\n\nIf a person is not able to tolerate a high-intensity statin aim to treat with the maximum tolerated dose. \n\nTell the person that any statin at any dose reduces CVD risk. If someone reports adverse effects when taking a high-intensity statin discuss the following possible strategies with them:\n\nstopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin\n\nchanging to a different statin in the same intensity group (rosuvastatin if already receiving atorvastatin)\n\nreducing the dose within the same intensity group\n\nchanging the statin to a lower intensity group. [2014, amended 2023]\n\nSeek specialist advice about options for treating people at high risk of CVD such as those with CKD, type 1 diabetes, type 2 diabetes or genetic dyslipidaemias, and those with CVD who are intolerant to 3 different statins. Seek advice by telephone, virtual clinic or referral. \n\n## Adherence to statin therapy\n\nDo not offer coenzyme Q10 or vitamin D to increase adherence to statin treatment. \n\n## Fibrates for preventing cardiovascular disease\n\nDo not routinely offer fibrates to prevent CVD to any of the following:\n\npeople who are being treated for primary prevention\n\npeople who are being treated for secondary prevention\n\npeople with CKD\n\npeople with type 1 diabetes\n\npeople with type 2 diabetes. For people with familial hypercholesterolaemia, follow the recommendations on drug treatment in NICE's guideline on familial hypercholesterolaemia.\n\n## Nicotinic acid for preventing cardiovascular disease\n\nDo not offer nicotinic acid (niacin) to prevent CVD to any of the following:\n\npeople who are being treated for primary prevention\n\npeople who are being treated for secondary prevention\n\npeople with CKD\n\npeople with type 1 diabetes\n\npeople with type 2 diabetes. \n\n## Bile acid sequestrants (anion exchange resins) for preventing cardiovascular disease\n\nDo not offer a bile acid sequestrant (anion exchange resin) to prevent CVD to any of the following:\n\npeople who are being treated for primary prevention\n\npeople who are being treated for secondary prevention\n\npeople with CKD\n\npeople with type 1 diabetes\n\npeople with type 2 diabetes. For people with familial hypercholesterolaemia, follow the recommendations on drug treatment in NICE's guideline on familial hypercholesterolaemia.\n\n## Omega 3 fatty acid compounds for preventing cardiovascular disease\n\nDo not offer omega 3 fatty acid compounds to prevent CVD to any of the following:\n\npeople who are being treated for primary prevention\n\npeople who are being treated for secondary prevention\n\npeople with CKD\n\npeople with type 1 diabetes\n\npeople with type 2 diabetes.Icosapent ethyl is an exception to this if used as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides. \n\nTell people that there is no evidence that omega 3 fatty acid compounds help to prevent CVD, except use of icosapent ethyl as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy. \n\n## Combination therapy for preventing cardiovascular disease\n\nTo prevent CVD, do not offer the combination of a statin with:\n\na bile acid sequestrant (anion exchange resin), a fibrate or nicotinic acid, or\n\nan omega 3 fatty acid compound, except icosapent ethyl as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy. For people with familial hypercholesterolaemia, follow the recommendations on drug treatment in NICE's guideline on familial hypercholesterolaemia.\n\n## Other treatment options\n\nFor other treatment options, see the NICE technology appraisal guidance on our topic page on lipid disorders.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## High-intensity statin\n\nThe following doses for statins are high intensity, based on the percentage reduction in low-density lipoprotein (LDL) cholesterol they can produce:\n\natorvastatin: 20\xa0mg to 80\xa0mg\n\nrosuvastatin: 10\xa0mg to 40\xa0mg\n\n## Severe mental illness\n\nA diagnosis of schizophrenia, bipolar disorder or other psychoses. (In line with the criteria for severe mental health conditions used in the NHS annual health check for people with severe mental health conditions.)", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\n# Simplifying risk assessment\n\nWhat is the effectiveness of age alone and other routinely available risk factors compared with the formal structured multifactorial risk assessment to identify people at high risk of developing CVD? \n\n# Statin therapy for older people\n\nWhat is the effectiveness of statin therapy in older people? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on statins for preventing CVD\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: statins: efficacy and adverse effects.\n\nLoading. Please wait.\n\n# Lipid modification therapy for people with type 1 diabetes\n\nWhat is the effectiveness of statins and/or other low-density lipoprotein (LDL) cholesterol‑lowering treatment in people with type 1 diabetes? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on statins for preventing CVD\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: statins: efficacy and adverse effects.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Full formal risk assessment\n\nRecommendations 1.1.7 to 1.1.11\n\n## Why the committee made the recommendations\n\nThe committee agreed that the evidence suggested QRISK3 performed best among tools evaluated in a UK population to assess the risk of a person without established CVD having a CVD event within the next 10\xa0years. They agreed that no tool is very good at accurately discriminating between who will and who will not have a CVD event, but that tools are useful for guiding decisions about interventions to prevent CVD based on estimated risk.\n\nA small amount of evidence suggested that the additional fields included in QRISK3 (such as severe mental illness, regular corticosteroid use and atypical antipsychotic use) enabled the tool to perform better than QRISK2 at predicting CVD events for people with these risk factors. Use of QRISK3 should, therefore, result in more people within these groups being appropriately considered for risk reduction approaches including statin treatment.\n\nIt was noted that the group of people with severe mental illness used to develop and validate QRISK3 included a high proportion of people with severe and moderate depression. This is reflected in the definition of severe mental illness in QRISK3 but does not reflect the definition used in electronic clinical systems in primary care. The committee agreed, informed by their clinical experience and expert opinion, that people with moderate to severe depression are not considered to have as great an increased risk of CVD as people with schizophrenia, bipolar disorder and other psychoses. By using data that grouped these conditions together, QRISK3 may underestimate CVD risk for people with schizophrenia, bipolar disorder and other psychoses. Despite this the committee agreed to recommend use of the tool for people with severe mental illness (however defined), but clinical judgement should inform interpretation.\n\nThe committee was aware that the NHS Health Check best practice guidance states that gender should be recorded as reported by the individual. If the individual discloses gender reassignment, they should be provided with CVD risk calculations based on both genders and advised to discuss with their GP which calculation is most appropriate for them as an individual. They agreed that healthcare professionals are expected to follow this guidance when undertaking formal risk assessments.\n\nAn age range is given for QRISK3 because it is only intended for people aged between 25 and 84\xa0years (inclusive).\n\nThe committee agreed that the use of a risk tool remains appropriate in people with type 2 diabetes to support shared decision making. They agreed, based on the evidence, that QRISK3 performed better than QRISK2 for the population as whole and so should be used for people with type 2 diabetes.\n\nThe committee agreed to remove a 2014 recommendation to complete as many fields of the risk assessment tool as possible because QRISK3 explains that the tool can overestimate risk if fields are left blank. They also noted that BMI, ethnicity and family history of CVD should be recorded in people's medical records, so the committee agreed that the 2014 recommendation on recording this information was no longer needed.\n\nEvidence on the performance of QRISK3 was not considered sufficient to suggest changing the 2014 recommendations against using a CVD risk tool in people with type 1 diabetes or CKD as it had not been validated in a separate population from that in which the tool was developed. The committee agreed these groups should be considered high risk, as should people with familial hypercholesterolaemia.\n\nBased on their clinical experience, the committee identified a list of factors for which all CVD risk tools underestimate risk. They highlighted the importance of using clinical judgement to interpret risk scores. As risk scores are used to guide decisions about interventions to prevent CVD, the committee agreed it was particularly important to ensure people are not incorrectly considered to be at low risk.\n\nThe 2014 recommendation to consider people aged 85 and older to be at increased risk of CVD was retained as the committee agreed with this statement and there are still no tools for this age group. The committee highlighted it is important that this group be considered for interventions to prevent CVD even though a formal risk assessment would not be carried out.\n\nThe evidence for lifetime risk tools was not considered sufficient to recommend their use instead of 10‑year risk tools. However, the committee agreed they can have value in communication of risk. See the rationale for communication about risk assessment, lifestyle changes and treatment\xa0.\n\nLoading. Please wait.\n\n## How the recommendations might affect practice\n\nQRISK2 is currently integrated into electronic clinical systems so 10‑year CVD risk assessments can be generated using data already available in a person's electronic records. At the time of development, the committee was aware of ongoing discussions about continuation of the inclusion of QRISK in electronic clinical systems.\n\nUsing QRISK3 instead of QRISK2 will require clinical systems to be updated by software developers for the impact on practice to be minimised. Public Health England issued guidance in August 2021 on using QRISK3 in NHS health checks and how to deal with the transition period (responsibility for the NHS Health Check programme has transferred to the Office for Health Improvement and Disparities, but the guidance produced by PHE remains current).\n\nQRISK3 requires some additional clinical information that was not required for QRISK2. However, if integrated into electronic clinical systems, QRISK3 is not likely to require additional resources over QRISK2. There may be some implementation costs as healthcare professionals become familiar with the additional information included in QRISK3 and in managing the transition period.\n\nReturn to recommendations\n\n# Communication about risk assessment, lifestyle changes and treatment\n\nRecommendation 1.1.16\n\n## Why the committee made the recommendation\n\nThe committee agreed that the evidence did not support using lifetime CVD risk assessment tools to guide decisions on the need for statin treatment, because their accuracy could not be reliably assessed.\n\nHowever, the committee noted that the usefulness of lifetime risk tools is primarily in communicating risk. They agreed by consensus that lifetime risk tools should be considered to help inform discussions about risk and motivate lifestyle changes. The committee highlighted that these tools may underestimate the ongoing benefit of lipid lowering treatments as they do not predict risk reduction from taking medicines, and noted this should be considered when interpreting the results. They agreed lifetime risk calculation would not be necessary for everyone, but it may be particularly useful for people with a QRISK3 score less than 10% or under 40s who have CVD risk factors.\n\n## How the recommendation might affect practice\n\nLifetime risk tools are not routinely used in current clinical practice. The committee noted that there may be resource implications for calculating lifetime risk score estimates because lifetime risk tools are not currently embedded into electronic clinical systems and so scores are not automatically generated. There may also be implementation costs related to educating healthcare professionals about lifetime risk calculators. It is not clear if use of lifetime risk tools will result in longer consultations.\n\nThe committee agreed that the online calculators for lifetime risk tools such as QRISK-lifetime were easy to complete and provided some interpretation of the risk scores to aid discussions, but acknowledged that lifetime risk assessment would not be done for everyone.\n\nThe committee believe that using lifetime risk tools may have a long-term benefit in encouraging people to participate in lifestyle changes or engage in treatment, if appropriate. Given this, any additional time costs were considered likely to improve management of CVD risk and so reduce future CVD events.\n\nReturn to recommendation\n\n# Aspirin for primary prevention of cardiovascular disease\n\nRecommendation 1.2.1\n\n## Why NICE made the recommendation\n\nNICE's surveillance team reviewed the evidence about aspirin for the primary prevention of CVD. Based on the review, NICE decided to add a do not routinely offer recommendation about this. For full details see the January 2023 exceptional surveillance report.\n\nReturn to recommendation\n\n# Cardioprotective diet\n\nRecommendation 1.3.2\n\n## Why the committee made the recommendation\n\nThere was no available evidence comparing the effectiveness of dietary cholesterol strategies with normal diets for adults with and without CVD, so the committee updated the 2014 recommendation based on their clinical experience and expert opinion. They removed the reference to restricting dietary cholesterol intake.\n\nOnly evidence on dietary cholesterol was in scope for review and therefore the guidance on total fat intake and proportion of saturated fat versus unsaturated fat was not changed.\n\n## How the recommendation might affect practice\n\nThe committee agreed healthcare professionals already better understand the lack of a relationship between dietary cholesterol and CVD risk, so the new recommendation reflects current practice. The committee agreed there should be no change in practice or resource impact to the NHS because of this updated recommendation.\n\nReturn to recommendation\n\n# Statins for preventing cardiovascular disease\n\nRecommendations 1.4.11 to 1.4.28\n\n## Why the committee made the recommendations\n\nEvidence on both the effectiveness and adverse effects of statins showed high-intensity statins are clinically effective and cost-effective compared to no statins, low-intensity statins, or medium-intensity statins for preventing CVD in people with or without CVD.\n\nMost of the 2014 recommendations were retained, including recommendations on:\n\nhow to discuss statin therapy with people and decide to start treatment\n\nthe tests and assessments that should happen before treatment starts\n\ndiscussing lifestyle changes\n\nsecondary prevention.\n\nThe recommendations state which high-intensity statin should be used initially, so the committee agreed that the recommendation to choose a high-intensity statin of low acquisition cost is no longer needed.\n\nThe definition of high intensity statins was updated to remove simvastatin 80\xa0mg. This is no longer used in current practice because of the risk of myopathy and muscle symptoms.\n\nEvidence showed that statins are cost effective for people with 10‑year CVD risk scores less than 10%.\n\nThe committee agreed that if more people took statins there would be a greater reduction in CVD events. However, they also recognised that practical considerations needed to be taken into account.\n\nThey agreed that risk scores are an important aid to shared decision making on statins. National audit data suggests that 56% of people with a QRISK score of 20% or more take statins, compared with less than 50% for people with scores between 10% and 20%. Therefore, the committee consensus was that an even smaller proportion of people with scores less than 10% may choose to take statins.\n\nThe committee agreed that focusing on increasing uptake among people with the most potential to benefit would have more impact than lowering the statin treatment threshold. The 10% 10‑year QRISK score was therefore retained as the threshold for offering statins. Although QRISK3 is specified in the recommendations, it is acknowledged that QRISK2 may be used in some circumstances until QRISK3 is embedded in electronic clinical systems (see the panel below recommendation 1.1.8 for details). The 10% threshold applies whether QRISK2 or 3 is used.\n\nDespite this, the committee agreed that a more person-centred approach should be adopted and recommended atorvastatin 20\xa0mg as an option for people who want to take statins, irrespective of their QRISK3 score, or where clinical judgement suggests the person may be at high risk of CVD (for example, if the person has CVD risk factors not covered by QRISK3).\n\nThe committee agreed to retain 20\xa0mg as the recommended starting dose for all people starting atorvastatin for primary prevention of CVD. Although there was committee consensus that higher doses have a greater effect, they agreed that starting at the lowest effective dose was likely to be preferable to patients, but that up-titration of the dose should be considered as appropriate, following recommendations in the section on follow-up of people started on statin treatment.\n\nThe committee agreed to retain the following recommendations for research because there is still a lack of direct evidence in these areas:\n\nstatin therapy for older people\n\nlipid modification therapy for people with type 1 diabetes.\n\n## How the recommendations might affect practice\n\nMost recommendations about statin treatment have been retained from the 2014 update of the guideline and so should not require a change in practice.\n\nNational audit data suggests that less than half of people with a QRISK score of 10% or more are on lipid-lowering therapy. It is unclear if people are not being offered statins or if they are declining or stopping treatment. Increased uptake of statins would result in higher medication and monitoring costs to the NHS. It would also contribute to workload burden in primary care GP practices and pharmacies and laboratories processing monitoring tests. The committee agreed this increase was necessary for downstream improvements in population health, and would be offset by savings due to a reduction in CVD events.\n\nThe recommendation to consider starting atorvastatin 20\xa0mg for people with QRISK3 scores less than 10% is a change in practice. The impact on medication and monitoring costs and workload will depend on the level of uptake. This will be offset by savings due to a reduction in CVD events and improvements in population health.\n\nReturn to recommendations\n\n# Follow-up of people started on statin treatment\n\nRecommendations 1.4.29 to 1.4.33\n\n## Why the committee made the recommendations\n\nThe committee reviewed the 2014 consensus recommendations on follow-up and agreed they were still valid and should be retained.\n\n## How the recommendations might affect practice\n\nAlthough these recommendations remain unchanged from 2014 so should reflect current practice, the committee acknowledged that any increase in statin use would result in an increase in follow-up activity, including cholesterol testing at 3 months of treatment, and in the number of annual medication reviews. This was considered when amending the recommendations on statins. For further details see the impact section for the recommendations on statins\xa0.\n\nReturn to recommendations\n\nLoading. Please wait.\n\n# Advice and monitoring for adverse effects\n\nRecommendations 1.4.34 to 1.4.45\n\n## Why the committee made the recommendations\n\nNew evidence on adverse effects while on statins supported the 2014 recommendations. Evidence on the risk of muscle pain and rhabdomyolysis with statin use demonstrated a real effect, but the large body of evidence showed this was a very small increased risk when compared with similar populations not on statins; that is, when using high-intensity statins approximately 16% of people reported experiencing muscle pain, but of these cases only around 1 in 12 were likely to be due to the statin.\n\nThe committee agreed to strengthen the recommendation to reassure people that the risk of these adverse effects occurring is low.\n\nThe evidence supported the other 2014 recommendations on advice and monitoring for adverse effects and so they were retained.\n\n## How the recommendations might affect practice\n\nThe recommendations have been strengthened to emphasise the low risk of experiencing severe muscle adverse effects because of statin treatment. They are not expected to have an impact on resource use as discussions on adverse effects are already an important part of current practice in prescribing and monitoring statins.\n\nReturn to recommendations", 'Context': 'Cardiovascular disease (CVD) is the leading cause of death worldwide, accounting for almost 18 million deaths each year (over 30% of all global deaths). Around 7\xa0million people in the UK have CVD.\n\nOver 70\xa0million prescriptions for statins are dispensed in England each year, costing the NHS around £100\xa0million. The total healthcare cost of CVD in England is estimated to be £7.4\xa0billion.\n\nDespite the weight of conclusive research and consistent national and international guidelines, many people at significant risk of CVD do not receive lipid-lowering therapies, or they receive inadequate treatment. Anxieties about the safety of statins may mean healthcare professionals are reticent about offering them, and people are reluctant to start or continue statin treatment. Depending on statin intensity, 30% to 50% of people stop taking statins within 6\xa0years.\n\nOver the past 5\xa0years, more evidence has become available on the benefits and adverse effects of statins.\n\nWays to estimate and explain CVD risk have also improved, and healthcare professionals now have more varied and accurate approaches available for individualised risk assessment. This can empower patients and professionals to discuss interventions to reduce short- and long-term CVD risk.\n\nUnderstanding of the relationship between dietary cholesterol and lipid levels has also evolved suggesting recommendations in the 2014 guideline required updating.\n\nIncreasing awareness of elevated lipids (including cholesterol) as a risk factor for CVD, so that appropriate intervention can be provided, is critical to the delivery of the NHS Long Term Plan. By 2029, the ambition in England is for at least 45% of people aged 40 to 74 who are at significant risk of developing CVD to be on appropriate lipid-lowering therapy. Local achievement of this ambition can be monitored using the CVDPREVENT audit.'}	https://www.nice.org.uk/guidance/cg181	This guideline covers the assessment and care of adults who are at risk of or who have cardiovascular disease (CVD), such as heart disease and stroke. It aims to help healthcare professionals identify people who are at risk of cardiovascular problems including people with type 1 or type 2 diabetes, or chronic kidney disease. It describes the lifestyle changes people can make and how statins can be used to reduce their risk.
7841c1b0c797f9268c051e3f6cdd7a8891a247cd	nice	MRI fusion biopsy systems for diagnosing prostate cancer	MRI fusion biopsy systems for diagnosing prostate cancer Evidence-based recommendations on MRI fusion biopsy systems for diagnosing prostate cancer. # Recommendations There is not enough evidence to recommend routine adoption of MRI fusion biopsy systems for diagnosing prostate cancer. Centres already using MRI fusion biopsy systems to diagnose prostate cancer may continue to do so but are encouraged to collect data or do further research. Further data collection and research is recommended (see the section on further research) to: assess the performance of MRI fusion biopsy systems compared with cognitive fusion biopsies to detect different grades of prostate cancer assess the impact of using the technology on the rate at which biopsies can be done, and on service capacity to do biopsies. Why the committee made these recommendations Biopsies for suspected prostate cancer are done using previously taken MRI images and live ultrasound imaging to help the operator guide the biopsy needle (cognitive fusion). In MRI fusion biopsy systems, software overlays the MRI image onto the live ultrasound image (MRI fusion). This could mean fewer cases of prostate cancer are missed and could reduce the number of repeat biopsies. The clinical evidence is limited because none of the studies are from the UK and none are of high quality. It suggests MRI fusion biopsy systems may detect more higher-grade cancers than with cognitive fusion biopsy, but this is unclear because few higher-grade cancers were detected overall. There is not much evidence comparing the different software fusion technologies with each other. And the technologies differ in their features, so it is not clear if any are better than the others. The cost-effectiveness estimates depend on how well MRI fusion biopsy systems detect higher-grade cancers compared with cognitive fusion. The estimates suggest that MRI fusion biopsy systems could be cost effective compared with cognitive fusion, but because the clinical evidence is uncertain, the cost-effectiveness estimates are very uncertain. MRI fusion biopsy systems show promise for better detection of prostate cancer and could help to standardise biopsy quality across the NHS, but more evidence is needed.# The diagnostic tests # Clinical need and practice ## Prostate cancer The NICE guideline on prostate cancer recommends that a multiparametric MRI test should be offered to people with suspected clinically localised prostate cancer. People with a significant lesion should be offered a multiparametric MRI-influenced prostate biopsy. Based on prostate-specific antigen test results, Gleason score determined by histological analysis of the biopsy, and clinical stage based on the multiparametric MRI scan, people are assigned to risk categories. This informs treatment options (such as active surveillance, radical prostatectomy and radiotherapy). ## Current care Targeted biopsies, which take only a small number of tissue samples or cores, are done for suspicious lesions identified by MRI. A systematic biopsy approach, in which multiple samples are taken from different regions of the left and right side of the prostate, can be done alongside a targeted biopsy. This can be done if radiologists are unsure if the lesion is malignant and clinical suspicion of cancer is high. Clinical experts explained that the biopsy approach depends on the information from the multiparametric MRI and individual clinician preference. They commented that practice in the NHS varies. Targeted biopsies are usually done using cognitive fusion, in which the previously captured MRI image is visually compared with the live transrectal ultrasound image to guide the biopsy needle. Because of the differences in positioning when a person has an MRI scan compared with when they have an ultrasound scan, the prostate shape differs on MRI and ultrasound images. This can make targeting the lesion difficult. ## Potential value of technologies In MRI fusion biopsy systems, the MRI image is fused onto the live ultrasound image to aid biopsy targeting. MRI fusion biopsy systems are indicated for targeted biopsies of suspicious lesions when a small number of tissue samples or cores are taken. The clinical experts commented that, as with cognitive fusion biopsies, systematic biopsies may be done alongside targeted biopsies done using MRI fusion. The more samples taken during a prostate biopsy, the higher the risk of adverse events. Refined targeting of the prostate for biopsy could avoid taking unnecessary samples. This could reduce the risk of adverse events such as urinary retention, infection and sepsis after the biopsy. More accurate targeting of suspicious prostate lesions could increase prostate cancer detection rates (missing fewer cases), particularly for people with small lesions. It could also reduce the number of repeat biopsies needed by reducing the risk of missing the cancer in the first biopsy. # The interventions The technologies are systems that include MRI fusion software to assist targeting of prostate biopsies. ## Artemis The Artemis fusion biopsy system (InnoMedicus Artemis) includes a semi-robotic mechanical arm and a mobile workstation. The system uses ProFuse radiology software for preparing MRI data for fusion and for reporting findings. The system uses both elastic and rigid estimation to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. The mechanical arm is used to track the prostate in real time and guide the biopsy needle. It is unclear if the system is compatible with third-party ultrasound systems or picture archiving and communication systems (PACS), what its image measurement capabilities are or if it can produce archivable cartograms. No information on costings or regulatory approval has been received from the company. ## Biojet The Biojet MR Fusion system (Healthcare Supply Solutions) comprises MRI fusion software, a mobile workstation, and is compatible with third-party ultrasound systems. The system uses elastic estimations to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. It supports stabilised and freehand biopsy approaches. For stabilised biopsies, patient movement is tracked through the stepper; freehand biopsies done without the stepper need more manual input from the user. The software enables image measurements and a report is generated, graphically showing the sampled areas with exact locations. Biojet can be connected to a local PACS. No information on costings or regulatory approval has been received from the company. ## BiopSee The BiopSee system (Medcom) consists of BiopSee software and a MedSta cart (workstation) and is compatible with third-party ultrasound systems. The system uses elastic and rigid estimation to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. It can be used for stabilised and freehand biopsy approaches. A stabilising arm is available for transperineal stabilised biopsies. Patient movement is tracked through the stepper during stabilised biopsies, or through a magnetic tracker attached to the probe during freehand biopsies. The system can automatically adjust for patient movement, or the user can manually adjust the contours when a patient moves. The BiopSee records all positions of the needle and shows the coverage of the prostate. Image measurements such as prostate and lesion volumes are also possible. The data is stored locally and can be connected to a PACS for import and export of images. The software costs £20,000 for transperineal biopsies and £15,000 for transrectal biopsies. The cart for transrectal biopsies costs £12,000, and the cart for transperineal biopsy costs £8,000 for stabilised biopsy and £20,000 for freehand biopsy. ## bkFusion BK Medical UK Ltd and MIM Software Inc offer 3 versions of bkFusion software: 1 for transrectal, 1 for freehand transperineal and 1 for stabilised transperineal biopsies. The software can be integrated into either the bk3000 or bk5000 ultrasound systems. The bkFusion system uses rigid estimation to account for changes in the shape of the prostate during the procedure. The stabilised transperineal fusion system uses a stepper to track the probe position. Image measurements such as prostate volume are possible. A report of the biopsy can be saved locally, or transferred to a PACS. The software and cart cost £52,250 (provided for transperineal biopsy only). ## FusionVu (ExactVU system) FusionVu is a software feature that enables MRI fusion biopsy as part of the ExactVu micro-ultrasound system (ExactImaging). A stabiliser arm or stepper is available for stabilised biopsies, and freehand biopsies are also possible. The system uses rigid estimation followed by real-time visualisation of the lesions using micro-ultrasound. It supports transperineal and transrectal biopsies. The system tracks and adjusts for patient movement using data from a movement sensor together with the live ultrasound images. The software provides image measurements such as prostate volume and lesion size. Information on the orientation of all images and video frames is recorded so that the same position can be found if a repeat biopsy is done. The system is PACS compatible, but Weasis DICOM viewer software is available where a PACS is not available. The ExactVu unit costs £124,958 (includes ultrasound components). ## Fusion Bx 2.0 The Fusion Bx 2.0 (Focal Healthcare) is a biopsy device comprising a counterbalanced, semi-robotic arm that is mounted on a mobile cart. The system uses Fusion MR software which is compatible with third-party ultrasound systems. It uses elastic and rigid estimation to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. The counterbalanced semi-robotic arm can be used as a stepper for stabilised biopsies, or can allow complete freedom of movement for a freehand biopsy. All patient movements are tracked with sensors in the semi-robotic arm. The software allows image measurements such as prostate volume and distances to be calculated. Data on the biopsied samples and the regions of interest are recorded on a 3D image of the prostate. The system can connect to a PACS using a wired ethernet or wireless connection. The software costs £24,244 (USD $30,000) and the cart costs £96,974 (USD $120,000). ## iSR'obot Mona Lisa The iSR'obot Mona Lisa (Biobot Surgical) is a robotic transperineal prostate biopsy system with MRI-ultrasound fusion capability. The system uses UroFusion software to highlight regions of interest on MRI images and fuses the MRI model with the ultrasound model. A robotic needle guide allows automated positioning and depth control of the biopsy needle to the targeted biopsy core. The system uses elastic estimation to account for changes in the shape of the prostate during the procedure. Reports are generated with 3D images and coordinates are recorded for each biopsy sample. No information was received from the company on the tracking of patient movement, whether freehand biopsies can be done, PACS compatibility, image measurement capabilities, costs or confirmation of regulatory approval. ## KOELIS Trinity The KOELIS Trinity (KOELIS and Kebomed) is a mobile ultrasound system with mapping fusion software. It comprises PROMAP 3D‑Prostate Suite software and the Trinity ultrasound system (workstation, ultrasound probes, guides specific to transperineal or transrectal biopsies, and a probe holder). The system uses elastic and rigid estimation to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. It supports stabilised and freehand probe biopsies. The software identifies and compensates for patient movements and changes in the shape of the prostate during the procedure to record each core location. The PROMAP software produces a 3D map of the prostate, recording the position of MRI lesion targets and the locations of biopsy samples. The KOELIS Trinity system provides image measurements such as prostate volume, measurements of the regions of interest and other quantitative measurements from the image. Data can be transferred to a PACS. The system costs £23,620, plus £39,948 for transrectal software, £41,754 for transperineal software, and £45,000 for the ultrasound components. ## UroNav The UroNav (Phillips) comprises an electromagnetic tracking system, a mobile workstation and DynaCAD Prostate fusion software. The system is compatible with third-party ultrasound systems. It supports transperineal and transrectal biopsies, with stabilised or freehand approaches. The system uses elastic and rigid estimation methods to create 3D images to account for changes in the shape of the prostate during the procedure. The system can be used with a mobile stepper system and 2 navigation sensors to track any movement the person makes. The UroNav system provides core location data, images and videos. It works with DynaCAD Prostate fusion software, an image analysis and reporting tool. No information was received from the company on PACS compatibility or costs. # The comparator The comparator for the evaluation is targeted transperineal or transrectal prostate biopsy using cognitive fusion biopsy (using an MRI image to visually estimate the location of interest) with or without systematic biopsy, under local or general anaesthesia.# Committee discussion The diagnostics advisory committee considered evidence on MRI fusion biopsy systems using Artemis, Biojet, BiopSee, bkFusion, Fusion Bx 2.0, FusionVu, iSR'obot Mona Lisa, KOELIS Trinity and UroNav from several sources, including a diagnostics assessment report and an overview of that report. Full details are in the project documents for this guidance. # Benefits of the technology for people with suspected prostate cancer Patient experts explained that technologies that help correctly diagnose prostate cancer could reduce the number of missed cancers and repeat biopsies. Overtreatment was highlighted as a particular issue and concern for patients. During consultation on the draft guidance, a stakeholder further highlighted concerns that higher rates of overdiagnosis from using MRI fusion could lead to potentially higher levels of overtreatment. Any reduction in the number of samples taken during the biopsy could lower the likelihood of biopsy-related complications. Any reduction in the need for further biopsies would help avoid some of the stress and anxiety associated with this. The external assessment group (EAG) stated that there is no evidence of a significant difference in safety outcomes between biopsies done with MRI fusion and cognitive fusion, but that the evidence is limited by poor reporting and at high risk of confounding because of differences in biopsy routes and anaesthesia methods. The patient experts also highlighted that a shorter procedure time could help to preserve dignity and minimise stress and anxiety during the biopsy. During consultation on the EAG's report, stakeholders highlighted the importance of minimising the biopsy procedure time and pain or discomfort, particularly for biopsies under local anaesthetic. They added that stress and anxiety over the biopsy can lead to a poor experience for the person, which can deter them from having additional procedures. # Clinical effectiveness ## Benefits of MRI fusion biopsy systems from the trials The committee agreed that the evidence for MRI fusion technology looked promising, but that there was a lot of uncertainty around the performance of the technology when compared with cognitive fusion. The EAG's network meta-analyses used pooled data from different MRI fusion technologies for its base-case analysis. The results suggested that MRI fusion, compared with cognitive fusion, may detect more International Society of Urological Pathology (ISUP) grade 2 or higher prostate cancer. But whether MRI fusion truly detected more higher-grade cancer, and if so by how much, was very uncertain. The EAG explained that few studies in the meta-analysis included people with higher-grade cancer, and few cases were detected in these studies. The committee discussed the limitations of the clinical evidence included in the EAG's meta-analyses. None of the studies were done in the UK. The EAG judged all studies used in the meta-analysis to be at high risk of bias, and it stated that no high-quality randomised controlled trials have been published. The meta-analyses also showed moderate heterogeneity that could not be explained by differences in individual MRI fusion biopsy systems. ## Performance differences between the different MRI fusion biopsy systems The committee was uncertain how appropriate it was to use data generated using 1 system to show the performance of others. There was limited data directly comparing the different systems, and evidence levels varied across the different MRI fusion technologies. The EAG combined data from different technologies in its base-case analysis, based on advice from clinical experts. The committee noted that there are fundamental differences between the MRI fusion biopsy systems, which may influence outcomes. Only 2 MRI fusion systems had more than 1 study included in the meta-analysis. For 1 of these (KOELIS Trinity), all studies used a previous version of the software included in the current device. The company commented that the KOELIS Trinity uses an updated version of the same software included in the KOELIS Urostation (which is now discontinued). The EAG did not identify any evidence for Fusion Bx 2.0 or FusionVu, and none of the identified studies for the bkFusion or ISR'obot Mona Lisa met the inclusion criteria for the meta-analysis. The EAG stated that evidence was insufficient to conclude whether any MRI fusion biopsy systems were superior to others. ## Potential impact on waiting times of adopting MRI fusion biopsy systems The committee considered that adopting MRI fusion biopsy systems could prolong waiting time for prostate biopsies, and that this was not captured in the cost-effectiveness estimates. The clinical experts explained that radiologist services are at full capacity in the NHS. Clinical experts with experience using MRI fusion biopsy systems highlighted that more preparatory time is needed per biopsy with MRI fusion than with cognitive fusion, although this does decrease with more experience in using the technology. This lowers the number of biopsies that can be done in a day. In its economic model, the EAG assumed that additional procedure time for MRI fusion use would be 10 minutes in a high throughput centre (5 minutes radiologist time to import and obtain appropriate MRI sequences and 5 minutes during the biopsy), based on expert advice. It was suggested that this would be longer when the technologies were first used, because of lack of experience. The additional time was added to the cost of doing MRI fusion biopsy in the model (for example, for staff time), but the model did not include any impact of this on slowing biopsy throughput. The clinical experts commented that MRI fusion could improve patient throughput if it reduced the repeat biopsies needed (for example, if there was more confidence in a negative biopsy). The EAG commented that how much MRI fusion increases wating times would depend on whether the capacity constraint was access to the biopsy procedure or to the initial MRI (which would be the same for MRI fusion and cognitive fusion biopsy). The committee was also concerned about how adopting software fusion technology could potentially impact how many biopsy procedures can be done per day, and consequently the effect on waiting times for this procedure. # Cost effectiveness ## Improving detection of higher-grade prostate cancer makes the technology more cost effective in the model The cost-effectiveness estimates for MRI fusion biopsy systems (with or without systematic biopsy), compared with cognitive fusion, were generally favourable, but uncertain. Potential adverse impacts on the capacity of services to do biopsies (see section 3.5) were not considered in the model. The EAG's analysis showed that cost effectiveness was most affected by the improved detection of localised or locally advanced higher-grade cancers (ISUP 2 or higher). When targeted fusion was combined with systematic biopsy, there were more cost savings and health benefits in the long-term model for MRI fusion than for cognitive fusion. The EAG cautioned that the uncertainties in the clinical evidence should be considered alongside the overall cost effectiveness, because the evidence used in its network meta-analysis underpinned its economic model. The committee recalled that although the data suggested that MRI fusion may detect more higher-grade cancers, this was very uncertain (see section 3.2). It noted that a scenario analysis done by the EAG in which any benefit to detecting cancer for MRI fusion was removed from the model, the incremental cost-effectiveness ratios (ICERs) increased to over £500,000 per quality-adjusted life year (QALY) gained. The committee concluded that the uncertainty about how much better MRI fusion is at detecting higher-grade cancers means that the cost effectiveness of these technologies, while potentially favourable, is also very uncertain. ## Benefits to less experienced health professionals The committee acknowledged that the technology could benefit less experienced healthcare professionals, and help to standardise care across different centres and improve accessibility. The clinical experts noted that biopsies are done by various healthcare professionals including urologists, radiologists and nurse specialists. The level of experience in doing biopsies varies, and specialist centres are more likely to have professionals with more experience. They suggested that the accuracy of cognitive fusion is highly dependent on the operator. The EAG identified 1 study that reported cancer biopsy positivity rates by operator experience (Stabile et al. 2018). It reported an increase in the biopsy positivity rates in the first 60 procedures, where it plateaued, regardless of the biopsy approach. Operator experience predicted the biopsy positivity rate of targeted biopsies, particularly for transrectal MRI fusion biopsy compared with transrectal cognitive fusion or transperineal MRI biopsy fusion. The clinical experts suggested that using MRI fusion biopsy systems could help standardise biopsy quality. They said that this could minimise geographical variation in procedure standard caused by the variation in operator expertise. Improving the ability of less experienced operators to do the procedure may allow it to be available more widely, improving accessibility. ## MRI fusion biopsy systems show promise, but better-quality evidence is needed The committee recognised that MRI fusion biopsy systems show promise, could help improve standards across the NHS and patient access (see section 3.9), and may be cost effective. But it felt there was too much uncertainty about how much it would improve detection of prostate cancer to recommend its use for routine adoption (see sections 3.6 and 3.7). Further research is needed to reduce this uncertainty, and so also reduce the uncertainty about the cost effectiveness. The committee was also concerned about how adopting MRI fusion technology could potentially impact how many biopsy procedures can be done per day, and consequently the effect on waiting times for this procedure (see section 3.5). Further data on this would help reduce concerns about the impact of adopting MRI fusion biopsy systems. # Research considerations ## An ongoing study may fill some evidence gaps The ongoing IP7-PACIFIC trial (see trial NCT05574647 on the ClinicalTrials.gov website, accessed 14 November 2022) is likely to provide further, potentially high-quality, data on MRI fusion biopsy systems for detecting clinically significant prostate cancers, compared with cognitive fusion biopsy. The primary outcome of the trial is the proportion of clinically significant cancers (defined as ISUP 2 or above) detected in people who had a biopsy with a suspicious MRI (MRI score 3, 4 or 5 on either the Likert or Prostate Imaging-Reporting and Data System schema). The EAG commented that the study aims to recruit 3,600 people with suspected prostate cancer in the UK, but that not all of these people will provide data on MRI fusion performance (the study includes 2 linked randomised controlled trials, and is also comparing biparametric and multiparametric MRI to detect clinically significant prostate cancers). The EAG emphasised that to help inform cost-effectiveness estimates from its model, the numbers of cancer detected by ISUP grade should be reported (rather than just the number of ISUP grade 2 or higher). During consultation on the draft guidance, a stakeholder further highlighted the importance of collecting data on the effect of MRI fusion technologies on detecting clinically insignificant prostate cancer, as well as higher-grade cancers. Given the uncertainty about the generalisability of data generated using 1 MRI fusion technology to others (see section 3.4), it would be beneficial if data was reported separately for each MRI fusion biopsy system. The committee concluded that this will be a useful trial for reducing uncertainty about MRI fusion biopsy performance, but noted that the estimated study completion data is not until 2026. It stated that people should be encouraged to participate in the trial. ## Existing data and resources to collect data The clinical experts highlighted that professional bodies such as the British Association of Urological Surgeons and the Royal College of Radiologists may have data that could contribute to a future assessment. They also suggested that establishing further registries may help data collection. The committee suggested that centres should consider contributing to existing audit tools such as the National Prostate Cancer Audit when possible.# Recommendations for further research Further research is recommended to determine the impact of MRI fusion biopsy systems compared with cognitive fusion biopsy on the detection of different grades of prostate cancer. Further data collection or research is recommended on the impact of implementing MRI fusion biopsy systems on the rate at which biopsies can be done, capacity resources and waiting times for this procedure.	{'Recommendations': 'There is not enough evidence to recommend routine adoption of MRI fusion biopsy systems for diagnosing prostate cancer. Centres already using MRI fusion biopsy systems to diagnose prostate cancer may continue to do so but are encouraged to collect data or do further research.\n\nFurther data collection and research is recommended (see the section on further research) to:\n\nassess the performance of MRI fusion biopsy systems compared with cognitive fusion biopsies to detect different grades of prostate cancer\n\nassess the impact of using the technology on the rate at which biopsies can be done, and on service capacity to do biopsies.\n\nWhy the committee made these recommendations\n\nBiopsies for suspected prostate cancer are done using previously taken MRI images and live ultrasound imaging to help the operator guide the biopsy needle (cognitive fusion). In MRI fusion biopsy systems, software overlays the MRI image onto the live ultrasound image (MRI fusion). This could mean fewer cases of prostate cancer are missed and could reduce the number of repeat biopsies.\n\nThe clinical evidence is limited because none of the studies are from the UK and none are of high quality. It suggests MRI fusion biopsy systems may detect more higher-grade cancers than with cognitive fusion biopsy, but this is unclear because few higher-grade cancers were detected overall. There is not much evidence comparing the different software fusion technologies with each other. And the technologies differ in their features, so it is not clear if any are better than the others.\n\nThe cost-effectiveness estimates depend on how well MRI fusion biopsy systems detect higher-grade cancers compared with cognitive fusion. The estimates suggest that MRI fusion biopsy systems could be cost effective compared with cognitive fusion, but because the clinical evidence is uncertain, the cost-effectiveness estimates are very uncertain.\n\nMRI fusion biopsy systems show promise for better detection of prostate cancer and could help to standardise biopsy quality across the NHS, but more evidence is needed.', 'The diagnostic tests': "# Clinical need and practice\n\n## Prostate cancer\n\nThe NICE guideline on prostate cancer recommends that a multiparametric MRI test should be offered to people with suspected clinically localised prostate cancer. People with a significant lesion should be offered a multiparametric MRI-influenced prostate biopsy. Based on prostate-specific antigen test results, Gleason score determined by histological analysis of the biopsy, and clinical stage based on the multiparametric MRI scan, people are assigned to risk categories. This informs treatment options (such as active surveillance, radical prostatectomy and radiotherapy).\n\n## Current care\n\nTargeted biopsies, which take only a small number of tissue samples or cores, are done for suspicious lesions identified by MRI. A systematic biopsy approach, in which multiple samples are taken from different regions of the left and right side of the prostate, can be done alongside a targeted biopsy. This can be done if radiologists are unsure if the lesion is malignant and clinical suspicion of cancer is high. Clinical experts explained that the biopsy approach depends on the information from the multiparametric MRI and individual clinician preference. They commented that practice in the NHS varies.\n\nTargeted biopsies are usually done using cognitive fusion, in which the previously captured MRI image is visually compared with the live transrectal ultrasound image to guide the biopsy needle. Because of the differences in positioning when a person has an MRI scan compared with when they have an ultrasound scan, the prostate shape differs on MRI and ultrasound images. This can make targeting the lesion difficult.\n\n## Potential value of technologies\n\nIn MRI fusion biopsy systems, the MRI image is fused onto the live ultrasound image to aid biopsy targeting. MRI fusion biopsy systems are indicated for targeted biopsies of suspicious lesions when a small number of tissue samples or cores are taken. The clinical experts commented that, as with cognitive fusion biopsies, systematic biopsies may be done alongside targeted biopsies done using MRI fusion.\n\nThe more samples taken during a prostate biopsy, the higher the risk of adverse events. Refined targeting of the prostate for biopsy could avoid taking unnecessary samples. This could reduce the risk of adverse events such as urinary retention, infection and sepsis after the biopsy. More accurate targeting of suspicious prostate lesions could increase prostate cancer detection rates (missing fewer cases), particularly for people with small lesions. It could also reduce the number of repeat biopsies needed by reducing the risk of missing the cancer in the first biopsy.\n\n# The interventions\n\nThe technologies are systems that include MRI fusion software to assist targeting of prostate biopsies.\n\n## Artemis\n\nThe Artemis fusion biopsy system (InnoMedicus Artemis) includes a semi-robotic mechanical arm and a mobile workstation. The system uses ProFuse radiology software for preparing MRI data for fusion and for reporting findings. The system uses both elastic and rigid estimation to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. The mechanical arm is used to track the prostate in real time and guide the biopsy needle.\n\nIt is unclear if the system is compatible with third-party ultrasound systems or picture archiving and communication systems (PACS), what its image measurement capabilities are or if it can produce archivable cartograms. No information on costings or regulatory approval has been received from the company.\n\n## Biojet\n\nThe Biojet MR Fusion system (Healthcare Supply Solutions) comprises MRI fusion software, a mobile workstation, and is compatible with third-party ultrasound systems. The system uses elastic estimations to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. It supports stabilised and freehand biopsy approaches. For stabilised biopsies, patient movement is tracked through the stepper; freehand biopsies done without the stepper need more manual input from the user.\n\nThe software enables image measurements and a report is generated, graphically showing the sampled areas with exact locations. Biojet can be connected to a local PACS. No information on costings or regulatory approval has been received from the company.\n\n## BiopSee\n\nThe BiopSee system (Medcom) consists of BiopSee software and a MedSta cart (workstation) and is compatible with third-party ultrasound systems. The system uses elastic and rigid estimation to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. It can be used for stabilised and freehand biopsy approaches. A stabilising arm is available for transperineal stabilised biopsies. Patient movement is tracked through the stepper during stabilised biopsies, or through a magnetic tracker attached to the probe during freehand biopsies. The system can automatically adjust for patient movement, or the user can manually adjust the contours when a patient moves.\n\nThe BiopSee records all positions of the needle and shows the coverage of the prostate. Image measurements such as prostate and lesion volumes are also possible. The data is stored locally and can be connected to a PACS for import and export of images. The software costs £20,000 for transperineal biopsies and £15,000 for transrectal biopsies. The cart for transrectal biopsies costs £12,000, and the cart for transperineal biopsy costs £8,000 for stabilised biopsy and £20,000 for freehand biopsy.\n\n## bkFusion\n\nBK Medical UK Ltd and MIM Software Inc offer 3\xa0versions of bkFusion software: 1 for transrectal, 1 for freehand transperineal and 1 for stabilised transperineal biopsies. The software can be integrated into either the bk3000 or bk5000 ultrasound systems. The bkFusion system uses rigid estimation to account for changes in the shape of the prostate during the procedure. The stabilised transperineal fusion system uses a stepper to track the probe position.\n\nImage measurements such as prostate volume are possible. A report of the biopsy can be saved locally, or transferred to a PACS. The software and cart cost £52,250 (provided for transperineal biopsy only).\n\n## FusionVu (ExactVU system)\n\nFusionVu is a software feature that enables MRI fusion biopsy as part of the ExactVu micro-ultrasound system (ExactImaging). A stabiliser arm or stepper is available for stabilised biopsies, and freehand biopsies are also possible. The system uses rigid estimation followed by real-time visualisation of the lesions using micro-ultrasound. It supports transperineal and transrectal biopsies. The system tracks and adjusts for patient movement using data from a movement sensor together with the live ultrasound images.\n\nThe software provides image measurements such as prostate volume and lesion size. Information on the orientation of all images and video frames is recorded so that the same position can be found if a repeat biopsy is done. The system is PACS compatible, but Weasis DICOM viewer software is available where a PACS is not available. The ExactVu unit costs £124,958 (includes ultrasound components).\n\n## Fusion Bx 2.0\n\nThe Fusion Bx\xa02.0 (Focal Healthcare) is a biopsy device comprising a counterbalanced, semi-robotic arm that is mounted on a mobile cart. The system uses Fusion MR software which is compatible with third-party ultrasound systems. It uses elastic and rigid estimation to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. The counterbalanced semi-robotic arm can be used as a stepper for stabilised biopsies, or can allow complete freedom of movement for a freehand biopsy. All patient movements are tracked with sensors in the semi-robotic arm.\n\nThe software allows image measurements such as prostate volume and distances to be calculated. Data on the biopsied samples and the regions of interest are recorded on a 3D image of the prostate. The system can connect to a PACS using a wired ethernet or wireless connection. The software costs £24,244 (USD\xa0$30,000) and the cart costs £96,974 (USD\xa0$120,000).\n\n## iSR'obot Mona Lisa\n\nThe iSR'obot Mona Lisa (Biobot Surgical) is a robotic transperineal prostate biopsy system with MRI-ultrasound fusion capability. The system uses UroFusion software to highlight regions of interest on MRI images and fuses the MRI model with the ultrasound model. A robotic needle guide allows automated positioning and depth control of the biopsy needle to the targeted biopsy core. The system uses elastic estimation to account for changes in the shape of the prostate during the procedure.\n\nReports are generated with 3D\xa0images and coordinates are recorded for each biopsy sample. No information was received from the company on the tracking of patient movement, whether freehand biopsies can be done, PACS compatibility, image measurement capabilities, costs or confirmation of regulatory approval.\n\n## KOELIS Trinity\n\nThe KOELIS Trinity (KOELIS and Kebomed) is a mobile ultrasound system with mapping fusion software. It comprises PROMAP\xa03D‑Prostate Suite software and the Trinity ultrasound system (workstation, ultrasound probes, guides specific to transperineal or transrectal biopsies, and a probe holder). The system uses elastic and rigid estimation to account for changes in the shape of the prostate during the procedure, and supports transrectal and transperineal biopsies. It supports stabilised and freehand probe biopsies. The software identifies and compensates for patient movements and changes in the shape of the prostate during the procedure to record each core location.\n\nThe PROMAP software produces a 3D\xa0map of the prostate, recording the position of MRI lesion targets and the locations of biopsy samples. The KOELIS Trinity system provides image measurements such as prostate volume, measurements of the regions of interest and other quantitative measurements from the image. Data can be transferred to a PACS. The system costs £23,620, plus £39,948 for transrectal software, £41,754 for transperineal software, and £45,000 for the ultrasound components.\n\n## UroNav\n\nThe UroNav (Phillips) comprises an electromagnetic tracking system, a mobile workstation and DynaCAD Prostate fusion software. The system is compatible with third-party ultrasound systems. It supports transperineal and transrectal biopsies, with stabilised or freehand approaches. The system uses elastic and rigid estimation methods to create 3D images to account for changes in the shape of the prostate during the procedure. The system can be used with a mobile stepper system and 2\xa0navigation sensors to track any movement the person makes.\n\nThe UroNav system provides core location data, images and videos. It works with DynaCAD Prostate fusion software, an image analysis and reporting tool. No information was received from the company on PACS compatibility or costs.\n\n# The comparator\n\nThe comparator for the evaluation is targeted transperineal or transrectal prostate biopsy using cognitive fusion biopsy (using an MRI image to visually estimate the location of interest) with or without systematic biopsy, under local or general anaesthesia.", 'Committee discussion': "The diagnostics advisory committee considered evidence on MRI fusion biopsy systems using Artemis, Biojet, BiopSee, bkFusion, Fusion Bx\xa02.0, FusionVu, iSR'obot Mona Lisa, KOELIS Trinity and UroNav from several sources, including a diagnostics assessment report and an overview of that report. Full details are in the project documents for this guidance.\n\n# Benefits of the technology for people with suspected prostate cancer\n\nPatient experts explained that technologies that help correctly diagnose prostate cancer could reduce the number of missed cancers and repeat biopsies. Overtreatment was highlighted as a particular issue and concern for patients. During consultation on the draft guidance, a stakeholder further highlighted concerns that higher rates of overdiagnosis from using MRI fusion could lead to potentially higher levels of overtreatment. Any reduction in the number of samples taken during the biopsy could lower the likelihood of biopsy-related complications. Any reduction in the need for further biopsies would help avoid some of the stress and anxiety associated with this. The external assessment group (EAG) stated that there is no evidence of a significant difference in safety outcomes between biopsies done with MRI fusion and cognitive fusion, but that the evidence is limited by poor reporting and at high risk of confounding because of differences in biopsy routes and anaesthesia methods. The patient experts also highlighted that a shorter procedure time could help to preserve dignity and minimise stress and anxiety during the biopsy. During consultation on the EAG's report, stakeholders highlighted the importance of minimising the biopsy procedure time and pain or discomfort, particularly for biopsies under local anaesthetic. They added that stress and anxiety over the biopsy can lead to a poor experience for the person, which can deter them from having additional procedures.\n\n# Clinical effectiveness\n\n## Benefits of MRI fusion biopsy systems from the trials\n\nThe committee agreed that the evidence for MRI fusion technology looked promising, but that there was a lot of uncertainty around the performance of the technology when compared with cognitive fusion. The EAG's network meta-analyses used pooled data from different MRI fusion technologies for its base-case analysis. The results suggested that MRI fusion, compared with cognitive fusion, may detect more International Society of Urological Pathology (ISUP) grade\xa02 or higher prostate cancer. But whether MRI fusion truly detected more higher-grade cancer, and if so by how much, was very uncertain. The EAG explained that few studies in the meta-analysis included people with higher-grade cancer, and few cases were detected in these studies.\n\nThe committee discussed the limitations of the clinical evidence included in the EAG's meta-analyses. None of the studies were done in the UK. The EAG judged all studies used in the meta-analysis to be at high risk of bias, and it stated that no high-quality randomised controlled trials have been published. The meta-analyses also showed moderate heterogeneity that could not be explained by differences in individual MRI fusion biopsy systems.\n\n## Performance differences between the different MRI fusion biopsy systems\n\nThe committee was uncertain how appropriate it was to use data generated using 1\xa0system to show the performance of others. There was limited data directly comparing the different systems, and evidence levels varied across the different MRI fusion technologies. The EAG combined data from different technologies in its base-case analysis, based on advice from clinical experts. The committee noted that there are fundamental differences between the MRI fusion biopsy systems, which may influence outcomes. Only 2\xa0MRI fusion systems had more than 1\xa0study included in the meta-analysis. For 1\xa0of these (KOELIS Trinity), all studies used a previous version of the software included in the current device. The company commented that the KOELIS Trinity uses an updated version of the same software included in the KOELIS Urostation (which is now discontinued). The EAG did not identify any evidence for Fusion Bx\xa02.0 or FusionVu, and none of the identified studies for the bkFusion or ISR'obot Mona Lisa met the inclusion criteria for the meta-analysis. The EAG stated that evidence was insufficient to conclude whether any MRI fusion biopsy systems were superior to others.\n\n## Potential impact on waiting times of adopting MRI fusion biopsy systems\n\nThe committee considered that adopting MRI fusion biopsy systems could prolong waiting time for prostate biopsies, and that this was not captured in the cost-effectiveness estimates. The clinical experts explained that radiologist services are at full capacity in the NHS. Clinical experts with experience using MRI fusion biopsy systems highlighted that more preparatory time is needed per biopsy with MRI fusion than with cognitive fusion, although this does decrease with more experience in using the technology. This lowers the number of biopsies that can be done in a day. In its economic model, the EAG assumed that additional procedure time for MRI fusion use would be 10\xa0minutes in a high throughput centre (5\xa0minutes radiologist time to import and obtain appropriate MRI sequences and 5\xa0minutes during the biopsy), based on expert advice. It was suggested that this would be longer when the technologies were first used, because of lack of experience. The additional time was added to the cost of doing MRI fusion biopsy in the model (for example, for staff time), but the model did not include any impact of this on slowing biopsy throughput. The clinical experts commented that MRI fusion could improve patient throughput if it reduced the repeat biopsies needed (for example, if there was more confidence in a negative biopsy). The EAG commented that how much MRI fusion increases wating times would depend on whether the capacity constraint was access to the biopsy procedure or to the initial MRI (which would be the same for MRI fusion and cognitive fusion biopsy). The committee was also concerned about how adopting software fusion technology could potentially impact how many biopsy procedures can be done per day, and consequently the effect on waiting times for this procedure.\n\n# Cost effectiveness\n\n## Improving detection of higher-grade prostate cancer makes the technology more cost effective in the model\n\nThe cost-effectiveness estimates for MRI fusion biopsy systems (with or without systematic biopsy), compared with cognitive fusion, were generally favourable, but uncertain. Potential adverse impacts on the capacity of services to do biopsies (see section\xa03.5) were not considered in the model. The EAG's analysis showed that cost effectiveness was most affected by the improved detection of localised or locally advanced higher-grade cancers (ISUP\xa02\xa0or higher). When targeted fusion was combined with systematic biopsy, there were more cost savings and health benefits in the long-term model for MRI fusion than for cognitive fusion.\n\nThe EAG cautioned that the uncertainties in the clinical evidence should be considered alongside the overall cost effectiveness, because the evidence used in its network meta-analysis underpinned its economic model. The committee recalled that although the data suggested that MRI fusion may detect more higher-grade cancers, this was very uncertain (see section\xa03.2). It noted that a scenario analysis done by the EAG in which any benefit to detecting cancer for MRI fusion was removed from the model, the incremental cost-effectiveness ratios (ICERs) increased to over £500,000 per quality-adjusted life year (QALY) gained. The committee concluded that the uncertainty about how much better MRI fusion is at detecting higher-grade cancers means that the cost effectiveness of these technologies, while potentially favourable, is also very uncertain.\n\n## Benefits to less experienced health professionals\n\nThe committee acknowledged that the technology could benefit less experienced healthcare professionals, and help to standardise care across different centres and improve accessibility. The clinical experts noted that biopsies are done by various healthcare professionals including urologists, radiologists and nurse specialists. The level of experience in doing biopsies varies, and specialist centres are more likely to have professionals with more experience. They suggested that the accuracy of cognitive fusion is highly dependent on the operator. The EAG identified 1\xa0study that reported cancer biopsy positivity rates by operator experience (Stabile et al.\xa02018). It reported an increase in the biopsy positivity rates in the first 60\xa0procedures, where it plateaued, regardless of the biopsy approach. Operator experience predicted the biopsy positivity rate of targeted biopsies, particularly for transrectal MRI fusion biopsy compared with transrectal cognitive fusion or transperineal MRI biopsy fusion.\n\nThe clinical experts suggested that using MRI fusion biopsy systems could help standardise biopsy quality. They said that this could minimise geographical variation in procedure standard caused by the variation in operator expertise. Improving the ability of less experienced operators to do the procedure may allow it to be available more widely, improving accessibility.\n\n## MRI fusion biopsy systems show promise, but better-quality evidence is needed\n\nThe committee recognised that MRI fusion biopsy systems show promise, could help improve standards across the NHS and patient access (see section\xa03.9), and may be cost effective. But it felt there was too much uncertainty about how much it would improve detection of prostate cancer to recommend its use for routine adoption (see sections\xa03.6\xa0and\xa03.7). Further research is needed to reduce this uncertainty, and so also reduce the uncertainty about the cost effectiveness. The committee was also concerned about how adopting MRI fusion technology could potentially impact how many biopsy procedures can be done per day, and consequently the effect on waiting times for this procedure (see section\xa03.5). Further data on this would help reduce concerns about the impact of adopting MRI fusion biopsy systems.\n\n# Research considerations\n\n## An ongoing study may fill some evidence gaps\n\nThe ongoing IP7-PACIFIC trial (see trial NCT05574647 on the ClinicalTrials.gov website, accessed 14\xa0November\xa02022) is likely to provide further, potentially high-quality, data on MRI fusion biopsy systems for detecting clinically significant prostate cancers, compared with cognitive fusion biopsy. The primary outcome of the trial is the proportion of clinically significant cancers (defined as ISUP\xa02 or above) detected in people who had a biopsy with a suspicious MRI (MRI score 3,\xa04\xa0or\xa05 on either the Likert or Prostate Imaging-Reporting and Data System [PI-RADS] schema). The EAG commented that the study aims to recruit 3,600\xa0people with suspected prostate cancer in the UK, but that not all of these people will provide data on MRI fusion performance (the study includes 2\xa0linked randomised controlled trials, and is also comparing biparametric and multiparametric MRI to detect clinically significant prostate cancers). The EAG emphasised that to help inform cost-effectiveness estimates from its model, the numbers of cancer detected by ISUP grade should be reported (rather than just the number of ISUP grade\xa02 or higher). During consultation on the draft guidance, a stakeholder further highlighted the importance of collecting data on the effect of MRI fusion technologies on detecting clinically insignificant prostate cancer, as well as higher-grade cancers. Given the uncertainty about the generalisability of data generated using 1\xa0MRI fusion technology to others (see section\xa03.4), it would be beneficial if data was reported separately for each MRI fusion biopsy system. The committee concluded that this will be a useful trial for reducing uncertainty about MRI fusion biopsy performance, but noted that the estimated study completion data is not until 2026. It stated that people should be encouraged to participate in the trial.\n\n## Existing data and resources to collect data\n\nThe clinical experts highlighted that professional bodies such as the British Association of Urological Surgeons and the Royal College of Radiologists may have data that could contribute to a future assessment. They also suggested that establishing further registries may help data collection. The committee suggested that centres should consider contributing to existing audit tools such as the National Prostate Cancer Audit when possible.", 'Recommendations for further research': 'Further research is recommended to determine the impact of MRI fusion biopsy systems compared with cognitive fusion biopsy on the detection of different grades of prostate cancer.\n\nFurther data collection or research is recommended on the impact of implementing MRI fusion biopsy systems on the rate at which biopsies can be done, capacity resources and waiting times for this procedure.'}	https://www.nice.org.uk/guidance/dg53	Evidence-based recommendations on MRI fusion biopsy systems for diagnosing prostate cancer.
e64b1dcb5c1f12aea3f03388c4db7dc9d561b4f8	nice	Automated ankle brachial pressure index measurement devices to detect peripheral arterial disease in people with leg ulcers	Automated ankle brachial pressure index measurement devices to detect peripheral arterial disease in people with leg ulcers Evidence-based recommendations on automated ankle brachial pressure index measurement devices to detect peripheral arterial disease in people with leg ulcers. # Recommendations There is not enough evidence to recommend routine adoption of automated ankle brachial pressure index (ABPI) measurement devices to detect peripheral arterial disease in people with leg ulcers. They should only be used in the context of research for these people. Centres already using automated ABPI measurement devices to detect peripheral arterial disease in people with leg ulcers can continue to use them, only if: they collect data or do research to assess their value and how well they identify people with peripheral arterial disease (see the section on further research) people using the devices have experience assessing peripheral arterial disease people using the devices are aware of their limitations, particularly diagnostic accuracy and the risk of missing peripheral arterial disease, and that there are differences between devices further assessment using other methods, including manual doppler, is available. Further research is recommended on automated ABPI measurement devices (see the section on further research) to: assess their ability to detect peripheral arterial disease in people with leg ulcers assess how they affect time to treatment for venous leg ulcers assess clinical outcomes for treatments started after ABPI assessment explore the most appropriate user (specialist and non-specialist in assessing peripheral arterial disease) and the most appropriate healthcare setting for their use explore whether different ABPI thresholds can improve their sensitivity for detecting peripheral arterial disease. Why the committee made these recommendations Treatment for leg ulcers caused by a problem with blood flow in the veins (venous) involves compression therapy with bandages or stockings. Compression therapy is not suitable for some people with peripheral arterial disease because it could disrupt blood flow to the leg. Measuring ABPI as part of a clinical assessment can help detect if someone has peripheral arterial disease and therefore should not have compression therapy. Currently, ABPI is measured and calculated manually. The assessment takes up to 1 hour and can be uncomfortable for people with leg ulcers. Automated ABPI measurement devices may potentially be easier and faster to use than manual doppler measurement, and more comfortable for people with leg ulcers. But there is limited evidence on whether automated devices can reduce the length of time an ABPI assessment takes. There is a lack of clinical evidence on automated ABPI measurement devices and most studies were done in people without leg ulcers. So, it is unclear how well automated devices detect peripheral arterial disease in people with leg ulcers. There is also uncertainty about which healthcare setting the devices should be used in (for example, hospital or community) and who should use them (specialist or non-specialist in assessing peripheral arterial disease). It is therefore unclear: whether automated devices reduce the length of time before starting treatment for venous leg ulcers how inaccurate test results impact clinical decision making and health outcomes. Economic modelling shows that automated ABPI devices are unlikely to be cost effective compared with manual doppler measurement unless they reduce the length of time before treatment starts, which is uncertain. The results of the economic model are also uncertain because there is no evidence on how results from automated ABPI measurement devices affect clinical decision making or clinical outcomes. So, automated ABPI measurement devices are only recommended in the context of research. Centres already using the devices can continue to use them if they do research and ensure safety.# The diagnostic tests # Clinical need and practice ## The condition Leg ulcers are slow-healing wounds that usually develop on the inside of the leg, just above the ankle. It is estimated that about 1 million or 2% of adults in the UK have a leg ulcer (Guest et al. 2020). Around 65% of leg ulcers are venous, meaning they are caused by a problem in the blood flow in the veins. Treatment involves using compression such as bandages or stockings. Strong compression therapy can disturb the arterial blood supply in the leg, so it should not be offered to people with peripheral arterial disease. People with peripheral arterial disease may not have any symptoms, but it can lead to serious complications such as chronic limb-threatening ischaemia. In this condition, loss of blood supply to the leg causes tissue to die and there is a significant risk of losing a limb and premature death. ## Care pathway The National Wound Care Strategy Programme (NWCSP) recommendations for lower limb ulcers advise using the ankle brachial pressure index (ABPI) to screen for peripheral arterial disease in people with leg ulcers alongside a full clinical assessment. This is currently measured manually using a handheld doppler ultrasound probe. People with leg ulcers may present in primary care. NWCSP guidance recommends that immediate care for ulcers should include cleaning, application of emollient and a simple low-adherent dressing. In the absence of any 'red flag symptoms' (such as infection, symptoms of sepsis, ischaemia, suspected deep vein thrombosis or skin cancer), mild graduated compression should be applied until full clinical assessment and ABPI measurement can take place. However, if there are not enough staff able to do manual doppler assessment, delayed assessment may lead to longer periods without compression or sub-optimal compression. Clinical experts noted that in practice some practitioners are uncomfortable applying even mild compression without ABPI measurement. People should be offered a full clinical assessment within 14 days of initial presentation, but clinical experts noted this is a challenge and it can take substantially longer in some areas. ## Potential value of the technologies Automated ABPI measurement devices may be easier to use than manual devices. This may reduce the time needed to complete the assessment and make ABPI measurement more comfortable for people with leg ulcers. A further potential benefit could be a reduction in the time to assessment and, consequently, treatment for people with venous ulcers when there are not enough staff able to do manual doppler assessment. # The interventions Automated ABPI devices include doppler-based, oscillometry-based and plethysmography-based devices. Doppler-based devices use a doppler probe and provide doppler waveform signals as an output. Oscillometry-based devices assess oscillations in the vessel wall, and plethysmography-based devices assess blood volume changes. These devices either estimate blood pressure directly or use a pressure cuff to help with the measurement. Diabetes, rheumatoid arthritis, systemic vasculitis, atherosclerotic disease and advanced chronic renal failure can cause calcium build-up and hardening of the arteries, which can make ABPI measurements appear misleadingly normal. Clinical experts highlighted the value of information provided by doppler waveform signals in these situations. Devices that do not provide doppler waveform signals may provide information about the quality of arterial circulation in the ankles, but there is uncertainty about whether these alternative outputs are comparable with doppler waveform signals. This evaluation considers 7 automated devices for measuring ABPI and assessing arterial circulation (see table 1). Costs shown in table 1 exclude VAT and include the cost of the equipment and other fixed costs such as purchase of additional cuffs to complete the set, and software when applicable. Automated device Technology Component Resting period needed Cost (£ per unit) BlueDop Vascular Expert Doppler Handheld doppler device No rest boso ABI-system 100 Oscillometry arm cuffs ankle cuffs minutes Dopplex Ability Plethysmography dual-chamber cuffs No rest MESI ABPI MD Plethysmography Oscillometry cuffs No rest MESI mTABLET ABI Plethysmography Oscillometry wireless cuffs minutes WatchBP Office ABI Oscillometry cuffs minutes WatchBP Office Vascular Oscillometry cuffs minutes # The comparators Currently, ABPI is measured in people with leg ulcers during initial clinical assessment. Blood pressure is measured using a handheld doppler ultrasound probe and a sphygmomanometer with a manually inflated cuff. The ABPI is calculated manually. People with leg ulcers need to lie down before and throughout the test. The test takes up to 1 hour and may be painful and uncomfortable for people with leg ulcers. ABPI measurement is typically done by district or community nurses at a person's home, care home or a leg ulcer clinic, or by practice nurses at GP practices. This is when they are trained in doing both the full clinical assessment and ABPI measurement. In some parts of the country, leg ulcer clinics are in use, or are being implemented. Some clinics may already do, or increasingly do in the future, initial ABPI assessment. In areas without enough practitioners trained to do manual doppler measurements, people may have initial ulcer care and then be referred to specialist vascular services for the full clinical assessment. The reference standard for detecting peripheral arterial disease is imaging such as duplex ultrasound, magnetic resonance angiography or CT angiography. However, these would not be used as part of the initial clinical assessment in practice.# Committee discussion The diagnostics advisory committee considered evidence on automated devices for measuring ankle brachial pressure index (ABPI) and assessing arterial circulation using one of the following: BlueDop Vascular Expert (BlueDop Medical) boso ABI-system 100 (BOSCH + SOHN) Dopplex Ability Automatic ABI System (Huntleigh Healthcare) MESI ABPI MD (MESI) MESI mTABLET ABI (MESI) WatchBP Office ABI (Microlife) WatchBP Office Vascular (Microlife). Evidence was considered from several sources, including a diagnostics assessment report and an overview of that report. Full details are in the project documents for this guidance. # Benefits of the technology ## Leg ulcers can be painful and ABPI assessment can be uncomfortable A patient expert explained that leg ulcers are unpleasant and painful. There is anxiety and shame about their appearance, which can lead to depression. Manual assessment for ABPI can cause pain and discomfort. People with leg ulcers often have mobility issues, making it difficult to travel to appointments, particularly if they are in a specialist setting. They noted a potential benefit of the automated devices is a shorter ABPI assessment, which may reduce discomfort for the person being assessed. A company also noted that their product was cuffless, which may increase comfort for people having ABPI assessment. The committee acknowledged that this was plausible but noted that there is no data available to demonstrate this. The patient expert also noted that automated devices may increase ease of carrying out the assessment in a home setting if they can be used more widely in primary and community care by staff less experienced in assessing peripheral arterial disease. This would improve access to the assessment for those less able to travel. ## Waiting times for ABPI assessment can be long, which may delay appropriate treatment A patient expert explained that it can take a long time between referral and ABPI assessment for peripheral arterial disease, which can cause anxiety, and that waiting times vary geographically. Clinical experts agreed that access to ABPI assessment varies across the UK, with people waiting between 2 weeks and 12 weeks for an appointment. The National Wound Care Strategy Programme (NWCSP) recommendations for lower limb ulcers advise applying mild compression while waiting for the full clinical assessment (including ABPI assessment) if peripheral arterial disease is not initially suspected. However, a clinical expert noted that this often does not happen in practice and that only about 25% of people with leg ulcers have mild compression before full clinical assessment. The NWCSP preventing and improving care of chronic lower limb wounds: implementation case reports that most people with leg ulcers have venous leg ulcers (about 65%). So, delays in ABPI assessment can delay starting treatment. The committee heard that one of the claimed benefits of the automated devices is improved access to ABPI assessment. This could lead to quicker treatment and healing of the leg ulcer for people without peripheral arterial disease. Clinical experts noted that the devices may be of more benefit in areas with limited availability of healthcare professionals able to do manual doppler assessment. The committee concluded that if evidence shows the automated devices lead to earlier access to treatment, then this could improve healing time and would be of substantial benefit. # Clinical effectiveness ## How the automated devices fit into the care pathway is unclear The committee discussed how the automated devices might be used in different settings or by staff with less expertise in ABPI measurement, including in primary care and the community. Clinical experts advised that if the devices could be safely used by staff with less expertise then this could improve time to assessment and therefore treatment and healing. It was noted that care pathways are evolving and that, in some parts of the country, tissue viability-led, dermatology-led or vascular service-led leg ulcer clinics are in use or are being implemented. These may increasingly do initial ABPI assessment. Clinical experts questioned whether treatment for venous leg ulcers could still be started alongside ABPI assessment if the automated devices are used in settings or by people with less expertise in ABPI measurement. The clinical experts highlighted that some treatments such as compression stockings needed less expertise but that others such as bandaging may still require a specialist to apply them. Therefore, in these cases, there may be no improvement in time to treatment even if the ABPI measurement could be done earlier. Most of the studies on using the automated devices were done in specialist settings. Clinical experts advised that this could impact the generalisability of the results to other, less-specialist settings. The committee noted that one of the studies (Green et al. 2020) identified by the external assessment group (EAG) was done in GP practices. The study reported that GPs thought that using the automated device improved clinical management of leg ulcers. However, it also reported that the GPs had concerns about whether they had time available and whether it was within their remit to assess wounds. Clinical experts commented that the number of ABPI assessments done in GP practices may vary widely and some may not do enough ABPI assessments to justify purchasing an automated device. The committee concluded that it is unclear where in the care pathway it is best to use the devices. It agreed that automated devices could have substantial benefits for people with leg ulcers. This is if they could be safely used in a wider range of settings or by a greater number of healthcare professionals, and if they lead to earlier access to treatment. ## The diagnostic accuracy evidence available for automated ABPI devices is not generalisable to people with leg ulcers The committee noted that only 2 observational studies from the 24 studies identified were in people with leg ulcers (1 study excluded marked oedema) and these did not report diagnostic accuracy data (sensitivity or specificity). The EAG extracted diagnostic accuracy data from 22 studies in people without leg ulcers, 6 of which reported results for people with diabetes. Clinical experts were concerned about the generalisability of these studies to the leg ulcer population because taking measurements in people with leg ulcers may be more difficult, particularly when they have oedema or swollen limbs. People with leg ulcers are more likely to have these complications and clinical experts advised that, in their experience, technical failure (failure of the device to produce a result) is more likely in people with oedema. They also commented that in their experience, technical failure is more likely in people with peripheral arterial disease, and this was seen in some of the studies. The committee noted that prevalence of peripheral arterial disease in the studies varied widely. Because of this, it is likely that the accuracy data in the available studies is not applicable to people with leg ulcers. There was also limited evidence of use of the devices in people with diabetes or other conditions associated with an increased risk of leg ulcers. These conditions can cause hardening of the arteries, which can make the ABPI result appear misleadingly normal. Consequently, there is considerable uncertainty about the accuracy of the test in these populations. The committee concluded that the diagnostic accuracy data on the automated devices could not be generalised to a leg ulcer population, so there is considerable uncertainty about the diagnostic accuracy of the devices in this population. ## Automated devices may increase risk of inappropriate treatment in people with peripheral arterial disease The committee discussed the accuracy of the automated devices. It commented that data suggested automated devices generally had good specificity but only moderate sensitivity for detecting peripheral arterial disease. The EAG report suggested that the automated devices tend to overestimate ABPI, which could lead to cases of peripheral arterial disease being missed. This could mean some people have inappropriate compression, causing harm. It noted, however, that some of the differences seen between the results from the automated devices and from manual doppler may not have been clinically significant. Clinical experts further noted that NWCSP guidance states that ABPI assessment should be done by someone with expertise to recognise symptoms of and red flags for peripheral arterial disease. There was concern that these red flags could be missed if automated devices were used in settings or by staff with less expertise in assessing peripheral arterial disease. This, combined with the suggested lower sensitivity of the automated devices, could cause cases of peripheral arterial disease to be missed, leading to inappropriate treatment and harm for people with arterial leg ulcers. Clinical experts also highlighted that ABPI results may be unreliable in people with certain comorbidities, such as diabetes. It is important that other outputs such as doppler waveform are used to validate the ABPI result in these cases. Some automated devices provide additional outputs such as doppler waveforms or similar, but interpreting doppler waveforms is a specialist skill, so staff with less experience in assessing peripheral arterial disease may still misinterpret it. The EAG confirmed that accuracy data reported in the studies was based on ABPI result alone and that no studies reporting on the use of other outputs of the devices or the impact of test results on clinical decision making were identified. Therefore, no conclusions could be drawn on the impact of the use of the devices on clinical decision making, but there was concern that cases of peripheral arterial disease would be missed because of an inaccurate result. The committee concluded that future studies should look at how the test result is used to direct treatment so that the impact of false results on clinical decisions can be fully understood. ## Impact of the automated devices on health outcomes is uncertain The committee heard that no evidence looking at the impact of inaccurate test results on clinical outcomes was found. Therefore, the impact of inaccurate test results on health outcomes is uncertain. Clinical experts discussed that inappropriate compression treatment of leg ulcers in people with peripheral arterial disease could risk harm. They also noted that misdiagnosing people with peripheral arterial disease could cause unnecessary delays to the treatment of venous leg ulcers. The committee concluded that the impact of misdiagnosis is uncertain but that consequences could be more severe for people with peripheral arterial disease. However, people with peripheral arterial disease would represent a smaller proportion of the population with leg ulcers (see section 3.2). The committee noted that it would be helpful to have further information on how incorrect results impact health outcomes, to inform decision making in the future. ## Impact of the automated devices on time to treatment is uncertain The committee discussed whether the use of automated devices in alternative settings or by staff with less specialist expertise could improve access to ABPI assessment and therefore reduce time to treatment and improve ulcer healing for some people (see section 3.2). It heard that there were no studies looking at the effect of automated devices on time to assessment or time to treatment. One study in people with leg ulcers reported that GPs felt that using the MESI ABPI MD automated device improved clinical management (Green et al. 2020). However, other studies were done in specialist settings. Clinical experts advised that the impact of the devices on time to treatment would depend on the setting and availability of expertise and that this varies widely across the country. They also noted it would depend on whether there was enough expertise in these settings to start treatment of leg ulcers in people without peripheral arterial disease more quickly (see section 3.3). The committee concluded that the devices may improve access to ABPI assessment and may therefore improve time to ulcer treatment and healing. However, no evidence was identified. ## The impact of automated devices on the time taken for ABPI assessment is uncertain The committee discussed how long the ABPI assessment takes and noted that evidence suggests automated devices can reduce the duration of the assessment. Patient experts explained that this may make assessments more comfortable for people with leg ulcers and could increase access to ABPI assessment by increasing the number of people who can be assessed. The committee heard that studies reported that most people with leg ulcers found the automated devices acceptable, but some felt discomfort when the cuff was fully inflated. It also heard that time taken for assessments was not consistently reported across studies and generally assessments with automated devices were only a few minutes faster than manual assessments. Clinical experts questioned whether the amount of time saved was enough to have a meaningful impact. They also noted that technical failure of the automated devices could mean manual doppler would then need to be done, increasing the length of the overall assessment. One clinical expert who had used an automated device as part of an evaluation confirmed that technical failure resulted in a longer assessment time in their experience. This could occur more often in people with peripheral arterial disease, oedema, diabetes or other conditions that cause calciphylaxis in tissues (see section 3.4). However, consultation comments submitted by a large community service provider that uses automated devices suggested that they could halve the assessment time compared with manual doppler. The committee concluded that evidence suggests automated devices reduce the time taken for ABPI assessment but that the amount of time saved and the impact of this are uncertain. # Cost effectiveness ## Automated devices are unlikely to be cost effective unless they reduce time to treatment The committee noted that the economic model results suggested that automated devices were unlikely to be cost effective unless improved access to ABPI assessment and treatment could be shown (see section 3.3). No evidence was identified to suggest that automated devices may speed up access to treatment (see section 3.7). The committee concluded that there is potential for the devices to be cost effective. However, there is currently not enough evidence on whether they improve time to treatment or ulcer healing. ## Economic model results are very uncertain The committee noted that there were substantial uncertainties in the economic model because of a lack of data to inform key model inputs. The model results appeared highly sensitive to improvements in ulcer healing time for venous ulcers (because of quicker access to treatment). The impact of inaccurate test results on clinical decision making and clinical outcomes was highly uncertain because no evidence was identified to inform these inputs in the model (see section 3.6). Clinical expert opinion was used to inform these inputs in the model. The committee further noted that diagnostic accuracy estimates in the model were based on single studies for each of the devices and these studies were done in people without leg ulcers (see section 3.4). The EAG advised that it pooled data on the devices when possible but that it did not consider the results to be robust because of the differences between studies. Only 2 devices had enough studies to allow for pooling of data and this reduced the sensitivity of both devices (MESI ABPI MD and WatchBP Office ABI). It therefore opted to use single estimates in the model. The committee concluded that evidence on the impact of the automated devices on clinical decision making or clinical outcomes would improve the robustness of the economic model results. Therefore, the devices can only be recommended for use in the context of research. Consultation comments submitted by a large community service provider highlighted that automated devices are already used in practice. Clinical experts commented that they were also aware that automated devices are used in some local areas and specialist services. The committee agreed that automated devices already purchased by the NHS and implemented within a care pathway can continue to be used, only if centres using them collect data to show their impact on people with leg ulcers. This is provided that people using the automated devices are aware of the: limitations of the devices lack of evidence showing the accuracy of the devices for detecting peripheral arterial disease in people with leg ulcers risk of missing peripheral arterial disease if devices are not used alongside a full clinical assessment by someone with experience assessing peripheral arterial disease. # Research considerations ## Consideration of the most appropriate care pathway is needed The committee considered that a key benefit of the automated devices could be improvements in time to treatment and healing of venous ulcers (see section 3.2). However, this could depend on how and where the devices are used in the care pathway and the availability of expertise. Clinical experts questioned whether staff with less expertise would be able to start some of the treatments such as compression bandaging for people identified as having venous leg ulcers (see section 3.3). They also raised concerns about whether less-experienced healthcare professionals would be able to perform a holistic assessment of the ulcer and recognise red flags for peripheral arterial disease (see section 3.5). The committee concluded that consideration of the most appropriate place for the automated devices in the care pathway was needed and that studies should be done in these settings. ## Consideration of alternative thresholds may be helpful The committee acknowledged that the EAG's report extracted data from some studies that looked at the optimal threshold for the automated devices. These studies reported that using an ABPI threshold higher than the commonly used value of 0.9 could improve sensitivity and therefore reduce the risk of missing peripheral arterial disease. The committee noted that it is possible that an alternative threshold may help prevent inappropriate treatment and associated consequences in some cases (see section 3.5). However, clinical experts advised that higher thresholds are not currently used in practice and they would therefore need validating in independent studies in people with leg ulcers.# Recommendations for further research # Diagnostic accuracy The committee recommends more research on diagnostic accuracy in people with leg ulcers. The following considerations should be made when doing this research: where the devices would be used in clinical practice and by who (specialist and non-specialist users; see section 3.11) the most appropriate threshold for the automated measurement (see section 3.12); if an alternative threshold to the currently established threshold is being researched, then a prespecified threshold should be used and research should be done in a population not used to derive this threshold (external validation) whether using additional outputs from other devices such as doppler waveform and pulse volume waveform impacts clinical decision making (see section 3.5). # Time to treatment The committee recommends collecting further data on the impact of the automated devices on time to treatment for people with leg ulcers to reduce uncertainty in the economic modelling. # Clinical outcomes The committee recommends collecting further data on clinical outcomes such as time to healing, and incorrect use of compression and its associated adverse consequences when possible.	{'Recommendations': 'There is not enough evidence to recommend routine adoption of automated ankle brachial pressure index (ABPI) measurement devices to detect peripheral arterial disease in people with leg ulcers. They should only be used in the context of research for these people.\n\nCentres already using automated ABPI measurement devices to detect peripheral arterial disease in people with leg ulcers can continue to use them, only if:\n\nthey collect data or do research to assess their value and how well they identify people with peripheral arterial disease (see the section on further research)\n\npeople using the devices have experience assessing peripheral arterial disease\n\npeople using the devices are aware of their limitations, particularly diagnostic accuracy and the risk of missing peripheral arterial disease, and that there are differences between devices\n\nfurther assessment using other methods, including manual doppler, is available.\n\nFurther research is recommended on automated ABPI measurement devices (see the section on further research) to:\n\nassess their ability to detect peripheral arterial disease in people with leg ulcers\n\nassess how they affect time to treatment for venous leg ulcers\n\nassess clinical outcomes for treatments started after ABPI assessment\n\nexplore the most appropriate user (specialist and non-specialist in assessing peripheral arterial disease) and the most appropriate healthcare setting for their use\n\nexplore whether different ABPI thresholds can improve their sensitivity for detecting peripheral arterial disease.\n\nWhy the committee made these recommendations\n\nTreatment for leg ulcers caused by a problem with blood flow in the veins (venous) involves compression therapy with bandages or stockings. Compression therapy is not suitable for some people with peripheral arterial disease because it could disrupt blood flow to the leg. Measuring ABPI as part of a clinical assessment can help detect if someone has peripheral arterial disease and therefore should not have compression therapy.\n\nCurrently, ABPI is measured and calculated manually. The assessment takes up to 1\xa0hour and can be uncomfortable for people with leg ulcers. Automated ABPI measurement devices may potentially be easier and faster to use than manual doppler measurement, and more comfortable for people with leg ulcers. But there is limited evidence on whether automated devices can reduce the length of time an ABPI assessment takes.\n\nThere is a lack of clinical evidence on automated ABPI measurement devices and most studies were done in people without leg ulcers. So, it is unclear how well automated devices detect peripheral arterial disease in people with leg ulcers. There is also uncertainty about which healthcare setting the devices should be used in (for example, hospital or community) and who should use them (specialist or non-specialist in assessing peripheral arterial disease). It is therefore unclear:\n\nwhether automated devices reduce the length of time before starting treatment for venous leg ulcers\n\nhow inaccurate test results impact clinical decision making and health outcomes.\n\nEconomic modelling shows that automated ABPI devices are unlikely to be cost effective compared with manual doppler measurement unless they reduce the length of time before treatment starts, which is uncertain. The results of the economic model are also uncertain because there is no evidence on how results from automated ABPI measurement devices affect clinical decision making or clinical outcomes. So, automated ABPI measurement devices are only recommended in the context of research. Centres already using the devices can continue to use them if they do research and ensure safety.', 'The diagnostic tests': "# Clinical need and practice\n\n## The condition\n\nLeg ulcers are slow-healing wounds that usually develop on the inside of the leg, just above the ankle. It is estimated that about 1\xa0million or 2% of adults in the UK have a leg ulcer (Guest et al. 2020). Around 65% of leg ulcers are venous, meaning they are caused by a problem in the blood flow in the veins. Treatment involves using compression such as bandages or stockings. Strong compression therapy can disturb the arterial blood supply in the leg, so it should not be offered to people with peripheral arterial disease.\n\nPeople with peripheral arterial disease may not have any symptoms, but it can lead to serious complications such as chronic limb-threatening ischaemia. In this condition, loss of blood supply to the leg causes tissue to die and there is a significant risk of losing a limb and premature death.\n\n## Care pathway\n\nThe National Wound Care Strategy Programme (NWCSP) recommendations for lower limb ulcers advise using the ankle brachial pressure index (ABPI) to screen for peripheral arterial disease in people with leg ulcers alongside a full clinical assessment. This is currently measured manually using a handheld doppler ultrasound probe.\n\nPeople with leg ulcers may present in primary care. NWCSP guidance recommends that immediate care for ulcers should include cleaning, application of emollient and a simple low-adherent dressing. In the absence of any 'red flag symptoms' (such as infection, symptoms of sepsis, ischaemia, suspected deep vein thrombosis or skin cancer), mild graduated compression should be applied until full clinical assessment and ABPI measurement can take place. However, if there are not enough staff able to do manual doppler assessment, delayed assessment may lead to longer periods without compression or sub-optimal compression. Clinical experts noted that in practice some practitioners are uncomfortable applying even mild compression without ABPI measurement. People should be offered a full clinical assessment within 14\xa0days of initial presentation, but clinical experts noted this is a challenge and it can take substantially longer in some areas.\n\n## Potential value of the technologies\n\nAutomated ABPI measurement devices may be easier to use than manual devices. This may reduce the time needed to complete the assessment and make ABPI measurement more comfortable for people with leg ulcers. A further potential benefit could be a reduction in the time to assessment and, consequently, treatment for people with venous ulcers when there are not enough staff able to do manual doppler assessment.\n\n# The interventions\n\nAutomated ABPI devices include doppler-based, oscillometry-based and plethysmography-based devices. Doppler-based devices use a doppler probe and provide doppler waveform signals as an output. Oscillometry-based devices assess oscillations in the vessel wall, and plethysmography-based devices assess blood volume changes. These devices either estimate blood pressure directly or use a pressure cuff to help with the measurement. Diabetes, rheumatoid arthritis, systemic vasculitis, atherosclerotic disease and advanced chronic renal failure can cause calcium build-up and hardening of the arteries, which can make ABPI measurements appear misleadingly normal. Clinical experts highlighted the value of information provided by doppler waveform signals in these situations. Devices that do not provide doppler waveform signals may provide information about the quality of arterial circulation in the ankles, but there is uncertainty about whether these alternative outputs are comparable with doppler waveform signals.\n\nThis evaluation considers 7 automated devices for measuring ABPI and assessing arterial circulation (see table\xa01). Costs shown in table\xa01 exclude VAT and include the cost of the equipment and other fixed costs such as purchase of additional cuffs to complete the set, and software when applicable.\n\nAutomated device\n\nTechnology\n\nComponent\n\nResting period needed\n\nCost (£ per unit)\n\nBlueDop Vascular Expert\n\nDoppler\n\nHandheld doppler device\n\nNo rest\n\n,995\n\nboso ABI-system\xa0100\n\nOscillometry\n\narm cuffs\n\nankle cuffs\n\nminutes\n\n,187\n\nDopplex Ability\n\nPlethysmography\n\ndual-chamber cuffs\n\nNo rest\n\n,937\n\nMESI ABPI MD\n\nPlethysmography\n\nOscillometry\n\ncuffs\n\nNo rest\n\n,499\n\nMESI mTABLET ABI\n\nPlethysmography\n\nOscillometry\n\nwireless cuffs\n\nminutes\n\n,874\n\nWatchBP Office ABI\n\nOscillometry\n\ncuffs\n\nminutes\n\n,145\n\nWatchBP Office Vascular\n\nOscillometry\n\ncuffs\n\nminutes\n\n,445\n\n# The comparators\n\nCurrently, ABPI is measured in people with leg ulcers during initial clinical assessment. Blood pressure is measured using a handheld doppler ultrasound probe and a sphygmomanometer with a manually inflated cuff. The ABPI is calculated manually. People with leg ulcers need to lie down before and throughout the test. The test takes up to 1\xa0hour and may be painful and uncomfortable for people with leg ulcers.\n\nABPI measurement is typically done by district or community nurses at a person's home, care home or a leg ulcer clinic, or by practice nurses at GP practices. This is when they are trained in doing both the full clinical assessment and ABPI measurement. In some parts of the country, leg ulcer clinics are in use, or are being implemented. Some clinics may already do, or increasingly do in the future, initial ABPI assessment. In areas without enough practitioners trained to do manual doppler measurements, people may have initial ulcer care and then be referred to specialist vascular services for the full clinical assessment.\n\nThe reference standard for detecting peripheral arterial disease is imaging such as duplex ultrasound, magnetic resonance angiography or CT angiography. However, these would not be used as part of the initial clinical assessment in practice.", 'Committee discussion': "The diagnostics advisory committee considered evidence on automated devices for measuring ankle brachial pressure index (ABPI) and assessing arterial circulation using one of the following:\n\nBlueDop Vascular Expert (BlueDop Medical)\n\nboso ABI-system\xa0100 (BOSCH + SOHN)\n\nDopplex Ability Automatic ABI System (Huntleigh Healthcare)\n\nMESI ABPI MD (MESI)\n\nMESI mTABLET ABI (MESI)\n\nWatchBP Office ABI (Microlife)\n\nWatchBP Office Vascular (Microlife).\n\nEvidence was considered from several sources, including a diagnostics assessment report and an overview of that report. Full details are in the project documents for this guidance.\n\n# Benefits of the technology\n\n## Leg ulcers can be painful and ABPI assessment can be uncomfortable\n\nA patient expert explained that leg ulcers are unpleasant and painful. There is anxiety and shame about their appearance, which can lead to depression. Manual assessment for ABPI can cause pain and discomfort. People with leg ulcers often have mobility issues, making it difficult to travel to appointments, particularly if they are in a specialist setting. They noted a potential benefit of the automated devices is a shorter ABPI assessment, which may reduce discomfort for the person being assessed. A company also noted that their product was cuffless, which may increase comfort for people having ABPI assessment. The committee acknowledged that this was plausible but noted that there is no data available to demonstrate this. The patient expert also noted that automated devices may increase ease of carrying out the assessment in a home setting if they can be used more widely in primary and community care by staff less experienced in assessing peripheral arterial disease. This would improve access to the assessment for those less able to travel.\n\n## Waiting times for ABPI assessment can be long, which may delay appropriate treatment\n\nA patient expert explained that it can take a long time between referral and ABPI assessment for peripheral arterial disease, which can cause anxiety, and that waiting times vary geographically. Clinical experts agreed that access to ABPI assessment varies across the UK, with people waiting between 2\xa0weeks and 12\xa0weeks for an appointment. The National Wound Care Strategy Programme (NWCSP) recommendations for lower limb ulcers advise applying mild compression while waiting for the full clinical assessment (including ABPI assessment) if peripheral arterial disease is not initially suspected. However, a clinical expert noted that this often does not happen in practice and that only about 25% of people with leg ulcers have mild compression before full clinical assessment. The NWCSP preventing and improving care of chronic lower limb wounds: implementation case reports that most people with leg ulcers have venous leg ulcers (about 65%). So, delays in ABPI assessment can delay starting treatment. The committee heard that one of the claimed benefits of the automated devices is improved access to ABPI assessment. This could lead to quicker treatment and healing of the leg ulcer for people without peripheral arterial disease. Clinical experts noted that the devices may be of more benefit in areas with limited availability of healthcare professionals able to do manual doppler assessment. The committee concluded that if evidence shows the automated devices lead to earlier access to treatment, then this could improve healing time and would be of substantial benefit.\n\n# Clinical effectiveness\n\n## How the automated devices fit into the care pathway is unclear\n\nThe committee discussed how the automated devices might be used in different settings or by staff with less expertise in ABPI measurement, including in primary care and the community. Clinical experts advised that if the devices could be safely used by staff with less expertise then this could improve time to assessment and therefore treatment and healing. It was noted that care pathways are evolving and that, in some parts of the country, tissue viability-led, dermatology-led or vascular service-led leg ulcer clinics are in use or are being implemented. These may increasingly do initial ABPI assessment. Clinical experts questioned whether treatment for venous leg ulcers could still be started alongside ABPI assessment if the automated devices are used in settings or by people with less expertise in ABPI measurement. The clinical experts highlighted that some treatments such as compression stockings needed less expertise but that others such as bandaging may still require a specialist to apply them. Therefore, in these cases, there may be no improvement in time to treatment even if the ABPI measurement could be done earlier. Most of the studies on using the automated devices were done in specialist settings. Clinical experts advised that this could impact the generalisability of the results to other, less-specialist settings. The committee noted that one of the studies (Green et al. 2020) identified by the external assessment group (EAG) was done in GP practices. The study reported that GPs thought that using the automated device improved clinical management of leg ulcers. However, it also reported that the GPs had concerns about whether they had time available and whether it was within their remit to assess wounds. Clinical experts commented that the number of ABPI assessments done in GP practices may vary widely and some may not do enough ABPI assessments to justify purchasing an automated device. The committee concluded that it is unclear where in the care pathway it is best to use the devices. It agreed that automated devices could have substantial benefits for people with leg ulcers. This is if they could be safely used in a wider range of settings or by a greater number of healthcare professionals, and if they lead to earlier access to treatment.\n\n## The diagnostic accuracy evidence available for automated ABPI devices is not generalisable to people with leg ulcers\n\nThe committee noted that only 2\xa0observational studies from the 24\xa0studies identified were in people with leg ulcers (1\xa0study excluded marked oedema) and these did not report diagnostic accuracy data (sensitivity or specificity). The EAG extracted diagnostic accuracy data from 22\xa0studies in people without leg ulcers, 6\xa0of which reported results for people with diabetes. Clinical experts were concerned about the generalisability of these studies to the leg ulcer population because taking measurements in people with leg ulcers may be more difficult, particularly when they have oedema or swollen limbs. People with leg ulcers are more likely to have these complications and clinical experts advised that, in their experience, technical failure (failure of the device to produce a result) is more likely in people with oedema. They also commented that in their experience, technical failure is more likely in people with peripheral arterial disease, and this was seen in some of the studies. The committee noted that prevalence of peripheral arterial disease in the studies varied widely. Because of this, it is likely that the accuracy data in the available studies is not applicable to people with leg ulcers. There was also limited evidence of use of the devices in people with diabetes or other conditions associated with an increased risk of leg ulcers. These conditions can cause hardening of the arteries, which can make the ABPI result appear misleadingly normal. Consequently, there is considerable uncertainty about the accuracy of the test in these populations. The committee concluded that the diagnostic accuracy data on the automated devices could not be generalised to a leg ulcer population, so there is considerable uncertainty about the diagnostic accuracy of the devices in this population.\n\n## Automated devices may increase risk of inappropriate treatment in people with peripheral arterial disease\n\nThe committee discussed the accuracy of the automated devices. It commented that data suggested automated devices generally had good specificity but only moderate sensitivity for detecting peripheral arterial disease. The EAG report suggested that the automated devices tend to overestimate ABPI, which could lead to cases of peripheral arterial disease being missed. This could mean some people have inappropriate compression, causing harm. It noted, however, that some of the differences seen between the results from the automated devices and from manual doppler may not have been clinically significant. Clinical experts further noted that NWCSP guidance states that ABPI assessment should be done by someone with expertise to recognise symptoms of and red flags for peripheral arterial disease. There was concern that these red flags could be missed if automated devices were used in settings or by staff with less expertise in assessing peripheral arterial disease. This, combined with the suggested lower sensitivity of the automated devices, could cause cases of peripheral arterial disease to be missed, leading to inappropriate treatment and harm for people with arterial leg ulcers. Clinical experts also highlighted that ABPI results may be unreliable in people with certain comorbidities, such as diabetes. It is important that other outputs such as doppler waveform are used to validate the ABPI result in these cases. Some automated devices provide additional outputs such as doppler waveforms or similar, but interpreting doppler waveforms is a specialist skill, so staff with less experience in assessing peripheral arterial disease may still misinterpret it. The EAG confirmed that accuracy data reported in the studies was based on ABPI result alone and that no studies reporting on the use of other outputs of the devices or the impact of test results on clinical decision making were identified. Therefore, no conclusions could be drawn on the impact of the use of the devices on clinical decision making, but there was concern that cases of peripheral arterial disease would be missed because of an inaccurate result. The committee concluded that future studies should look at how the test result is used to direct treatment so that the impact of false results on clinical decisions can be fully understood.\n\n## Impact of the automated devices on health outcomes is uncertain\n\nThe committee heard that no evidence looking at the impact of inaccurate test results on clinical outcomes was found. Therefore, the impact of inaccurate test results on health outcomes is uncertain. Clinical experts discussed that inappropriate compression treatment of leg ulcers in people with peripheral arterial disease could risk harm. They also noted that misdiagnosing people with peripheral arterial disease could cause unnecessary delays to the treatment of venous leg ulcers. The committee concluded that the impact of misdiagnosis is uncertain but that consequences could be more severe for people with peripheral arterial disease. However, people with peripheral arterial disease would represent a smaller proportion of the population with leg ulcers (see section\xa03.2). The committee noted that it would be helpful to have further information on how incorrect results impact health outcomes, to inform decision making in the future.\n\n## Impact of the automated devices on time to treatment is uncertain\n\nThe committee discussed whether the use of automated devices in alternative settings or by staff with less specialist expertise could improve access to ABPI assessment and therefore reduce time to treatment and improve ulcer healing for some people (see section\xa03.2). It heard that there were no studies looking at the effect of automated devices on time to assessment or time to treatment. One study in people with leg ulcers reported that GPs felt that using the MESI\xa0ABPI\xa0MD automated device improved clinical management (Green et al. 2020). However, other studies were done in specialist settings. Clinical experts advised that the impact of the devices on time to treatment would depend on the setting and availability of expertise and that this varies widely across the country. They also noted it would depend on whether there was enough expertise in these settings to start treatment of leg ulcers in people without peripheral arterial disease more quickly (see section\xa03.3). The committee concluded that the devices may improve access to ABPI assessment and may therefore improve time to ulcer treatment and healing. However, no evidence was identified.\n\n## The impact of automated devices on the time taken for ABPI assessment is uncertain\n\nThe committee discussed how long the ABPI assessment takes and noted that evidence suggests automated devices can reduce the duration of the assessment. Patient experts explained that this may make assessments more comfortable for people with leg ulcers and could increase access to ABPI assessment by increasing the number of people who can be assessed. The committee heard that studies reported that most people with leg ulcers found the automated devices acceptable, but some felt discomfort when the cuff was fully inflated. It also heard that time taken for assessments was not consistently reported across studies and generally assessments with automated devices were only a few minutes faster than manual assessments. Clinical experts questioned whether the amount of time saved was enough to have a meaningful impact. They also noted that technical failure of the automated devices could mean manual doppler would then need to be done, increasing the length of the overall assessment. One clinical expert who had used an automated device as part of an evaluation confirmed that technical failure resulted in a longer assessment time in their experience. This could occur more often in people with peripheral arterial disease, oedema, diabetes or other conditions that cause calciphylaxis in tissues (see section\xa03.4). However, consultation comments submitted by a large community service provider that uses automated devices suggested that they could halve the assessment time compared with manual doppler. The committee concluded that evidence suggests automated devices reduce the time taken for ABPI assessment but that the amount of time saved and the impact of this are uncertain.\n\n# Cost effectiveness\n\n## Automated devices are unlikely to be cost effective unless they reduce time to treatment\n\nThe committee noted that the economic model results suggested that automated devices were unlikely to be cost effective unless improved access to ABPI assessment and treatment could be shown (see section\xa03.3). No evidence was identified to suggest that automated devices may speed up access to treatment (see section\xa03.7). The committee concluded that there is potential for the devices to be cost effective. However, there is currently not enough evidence on whether they improve time to treatment or ulcer healing.\n\n## Economic model results are very uncertain\n\nThe committee noted that there were substantial uncertainties in the economic model because of a lack of data to inform key model inputs. The model results appeared highly sensitive to improvements in ulcer healing time for venous ulcers (because of quicker access to treatment). The impact of inaccurate test results on clinical decision making and clinical outcomes was highly uncertain because no evidence was identified to inform these inputs in the model (see section\xa03.6). Clinical expert opinion was used to inform these inputs in the model. The committee further noted that diagnostic accuracy estimates in the model were based on single studies for each of the devices and these studies were done in people without leg ulcers (see section\xa03.4). The EAG advised that it pooled data on the devices when possible but that it did not consider the results to be robust because of the differences between studies. Only 2\xa0devices had enough studies to allow for pooling of data and this reduced the sensitivity of both devices (MESI\xa0ABPI\xa0MD and WatchBP\xa0Office\xa0ABI). It therefore opted to use single estimates in the model. The committee concluded that evidence on the impact of the automated devices on clinical decision making or clinical outcomes would improve the robustness of the economic model results. Therefore, the devices can only be recommended for use in the context of research. Consultation comments submitted by a large community service provider highlighted that automated devices are already used in practice. Clinical experts commented that they were also aware that automated devices are used in some local areas and specialist services. The committee agreed that automated devices already purchased by the NHS and implemented within a care pathway can continue to be used, only if centres using them collect data to show their impact on people with leg ulcers. This is provided that people using the automated devices are aware of the:\n\nlimitations of the devices\n\nlack of evidence showing the accuracy of the devices for detecting peripheral arterial disease in people with leg ulcers\n\nrisk of missing peripheral arterial disease if devices are not used alongside a full clinical assessment by someone with experience assessing peripheral arterial disease.\n\n# Research considerations\n\n## Consideration of the most appropriate care pathway is needed\n\nThe committee considered that a key benefit of the automated devices could be improvements in time to treatment and healing of venous ulcers (see section\xa03.2). However, this could depend on how and where the devices are used in the care pathway and the availability of expertise. Clinical experts questioned whether staff with less expertise would be able to start some of the treatments such as compression bandaging for people identified as having venous leg ulcers (see section\xa03.3). They also raised concerns about whether less-experienced healthcare professionals would be able to perform a holistic assessment of the ulcer and recognise red flags for peripheral arterial disease (see section\xa03.5). The committee concluded that consideration of the most appropriate place for the automated devices in the care pathway was needed and that studies should be done in these settings.\n\n## Consideration of alternative thresholds may be helpful\n\nThe committee acknowledged that the EAG's report extracted data from some studies that looked at the optimal threshold for the automated devices. These studies reported that using an ABPI threshold higher than the commonly used value of 0.9 could improve sensitivity and therefore reduce the risk of missing peripheral arterial disease. The committee noted that it is possible that an alternative threshold may help prevent inappropriate treatment and associated consequences in some cases (see section\xa03.5). However, clinical experts advised that higher thresholds are not currently used in practice and they would therefore need validating in independent studies in people with leg ulcers.", 'Recommendations for further research': '# Diagnostic accuracy\n\nThe committee recommends more research on diagnostic accuracy in people with leg ulcers. The following considerations should be made when doing this research:\n\nwhere the devices would be used in clinical practice and by who (specialist and non-specialist users; see section\xa03.11)\n\nthe most appropriate threshold for the automated measurement (see section\xa03.12); if an alternative threshold to the currently established threshold is being researched, then a prespecified threshold should be used and research should be done in a population not used to derive this threshold (external validation)\n\nwhether using additional outputs from other devices such as doppler waveform and pulse volume waveform impacts clinical decision making (see section\xa03.5).\n\n# Time to treatment\n\nThe committee recommends collecting further data on the impact of the automated devices on time to treatment for people with leg ulcers to reduce uncertainty in the economic modelling.\n\n# Clinical outcomes\n\nThe committee recommends collecting further data on clinical outcomes such as time to healing, and incorrect use of compression and its associated adverse consequences when possible.'}	https://www.nice.org.uk/guidance/dg52	Evidence-based recommendations on automated ankle brachial pressure index measurement devices to detect peripheral arterial disease in people with leg ulcers.
86850d67a2fa2b5ab6ec6eaf2b662d6baaaa9fa0	nice	Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure from high spinal cord injuries	Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure from high spinal cord injuries Evidence-based recommendations on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure from high spinal cord injuries. This involves keyhole abdominal surgery. The aim is to stimulate and possibly strengthen the diaphragm to help people breathe without a ventilator. # Recommendations Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure from high spinal cord injuries should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure from high spinal cord injuries should: Inform the clinical governance leads in their healthcare organisation. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Take account of NICE's advice on shared decision making and NICE's information for the public. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a multidisciplinary team with experience in managing high spinal cord injury and in managing home ventilation. The procedure should only be done by surgeons with experience and training in this procedure. Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme. Further research should be randomised controlled trials or observational data from registries or other sources of real-world evidence. Why the committee made these recommendations The evidence for this procedure is limited because there is a lack of long-term data and no high-quality clinical trials. But the evidence does suggest that this procedure may improve quality of life and enable people to have some ventilator-free time each day. The evidence on safety includes reports of electrode insertion site infection and pneumonia, but it is not certain if pneumonia is directly caused by the procedure. More research will offer more evidence on safety and long-term outcomes. High spinal cord injury is severely disabling. For people who are dependent on mechanical ventilation, this procedure offers one of few options that could enable them to have some ventilator-free time. So, this procedure is recommended but only with special arrangements.# The condition, current treatments and procedure # The condition High spinal cord injuries can damage the nerves that control breathing and cause chronic respiratory failure. # Current treatments Standard care for managing chronic respiratory failure in people with high spinal cord injuries includes non-invasive forms of ventilation support (such as bi-level positive airway pressure). In advanced stages of respiratory failure, mechanical ventilation is done through a permanent tracheostomy. Phrenic nerve pacing is an alternative treatment for people who have intact phrenic nerves (the nerves that contract the diaphragm). The diaphragm is stimulated to contract by electrodes placed on the phrenic nerve in the neck or thorax. # The procedure The aim of intramuscular diaphragm stimulation is to make the diaphragm contract, enabling a full or partial weaning from mechanical ventilation. This procedure needs intact phrenic nerve function. It avoids the need to access the phrenic nerve through the neck or thorax, as well as reducing the risk of phrenic nerve damage. The procedure is done laparoscopically with general anaesthesia. Areas of the diaphragm where minimal electrical stimulation causes maximal diaphragm contraction (known as the motor points) are mapped. Two intramuscular electrodes are implanted on the abdominal surface of each hemi-diaphragm at the motor points. The electrode leads are tunnelled subcutaneously to an exit site in the chest where they are connected to an external battery-powered pulse generator. A reference electrode (anode) is also implanted, and the leads tunnelled with the other electrodes. Intraoperative stimulation and voltage calibration tests are done to confirm there is adequate contraction of the diaphragm. After implantation the person follows a diaphragm conditioning programme, which involves progressive use of the system for increasing periods of time with gradual weaning from the ventilator.	{'Recommendations': "Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure from high spinal cord injuries should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure from high spinal cord injuries should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nTake account of NICE's advice on shared decision making and NICE's information for the public.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team with experience in managing high spinal cord injury and in managing home ventilation.\n\nThe procedure should only be done by surgeons with experience and training in this procedure.\n\nReport any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nFurther research should be randomised controlled trials or observational data from registries or other sources of real-world evidence.\n\nWhy the committee made these recommendations\n\nThe evidence for this procedure is limited because there is a lack of long-term data and no high-quality clinical trials. But the evidence does suggest that this procedure may improve quality of life and enable people to have some ventilator-free time each day. The evidence on safety includes reports of electrode insertion site infection and pneumonia, but it is not certain if pneumonia is directly caused by the procedure. More research will offer more evidence on safety and long-term outcomes.\n\nHigh spinal cord injury is severely disabling. For people who are dependent on mechanical ventilation, this procedure offers one of few options that could enable them to have some ventilator-free time. So, this procedure is recommended but only with special arrangements.", 'The condition, current treatments and procedure': '# The condition\n\nHigh spinal cord injuries can damage the nerves that control breathing and cause chronic respiratory failure.\n\n# Current treatments\n\nStandard care for managing chronic respiratory failure in people with high spinal cord injuries includes non-invasive forms of ventilation support (such as bi-level positive airway pressure). In advanced stages of respiratory failure, mechanical ventilation is done through a permanent tracheostomy. Phrenic nerve pacing is an alternative treatment for people who have intact phrenic nerves (the nerves that contract the diaphragm). The diaphragm is stimulated to contract by electrodes placed on the phrenic nerve in the neck or thorax.\n\n# The procedure\n\nThe aim of intramuscular diaphragm stimulation is to make the diaphragm contract, enabling a full or partial weaning from mechanical ventilation. This procedure needs intact phrenic nerve function. It avoids the need to access the phrenic nerve through the neck or thorax, as well as reducing the risk of phrenic nerve damage.\n\nThe procedure is done laparoscopically with general anaesthesia. Areas of the diaphragm where minimal electrical stimulation causes maximal diaphragm contraction (known as the motor points) are mapped. Two intramuscular electrodes are implanted on the abdominal surface of each hemi-diaphragm at the motor points. The electrode leads are tunnelled subcutaneously to an exit site in the chest where they are connected to an external battery-powered pulse generator. A reference electrode (anode) is also implanted, and the leads tunnelled with the other electrodes. Intraoperative stimulation and voltage calibration tests are done to confirm there is adequate contraction of the diaphragm. After implantation the person follows a diaphragm conditioning programme, which involves progressive use of the system for increasing periods of time with gradual weaning from the ventilator.'}	https://www.nice.org.uk/guidance/ipg762	Evidence-based recommendations on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure from high spinal cord injuries. This involves keyhole abdominal surgery. The aim is to stimulate and possibly strengthen the diaphragm to help people breathe without a ventilator.
6aa4321bbd3f731119c792480121ffeaca9db60a	nice	Head injury: assessment and early management	Head injury: assessment and early management This guideline covers assessment and early management of head injury in babies, children, young people and adults. It aims to ensure that people have the right care for the severity of their head injury, including direct referral to specialist care if needed. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. For the purposes of this guideline, a head injury is defined as any trauma to the head other than superficial injuries to the face. Also, babies are defined as being under 1 year, and children and young people as being 1 year to under 16 years. # Decision making and mental capacity For recommendations on promoting ways for healthcare professionals and people using services to work together to make decisions about treatment and care, see NICE's guideline on shared decision making. For recommendations on decision making in people 16 and over who may lack capacity now or in the future, including information on advance care plans, see NICE's guideline on decision making and mental capacity. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on decision making and mental capacity . Loading. Please wait. # Pre-hospital assessment, advice and referral to hospital Public health literature and other non-medical sources of advice (for example, St John Ambulance and police officers) should encourage people who have any concerns after a head injury to themselves or to another person, regardless of the injury severity, to seek immediate medical advice. ## Remote advice services Remote advice services (for example, NHS 111) should refer people who have sustained a head injury to the emergency ambulance services (that is, 999) for emergency transport to the emergency department if there are any of these risk factors (see NICE's guidelines on shared decision making and decision making and mental capacity): unconsciousness or lack of full consciousness (for example, problems keeping eyes open) any focal neurological deficit since the injury any suspicion of a complex skull fracture or penetrating head injury any seizure ('convulsion' or 'fit') since the injury a high-energy head injury there is no other way of safely transporting the person to the hospital emergency department (see recommendation 1.2.3). Remote advice services (for example, NHS 111) should refer people who have sustained a head injury to a hospital emergency department if there are any of these risk factors (see NICE's guidelines on shared decision making and decision making and mental capacity): any loss of consciousness ('knocked out') because of the injury, from which the person has now recovered amnesia for events before or after the injury ('problems with memory'; it will not be possible to assess amnesia in children who are preverbal and is unlikely to be possible in children under 5) a persistent headache since the injury any vomiting episodes since the injury any previous brain surgery any history of bleeding or clotting disorders current anticoagulant and antiplatelet (except aspirin monotherapy) treatment current drug or alcohol intoxication any safeguarding concerns (for example, possible non-accidental injury or a vulnerable person is affected) irritability or altered behaviour (easily distracted, not themselves, no concentration, no interest in things around them), particularly in babies and children under 5 continuing concern by helpline staff about the diagnosis. ## Community health services and inpatient units without an emergency department Community health services (GPs, ambulance crews, NHS walk-in or minor injury centres, dental practitioners) and inpatient units without an emergency department should refer people who have sustained a head injury to a hospital emergency department, using the ambulance service if necessary, if there are any of these risk factors (see NICE's guidelines on shared decision making and decision making and mental capacity): a Glasgow Coma Scale (GCS) score of less than 15 on initial assessment any loss of consciousness because of the injury any focal neurological deficit since the injury any suspicion of a complex skull fracture or penetrating head injury since the injury amnesia for events before or after the injury (it will not be possible to assess amnesia in children who are preverbal and is unlikely to be possible in children under 5) a persistent headache since the injury any vomiting episodes since the injury (use clinical judgement about the cause of vomiting in children 12 years or under and the need for referral) any seizure since the injury any previous brain surgery a high-energy head injury any history of bleeding or clotting disorders current anticoagulant and antiplatelet (except aspirin monotherapy) treatment current drug or alcohol intoxication any safeguarding concerns (for example, possible non-accidental injury or a vulnerable person is affected) continuing concern by the professional about the diagnosis. In the absence of any risk factors in recommendation 1.2.4, consider referral to an emergency department if any of these factors are present, depending on judgement of severity (see NICE's guidelines on shared decision making and decision making and mental capacity): irritability or altered behaviour, particularly in babies and children under 5 visible trauma to the head not covered in recommendation 1.2.4 but still of concern to the professional no one is able to observe the injured person at home continuing concern by the injured person, or their family or carer, about the diagnosis. ## Transport to hospital from community health services and inpatient units without an emergency department Ensure people referred from community health services are accompanied by a competent adult during transport to the emergency department. The referring professional should determine if an ambulance is needed, based on the person's clinical condition. If an ambulance is not needed, provided the person is accompanied, public transport or being driven in a car are appropriate means of transport. The referring professional should inform the destination hospital (by phone) of the impending transfer. In non-emergencies, a letter summarising signs and symptoms should be sent with the person. ## Training in risk assessment Train GPs, nurse practitioners, dentists and ambulance crews, as necessary, to ensure that they are capable of assessing the presence or absence of the risk factors listed in the section on community health services and inpatient units without an emergency department. # Immediate management at the scene and transport to hospital ## Glasgow Coma Scale Base monitoring and exchange of information about people with a head injury on the 3 separate responses on the GCS (for example, describe a person with a GCS score of 13 based on scores of 4 on eye opening, 4 on verbal response and 5 on motor response as E4, V4, M5). When recording or passing on information about total GCS score, give this as a score out of 15 (for example, 13 out of 15). Describe the individual components of the GCS in all communications and every patient record and ensure that they always accompany the total score. In the paediatric version of the GCS, include a 'grimace' alternative to the verbal score to enable scoring in children who are preverbal. In some people (for example, people with dementia, underlying chronic neurological disorders or learning disabilities), the pre-injury baseline GCS score may be less than 15. Establish this when possible and take it into account during assessment. ## Initial assessment and care Initially assess people 16 and over who have sustained a head injury and manage their care according to clear principles and standard practice, as embodied in the: Advanced Trauma Life Support course or European Trauma course International Trauma Life Support course Pre-hospital Trauma Life Support course Advanced Trauma Nurse Course Trauma Nursing Core Course Joint Royal Colleges Ambulance Service Liaison Committee Clinical Practice Guidelines for Head Trauma. Initially assess people under 16 who have sustained a head injury and manage their care according to clear principles outlined in the: Advanced Paediatric Life Support course or European Paediatric Life Support course Pre-hospital Paediatric Life Support course Paediatric Education for Pre-hospital Professionals course. When administering immediate care, first treat the greatest threat to life and avoid further harm. For advice on volume resuscitation for people with a traumatic brain injury and haemorrhagic shock, see NICE's guideline on major trauma: assessment and initial management. For recommendations on when to carry out full in-line spine immobilisation and how long immobilisation is needed if indicated, see NICE's guideline on spinal injury. Make pre-alert calls to the destination emergency department for anyone with a GCS score of 8 or less to ensure appropriately experienced professionals are available for their treatment and to prepare for imaging. Manage pain effectively because it can lead to a rise in intracranial pressure. Provide reassurance, splint limb fractures and catheterise a full bladder when needed. Also see NICE's guideline on major trauma: assessment and initial management. Always follow best practice in paediatric coma observation and recording, as detailed by the National Paediatric Neuroscience Benchmarking Group. ## Transport to hospital Transport people who have sustained a head injury directly to a major trauma centre or trauma unit that has the age-appropriate resources to further resuscitate them, and to investigate and initially manage multiple injuries. For guidance on the care of people with major trauma, see NICE's guideline on major trauma: service delivery. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on transport to hospital . Full details of the evidence and the committee's discussion are in evidence review B: transport to a distant specialist neuroscience centre. Loading. Please wait. ## Training for ambulance crews and paramedics Ambulance crews and paramedics should be fully trained in the use of the adult and paediatric versions of the GCS and its derived score. Ambulance crews and paramedics should be trained in the safeguarding of people under 16 and people 16 and over who are vulnerable. They should document and verbally inform emergency department staff of any safeguarding concerns. ## Tranexamic acid For people with a head injury and a GCS score of 12 or less who are not thought to have active extracranial bleeding, consider: a 2 g intravenous bolus injection of tranexamic acid for people 16 and over a 15 mg/kg to 30 mg/kg (up to a maximum of 2 g) intravenous bolus injection of tranexamic acid for people under 16.Give the tranexamic acid as soon as possible within 2 hours of the injury, in the pre-hospital or hospital setting and before imaging. In March 2023, these were off-label uses of tranexamic acid. See NICE's information on prescribing medicines. For people with a head injury, and suspected or confirmed extracranial bleeding, see the recommendations in the section on haemostatic agents in pre-hospital and hospital settings in NICE's guideline on major trauma: assessment and initial management. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on tranexamic acid . Full details of the evidence and the committee's discussion are in evidence review A: tranexamic acid. Loading. Please wait. ## Direct access from the community to imaging Do not refer people who have had a head injury for neuroimaging by direct access from the community. For a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on direct access from the community to imaging . Full details of the evidence and the committee's discussion are in evidence review C: direct access from the community to imaging. Loading. Please wait. # Assessment in the emergency department Be aware that the priority for all people admitted to an emergency department is to stabilise the airway, breathing and circulation (ABC) before attending to other injuries. See NICE's guideline on major trauma: assessment and initial management. Only assume a depressed conscious level is due to intoxication after an important traumatic brain injury has been excluded. Ensure all emergency department clinicians involved in assessing people with a head injury are capable of assessing the presence or absence of the risk factors for CT head imaging listed in the recommendations on the criteria for doing a CT head scan and the criteria for doing a cervical spine scan in people 16 and over and people under 16. Make training available as needed to ensure this. Ensure people presenting to the emergency department with impaired consciousness (a GCS score of less than 15) are assessed immediately by a trained member of staff. For people with a GCS score of 12 or less, see the recommendations on tranexamic acid. For people with a GCS score of 8 or less, ensure early involvement of an appropriately trained clinician to provide advanced airway management, as described in recommendations 1.8.7 and 1.8.8 in the section on transfer of people 16 and over, and to assist with resuscitation. Ensure a trained member of staff assesses anyone presenting to an emergency department with a head injury within a maximum of 15 minutes of arrival at hospital. Part of this assessment should establish whether they are at high or low risk for clinically important traumatic brain or cervical spine injury, as described in the recommendations on the criteria for doing a CT head scan and the criteria for doing a CT cervical spine scan in people 16 and over and people under 16. In people considered to be at high risk for clinically important traumatic brain or cervical spine injury, extend assessment to full clinical examination to establish any need for CT imaging of the head, or imaging of the cervical spine and other body areas. Use the recommendations on the criteria for doing a CT head scan and the criteria for doing a CT cervical spine scan in people 16 and over and people under 16 as the basis for the final decision on imaging after discussion with the radiology department. Anyone triaged to be at low risk for clinically important traumatic brain or cervical spine injury at initial assessment should be re-examined by an emergency department clinician. They should establish whether CT imaging of the head or cervical spine will be needed. Use the recommendations on the criteria for doing a CT head scan and the criteria for doing a cervical spine scan in people 16 and over and people under 16 as the basis for the final decision on imaging after discussion with the radiology department. Review people who return to an emergency department with any persistent complaint relating to the initial head injury and discuss them with a senior clinician experienced in head injuries. Consider whether a CT scan is needed. Manage pain effectively to help prevent any rise in intracranial pressure. Provide reassurance, splint limb fractures and catheterise a full bladder when needed. See NICE's guideline on major trauma: assessment and initial management for information on pain management. Consider or suspect abuse, neglect or other safeguarding issues as a contributory factor to, or cause of, a head injury. See NICE's guidelines on child maltreatment, child abuse and neglect, domestic violence and abuse and safeguarding adults in care homes for clinical features that may be associated with maltreatment. For a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on assessment in the emergency department . Full details of the evidence and the committee's discussion are in evidence review D: clinical decision rules selecting people with head injury for imaging. Loading. Please wait. Involve a clinician with training in safeguarding in the initial assessment of any person with a head injury presenting to the emergency department. If there are any concerns identified, document these and follow local safeguarding procedures appropriate to the person's age. Use a standard head injury proforma for documentation when assessing and observing people with a head injury throughout their time in hospital. This form should be of a consistent format across all clinical departments and hospitals in which a person might be treated. Use a separate proforma for people under 16. Include areas to allow extra documentation (for example, in cases of non-accidental injury). ## Involving the neurosurgical department Discuss with a neurosurgeon the care of anyone with new and surgically significant abnormalities on imaging. The definition of 'surgically significant' should be developed by local neurosurgical centres and agreed with referring hospitals, along with referral procedures. Regardless of imaging, discuss a person's care plan with a neurosurgeon if they have: persisting coma (a GCS score of 8 or less) after initial resuscitation unexplained confusion that persists for more than 4 hours deterioration in GCS score after admission (pay more attention to motor response deterioration) progressive focal neurological signs a seizure without full recovery a definite or suspected penetrating injury a cerebrospinal fluid leak. # Investigating clinically important traumatic brain injuries The current primary investigation of choice for detecting an acute clinically important traumatic brain injury is CT imaging of the head. For safety, logistic and resource reasons, do not do MRI scanning as the primary investigation for clinically important traumatic brain injury in people who have sustained a head injury. But additional information of importance to prognosis can sometimes be detected using MRI. Ensure that there is appropriate equipment for monitoring people with a head injury who are having an MRI scan. Also ensure that all staff involved are aware of the dangers and necessary precautions for working near an MRI scanner. Do not use plain X‑rays of the skull to diagnose important traumatic brain injury before a discussion with a neuroscience unit. However, people under 16 presenting with suspected non-accidental injury may need a skeletal survey. Arrange transfer to a suitable hospital for people with indications for a CT scan who present to a hospital where CT scans are not available (see the recommendations on the criteria for doing a CT head scan and the criteria for doing a CT cervical spine scan in people 16 and over and people under 16). Trauma networks should make sure that people can be transferred as indicated in recommendation 1.5.5. In line with good radiation exposure practice, make every effort to minimise radiation dose during imaging of the head and cervical spine, while ensuring that image quality and coverage is sufficient to achieve an adequate diagnostic study. ## Criteria for doing a CT head scan For people 16 and over who have sustained a head injury, do a CT head scan within 1 hour of any of these risk factors being identified: a GCS score of 12 or less on initial assessment in the emergency department a GCS score of less than 15 at 2 hours after the injury on assessment in the emergency department suspected open or depressed skull fracture any sign of basal skull fracture (haemotympanum, 'panda' eyes, cerebrospinal fluid leakage from the ear or nose, Battle's sign) post-traumatic seizure focal neurological deficit more than 1 episode of vomiting. For people 16 and over who have had some loss of consciousness or amnesia since the injury, do a CT head scan within 8 hours of the head injury, or within the hour in someone presenting more than 8 hours after the injury, if they have any of these risk factors: age 65 or over any current bleeding or clotting disorders dangerous mechanism of injury (a pedestrian or cyclist struck by a motor vehicle, an occupant ejected from a motor vehicle or a fall from a height of more than 1 m or 5 stairs) more than 30 minutes' retrograde amnesia of events immediately before the head injury. For people under 16 who have sustained a head injury, do a CT head scan within 1 hour of any of these risk factors being identified: suspicion of non-accidental injury post-traumatic seizure -n initial emergency department assessment, a GCS score of less than 14 or, for babies under 1 year, a GCS score (paediatric) of less than 15 at 2 hours after the injury, a GCS score of less than 15 suspected open or depressed skull fracture, or tense fontanelle any sign of basal skull fracture (haemotympanum, 'panda' eyes, cerebrospinal fluid leakage from the ear or nose, Battle's sign) focal neurological deficit for babies under 1 year, a bruise, swelling or laceration of more than 5 cm on the head. For people under 16 who have sustained a head injury and have more than 1 of these risk factors, do a CT head scan within 1 hour of the risk factors being identified: loss of consciousness lasting more than 5 minutes (witnessed) abnormal drowsiness -r more discrete episodes of vomiting dangerous mechanism of injury (high-speed road traffic accident as a pedestrian, cyclist or vehicle occupant, fall from a height of more than 3 m, high-speed injury from a projectile or other object) amnesia (anterograde or retrograde) lasting more than 5 minutes (it will not be possible to assess amnesia in children who are preverbal and is unlikely to be possible in children under 5) any current bleeding or clotting disorder. Observe people under 16 who have sustained a head injury but have only 1 of the risk factors in recommendation 1.5.11 for a minimum of 4 hours in hospital. If, during observation, any of the following risk factors are identified, do a CT head scan within 1 hour: a GCS score of less than 15 further vomiting a further episode of abnormal drowsiness.If none of these risk factors occur during observation, use clinical judgement to determine whether a longer period of observation is needed. For people who have sustained a head injury and have no other indications for a CT head scan, but are on anticoagulant treatment (including vitamin K antagonists, direct-acting oral anticoagulants, heparin and low molecular weight heparins) or antiplatelet treatment (excluding aspirin monotherapy), consider doing a CT head scan: within 8 hours of the injury (for example, if it is difficult to do a risk assessment or if the person might not return to the emergency department if they have signs of deterioration) or within the hour if they present more than 8 hours after the injury.For advice on reversing vitamin K antagonists and direct-acting oral anticoagulants for people with traumatic intracranial haemorrhage, see NICE's guideline on blood transfusion and NICE's technology appraisal guidance on andexanet alfa for reversing anticoagulation from apixaban or rivaroxaban. Make a provisional written radiology report available within 1 hour of a CT scan. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on criteria for doing a CT head scan . Full details of the evidence and the committee's discussion are in: evidence review D: clinical decision rules selecting people with head injury for imaging evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups. Loading. Please wait. ## Investigation to predict post-concussion syndrome For information on referring people with possible post-concussion syndrome, see recommendation 1.10.14 in the section on follow up. For a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on post-concussion syndrome . Full details of the evidence and the committee's discussion are in evidence review F: brain injury biomarkers and/or MRI for predicting post-concussion syndrome. Loading. Please wait. # Investigating injuries to the cervical spine ## Assessing range of movement in the neck Be aware that range of movement in the neck when there is clinical suspicion of a cervical spine injury can only be assessed safely before imaging in people with a head injury if they have no high-risk factors (see recommendation 1.6.2, and recommendations 1.6.4 and 1.6.6). Only do the assessment if they have at least 1 of these low-risk features: they were in a simple rear-end motor vehicle collision they are comfortable in a sitting position they have been ambulatory at any time since injury there is no midline cervical spine tenderness they present with delayed onset of neck pain.See also NICE's guideline on spinal injury: assessment and initial management. ## Criteria for doing a CT cervical spine scan in people 16 and over For people 16 and over who have sustained a head injury (including people with delayed presentation), do a CT cervical spine scan within 1 hour of the risk factor being identified if any of these high-risk factors apply: the GCS score is 12 or less on initial assessment the person has been intubated a definitive diagnosis of a cervical spine injury is urgently needed (for example, if cervical spine manipulation is needed during surgery or anaesthesia) there has been blunt polytrauma involving the head and chest, abdomen or pelvis in someone who is alert and stable there is clinical suspicion of a cervical spine injury and any of these factors: age 65 or over a dangerous mechanism of injury (that is, a fall from a height of more than 1 m or 5 stairs, an axial load to the head such as from diving, a high-speed motor vehicle collision, a rollover motor accident, ejection from a motor vehicle, an accident involving motorised recreational vehicles or a bicycle collision) focal peripheral neurological deficit paraesthesia in the upper or lower limbs. For people 16 and over who have sustained a head injury, and have neck pain or tenderness but no high-risk indications for a CT cervical spine scan (see recommendation 1.6.2), do a CT cervical spine scan within 1 hour for any of these risk factors: it is not thought to be safe to assess the range of movement in the neck (see recommendation 1.6.1) safe assessment of range of neck movement shows that the person cannot actively rotate their neck 45 degrees to the left and right the person has a condition predisposing them to a higher risk of injury to the cervical spine (for example, axial spondyloarthritis). ## Criteria for doing a CT cervical spine scan in people under 16 For people under 16 who have sustained a head injury (including those with delayed presentation), only do a CT cervical spine scan if any of these risk factors apply: the GCS score is 12 or less on initial assessment the person has been intubated there are focal peripheral neurological signs there is paraesthesia in the upper or lower limbs a definitive diagnosis of a cervical spine injury is needed urgently (for example, if manipulation of the cervical spine is needed during surgery or anaesthesia) the person is having other body areas scanned for head injury or multisystem trauma, and there is clinical suspicion of a cervical spine injury there is strong clinical suspicion of injury despite normal X‑rays plain X‑rays are technically difficult or inadequate plain X‑rays identify a significant bony injury.Do the scan within 1 hour of the risk factor being identified. For people under 16 who have sustained a head injury, and have neck pain or tenderness but no indications for a CT cervical spine scan (see recommendation 1.6.4), do 3‑view cervical spine X‑rays before assessing range of movement in the neck if any of these risk factors are identified: there was a dangerous mechanism of injury (that is, a fall from a height of more than 1 m or 5 stairs, an axial load to the head such as from diving, a high-speed motor vehicle collision, a rollover motor accident, ejection from a motor vehicle, an accident involving motorised recreational vehicles or a bicycle collision) safe assessment of range of movement in the neck is not possible (see recommendation 1.6.1) the person has a condition that predisposes them to a higher risk of injury to the cervical spine (for example, collagen vascular disease, osteogenesis imperfecta, axial spondyloarthritis).The X‑rays should be done within 1 hour of the risk factor being identified and reviewed by a clinician trained in their interpretation. If range of neck movement can be assessed safely (see recommendation 1.6.1) in a person under 16 who has sustained a head injury, and has neck pain or tenderness but no indications for a CT cervical spine scan, do 3‑view cervical spine X‑rays if they cannot actively rotate their neck 45 degrees to the left and right. When the person is unable to understand commands or open their mouth, a peg view may be omitted. The X‑rays should be done within 1 hour of this risk factor being identified, and reviewed by a clinician trained in their interpretation. ## Timing of radiology report Make a provisional written radiology report available within 1 hour of a CT scan. ## Imaging investigations Ensure that imaging reports are based on high-resolution source data and multiplanar reformatting of the entire cervical spine. Do MRI in addition to CT if there are neurological signs and symptoms suggesting injury to the cervical spine. Do CT or MRI angiography of the neck vessels if there is a suspicion of vascular injury, for example, because of: vertebral malalignment a high-risk fracture (that is, a high-grade or complex facial fracture or a base of skull fracture likely to involve the internal carotid artery or vertebral artery) posterior circulation syndrome. Consider MRI for assessing ligamentous and disc injuries suggested by CT or clinical findings. For a short explanation of why the committee made these recommendations and how they might affect practices or services, see the rationale and impact section on investigating injuries to the cervical spine . Full details of the evidence and the committee's discussion are in evidence review H: CT, MRI and X-ray of the cervical spine in people with head injury – diagnostic. Loading. Please wait. # Information and support for families and carers Staff caring for people with a head injury should introduce themselves to family members or carers, and briefly explain what they are doing. Ensure that information for families and carers explains the nature of the head injury and the likely care pathway. Staff should think about how best to share information with people under 16, and introduce them to the possibility of long-term complex changes in their parent or sibling who has had a head injury. Literature produced by patient support groups may be helpful. Encourage family members and carers to talk to and make physical contact (for example, holding hands) with the person with a head injury. But ensure that relatives and friends do not feel obliged to spend long periods at the bedside. If they wish to stay with the person with a head injury, encourage them to take regular breaks. Ensure there is a board or area displaying leaflets or contact details for local and national patient support organisations to help family members and carers gather further information. # Transfer from hospital to a neuroscience unit ## Transfer of people 16 and over Ensure local guidelines on the transfer of people with a severe traumatic brain injury are drawn up between the referring hospital trusts, the neuroscience unit and the local ambulance service, and recognise that: transfer would benefit anyone with serious head injuries (a GCS score of 8 or less), irrespective of the need for neurosurgery if transfer of people who do not need neurosurgery is not possible, ongoing liaison with the neuroscience unit over clinical management is essential. Also see the recommendations on transfer between emergency departments in NICE's guideline on major trauma: service delivery. Think about the possibility of occult extracranial injuries in people 16 and over with multiple injuries, and do not transfer them to a service that is unable to deal with other aspects of trauma. Ensure there is a designated consultant in the referring hospital with responsibility for establishing arrangements for the transfer of people with head injuries to a neuroscience unit. Also ensure there is another consultant at the neuroscience unit with responsibility for establishing arrangements for communication with referring hospitals, and for receiving people transferred. Ensure that people with traumatic brain injuries needing emergency transfer to a neuroscience unit are accompanied by healthcare staff with appropriate training and experience in the transfer of people with an acute traumatic brain injury. They should: be familiar with the pathophysiology of traumatic brain injuries, the medicines and equipment they will use, and working in the confines of an ambulance (or helicopter if appropriate) have a dedicated and adequately trained assistant be provided with appropriate clothing for the transfer, medical indemnity and personal accident insurance.Ensure that people needing non-emergency transfer are accompanied by appropriate clinical staff. Provide the transfer team responsible for transferring a person with a head injury with a means of communicating changes in the person's status with their base hospital and the neurosurgical unit during the transfer. Although it is understood that transfer is often urgent, complete the initial resuscitation and stabilisation of the person, and establish comprehensive monitoring before transfer, to avoid complications during the journey. Do not transport someone with persistent hypotension, despite resuscitation, until the cause has been identified and they are stabilised. Intubate and ventilate anyone with a GCS score of 8 or less needing transfer to a neuroscience unit, and anyone with the indications detailed in recommendation 1.8.8. Intubate and ventilate the person immediately when there is: coma, that is, they are not obeying commands, not speaking and not eye opening (a GCS score of 8 or less) loss of protective laryngeal reflexes ventilatory insufficiency, as judged by blood gases: hypoxaemia (PaO2 less than 13 kPa on oxygen) or hypercarbia (PaCO2 more than 6 kPa) irregular respirations. Use intubation and ventilation before the start of the journey when the person has: significantly deteriorating conscious level (1 or more points on the motor score), even if not coma unstable fractures of the facial skeleton copious bleeding into the mouth (for example, from a skull base fracture) seizures. Anyone whose trachea is intubated should have appropriate sedation and analgesia along with a neuromuscular blocking drug. Aim for a PaO2 of more than 13 kPa, and a PaCO2 of 4.5 kPa to 5.0 kPa, unless there is clinical or radiological evidence of raised intracranial pressure, in which case more aggressive hyperventilation is justified. If hyperventilation is used, increase the inspired oxygen concentration. Maintain the mean arterial pressure at 80 mmHg or more by infusion of fluid and vasopressors, as indicated. Give family members and carers as much access to the person with a head injury as is practical during transfer. If possible, give them an opportunity to discuss the reasons for transfer and how the transfer process works with a member of the healthcare team. ## Transfer of people under 16 Recommendations 1.8.1 to 1.8.9 and 1.8.11 were written for people 16 and over, but apply these principles to people under 16, providing that the paediatric modification of the GCS is used for preverbal and non-verbal children. Ventilate people under 16 according to the age-appropriate level of oxygen saturation and maintain blood pressure at a level appropriate for their age. Ensure that service provision for transfer to tertiary care follows the principles outlined in the NHS England service specification for paediatric intensive care retrieval (transport) and the Paediatric Critical Care Society quality standards for the care of critically ill or injured children. Think about the possibility of occult extracranial injuries for people under 16 with multiple injuries. Do not transfer them to a service that is unable to deal with other aspects of trauma. Ensure that transfer of people under 16 to a specialist neurosurgical unit is done either by staff experienced in the transfer of people under 16 who are critically ill or according to local guidelines with specialist paediatric retrieval teams. Give family members and carers as much access to their child as is practical during transfer. If possible, give them an opportunity to discuss the reasons for transfer and how the transfer process works with a member of the healthcare team. # Admission and observation Use these criteria for admitting people to hospital after a head injury: new, clinically important abnormalities on imaging (an isolated simple linear non-displaced skull fracture is unlikely to be a clinically important abnormality unless they are taking anticoagulant or antiplatelet medication) after imaging, a GCS score that has not returned to 15 or their pre-injury baseline, regardless of the imaging results when there are indications for CT scanning but this cannot be done within the appropriate time period, either because CT is not available or because the person is not sufficiently cooperative to allow scanning continuing worrying symptoms (for example, persistent vomiting, severe headaches or seizures) of concern to the clinician -ther sources of concern to the clinician (for example, drug or alcohol intoxication, other injuries, shock, suspected non-accidental injury, meningism, cerebrospinal fluid leak, or suspicion of ongoing post-traumatic amnesia).See the section on discharge and follow up for recommendations about other factors to consider, such as whether supervision at home is available. Be aware that some people may need an extended period in a recovery setting because of having general anaesthesia during CT imaging. Admit people with multiple injuries under the care of the team that is trained to deal with their most severe and urgent problem. When someone with a head injury needs hospital admission, admit them under the care of a team led by a consultant who has been trained in managing this condition. The consultant and their team should have competence (defined by local agreement with the neuroscience unit) in: assessment, observation and indications for imaging (see the sections on the criteria for doing a CT head scan and the criteria for doing a CT cervical spine scan in people 16 and over and people under 16) inpatient management indications for transfer to a neuroscience unit (see the section on transfer from hospital to a neuroscience unit) hospital discharge and follow up (see the section on discharge and follow up). ## Admission and observation of people with concussion symptoms For people with concussion symptoms after normal brain imaging or no indication for early imaging, follow the indications for admission in recommendation 1.9.1. Also see the section on discharge advice. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on admission and observation . Full details of the evidence and the committee's discussion are in: evidence review I: admission and observation in hospital of people with head injury who are on anticoagulant or antiplatelet therapy after normal brain imaging or no indication for early imaging evidence review J: admission and observation of people with concussion symptoms evidence review K: hospital admission in people with small intracranial injuries evidence review L: isolated skull fracture. Loading. Please wait. ## Early diagnosis of hypopituitarism Be aware that any severity of head injury can cause pituitary dysfunction. This may present immediately, hours, weeks or months after the injury. A variety of symptoms could indicate hypopituitarism. In people admitted to hospital with a head injury who have persistently abnormal low sodium levels or low blood pressure, consider investigations for hypopituitarism. In people presenting to primary or community care with persistent symptoms consistent with hypopituitarism in the weeks or months after a head injury, consider investigations or referral for hypopituitarism. For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on early diagnosis of hypopituitarism . Full details of the evidence and the committee's discussion are in: evidence review M: identification of hypopituitarism (who to investigate) evidence review N: identification of hypopituitarism (when to investigate). Loading. Please wait. ## Observation of people who are admitted Ensure that in-hospital observation of people with a head injury is only done by professionals competent in assessing head injuries. For people admitted for head injury observation, the minimum acceptable documented neurological observations are: GCS score, pupil size and reactivity, limb movements, respiratory rate, heart rate, blood pressure, temperature and blood oxygen saturation. Carry out and record observations on a half-hourly basis until there is a GCS score of 15. Observations for people with a GCS score of 15 should start after the initial assessment in the emergency department and the minimum frequency should be: half-hourly for 2 hours, then hourly for 4 hours, then hourly. Revert to half-hourly observations and follow the original frequency schedule for people with a GCS score of 15 who deteriorate at any time after the initial 2‑hour period. Urgently reassess a person with a head injury if they have any of these signs of neurological deterioration: agitation or abnormal behaviour a sustained (that is, for at least 30 minutes) drop of 1 point in GCS score (give more weight to a drop of 1 point in the motor response score of the GCS score) any drop of 3 or more points in the eye opening or verbal response scores of the GCS score, or 2 or more points in the motor response score severe or increasing headache, or persistent vomiting new or evolving neurological symptoms or signs such as pupil inequality or asymmetry of limb or facial movement.A supervising doctor should do the appraisal. To reduce interobserver variability and unnecessary referrals, get a second member of staff competent in observations to confirm deterioration before involving the supervising doctor. Do this immediately if possible. If not possible (for example, because no staff member is available to do the second observation), contact the supervising doctor without the confirmation being done. If any of the changes noted in recommendation 1.9.13 are confirmed, consider doing an immediate CT scan, and reassess the person's clinical condition and manage appropriately. If a person has had a normal CT scan but does not have a GCS score of 15 after 24 hours of observation, consider a further CT or MRI scan and discuss with the radiology department. ## Observation of babies and children under 5 Be aware that observation of babies and children under 5 is difficult, so should only be done by units with staff experienced in the observation of under 5s with a head injury. Babies and children under 5 may be observed in normal paediatric observation settings, as long as staff have the appropriate experience. ## Training in observation All staff caring for people with a head injury admitted for observation should be trained in doing the observations listed in recommendations 1.9.10 to 1.9.14 in the section on observation of people who are admitted, and the recommendation on observation of babies and children under 5. Make dedicated training available to all relevant staff to enable them to acquire and maintain observation and recording skills. Specific training is needed for the observation of people under 16. # Discharge and follow up If CT is not indicated based on history and examination and there is no suspicion of clinically important traumatic brain injury, discharge the person from hospital if there are: no other factors that would warrant a hospital admission (for example, drug or alcohol intoxication, other injuries, shock, suspected non-accidental injury, meningism, or cerebrospinal fluid leak) appropriate support structures for safe discharge to the community and for subsequent care (for example, competent supervision at home). If imaging of the head is normal and the risk of clinically important traumatic brain injury is low, transfer the person to the community if: the GCS score has returned to 15 or the pre-injury baseline GCS score there are no other factors that would warrant a hospital admission (for example, drug or alcohol intoxication, other injuries, shock, suspected non-accidental injury, meningism, or cerebrospinal fluid leak) there are appropriate support structures for safe transfer to the community and for subsequent care (for example, competent supervision at home). After normal imaging of the cervical spine, risk of injury to the cervical spine is low enough to warrant transfer to the community if: the GCS score is 15 clinical examination is normal there are no other factors that would warrant a hospital admission present (for example, drug or alcohol intoxication, other injuries, shock, suspected non-accidental injury, meningism, or cerebrospinal fluid leak) there are appropriate support structures for safe transfer to the community and for subsequent care (for example, competent supervision at home). Do not discharge people presenting with a head injury until their GCS score is 15 or, in preverbal and non-verbal children, consciousness is normal as assessed by the paediatric version of the GCS. In people with pre-injury cognitive impairment, their GCS score should be back to that documented before the injury. Only transfer people with any degree of head injury to their home if there is somebody suitable at home to supervise them. Discharge people with no carer at home only if suitable supervision arrangements have been organised, or when the risk of late complications is thought to be negligible. ## People with pre-injury cognitive impairment Ensure that people with pre-injury cognitive impairment (for example, dementia or a learning disability) and people returning to a custodial setting are supervised and monitored. Also, make sure that arrangements are in place should there be any signs of deterioration. For a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on discharge and follow up . Full details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups. Loading. Please wait. ## Discharge after observation People admitted after a head injury may be discharged after resolution of all significant symptoms and signs, provided they have suitable supervision arrangements at home, in custody or in continued care. ## Discharge advice Give verbal and printed discharge advice to people with any degree of head injury who are discharged from an emergency department or observation ward. This should also be provided to the person responsible for their care after discharge. This may include their families, carers, social workers or custodial staff. Follow the recommendations in NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, including on providing information in an accessible format. Ensure that printed advice for people with a head injury, and their families and carers, is age appropriate and includes: details of the nature and severity of the injury risk factors that mean people need to return to the emergency department (see the recommendations on community health services and inpatient units without an emergency department) a specification that a responsible adult should stay with the person for the first 24 hours after their injury details about the recovery process, including the fact that some people may appear to make a quick recovery but later have difficulties or complications contact details of community and hospital services in case of delayed complications information about return to everyday activities, including school, work, sports and driving details of support organisations. Offer information and advice on alcohol or drug misuse to people who presented to the emergency department with drug or alcohol intoxication when they are fit for discharge. Inform people with a head injury, and their families and carers, about the possibility of persistent or delayed symptoms after a head injury and who to contact if they have ongoing problems. For anyone who has attended the emergency department with a head injury, write to their GP within 48 hours of discharge, giving details of clinical history and examination. Also share this letter with health visitors (for preschool children) and school nurses (for school-age children and young people). If appropriate, provide a copy of the letter for the person with a head injury, and their family or carers, custodial staff or social worker. ## Follow up Refer people with a head injury to investigate its causes and manage contributing factors, if appropriate. This could include, for example, referral for a falls assessment or to safeguarding services. Consider referring people who have persisting problems to a clinician trained in assessing and managing the consequences of traumatic brain injury (for example, a neurologist, neuropsychologist, clinical psychologist, neurosurgeon or endocrinologist, or a multidisciplinary neurorehabilitation team). For a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on follow up . Full details of the evidence and the committee's discussion are in: evidence review J: admission and observation of people with concussion symptoms evidence review N: identification of hypopituitarism (when to investigate). Loading. Please wait. ## Investigations for hypopituitarism Consider further endocrinology investigations for people who have been discharged after a head injury if they have persistent symptoms consistent with hypopituitarism or are not recovering as expected. For a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on investigations for hypopituitarism . Full details of the evidence and the committee's discussion are in: evidence review M: identification of hypopituitarism (who to investigate) evidence review N: identification of hypopituitarism (when to investigate). Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## Complex skull fracture or penetrating head injury Signs of a basal, open or depressed skull fracture or penetrating head injury include: clear fluid running from the ears or nose a black eye with no associated damage around the eyes bleeding from 1 or both ears bruising behind 1 or both ears penetrating injury signs visible trauma to the scalp or skull of concern to the professional. ## Focal neurological deficit Neurological problems restricted to a particular part of the body or a particular activity, for example: difficulties with understanding, speaking, reading or writing decreased sensation loss of balance weakness visual changes nystagmus abnormal reflexes problems walking amnesia since the injury. ## Glasgow Coma Scale In people with a head injury, the Glasgow Coma Scale (GCS) is an early assessment of the severity of any associated traumatic brain injury. It is a standardised system used to assess the degree of brain impairment and to identify the seriousness of injury in relation to outcome. The scale has 3 domains: eye opening, verbal and motor responses. These are all evaluated independently in the scale according to a numerical value that indicates the level of consciousness and degree of dysfunction. The scores in each element of the GCS are summed to give the overall GCS score, which ranges from 3 (unresponsive in all domains) to 15 (no deficits in responsiveness): Mild traumatic brain injury is a GCS score of 13 to 15. Moderate traumatic brain injury is a GCS score of 9 to 12. Severe traumatic brain injury is a GCS score of 8 or less. ## High-energy head injury An injury arising from, for example, a pedestrian being struck by a motor vehicle, an occupant being ejected from a motor vehicle, a fall from a height of more than 1 m or more than 5 stairs, a diving accident, a high-speed motor vehicle collision, a rollover motor accident, an accident involving motorised recreational vehicles, a bicycle collision or any other potentially high-energy mechanism. ## Hypopituitarism Underactivity of the pituitary gland that can lead to: adrenocorticotropic hormone deficiency causing weakness, fatigue, weight loss, hypotension, hyponatraemia, hypoglycaemia, hypercalcaemia, anaemia and fatigue growth hormone deficiency causing decreased energy, low mood, neuropsychiatric and cognitive symptoms, decreased lean body mass, increased fat mass, altered metabolic profile and decreased exercise capacity lack of sex hormones that can cause later puberty, hot flushes, fatigue, tiredness, loss of body hair, reduced sex drive, irregular periods, erectile dysfunction and reduced fertility thyroid-stimulating hormone deficiency presenting with slow growth, fatigue, lethargy, cold intolerance and weight gain vasopressin deficiency causing polyuria, polydipsia, nocturia and incontinence. ## Isolated simple linear non-displaced skull fracture A single or solitary linear fracture that does not exhibit any inward or outward displacement, does not consist of multiple fracture lines and does not involve or cross the normal sutures of the skull. ## Paraesthesia Pins and needles, or a prickling sensation, tingling or itching in any part of the body. ## Post-concussion syndrome Post-concussion syndrome (or post-concussion symptoms) is seen in all severities of head injury and is under-recognised in mild head injuries. It is the term used in evidence review F: brain injury biomarkers and/or MRI for predicting post-concussion syndrome. The term 'concussion' is used in evidence review J: admission and observation of people with concussion symptoms. Examples of symptoms in these reviews include, but are not limited to: Sensory and motor: headache dizziness nausea changes in vision, such as blurred vision, double vision, 'seeing stars' and 'looking through a haze' visual processing problems, such as not taking in what you are seeing difficulties staying awake, sleeping for many more hours than usual and chronic fatigue when awake unusual sensitivity to noise (hyperacusis) unusual sensitivity to bright lights (photophobia) difficulties with balance, coordination and mobility, often resulting in falls, banging into objects and, at times, further traumatic brain injuries speech problems. Cognition: cognitive difficulties (as long as the GCS score is 15), sometimes described as 'brain fog', which may include problems finding words or numbers, difficulty speaking, slowed responsiveness, short-term memory problems, difficulty concentrating and problems with information processing, such as following conversations, digesting text and finding words difficulties with executive functions, such as organising, planning and multitasking amnesia problems with spatial awareness and proprioception, including the sensation of touching something as if through a layer of numbness. Emotional: lability, such as unusual laughing or crying (because of being overwhelmed by sense impressions) or irritability depression anxiety. Additional symptoms that may present in children under 5: changes in normal behaviour after a head injury, such as crying a lot or irritability changes in feeding or sleeping habits loss of interest in people or objects listlessness. ## Traumatic brain injury An alteration in brain function, or other evidence of brain pathology, caused by an external force.# Recommendations for research The guideline committee has made these recommendations for research. # Key recommendations for research ## Indications for admission in people with a mild head injury and a confirmed abnormality on a CT scan What are the indications for admission using clinical decision rules in people with a Glasgow Coma Scale (GCS) score of 13 to 15 (a mild head injury) and a confirmed abnormality on a CT scan? For a short explanation of why the committee made this recommendation for research, see the rationale section on admission and observation . Full details of the evidence and the committee's discussion are in evidence review K: hospital admission in people with small intracranial injuries. Loading. Please wait. ## Using biomarkers for predicting acute post-traumatic brain injury complications What is the diagnostic accuracy of brain injury biomarkers for predicting acute complications after a traumatic brain injury? For a short explanation of why the committee made this recommendation for research, see the rationale section on post-concussion syndrome . Full details of the evidence and the committee's discussion are in evidence review G: brain injury biomarkers for predicting acute post-brain injury complications. Loading. Please wait. ## Indications for imaging for people with a history of recurrent head injuries What is the risk of intracranial injuries in people with a history of recurrent head injuries, including from sports and falls, and no other indications for a CT scan? For a short explanation of why the committee made this recommendation for research, see the rationale section on criteria for doing a CT head scan . Full details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups. Loading. Please wait. ## Risk of bleeding for people with a pre-injury coagulopathy What is the risk of any intracranial bleeding or intracranial bleeding associated with clinical deterioration after head injury in people with a pre-injury coagulopathy? This includes medical conditions such as liver failure or haemophilia, or taking anticoagulants or antiplatelets in people who: have a GCS score of 15 at 2 hours after the head injury and medium risk factors for intracranial bleeding or loss of consciousness or amnesia with no additional risk factors (that is, they are under 65, had a low-energy transfer injury and any retrograde amnesia has lasted for less than 30 minutes) or there is no loss of consciousness or amnesia For a short explanation of why the committee made this recommendation for research, see the rationale section on criteria for doing a CT head scan . Full details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups. Loading. Please wait. ## Indications for imaging for people with a pre-injury cognitive impairment What are the indications for selecting imaging in adults, young people, children and babies with a head injury sustained through a low-energy fall and with suspected pre-injury cognitive impairment when loss of consciousness or amnesia is difficult to assess or the pre-injury GCS score is not 15? For a short explanation of why the committee made this recommendation for research, see the rationale section on criteria for doing a CT head scan . Full details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups. Loading. Please wait. # Other recommendations for research ## Transport to a neuroscience centre What is the clinical and cost effectiveness of pre-hospital strategies to take people with a head injury to a distant specialist neuroscience centre instead of a closer non-specialist unit? For a short explanation of why the committee made this recommendation for research, see the rationale section on transport to hospital . Full details of the evidence and the committee's discussion are in evidence review B: transfer to a distant specialist neuroscience centre. Loading. Please wait. ## Tranexamic acid What is the clinical and cost effectiveness of tranexamic acid before imaging in people presenting within 2 hours of a head injury with a GCS score of 13 to 15 and high-risk indications for intracranial bleeding? For a short explanation of why the committee made this recommendation for research, see the rationale section on tranexamic acid . Full details of the evidence and the committee's discussion are in evidence review A: tranexamic acid. Loading. Please wait. ## Indications for selecting people for imaging when they present more than 24 hours after a head injury What are the indications for selecting people of any age who present more than 24 hours after a head injury for a CT or MRI head scan? For a short explanation of why the committee made this recommendation for research, see the rationale section on criteria for doing a CT head scan . Full details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups. Loading. Please wait. ## Using biomarkers and MRI for predicting post-concussion syndrome What is the prognostic accuracy of brain injury biomarkers or MRI for predicting post-concussion syndrome? For a short explanation of why the committee made this recommendation for research, see the rationale section on post-concussion syndrome . Full details of the evidence and the committee's discussion are in evidence review F: brain injury biomarkers and/or MRI for predicting post-concussion syndrome. Loading. Please wait. ## Timing of testing for hypopituitarism When should people with a head injury be investigated for hypopituitarism? For a short explanation of why the committee made this recommendation for research, see the rationale section on early diagnosis of hypopituitarism . Full details of the evidence and the committee's discussion are in evidence review N: identification of hypopituitarism (when to investigate). Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice or services. # Decision making and mental capacity Recommendations 1.1.1 and 1.1.2 ## Why the committee made the recommendations The committee recognised the need to involve people with a head injury, and their family and carers, in decisions about their care, including referral to the emergency department. They also highlighted the importance of making decisions for people who may lack capacity now or in the future, and to follow any advance care plans. ## How the recommendations might affect practice or services There is not expected to be any change to practice or services. Return to recommendations # Transport to hospital Recommendations 1.3.13 and 1.3.14 ## Why the committee made the recommendations Evidence from 1 randomised controlled trial (RCT) and 1 retrospective cohort study was identified. This compared transport for a head injury to a specialist neuroscience centre with transport to the nearest non-specialist acute hospital or general hospital emergency department. All the evidence was in people 16 and over. No evidence was available for people under 16. The evidence from the RCT suggested some benefit for transfer to a non-specialist general hospital for the outcome of mortality, but this was uncertain. The evidence from the retrospective cohort study suggested that there was no difference between the 2 groups for the outcome of survival benefit. The committee agreed that there was limited evidence of a possible benefit for transfer to a specialist neuroscience centre for some outcomes but that this was uncertain. They agreed that there was no compelling evidence to change practice, and to cross refer to NICE's guideline on major trauma: service delivery. The committee noted that the data collection for the RCT was in 2012. This was when trauma care was reorganised in the UK to enable rapid and safe transfer of people to major trauma centres. So, the evidence does not reflect the recent trauma care system, which includes more consultants, quicker CT scans and rehabilitation. So, the committee agreed that further research should be done in this area to determine the effectiveness of transport to specialist neuroscience centres in people with a head injury. They developed a recommendation for research on transport to a neuroscience centre. ## How the recommendations might affect practice or services There is not expected to be any change. Return to recommendations # Tranexamic acid Recommendations 1.3.17 and 1.3.18 ## Why the committee made the recommendations There was evidence from 2 RCTs for tranexamic acid, both of which included adults with no suspicion of extracranial bleeding. One trial was in a pre-hospital (out-of-hospital) setting and the other was in a hospital setting. There was no evidence available for people under 16 (1 trial included a few people aged 15 and 16). In the pre-hospital setting, a single 2 g bolus dose of tranexamic acid was given within 2 hours of a head injury. The evidence suggested that it reduced all-cause mortality at 28 days and 6 months in people with moderate or severe traumatic brain injury. But there was no clinically important difference between tranexamic acid and placebo for hospital-free days at 28 days, degree of disability at discharge and after 6 months (Glasgow Outcome Scale–Extended more than 4), and serious adverse events (that is, myocardial infarction, pulmonary embolism, deep vein thrombosis and stroke). In the hospital setting, a 1 g bolus dose of tranexamic acid was given within 3 hours of injury, followed by an 8‑hour intravenous infusion of 1 g of tranexamic acid. The evidence suggested that this reduced death from traumatic brain injury at 28 days in groups with mild or moderate traumatic brain injury. Evidence suggested reduced mortality related to severe traumatic brain injury at 28 days in high-income countries, but there was no difference in mortality related to traumatic brain injury in low- and middle-income countries. No evidence was available separating the mild from moderate severity groups for mortality related to traumatic brain injury and all-cause mortality, but communication with the study authors suggested significant uncertainty about tranexamic acid's effect in mild traumatic brain injury. There was no clinically important difference between tranexamic acid and placebo for serious adverse events (that is, myocardial infarction, pulmonary embolism, deep vein thrombosis and stroke) and disability rating scale scores in a mixed severity group (mild, moderate and severe) across all income groups. The committee considered that, despite the uncertainty in the clinical evidence, there was a benefit with tranexamic acid in terms of reducing all-cause mortality and mortality from traumatic brain injury. They also considered that the evidence showed that it caused very few adverse events. Based on the evidence, they agreed that a 2 g intravenous bolus dose of tranexamic acid, given within 2 hours of a head injury and before imaging, could be considered for people 16 and over with moderate or severe traumatic brain injury. The committee recommended a 2 g intravenous bolus injection of tranexamic acid because this dose was found to be the most safe and effective. An economic model was developed that looked at each traumatic brain injury severity subgroup separately. It was based primarily on the pre-hospital clinical trial because: that provided data for moderate traumatic brain injury separately from that for mild injury the benefits of tranexamic acid were found to be greater when it was given earlier. For moderate traumatic brain injury, the health benefits associated with a 2 g bolus given in the pre-hospital setting outweighed the costs in all scenarios. For severe traumatic brain injury, the cost-effectiveness estimate was more borderline. But, when limitations in the modelling were taken into account, the committee concluded that the health benefits were likely to outweigh the costs in this group too. Because of a lack of trial evidence for tranexamic use in people under 16, the committee used extrapolated evidence from the trials in adults, and their expertise and knowledge. In NHS clinical practice, a tranexamic acid dose of 15 mg/kg is used in people under 16 with extracranial injuries. But, in this age group, tranexamic acid is not currently widely used for isolated head injury and dosing is variable (15 mg/kg to 30 mg/kg). Evidence for people 16 and over with a head injury from a pre-hospital setting suggested that a 2 g dose of tranexamic acid reduced all-cause mortality (at 28 days and 6 months), with no evidence of negative effects. So, the committee concluded that it could recommend the equivalent of a 2 g dose of tranexamic acid for people under 16. They discussed that, based on the average weight of people 16 and over being 70 kg, a 2 g dose of tranexamic acid for people 16 and over would equate to a 30 mg/kg dose for people under 16. So, they concluded that a dose range of 15 mg/kg to 30 mg/kg was appropriate for people under 16. For people with mild traumatic brain injury, it is less clear whether the benefits of tranexamic acid outweigh the potential risk of blood clots. So, the committee made a recommendation for research on tranexamic acid for this group. ## How the recommendations might affect practice or services Tranexamic acid is already used for people who have a head injury and other major trauma. NICE has not previously recommended it for people with an isolated head injury. It is expected that doing so will increase tranexamic acid use by paramedics. This should lead to improved survival for people with a head injury. More resources might be needed for treatment, rehabilitation and care for the people who would not have survived without tranexamic acid. Return to recommendations # Direct access from the community to imaging Recommendation 1.3.19 ## Why the committee made the recommendation No evidence was identified for direct access from the community for CT scans or MRI of the head compared with usual care for a suspected or confirmed head injury (including people with delayed presentation, and people in residential and care homes). The committee discussed that imaging ordered in the community setting is mainly used to exclude intracranial bleeding or provide reassurance. They noted that the timing of imaging depends on whether there is an acute injury or the person has post-concussion syndrome. Based on their experience, the committee agreed that people should go to hospital if: there has been important traumatic brain injury within 24 hours or there is a reduced Glasgow Coma Scale (GCS) score. The committee were aware that some trusts have referral pathways that allow for imaging to be requested directly from the community setting or primary care. But they noted the logistical challenges in the acute phase of a head injury in getting access to, and timely reporting of, imaging. They also noted the challenges faced in primary care and general practice in interpreting complex neuroradiology reports. The committee therefore agreed that people should not be referred to imaging directly from the community. ## How the recommendation might affect practice or services This is expected to be a change in practice for a few centres that will now have to send people for imaging by the emergency department route. Return to recommendation # Assessment in the emergency department Recommendation 1.4.12 ## Why the committee made the recommendation The committee highlighted the need to follow relevant guidance if abuse or other safeguarding issues may be factors in a head injury. ## How the recommendation might affect practice or services There is not expected to be any change to practice or services. Return to recommendation # Criteria for doing a CT head scan Recommendations 1.5.8 to 1.5.14 ## Why the committee made the recommendations Several diagnostic accuracy studies were identified but there were no diagnostic RCTs. Most of the evidence was of low to very low quality and was in people with a mild head injury (defined as a GCS score of 13 to 15 in many studies, but sometimes limited to a GCS score of 14 to 15). The committee noted that the existing recommendations for clinical decision rules for head imaging in people 16 and over were largely based on the Canadian CT Head Rule (CCHR). This involves identifying high and medium risk factors, with some modifications aimed at improving sensitivity. Updated evidence for this decision rule showed that it has good sensitivity when used as intended but that its specificity values are poor. The committee noted that specificity values of decision rules are often low because they prioritise very high sensitivity. Evidence identified for other decision rules showed sensitivity values similar to those of the CCHR. However, specificity values were lower compared with the CCHR high and medium risk rule. Limited evidence showed that the NEXUS 2 decision rule has specificity values similar to those of the CCHR. Only 1 study had assessed the performance of the 2014 update of NICE's head injury guideline recommendations for head imaging. This reported sensitivity values that were poorer than those for the CCHR. But the specificity values were better compared with other decision rules. The committee agreed that it was unclear why the sensitivity of the NICE recommendations would be worse than those of CCHR. They also agreed that it was unclear why the CCHR did not do as well in this study as in other studies. They thought that this possibly suggested some differences between study populations, which may have affected the results. The committee also agreed that, in their clinical experience, the sensitivity of the NICE recommendations was not as low as suggested in this study. The committee agreed that there was insufficient evidence to support changing the clinical decision rule recommendations for head imaging in people 16 and over. Because the NICE recommendations were largely based on the CCHR rule, this decision was further supported by cost-effectiveness evidence. This showed the CCHR rule to be the most cost effective of the multiple decision rules assessed. The committee noted that the existing recommendations for clinical decision rules for head imaging in people under 16 were largely based on the CHALICE rules with some modifications. These modifications were based on current practice and experience allowing for the option of an observation period with imaging if the condition of some people deteriorated, rather than immediate imaging. Updated evidence identified for this decision rule showed that it had good sensitivity when considering clinically important injuries or neurosurgical outcomes. In the 2014 update of this guideline, the committee stated that an improvement in specificity relative to the NICE recommendations would be needed to warrant switching to another decision rule for people under 16. They noted that PECARN and CATCH‑7 may have slightly better sensitivity values compared with CHALICE, but agreed that, overall: the specificity values for CHALICE are much better than for other rules assessed the sensitivity values for CHALICE are still over 90% for clinically important injuries and neurosurgical outcomes. The committee noted that, in terms of the content of the rules, PECARN and the NICE guideline are not very different but that PECARN is vaguer and does not give timings. They thought this less useful. In addition, they noted that the PECARN and CATCH-7 rules apply to more specific populations than the NICE guideline recommendations. The committee agreed that the recommendations in the NICE guideline are in widespread use in current practice, and used with little variation. Their opinion was that they are currently well-accepted and used with good effect. The committee therefore agreed that there was insufficient evidence to support changing the clinical decision rule recommendations for head imaging in people under 16. The committee agreed to keep the existing recommendations in from the 2014 update of NICE's head injury guideline for people with bleeding and clotting disorders. This was because there was no new evidence to change practice in adults, and the committee agreed to extrapolate from an existing recommendation to make a new recommendation for people under 16. However, they changed the recommendation wording from 'history of bleeding or clotting disorders' to 'current bleeding or clotting disorders'. In children, some disorders are short-lived or resolve in a couple of months. In adults, a history of bleeding or clotting disorders is used to help screen people before surgery. However, this is a crude tool and may not be appropriate in this setting. So, the committee agreed to keep the changed wording for all age groups to help provide a consistent message. There was conflicting evidence from cohort studies on whether people who are on anticoagulants or antiplatelets are at higher risk of intracranial haemorrhage than people not on anticoagulants or antiplatelets. CT scans could be limited to people with symptoms of traumatic brain injury such as loss of consciousness or amnesia. However, the committee thought that the new evidence was not strong enough to warrant stopping imaging in people with a head injury who are on anticoagulants but have no other indication for imaging. So, they decided CT scanning should be considered rather than automatically done in this group. They also agreed that antiplatelets other than aspirin monotherapy should be included in this. The review findings suggested that people on anticoagulants (including warfarin and direct-acting oral anticoagulants) or antiplatelets (excluding people on aspirin monotherapy) with low-risk factors (no loss of consciousness, amnesia, a GCS score of 15 and no other indications for CT brain scan) can be risk assessed (including for other injuries, supervision at home, cause of incident and risk of further falls). Then, if there are no risk factors and after shared decision making, they could be discharged safely without a CT scan, with the usual discharge advice (see the section on discharge and follow up). The committee highlighted that clinicians would either scan or admit someone for monitoring if any risks were identified. This might be, for example, if a person (with pre-existing cognitive impairment) may be less likely to return to the emergency department urgently if they have any signs of deterioration. The committee noted that, if an intracranial haemorrhage is not detected at initial presentation, delayed recovery is more likely rather than death. They also discussed that neurosurgical intervention for traumatic brain injury is less likely to be offered for people over 74 because risks outweigh the benefits. In current practice, in accordance with the 2014 update of NICE's head injury guideline recommendations, a CT head scan is done within 8 hours of a head injury in people with no other indications for a CT head scan who are having anticoagulant treatment. The 2014 update did not make specific recommendations for people on antiplatelets. The committee agreed that, in clinical practice, there is variation, with some services offering imaging to people on antiplatelets. Based on the evidence, they also agreed that antiplatelets other than aspirin monotherapy should be included but did not specify which antiplatelets. This was because they did not want to be prescriptive and exclude any newer antiplatelets in development. Based on their experience and extrapolation of evidence in people presenting within 8 hours of injury, the committee agreed that these recommendations could be applicable to people presenting more than 8 hours after their injury. However, they agreed that imaging should be done within an hour of confirming that the person with head injury is on anticoagulant or antiplatelet medication. There was limited evidence on aspirin. From their knowledge and clinical experience, the committee highlighted that the risk of intracranial haemorrhage is low with aspirin. This is even so in people with neurological symptoms such as loss of consciousness or amnesia. So, they agreed that people on aspirin monotherapy could be discharged without a CT head scan after shared decision making if there is no other indication for a CT brain scan or hospital admission. The committee made a recommendation for research on risk of bleeding for people with pre-injury coagulopathy. People with liver or coagulopathy disorders There was no evidence for people with liver or coagulopathy disorders. Current practice is variable, with some services offering imaging to people with liver disease who have no symptoms. People with liver or coagulopathy disorders are at increased risk of bleeding, although some people will have a tendency for increased clotting. People with acquired coagulation defects can be a heterogenous and complex group. They can include people with acquired haemophilia through to people with other abnormalities such as disseminated intravascular coagulation. The committee agreed to keep the existing recommendations from the 2014 update of NICE's head injury guideline for people with bleeding and clotting disorders. This was because there was no new evidence to change practice. But they changed the recommendation wording from 'history of bleeding or clotting disorders' to 'current bleeding or clotting disorders'. In people under 16, some disorders are short-lived or resolve in a couple of months. In adults, a history of bleeding or clotting disorders is used to help screen people before surgery. However, this may not be appropriate in the emergency department setting. So, the committee agreed to keep the changed wording for all age groups to help provide a consistent message. People with pre-injury cognitive impairment who have a head injury through low-energy impact or low-level falls Limited evidence from cohort studies suggested that, in people 16 and over, falling from a standing position, being over 70, having a reduced GCS score compared with normal, taking antiplatelet medication including aspirin, and having neurological symptoms (loss of consciousness, vomiting after fall) were risk factors associated with the diagnosis of an intracranial bleed. Anticoagulant medication in this population was not associated with an intracranial bleed. It was not clear if people in the studies had pre-injury cognitive impairment, so the applicability of this evidence is limited. The committee discussed the challenges in assessing risk in people with cognitive impairment. For example, people with dementia may under-report or may be unaware of symptoms such as loss of consciousness or amnesia. It is also difficult to differentiate head injury symptoms from the pre-existing dementia in these people. There was no evidence for people under 16. The committee acknowledged the limited evidence for this group. They made a recommendation for research on indications for imaging for people with pre-injury cognitive impairment. People with recurrent head injuries There was no evidence for recurrent head injuries in any age group. Recurrent head injuries could occur in people with epilepsy, people with mobility issues at high risk of falls and with some sports activities. Particularly in the context of sports injuries, these injuries can be repeated and lead to cumulative risks. Because of a lack of evidence, the committee decided to make a recommendation for research on indications for imaging for people with a history of recurrent traumatic head injuries. Evidence from 1 observational study suggested that there was an increased risk of any traumatic brain injury or important traumatic brain injury on a CT head scan in babies and children under 2 years: the younger their age if they have a GCS score of less than 15 if they present more than 24 hours after head injury. There was no evidence for people 2 years or over. The committee discussed that people 16 and over presenting more than 24 hours after injury have increased risk factors such as vomiting and loss of consciousness. This is because they would be attending because of worsening symptoms. The 2014 update of NICE's head injury guideline recommendations are for people presenting within 24 hours of injury. But, because of a lack of evidence, the committee agreed that these could be extrapolated to people presenting more than 24 hours after a head injury (see the recommendations on the criteria for doing a CT head scan). They also agreed that this was an important area, so proposed a recommendation for research on indications for selecting people for imaging when they present more than 24 hours after a head injury. ## How the recommendations might affect practice or services Weakening the recommendation for people with a head injury who are on anticoagulants but have no other indication for imaging from 'offer' to 'consider' is expected to result in fewer scans. But expanding the recommendation to include people with a head injury who are on clopidogrel, prasugrel or ticagrelor is expected to result in more scans. It is uncertain whether this will lead to an overall increase or decrease in scanning. Return to recommendations # Post-concussion syndrome Recommendation 1.5.15 ## Why the committee made the recommendation The committee agreed that high specificity is needed for brain injury biomarkers for post-concussion syndrome. This was because the population with a mild head injury is large but only a small proportion go on to develop post-concussion syndrome. So, false positives would have a negative effect on resources if biomarkers were to be used to direct everyone towards interventions or monitoring. Overall, the committee agreed that the evidence was too limited to be able to make recommendations for using biomarkers (including fluid biomarkers or MRI) to predict post-concussion syndrome in people with mild traumatic brain injury. There was no evidence from prognostic test-and-treat studies comparing clinical outcomes, so the committee agreed to highlight the criteria for doing a CT head scan. They also made a recommendation for research on using biomarkers and MRI for predicting post-concussion syndrome. Evidence from diagnostic accuracy studies suggested that there were high sensitivity values for some biomarkers at certain thresholds for predicting acute complications after a traumatic brain injury, but the specificity values were not high enough across the evidence. Also, many biomarkers were only tested in small samples, which led to imprecise estimates. The committee noted that accuracy differed quite widely between different studies looking at the same biomarker test measured with different assays on different platforms. Also, the evidence was heterogenous, with variable thresholds and time points for different biomarkers. Most people with a head injury present to hospital within 3 hours, and the manufacturers recommend this timeframe for optimal test results. Many of the studies assessed biomarkers beyond this time point. The committee agreed that the specificity values were equally as important as the sensitivity values, given the consequences of unnecessary radiation from CT scans. They thought this was particularly important in people under 16. But, after considering the limitations of the evidence, the committee were unable to make recommendations for using biomarkers to predict acute complications after a mild traumatic brain injury. They did think that biomarker tests had promise, so they proposed a recommendation for research on using biomarkers for predicting acute post-traumatic brain injury complications. ## How the recommendation might affect practice or services Biomarkers are not routinely used in people with acute head injury and the recommendation for MRI has not changed. So, there is not expected to be a change in practice. Return to recommendation # Investigating injuries to the cervical spine Recommendations 1.6.1 to 1.6.11 ## Why the committee made the recommendations The committee considered sensitivity to be the most important measure for types of investigation for cervical spine injuries in people with head injuries. This is to ensure the investigation does not miss important cervical spine injuries, which could result in subsequent negative consequences such as disability. The evidence was limited because the proportion of people with a confirmed head injury was not reported in the diagnostic accuracy studies, but it suggested that X‑rays have poor sensitivity compared with CT scans in people 16 and over. Based on the evidence, and the committee's experience and knowledge of current practice, the committee agreed that X‑rays of the cervical spine should not be done initially in people 16 and over with a head injury. They also agreed that CT scans of the cervical spine should be used in people 16 and over in a way consistent with current clinical practice. There was limited evidence for MRI (less accurate at showing bony injuries, takes longer to do and younger people might need sedation). Also, MRI is rarely used as an initial imaging strategy. So, MRI is recommended as an additional form of imaging in certain circumstances (as in previous versions of the guideline). For people under 16, limitations in the evidence, and radiation exposure and risk of cancer, contributed to the committee's decision not to make any major changes to the recommendations. ## How the recommendations might affect practice or services CT scanning of the neck in people 16 and over with a head injury has already replaced X‑rays when there is at least a medium risk of serious spinal injury. So, there is not expected to be a change in practice. Return to recommendations # Admission and observation Recommendations 1.9.1 to 1.9.5 ## Why the committee made the recommendations Limited evidence from cohort studies in people with intracranial injuries suggested that effect sizes for the clinical decision rules were larger overall than those for individual risk factors. So, the committee agreed that clinical decision rules were likely to be the way to identify people who should be admitted in the future. This was because they thought it would be difficult to make decisions based on individual risk factors in clinical practice. But the evidence for clinical decision rules was all retrospective. So, the committee did not think any specific clinical decision rules could be recommended, particularly because they would be new to clinical practice. For individual risk factors, the committee noted that there was consistent evidence across all studies (including 1 study in people under 16) that GCS scores of 13 and 14 were associated with a worse outcome than a GCS score of 15. But this is already an existing indication for admission (see recommendation 1.9.1). Evidence for specific thresholds and findings on CT (including thresholds for subdural or epidural haemorrhage size, or findings such as midline shift or mass effect on CT) also indicated larger effect sizes than for some other risk factors. But, for factors such as midline shift, the committee noted that a threshold for degree of shift would be more useful in practice. They also noted that the varying thresholds used for subdural and epidural haemorrhage across the different studies made the ideal threshold to use unclear. The evidence also suggested that thresholds for age could be associated with a worse outcome in higher age groups. But the committee noted that older age would not solely be used in practice to make decisions about admission. This is particularly because admission in older age groups can also be associated with harms such as hospital-acquired infections. The committee agreed that age or frailty may be a concern but should not be a sole indicator for admission. Overall, the committee agreed that prospective studies are needed in people with a GCS score of 13, 14 or 15 and a head injury of any size confirmed with CT to validate existing clinical decision rules for predicting deterioration. The aim would be to refine indications for admission in this group. So, the committee made a recommendation for research on indications for admission in people with a mild head injury and a confirmed abnormality on a CT scan. Evidence from several case series suggested that there was low risk of death, neurosurgery, admission to critical care, unplanned hospital admission and delayed intracranial injury in babies and children (age cut-off varied across studies) with an isolated skull fracture. The evidence suggested that there was a slightly higher risk of seizure (at presentation) and evaluation for suspected non-accidental injury in this group. According to current guidelines (recommendations 1.5.8 and 1.5.10), people with seizures and suspected non-accidental injuries will be admitted to hospital after a head injury. Based on the evidence, the committee agreed that simple linear non-displaced fractures are not likely to be a clinically important injury. So, they agreed that, after shared decision making, people under 16 with such fractures can be safely discharged if they have normal neurological status and there are no safeguarding concerns. There was no direct evidence for people 16 and over with an isolated skull fracture. Indirect evidence from cohort studies suggested that there was low risk of clinical deterioration from a simple skull fracture compared with: a complex skull fracture to 2 bleeds bleeds less than 5 mm in diameter no or minimal mass effect significant midline shift a high- or mixed-density lesion cerebellar or brain stem injury. Clinical deterioration was measured by a composite of death due to traumatic brain injury, neurosurgery, seizure, a fall in GCS score of more than 1, admission into intensive care for traumatic brain injury, intubation or hospital readmission for traumatic brain injury. The simple skull fracture group included both isolated and non-isolated skull fractures. But the committee agreed that the evidence is still likely to be broadly applicable for people 16 and over with an isolated skull fracture. Based on the evidence and their collective experience, the committee agreed that, after shared decision making, people 16 and over with an isolated skull fracture can be discharged safely (except for people on anticoagulants or antiplatelets) if there are no safety concerns. The evidence was limited on admission to and observation in hospital of people who have a head injury and are on anticoagulants (warfarin and other vitamin K antagonists, and direct-acting oral anticoagulants) or antiplatelets (including aspirin, ticlopidine, clopidogrel, prasugrel and ticagrelor), and have normal brain imaging or no indication for early imaging. Limited evidence from non-randomised studies suggested that there was no clinically important difference between pre-injury anticoagulant or no anticoagulant treatment in terms of delayed bleeding. The evidence included at least 1 propensity matched study including about 70,000 people. The committee agreed that the evidence was not strong enough to recommend using anticoagulation status as a sole indicator for admission for people with a negative initial CT head scan. They highlighted that admission based solely on this could cause harm in people already vulnerable (because of, for example, frailty, an underlying condition such as delirium or risk of hospital-acquired infections). This is particularly so if there is not a large increase in risk of delayed bleeding. Also, when these events do occur, they are usually not clinically important. Evidence from non-randomised studies for antiplatelet comparisons was more limited than that for anticoagulants. There were no large studies, and all reported effects were based on a difference of only 1 to 2 events between pre-injury antiplatelet and no-antiplatelet groups per study. The committee agreed that the evidence was not strong enough to recommend using antiplatelet status as a sole indicator for admission for people with a negative initial CT or no indication for a CT. The committee did not make a recommendation for research for this group because they did not consider it to be a priority for research. There was no evidence on admission or discharge of people with concussion symptoms after normal imaging or no indication for imaging. The committee agreed that their discharge is based on clinical discretion, and admission is considered if non-accidental injury is suspected. From their experience, the committee also agreed that most people with concussion symptoms and normal imaging do not need further intervention and are safe to be discharged from the emergency department. They highlighted that current practice is to not admit people with concussion symptoms unless they have any of the indications in recommendation 1.9.1. The committee were unaware of any evidence indicating that current practice was causing harm (coroners reports, safety reports, patient group feedback). They also noted that someone's condition may worsen if they are admitted, for example, because of being in a noisy and unfamiliar environment, and because the risk of hospital-acquired infections could increase. When people with concussion symptoms are discharged, information is provided on when to return to hospital to seek further immediate care and ongoing support for persistent symptoms (see the recommendations on discharge advice). The committee agreed that this is important and did not think there was any evidence on which to base a change in practice. ## How the recommendations might affect practice or services Currently, most people with an isolated skull fracture are admitted for observation. It is expected that many of these people could be discharged from the emergency department without admission to hospital unless there are other indications for admission. For people on anticoagulants or antiplatelets, and people with concussion symptoms, there are no significant changes in practice recommended, and the recommendations are thought to reflect current practice. Return to recommendations # Early diagnosis of hypopituitarism Recommendations 1.9.6 to 1.9.8 ## Why the committee made the recommendations The committee highlighted that there is a higher risk of hypopituitarism with more severe head injuries, but noted that it can be caused by a mild head injury. Also, the condition can occur immediately after a head injury or in the weeks to months afterwards. This, and the wide variety of symptoms of hypopituitarism, can make the condition difficult to diagnose. The committee supplemented the small amount of observational evidence (cohort studies) with their expertise. They discussed that why head injury causes hypopituitarism is not fully understood, and that there could be various reasons. Current practice for screening for hypopituitarism is variable, but it is not commonly identified on CT scanning in the emergency department. The clinician's familiarity and suspicion of hypopituitarism may affect diagnosis rates. Also, testing in the emergency department may not be useful because the acute injury phase stimulates cortisol secretion. This makes it difficult to tell if there is hypoadrenalism. So, the committee agreed that it would be better to investigate for hypopituitarism in people admitted to hospital with a head injury if they have clinical symptoms or biochemical findings such as hypotension or hyponatraemia. The committee suggested this would provide an opportunity for referral to a specialist. In the absence of evidence on the timing of investigations, the committee also made a recommendation for research on timing of testing for hypopituitarism. ## How the recommendations might affect practice or services Hospital staff are advised to look out for symptoms of hypopituitarism in people admitted to hospital after a head injury. So, there might be an increase in testing for hypopituitarism in hospital. It is also intended that people will get referred for specialist care sooner. Return to recommendations # Discharge and follow up Recommendation 1.10.6 ## Why the committee made the recommendation Pre-existing cognitive impairment such as dementia, Parkinson's disease or stroke was reported in some studies in people taking anticoagulants and antiplatelets, but the studies did not report the effect of pre-injury cognitive impairment on the outcomes. Examples of pre-injury cognitive impairments and neurodivergence seen in people of any age include developmental delay, Down's syndrome, cerebral palsy, fetal alcohol syndrome, a learning disability, autism spectrum disorder and other conditions with altered sensation. Examples of pre-injury cognitive impairment seen only in adults include depression, dementia and medication side effects. The committee noted from their experience that people with pre-existing conditions affecting cognition are less likely to recognise and to raise an alarm about the early signs of a late intracranial bleed (such as a severe headache, drowsiness and vomiting) than people with no pre-existing cognitive impairment. So, in current practice, a short overnight admission for observation is arranged for people with a pre-existing cognitive impairment when no supervision at home is available. The committee agreed that people with a pre-existing cognitive impairment will need to be appropriately supervised and monitored to ensure that their symptoms are not worsening if they are discharged from the emergency department. Supervision and monitoring was also noted to be important for people discharged to custodial settings. The committee noted that, at discharge, it is important for people and their carers to be given a written copy of the head injury discharge advice. ## How the recommendation might affect practice or services There might be a small increase in overnight admissions for people with a pre-existing cognitive impairment when no supervision is available at home. This should lead to better outcomes for people who do deteriorate and reduced longer-term care costs. Return to recommendation # Follow up Recommendations 1.10.13 and 1.10.14 ## Why the committee made the recommendations People with a head injury may need investigation for the causes of the injury or to manage contributing factors. People with a head injury may have persisting problems, including physical, sensory, motor, cognitive, emotional and hormonal (hypopituitarism). These can occur even in people who are not admitted to hospital or have normal imaging at the time of their injury. It is important that people know how to seek help and ongoing support for these symptoms. It is also important for healthcare professionals to make appropriate outpatient referrals to other healthcare professionals trained in managing these symptoms. Some people who have had a head injury will be at increased risk of further injury. It is important that these people can access relevant services. ## How the recommendation might affect practice or services There might be an increase in referrals from primary care to hospital outpatient clinics for people who were not admitted to hospital, or had a normal scan or no scan at the time of their head injury. This should mean that people get earlier access to effective treatment for persisting symptoms resulting from their head injury and prevention services. Return to recommendation # Investigations for hypopituitarism Recommendation 1.10.15 ## Why the committee made the recommendation The committee discussed further endocrinology investigations for suspected hypopituitarism in people who have been discharged after a head injury if symptoms persist or they are not recovering as expected. They noted that some of the symptoms of hypopituitarism may be non-specific and caused by other conditions, making diagnosis difficult. They agreed that investigation in endocrinology may be needed. In people under 16, delayed symptoms may include slow growth, tiredness and late puberty. The committee emphasised that, if hypopituitarism is suspected, it is important to urgently refer the person under 16 to a paediatric endocrinologist. ## How the recommendation might affect practice or services The guideline raises awareness of the symptoms of hypopituitarism for people with a head injury, and their carers and clinicians. So, there might be an increase in testing for hypopituitarism in primary care. It is also intended that people will get referred for appropriate care sooner. Return to recommendation# Context Head injuries are a major cause of death and disability in people aged 1 to 40 in the UK. Each year, over 1 million people attend emergency departments in England and Wales with a recent head injury. Between 33% and 50% of these people are aged under 15. About 200,000 people are admitted to hospital with a head injury every year. Of these, about 40,000 have evidence of traumatic brain injury. Most people with a head injury recover without specific or specialist intervention. Others have long-term disability or even die from associated traumatic brain or other injuries. An increasing proportion of people presenting with head injury are over 65. Many people are injured through low-level falls, which can be sustained in the context of acute illness. The incidence of death from head injuries is low. As few as 0.2% of people attending emergency departments with a head injury die because of their injury. Of people who have sustained a head injury, 95% present with a normal or minimally impaired conscious level, that is, a Glasgow Coma Scale (GCS) score of 13 or more. Most fatal outcomes are in the groups with a moderate (GCS score of 9 to 12) or severe (GCS score of 8 or less) head injury, and account for only 5% of attenders. This means emergency departments need to identify the small number who will go on to have serious acute intracranial complications. It is estimated that, in 25% to 30% of children under 2 who are hospitalised with a head injury, it is caused by abuse. This guideline has updated some of the terminology used in relation to safeguarding people under 18 and vulnerable adults. This update addresses these areas, including in particular: indications for transporting people with a head injury from the scene of injury directly to the nearest neuroscience centre, bypassing the nearest emergency department indications for, and timing of, CT head scans and imaging of the cervical spine in the emergency department, with particular reference to anticoagulant treatment and levels of circulating brain injury biomarkers the clinical and cost effectiveness of administering tranexamic acid to people who have sustained a head injury and have suspected intracranial bleeding consideration of traumatic injury to the pituitary gland in people with a head injury information that should be provided to people with a head injury, and their family members and carers, on discharge from the emergency department or observation ward.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nFor the purposes of this guideline, a head injury is defined as any trauma to the head other than superficial injuries to the face. Also, babies are defined as being under 1\xa0year, and children and young people as being 1\xa0year to under 16\xa0years.\n\n# Decision making and mental capacity\n\nFor recommendations on promoting ways for healthcare professionals and people using services to work together to make decisions about treatment and care, see NICE's guideline on shared decision making. \n\nFor recommendations on decision making in people 16 and over who may lack capacity now or in the future, including information on advance care plans, see NICE's guideline on decision making and mental capacity. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on decision making and mental capacity\xa0.\n\nLoading. Please wait.\n\n# Pre-hospital assessment, advice and referral to hospital\n\nPublic health literature and other non-medical sources of advice (for example, St John Ambulance and police officers) should encourage people who have any concerns after a head injury to themselves or to another person, regardless of the injury severity, to seek immediate medical advice. \n\n## Remote advice services\n\nRemote advice services (for example, NHS 111) should refer people who have sustained a head injury to the emergency ambulance services (that is, 999) for emergency transport to the emergency department if there are any of these risk factors (see NICE's guidelines on shared decision making and decision making and mental capacity):\n\nunconsciousness or lack of full consciousness (for example, problems keeping eyes open)\n\nany focal neurological deficit since the injury\n\nany suspicion of a complex skull fracture or penetrating head injury\n\nany seizure ('convulsion' or 'fit') since the injury\n\na high-energy head injury\n\nthere is no other way of safely transporting the person to the hospital emergency department (see recommendation\xa01.2.3). [2003, amended 2007, 2014 and 2023]\n\nRemote advice services (for example, NHS 111) should refer people who have sustained a head injury to a hospital emergency department if there are any of these risk factors (see NICE's guidelines on shared decision making and decision making and mental capacity):\n\nany loss of consciousness ('knocked out') because of the injury, from which the person has now recovered\n\namnesia for events before or after the injury ('problems with memory'; it will not be possible to assess amnesia in children who are preverbal and is unlikely to be possible in children under 5)\n\na persistent headache since the injury\n\nany vomiting episodes since the injury\n\nany previous brain surgery\n\nany history of bleeding or clotting disorders\n\ncurrent anticoagulant and antiplatelet (except aspirin monotherapy) treatment\n\ncurrent drug or alcohol intoxication\n\nany safeguarding concerns (for example, possible non-accidental injury or a vulnerable person is affected)\n\nirritability or altered behaviour (easily distracted, not themselves, no concentration, no interest in things around them), particularly in babies and children under 5\n\ncontinuing concern by helpline staff about the diagnosis. [2003, amended 2014 and 2023]\n\n## Community health services and inpatient units without an emergency department\n\nCommunity health services (GPs, ambulance crews, NHS walk-in or minor injury centres, dental practitioners) and inpatient units without an emergency department should refer people who have sustained a head injury to a hospital emergency department, using the ambulance service if necessary, if there are any of these risk factors (see NICE's guidelines on shared decision making and decision making and mental capacity):\n\na Glasgow Coma Scale (GCS) score of less than 15 on initial assessment\n\nany loss of consciousness because of the injury\n\nany focal neurological deficit since the injury\n\nany suspicion of a complex skull fracture or penetrating head injury since the injury\n\namnesia for events before or after the injury (it will not be possible to assess amnesia in children who are preverbal and is unlikely to be possible in children under 5)\n\na persistent headache since the injury\n\nany vomiting episodes since the injury (use clinical judgement about the cause of vomiting in children 12 years or under and the need for referral)\n\nany seizure since the injury\n\nany previous brain surgery\n\na high-energy head injury\n\nany history of bleeding or clotting disorders\n\ncurrent anticoagulant and antiplatelet (except aspirin monotherapy) treatment\n\ncurrent drug or alcohol intoxication\n\nany safeguarding concerns (for example, possible non-accidental injury or a vulnerable person is affected)\n\ncontinuing concern by the professional about the diagnosis. [2003, amended 2007, 2014 and 2023]\n\nIn the absence of any risk factors in recommendation\xa01.2.4, consider referral to an emergency department if any of these factors are present, depending on judgement of severity (see NICE's guidelines on shared decision making and decision making and mental capacity):\n\nirritability or altered behaviour, particularly in babies and children under 5\n\nvisible trauma to the head not covered in recommendation\xa01.2.4 but still of concern to the professional\n\nno one is able to observe the injured person at home\n\ncontinuing concern by the injured person, or their family or carer, about the diagnosis. [2003, amended 2014 and 2023]\n\n## Transport to hospital from community health services and inpatient units without an emergency department\n\nEnsure people referred from community health services are accompanied by a competent adult during transport to the emergency department. \n\nThe referring professional should determine if an ambulance is needed, based on the person's clinical condition. If an ambulance is not needed, provided the person is accompanied, public transport or being driven in a car are appropriate means of transport. \n\nThe referring professional should inform the destination hospital (by phone) of the impending transfer. In non-emergencies, a letter summarising signs and symptoms should be sent with the person. \n\n## Training in risk assessment\n\nTrain GPs, nurse practitioners, dentists and ambulance crews, as necessary, to ensure that they are capable of assessing the presence or absence of the risk factors listed in the section on community health services and inpatient units without an emergency department. [2003, amended 2007]\n\n# Immediate management at the scene and transport to hospital\n\n## Glasgow Coma Scale\n\nBase monitoring and exchange of information about people with a head injury on the 3 separate responses on the GCS (for example, describe a person with a GCS score of 13 based on scores of 4 on eye opening, 4 on verbal response and 5 on motor response as E4, V4, M5). \n\nWhen recording or passing on information about total GCS score, give this as a score out of 15 (for example, 13 out of 15). \n\nDescribe the individual components of the GCS in all communications and every patient record and ensure that they always accompany the total score. \n\nIn the paediatric version of the GCS, include a 'grimace' alternative to the verbal score to enable scoring in children who are preverbal. \n\nIn some people (for example, people with dementia, underlying chronic neurological disorders or learning disabilities), the pre-injury baseline GCS score may be less than 15. Establish this when possible and take it into account during assessment. \n\n## Initial assessment and care\n\nInitially assess people 16 and over who have sustained a head injury and manage their care according to clear principles and standard practice, as embodied in the:\n\nAdvanced Trauma Life Support course or European Trauma course\n\nInternational Trauma Life Support course\n\nPre-hospital Trauma Life Support course\n\nAdvanced Trauma Nurse Course\n\nTrauma Nursing Core Course\n\nJoint Royal Colleges Ambulance Service Liaison Committee Clinical Practice Guidelines for Head Trauma. [2003, amended 2007]\n\nInitially assess people under 16 who have sustained a head injury and manage their care according to clear principles outlined in the:\n\nAdvanced Paediatric Life Support course or European Paediatric Life Support course\n\nPre-hospital Paediatric Life Support course\n\nPaediatric Education for Pre-hospital Professionals course. [2003, amended 2007]\n\nWhen administering immediate care, first treat the greatest threat to life and avoid further harm. For advice on volume resuscitation for people with a traumatic brain injury and haemorrhagic shock, see NICE's guideline on major trauma: assessment and initial management. \n\nFor recommendations on when to carry out full in-line spine immobilisation and how long immobilisation is needed if indicated, see NICE's guideline on spinal injury. [2003, amended 2007]\n\nMake pre-alert calls to the destination emergency department for anyone with a GCS score of 8 or less to ensure appropriately experienced professionals are available for their treatment and to prepare for imaging. \n\nManage pain effectively because it can lead to a rise in intracranial pressure. Provide reassurance, splint limb fractures and catheterise a full bladder when needed. Also see NICE's guideline on major trauma: assessment and initial management. [2007, amended 2014]\n\nAlways follow best practice in paediatric coma observation and recording, as detailed by the National Paediatric Neuroscience Benchmarking Group. \n\n## Transport to hospital\n\nTransport people who have sustained a head injury directly to a major trauma centre or trauma unit that has the age-appropriate resources to further resuscitate them, and to investigate and initially manage multiple injuries. \n\nFor guidance on the care of people with major trauma, see NICE's guideline on major trauma: service delivery. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on transport to hospital\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: transport to a distant specialist neuroscience centre.\n\nLoading. Please wait.\n\n## Training for ambulance crews and paramedics\n\nAmbulance crews and paramedics should be fully trained in the use of the adult and paediatric versions of the GCS and its derived score. \n\nAmbulance crews and paramedics should be trained in the safeguarding of people under 16 and people 16 and over who are vulnerable. They should document and verbally inform emergency department staff of any safeguarding concerns. [2003, amended 2014]\n\n## Tranexamic acid\n\nFor people with a head injury and a GCS score of 12 or less who are not thought to have active extracranial bleeding, consider:\n\na 2\xa0g intravenous bolus injection of tranexamic acid for people 16 and over\n\na 15\xa0mg/kg to 30\xa0mg/kg (up to a maximum of 2\xa0g) intravenous bolus injection of tranexamic acid for people under 16.Give the tranexamic acid as soon as possible within 2\xa0hours of the injury, in the pre-hospital or hospital setting and before imaging. In March\xa02023, these were off-label uses of tranexamic acid. See NICE's information on prescribing medicines. \n\nFor people with a head injury, and suspected or confirmed extracranial bleeding, see the recommendations in the section on haemostatic agents in pre-hospital and hospital settings in NICE's guideline on major trauma: assessment and initial management. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on tranexamic acid\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: tranexamic acid.\n\nLoading. Please wait.\n\n## Direct access from the community to imaging\n\nDo not refer people who have had a head injury for neuroimaging by direct access from the community.\xa0\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on direct access from the community to imaging\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: direct access from the community to imaging.\n\nLoading. Please wait.\n\n# Assessment in the emergency department\n\nBe aware that the priority for all people admitted to an emergency department is to stabilise the airway, breathing and circulation (ABC) before attending to other injuries. See NICE's guideline on major trauma: assessment and initial management. \n\nOnly assume a depressed conscious level is due to intoxication after an important traumatic brain injury has been excluded. \n\nEnsure all emergency department clinicians involved in assessing people with a head injury are capable of assessing the presence or absence of the risk factors for CT head imaging listed in the recommendations on the criteria for doing a CT head scan and the criteria for doing a cervical spine scan in people 16\xa0and over and people under\xa016. Make training available as needed to ensure this. \n\nEnsure people presenting to the emergency department with impaired consciousness (a GCS score of less than\xa015) are assessed immediately by a trained member of staff. \n\nFor people with a GCS score of\xa012 or less, see the recommendations on tranexamic acid. \n\nFor people with a GCS score of\xa08 or less, ensure early involvement of an appropriately trained clinician to provide advanced airway management, as described in recommendations 1.8.7 and 1.8.8 in the section on transfer of people 16\xa0and over, and to assist with resuscitation. \n\nEnsure a trained member of staff assesses anyone presenting to an emergency department with a head injury within a maximum of 15\xa0minutes of arrival at hospital. Part of this assessment should establish whether they are at high or low risk for clinically important traumatic brain or cervical spine injury, as described in the recommendations on the criteria for doing a CT head scan and the criteria for doing a CT cervical spine scan in people\xa016 and over and people under\xa016. \n\nIn people considered to be at high risk for clinically important traumatic brain or cervical spine injury, extend assessment to full clinical examination to establish any need for CT imaging of the head, or imaging of the cervical spine and other body areas. Use the recommendations on the criteria for doing a CT head scan and the criteria for doing a CT cervical spine scan in people 16\xa0and over and people under\xa016 as the basis for the final decision on imaging after discussion with the radiology department. [2003, amended 2007]\n\nAnyone triaged to be at low risk for clinically important traumatic brain or cervical spine injury at initial assessment should be re-examined by an emergency department clinician. They should establish whether CT imaging of the head or cervical spine will be needed. Use the recommendations on the criteria for doing a CT head scan and the criteria for doing a cervical spine scan in people 16\xa0and over and people under\xa016 as the basis for the final decision on imaging after discussion with the radiology department. [2003, amended 2007 and 2023]\n\nReview people who return to an emergency department with any persistent complaint relating to the initial head injury and discuss them with a senior clinician experienced in head injuries. Consider whether a CT scan is needed. [2003, amended 2023]\n\nManage pain effectively to help prevent any rise in intracranial pressure. Provide reassurance, splint limb fractures and catheterise a full bladder when needed. See NICE's guideline on major trauma: assessment and initial management for information on pain management. \n\nConsider or suspect abuse, neglect or other safeguarding issues as a contributory factor to, or cause of, a head injury. See NICE's guidelines on child maltreatment, child abuse and neglect, domestic violence and abuse and safeguarding adults in care homes for clinical features that may be associated with maltreatment. \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on assessment in the emergency department\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: clinical decision rules selecting people with head injury for imaging.\n\nLoading. Please wait.\n\nInvolve a clinician with training in safeguarding in the initial assessment of any person with a head injury presenting to the emergency department. If there are any concerns identified, document these and follow local safeguarding procedures appropriate to the person's age. [2003, amended 2014]\n\nUse a standard head injury proforma for documentation when assessing and observing people with a head injury throughout their time in hospital. This form should be of a consistent format across all clinical departments and hospitals in which a person might be treated. Use a separate proforma for people under\xa016. Include areas to allow extra documentation (for example, in cases of non-accidental injury). [2003, amended 2007]\n\n## Involving the neurosurgical department\n\nDiscuss with a neurosurgeon the care of anyone with new and surgically significant abnormalities on imaging. The definition of 'surgically significant' should be developed by local neurosurgical centres and agreed with referring hospitals, along with referral procedures. [2003, amended 2014]\n\nRegardless of imaging, discuss a person's care plan with a neurosurgeon if they have:\n\npersisting coma (a GCS score of\xa08 or less) after initial resuscitation\n\nunexplained confusion that persists for more than 4\xa0hours\n\ndeterioration in GCS score after admission (pay more attention to motor response deterioration)\n\nprogressive focal neurological signs\n\na seizure without full recovery\n\na definite or suspected penetrating injury\n\na cerebrospinal fluid leak. \n\n# Investigating clinically important traumatic brain injuries\n\nThe current primary investigation of choice for detecting an acute clinically important traumatic brain injury is CT imaging of the head. \n\nFor safety, logistic and resource reasons, do not do MRI scanning as the primary investigation for clinically important traumatic brain injury in people who have sustained a head injury. But additional information of importance to prognosis can sometimes be detected using MRI. \n\nEnsure that there is appropriate equipment for monitoring people with a head injury who are having an MRI scan. Also ensure that all staff involved are aware of the dangers and necessary precautions for working near an MRI scanner. \n\nDo not use plain X‑rays of the skull to diagnose important traumatic brain injury before a discussion with a neuroscience unit. However, people under\xa016 presenting with suspected non-accidental injury may need a skeletal survey. \n\nArrange transfer to a suitable hospital for people with indications for a CT scan who present to a hospital where CT scans are not available (see the recommendations on the criteria for doing a CT head scan and the criteria for doing a CT cervical spine scan in people 16\xa0and over and people under\xa016). [2007, amended 2023]\n\nTrauma networks should make sure that people can be transferred as indicated in recommendation\xa01.5.5. [2007, amended 2023]\n\nIn line with good radiation exposure practice, make every effort to minimise radiation dose during imaging of the head and cervical spine, while ensuring that image quality and coverage is sufficient to achieve an adequate diagnostic study. \n\n## Criteria for doing a CT head scan\n\nFor people 16\xa0and over who have sustained a head injury, do a CT head scan within 1\xa0hour of any of these risk factors being identified:\n\na GCS score of\xa012 or less on initial assessment in the emergency department\n\na GCS score of less than\xa015 at 2\xa0hours after the injury on assessment in the emergency department\n\nsuspected open or depressed skull fracture\n\nany sign of basal skull fracture (haemotympanum, 'panda' eyes, cerebrospinal fluid leakage from the ear or nose, Battle's sign)\n\npost-traumatic seizure\n\nfocal neurological deficit\n\nmore than 1\xa0episode of vomiting. \n\nFor people 16\xa0and over who have had some loss of consciousness or amnesia since the injury, do a CT head scan within 8\xa0hours of the head injury, or within the hour in someone presenting more than 8\xa0hours after the injury, if they have any of these risk factors:\n\nage 65\xa0or over\n\nany current bleeding or clotting disorders\n\ndangerous mechanism of injury (a pedestrian or cyclist struck by a motor vehicle, an occupant ejected from a motor vehicle or a fall from a height of more than 1\xa0m or 5\xa0stairs)\n\nmore than 30\xa0minutes' retrograde amnesia of events immediately before the head injury. \n\nFor people under\xa016 who have sustained a head injury, do a CT head scan within 1\xa0hour of any of these risk factors being identified:\n\nsuspicion of non-accidental injury\n\npost-traumatic seizure\n\non initial emergency department assessment, a GCS score of less than\xa014 or, for babies under 1\xa0year, a GCS score (paediatric) of less than\xa015\n\nat 2\xa0hours after the injury, a GCS score of less than\xa015\n\nsuspected open or depressed skull fracture, or tense fontanelle\n\nany sign of basal skull fracture (haemotympanum, 'panda' eyes, cerebrospinal fluid leakage from the ear or nose, Battle's sign)\n\nfocal neurological deficit\n\nfor babies under 1\xa0year, a bruise, swelling or laceration of more than 5\xa0cm on the head. \n\nFor people under\xa016 who have sustained a head injury and have more than\xa01 of these risk factors, do a CT head scan within 1\xa0hour of the risk factors being identified:\n\nloss of consciousness lasting more than 5\xa0minutes (witnessed)\n\nabnormal drowsiness\n\nor more discrete episodes of vomiting\n\ndangerous mechanism of injury (high-speed road traffic accident as a pedestrian, cyclist or vehicle occupant, fall from a height of more than 3\xa0m, high-speed injury from a projectile or other object)\n\namnesia (anterograde or retrograde) lasting more than 5\xa0minutes (it will not be possible to assess amnesia in children who are preverbal and is unlikely to be possible in children under\xa05)\n\nany current bleeding or clotting disorder. \n\nObserve people under 16 who have sustained a head injury but have only 1\xa0of the risk factors in recommendation\xa01.5.11 for a minimum of 4\xa0hours in hospital. If, during observation, any of the following risk factors are identified, do a CT head scan within 1\xa0hour:\n\na GCS score of less than\xa015\n\nfurther vomiting\n\na further episode of abnormal drowsiness.If none of these risk factors occur during observation, use clinical judgement to determine whether a longer period of observation is needed. \n\nFor people who have sustained a head injury and have no other indications for a CT head scan, but are on anticoagulant treatment (including vitamin\xa0K antagonists, direct-acting oral anticoagulants, heparin and low molecular weight heparins) or antiplatelet treatment (excluding aspirin monotherapy), consider doing a CT head scan:\n\nwithin 8\xa0hours of the injury (for example, if it is difficult to do a risk assessment or if the person might not return to the emergency department if they have signs of deterioration) or\n\nwithin the hour if they present more than 8\xa0hours after the injury.For advice on reversing vitamin\xa0K antagonists and direct-acting oral anticoagulants for people with traumatic intracranial haemorrhage, see NICE's guideline on blood transfusion and NICE's technology appraisal guidance on andexanet alfa for reversing anticoagulation from apixaban or rivaroxaban. \n\nMake a provisional written radiology report available within 1\xa0hour of a CT scan. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on criteria for doing a CT head scan\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: clinical decision rules selecting people with head injury for imaging\n\nevidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups.\n\nLoading. Please wait.\n\n## Investigation to predict post-concussion syndrome\n\nFor information on referring people with possible post-concussion syndrome, see recommendation\xa01.10.14 in the section on follow up. \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on post-concussion syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: brain injury biomarkers and/or MRI for predicting post-concussion syndrome.\n\nLoading. Please wait.\n\n# Investigating injuries to the cervical spine\n\n## Assessing range of movement in the neck\n\nBe aware that range of movement in the neck when there is clinical suspicion of a cervical spine injury can only be assessed safely before imaging in people with a head injury if they have no high-risk factors (see recommendation\xa01.6.2, and recommendations\xa01.6.4 and\xa01.6.6). Only do the assessment if they have at least\xa01 of these low-risk features:\n\nthey were in a simple rear-end motor vehicle collision\n\nthey are comfortable in a sitting position\n\nthey have been ambulatory at any time since injury\n\nthere is no midline cervical spine tenderness\n\nthey present with delayed onset of neck pain.See also NICE's guideline on spinal injury: assessment and initial management. \n\n## Criteria for doing a CT cervical spine scan in people 16\xa0and over\n\nFor people 16\xa0and over who have sustained a head injury (including people with delayed presentation), do a CT cervical spine scan within 1\xa0hour of the risk factor being identified if any of these high-risk factors apply:\n\nthe GCS score is 12\xa0or less on initial assessment\n\nthe person has been intubated\n\na definitive diagnosis of a cervical spine injury is urgently needed (for example, if cervical spine manipulation is needed during surgery or anaesthesia)\n\nthere has been blunt polytrauma involving the head and chest, abdomen or pelvis in someone who is alert and stable\n\nthere is clinical suspicion of a cervical spine injury and any of these factors:\n\n\n\nage 65\xa0or over\n\na dangerous mechanism of injury (that is, a fall from a height of more than 1\xa0m or 5\xa0stairs, an axial load to the head such as from diving, a high-speed motor vehicle collision, a rollover motor accident, ejection from a motor vehicle, an accident involving motorised recreational vehicles or a bicycle collision)\n\nfocal peripheral neurological deficit\n\nparaesthesia in the upper or lower limbs. \n\n\n\nFor people 16\xa0and over who have sustained a head injury, and have neck pain or tenderness but no high-risk indications for a CT cervical spine scan (see recommendation 1.6.2), do a CT cervical spine scan within 1\xa0hour for any of these risk factors:\n\nit is not thought to be safe to assess the range of movement in the neck (see recommendation 1.6.1)\n\nsafe assessment of range of neck movement shows that the person cannot actively rotate their neck 45\xa0degrees to the left and right\n\nthe person has a condition predisposing them to a higher risk of injury to the cervical spine (for example, axial spondyloarthritis). \n\n## Criteria for doing a CT cervical spine scan in people under\xa016\n\nFor people under\xa016 who have sustained a head injury (including those with delayed presentation), only do a CT cervical spine scan if any of these risk factors apply:\n\nthe GCS score is 12\xa0or less on initial assessment\n\nthe person has been intubated\n\nthere are focal peripheral neurological signs\n\nthere is paraesthesia in the upper or lower limbs\n\na definitive diagnosis of a cervical spine injury is needed urgently (for example, if manipulation of the cervical spine is needed during surgery or anaesthesia)\n\nthe person is having other body areas scanned for head injury or multisystem trauma, and there is clinical suspicion of a cervical spine injury\n\nthere is strong clinical suspicion of injury despite normal X‑rays\n\nplain X‑rays are technically difficult or inadequate\n\nplain X‑rays identify a significant bony injury.Do the scan within 1\xa0hour of the risk factor being identified. \n\nFor people under\xa016 who have sustained a head injury, and have neck pain or tenderness but no indications for a CT cervical spine scan (see recommendation 1.6.4), do 3‑view cervical spine X‑rays before assessing range of movement in the neck if any of these risk factors are identified:\n\nthere was a dangerous mechanism of injury (that is, a fall from a height of more than 1\xa0m or 5\xa0stairs, an axial load to the head such as from diving, a high-speed motor vehicle collision, a rollover motor accident, ejection from a motor vehicle, an accident involving motorised recreational vehicles or a bicycle collision)\n\nsafe assessment of range of movement in the neck is not possible (see recommendation 1.6.1)\n\nthe person has a condition that predisposes them to a higher risk of injury to the cervical spine (for example, collagen vascular disease, osteogenesis imperfecta, axial spondyloarthritis).The X‑rays should be done within 1\xa0hour of the risk factor being identified and reviewed by a clinician trained in their interpretation. \n\nIf range of neck movement can be assessed safely (see recommendation 1.6.1) in a person under\xa016 who has sustained a head injury, and has neck pain or tenderness but no indications for a CT cervical spine scan, do 3‑view cervical spine X‑rays if they cannot actively rotate their neck 45\xa0degrees to the left and right. When the person is unable to understand commands or open their mouth, a peg view may be omitted. The X‑rays should be done within 1\xa0hour of this risk factor being identified, and reviewed by a clinician trained in their interpretation. \n\n## Timing of radiology report\n\nMake a provisional written radiology report available within 1\xa0hour of a CT scan. \n\n## Imaging investigations\n\nEnsure that imaging reports are based on high-resolution source data and multiplanar reformatting of the entire cervical spine. [2003, amended 2014 and 2023]\n\nDo MRI in addition to CT if there are neurological signs and symptoms suggesting injury to the cervical spine. [2003, amended 2014 and 2023]\n\nDo CT or MRI angiography of the neck vessels if there is a suspicion of vascular injury, for example, because of:\n\nvertebral malalignment\n\na high-risk fracture (that is, a high-grade or complex facial fracture or a base of skull fracture likely to involve the internal carotid artery or vertebral artery)\n\nposterior circulation syndrome. [2003, amended 2014 and 2023]\n\nConsider MRI for assessing ligamentous and disc injuries suggested by CT or clinical findings. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practices or services, see the rationale and impact section on investigating injuries to the cervical spine\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: CT, MRI and X-ray of the cervical spine in people with head injury – diagnostic.\n\nLoading. Please wait.\n\n# Information and support for families and carers\n\nStaff caring for people with a head injury should introduce themselves to family members or carers, and briefly explain what they are doing. [2003, amended 2014]\n\nEnsure that information for families and carers explains the nature of the head injury and the likely care pathway. \n\nStaff should think about how best to share information with people under\xa016, and introduce them to the possibility of long-term complex changes in their parent or sibling who has had a head injury. Literature produced by patient support groups may be helpful. \n\nEncourage family members and carers to talk to and make physical contact (for example, holding hands) with the person with a head injury. But ensure that relatives and friends do not feel obliged to spend long periods at the bedside. If they wish to stay with the person with a head injury, encourage them to take regular breaks. [2003, amended 2007]\n\nEnsure there is a board or area displaying leaflets or contact details for local and national patient support organisations to help family members and carers gather further information. \n\n# Transfer from hospital to a neuroscience unit\n\n## Transfer of people 16\xa0and over\n\nEnsure local guidelines on the transfer of people with a severe traumatic brain injury are drawn up between the referring hospital trusts, the neuroscience unit and the local ambulance service, and recognise that:\n\ntransfer would benefit anyone with serious head injuries (a GCS score of\xa08 or less), irrespective of the need for neurosurgery\n\nif transfer of people who do not need neurosurgery is not possible, ongoing liaison with the neuroscience unit over clinical management is essential. Also see the recommendations on transfer between emergency departments in NICE's guideline on major trauma: service delivery. [2003, amended 2007]\n\nThink about the possibility of occult extracranial injuries in people 16\xa0and over with multiple injuries, and do not transfer them to a service that is unable to deal with other aspects of trauma. \n\nEnsure there is a designated consultant in the referring hospital with responsibility for establishing arrangements for the transfer of people with head injuries to a neuroscience unit. Also ensure there is another consultant at the neuroscience unit with responsibility for establishing arrangements for communication with referring hospitals, and for receiving people transferred. \n\nEnsure that people with traumatic brain injuries needing emergency transfer to a neuroscience unit are accompanied by healthcare staff with appropriate training and experience in the transfer of people with an acute traumatic brain injury. They should:\n\nbe familiar with the pathophysiology of traumatic brain injuries, the medicines and equipment they will use, and working in the confines of an ambulance (or helicopter if appropriate)\n\nhave a dedicated and adequately trained assistant\n\nbe provided with appropriate clothing for the transfer, medical indemnity and personal accident insurance.Ensure that people needing non-emergency transfer are accompanied by appropriate clinical staff. [2003, amended 2007]\n\nProvide the transfer team responsible for transferring a person with a head injury with a means of communicating changes in the person's status with their base hospital and the neurosurgical unit during the transfer. [2003, amended 2014]\n\nAlthough it is understood that transfer is often urgent, complete the initial resuscitation and stabilisation of the person, and establish comprehensive monitoring before transfer, to avoid complications during the journey. Do not transport someone with persistent hypotension, despite resuscitation, until the cause has been identified and they are stabilised. [2003, amended 2007]\n\nIntubate and ventilate anyone with a GCS score of\xa08 or less needing transfer to a neuroscience unit, and anyone with the indications detailed in recommendation\xa01.8.8. \n\nIntubate and ventilate the person immediately when there is:\n\ncoma, that is, they are not obeying commands, not speaking and not eye opening (a GCS score of\xa08 or less)\n\nloss of protective laryngeal reflexes\n\nventilatory insufficiency, as judged by blood gases: hypoxaemia (PaO2 less than 13\xa0kPa on oxygen) or hypercarbia (PaCO2 more than 6\xa0kPa)\n\nirregular respirations. [2003, amended 2007]\n\nUse intubation and ventilation before the start of the journey when the person has:\n\nsignificantly deteriorating conscious level (1\xa0or more points on the motor score), even if not coma\n\nunstable fractures of the facial skeleton\n\ncopious bleeding into the mouth (for example, from a skull base fracture)\n\nseizures. [2003, amended 2007]\n\nAnyone whose trachea is intubated should have appropriate sedation and analgesia along with a neuromuscular blocking drug. Aim for a PaO2 of more than 13\xa0kPa, and a PaCO2 of 4.5\xa0kPa to 5.0\xa0kPa, unless there is clinical or radiological evidence of raised intracranial pressure, in which case more aggressive hyperventilation is justified. If hyperventilation is used, increase the inspired oxygen concentration. Maintain the mean arterial pressure at 80\xa0mmHg or more by infusion of fluid and vasopressors, as indicated. [2003, amended 2007]\n\nGive family members and carers as much access to the person with a head injury as is practical during transfer. If possible, give them an opportunity to discuss the reasons for transfer and how the transfer process works with a member of the healthcare team. [2003, amended 2014]\n\n## Transfer of people under\xa016\n\nRecommendations 1.8.1 to 1.8.9 and 1.8.11 were written for people 16\xa0and over, but apply these principles to people under\xa016, providing that the paediatric modification of the GCS is used for preverbal and non-verbal children. Ventilate people under\xa016 according to the age-appropriate level of oxygen saturation and maintain blood pressure at a level appropriate for their age. [2003, amended 2023]\n\nEnsure that service provision for transfer to tertiary care follows the principles outlined in the NHS England service specification for paediatric intensive care retrieval (transport) and the Paediatric Critical Care Society quality standards for the care of critically ill or injured children. \n\nThink about the possibility of occult extracranial injuries for people under\xa016 with multiple injuries. Do not transfer them to a service that is unable to deal with other aspects of trauma. \n\nEnsure that transfer of people under\xa016 to a specialist neurosurgical unit is done either by staff experienced in the transfer of people under\xa016 who are critically ill or according to local guidelines with specialist paediatric retrieval teams. [2003, amended 2023]\n\nGive family members and carers as much access to their child as is practical during transfer. If possible, give them an opportunity to discuss the reasons for transfer and how the transfer process works with a member of the healthcare team. [2003, amended 2014]\n\n# Admission and observation\n\nUse these criteria for admitting people to hospital after a head injury:\n\nnew, clinically important abnormalities on imaging (an isolated simple linear non-displaced skull fracture is unlikely to be a clinically important abnormality unless they are taking anticoagulant or antiplatelet medication)\n\nafter imaging, a GCS score that has not returned to\xa015 or their pre-injury baseline, regardless of the imaging results\n\nwhen there are indications for CT scanning but this cannot be done within the appropriate time period, either because CT is not available or because the person is not sufficiently cooperative to allow scanning\n\ncontinuing worrying symptoms (for example, persistent vomiting, severe headaches or seizures) of concern to the clinician\n\nother sources of concern to the clinician (for example, drug or alcohol intoxication, other injuries, shock, suspected non-accidental injury, meningism, cerebrospinal fluid leak, or suspicion of ongoing post-traumatic amnesia).See the section on discharge and follow up for recommendations about other factors to consider, such as whether supervision at home is available. [2003, amended 2023]\n\nBe aware that some people may need an extended period in a recovery setting because of having general anaesthesia during CT imaging. [2003, amended 2007]\n\nAdmit people with multiple injuries under the care of the team that is trained to deal with their most severe and urgent problem. \n\nWhen someone with a head injury needs hospital admission, admit them under the care of a team led by a consultant who has been trained in managing this condition. The consultant and their team should have competence (defined by local agreement with the neuroscience unit) in:\n\nassessment, observation and indications for imaging (see the sections on the criteria for doing a CT head scan and the criteria for doing a CT cervical spine scan in people 16\xa0and over and people under\xa016)\n\ninpatient management\n\nindications for transfer to a neuroscience unit (see the\xa0section on transfer from hospital to a neuroscience unit)\n\nhospital discharge and follow up (see the section on discharge and follow up). [2003, amended 2007]\n\n## Admission and observation of people with concussion symptoms\n\nFor people with concussion symptoms after normal brain imaging or no indication for early imaging, follow the indications for admission in recommendation\xa01.9.1. Also see the section on discharge advice. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on admission and observation\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review I: admission and observation in hospital of people with head injury who are on anticoagulant or antiplatelet therapy after normal brain imaging or no indication for early imaging\n\nevidence review J: admission and observation of people with concussion symptoms\n\nevidence review K: hospital admission in people with small intracranial injuries\n\nevidence review L: isolated skull fracture.\n\nLoading. Please wait.\n\n## Early diagnosis of hypopituitarism\n\nBe aware that any severity of head injury can cause pituitary dysfunction. This may present immediately, hours, weeks or months after the injury. A variety of symptoms could indicate hypopituitarism. \n\nIn people admitted to hospital with a head injury who have persistently abnormal low sodium levels or low blood pressure, consider investigations for hypopituitarism. \n\nIn people presenting to primary or community care with persistent symptoms consistent with hypopituitarism in the weeks or months after a head injury, consider investigations or referral for hypopituitarism. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on early diagnosis of hypopituitarism\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review M: identification of hypopituitarism (who to investigate)\n\nevidence review N: identification of hypopituitarism (when to investigate).\n\nLoading. Please wait.\n\n## Observation of people who are admitted\n\nEnsure that in-hospital observation of people with a head injury is only done by professionals competent in assessing head injuries. \n\nFor people admitted for head injury observation, the minimum acceptable documented neurological observations are: GCS score, pupil size and reactivity, limb movements, respiratory rate, heart rate, blood pressure, temperature and blood oxygen saturation. \n\nCarry out and record observations on a half-hourly basis until there is a GCS score of\xa015. Observations for people with a GCS score of\xa015 should start after the initial assessment in the emergency department and the minimum frequency should be:\n\nhalf-hourly for 2\xa0hours, then\n\nhourly for 4\xa0hours, then\n\nhourly. \n\nRevert to half-hourly observations and follow the original frequency schedule for people with a GCS score of\xa015 who deteriorate at any time after the initial 2‑hour period. \n\nUrgently reassess a person with a head injury if they have any of these signs of neurological deterioration:\n\nagitation or abnormal behaviour\n\na sustained (that is, for at least 30\xa0minutes) drop of 1\xa0point in GCS score (give more weight to a drop of 1\xa0point in the motor response score of the GCS score)\n\nany drop of 3\xa0or more points in the eye opening or verbal response scores of the GCS score, or 2\xa0or more points in the motor response score\n\nsevere or increasing headache, or persistent vomiting\n\nnew or evolving neurological symptoms or signs such as pupil inequality or asymmetry of limb or facial movement.A supervising doctor should do the appraisal. [2003, amended 2007]\n\nTo reduce interobserver variability and unnecessary referrals, get a second member of staff competent in observations to confirm deterioration before involving the supervising doctor. Do this immediately if possible. If not possible (for example, because no staff member is available to do the second observation), contact the supervising doctor without the confirmation being done. \n\nIf any of the changes noted in recommendation\xa01.9.13 are confirmed, consider doing an immediate CT scan, and reassess the person's clinical condition and manage appropriately. [2003, amended 2007]\n\nIf a person has had a normal CT scan but does not have a GCS score of\xa015 after 24\xa0hours of observation, consider a further CT or MRI scan and discuss with the radiology department. \n\n## Observation of babies and children under\xa05\n\nBe aware that observation of babies and children under\xa05 is difficult, so should only be done by units with staff experienced in the observation of under\xa05s with a head injury. Babies and children under\xa05 may be observed in normal paediatric observation settings, as long as staff have the appropriate experience. \n\n## Training in observation\n\nAll staff caring for people with a head injury admitted for observation should be trained in doing the observations listed in recommendations 1.9.10 to 1.9.14 in the section on observation of people who are admitted, and the recommendation on observation of babies and children under\xa05. \n\nMake dedicated training available to all relevant staff to enable them to acquire and maintain observation and recording skills. Specific training is needed for the observation of people under\xa016. \n\n# Discharge and follow up\n\nIf CT is not indicated based on history and examination and there is no suspicion of clinically important traumatic brain injury, discharge the person from hospital if there are:\n\nno other factors that would warrant a hospital admission (for example, drug or alcohol intoxication, other injuries, shock, suspected non-accidental injury, meningism, or cerebrospinal fluid leak)\n\nappropriate support structures for safe discharge to the community and for subsequent care (for example, competent supervision at home). \n\nIf imaging of the head is normal and the risk of clinically important traumatic brain injury is low, transfer the person to the community if:\n\nthe GCS score has returned to\xa015 or the pre-injury baseline GCS score\n\nthere are no other factors that would warrant a hospital admission (for example, drug or alcohol intoxication, other injuries, shock, suspected non-accidental injury, meningism, or cerebrospinal fluid leak)\n\nthere are appropriate support structures for safe transfer to the community and for subsequent care (for example, competent supervision at home). \n\nAfter normal imaging of the cervical spine, risk of injury to the cervical spine is low enough to warrant transfer to the community if:\n\nthe GCS score is\xa015\n\nclinical examination is normal\n\nthere are no other factors that would warrant a hospital admission present (for example, drug or alcohol intoxication, other injuries, shock, suspected non-accidental injury, meningism, or cerebrospinal fluid leak)\n\nthere are appropriate support structures for safe transfer to the community and for subsequent care (for example, competent supervision at home). \n\nDo not discharge people presenting with a head injury until their GCS score is\xa015 or, in preverbal and non-verbal children, consciousness is normal as assessed by the paediatric version of the GCS. In people with pre-injury cognitive impairment, their GCS score should be back to that documented before the injury. \n\nOnly transfer people with any degree of head injury to their home if there is somebody suitable at home to supervise them. Discharge people with no carer at home only if suitable supervision arrangements have been organised, or when the risk of late complications is thought to be negligible. \n\n## People with pre-injury cognitive impairment\n\nEnsure that people with pre-injury cognitive impairment (for example, dementia or a learning disability) and people returning to a custodial setting are supervised and monitored. Also, make sure that arrangements are in place should there be any signs of deterioration. \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on discharge and follow up\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups.\n\nLoading. Please wait.\n\n## Discharge after observation\n\nPeople admitted after a head injury may be discharged after resolution of all significant symptoms and signs, provided they have suitable supervision arrangements at home, in custody or in continued care. [2003, amended 2023]\n\n## Discharge advice\n\nGive verbal and printed discharge advice to people with any degree of head injury who are discharged from an emergency department or observation ward. This should also be provided to the person responsible for their care after discharge. This may include their families, carers, social workers or custodial staff. Follow the recommendations in NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, including on providing information in an accessible format. [2014, amended 2023]\n\nEnsure that printed advice for people with a head injury, and their families and carers, is age appropriate and includes:\n\ndetails of the nature and severity of the injury\n\nrisk factors that mean people need to return to the emergency department (see the recommendations on community health services and inpatient units without an emergency department)\n\na specification that a responsible adult should stay with the person for the first 24\xa0hours after their injury\n\ndetails about the recovery process, including the fact that some people may appear to make a quick recovery but later have difficulties or complications\n\ncontact details of community and hospital services in case of delayed complications\n\ninformation about return to everyday activities, including school, work, sports and driving\n\ndetails of support organisations. \n\nOffer information and advice on alcohol or drug misuse to people who presented to the emergency department with drug or alcohol intoxication when they are fit for discharge. \n\nInform people with a head injury, and their families and carers, about the possibility of persistent or delayed symptoms after a head injury and who to contact if they have ongoing problems. \n\nFor anyone who has attended the emergency department with a head injury, write to their GP within 48\xa0hours of discharge, giving details of clinical history and examination. Also share this letter with health visitors (for preschool children) and school nurses (for school-age children and young people). If appropriate, provide a copy of the letter for the person with a head injury, and their family or carers, custodial staff or social worker. \n\n## Follow up\n\nRefer people with a head injury to investigate its causes and manage contributing factors, if appropriate. This could include, for example, referral for a falls assessment or to safeguarding services. \n\nConsider referring people who have persisting problems to a clinician trained in assessing and managing the consequences of traumatic brain injury (for example, a neurologist, neuropsychologist, clinical psychologist, neurosurgeon or endocrinologist, or a multidisciplinary neurorehabilitation team). [2003, amended 2023]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice or services, see the rationale and impact section on follow up\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review J: admission and observation of people with concussion symptoms\n\nevidence review N: identification of hypopituitarism (when to investigate).\n\nLoading. Please wait.\n\n## Investigations for hypopituitarism\n\nConsider further endocrinology investigations for people who have been discharged after a head injury if they have persistent symptoms consistent with hypopituitarism or are not recovering as expected. \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice or services, see the rationale and impact section on investigations for hypopituitarism\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review M: identification of hypopituitarism (who to investigate)\n\nevidence review N: identification of hypopituitarism (when to investigate).\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Complex skull fracture or penetrating head injury\n\nSigns of a basal, open or depressed skull fracture or penetrating head injury include:\n\nclear fluid running from the ears or nose\n\na black eye with no associated damage around the eyes\n\nbleeding from 1\xa0or both ears\n\nbruising behind 1\xa0or both ears\n\npenetrating injury signs\n\nvisible trauma to the scalp or skull of concern to the professional.\n\n## Focal neurological deficit\n\nNeurological problems restricted to a particular part of the body or a particular activity, for example:\n\ndifficulties with understanding, speaking, reading or writing\n\ndecreased sensation\n\nloss of balance\n\nweakness\n\nvisual changes\n\nnystagmus\n\nabnormal reflexes\n\nproblems walking\n\namnesia since the injury.\n\n## Glasgow Coma Scale\n\nIn people with a head injury, the Glasgow Coma Scale (GCS) is an early assessment of the severity of any associated traumatic brain injury. It is a standardised system used to assess the degree of brain impairment and to identify the seriousness of injury in relation to outcome. The scale has 3\xa0domains: eye opening, verbal and motor responses. These are all evaluated independently in the scale according to a numerical value that indicates the level of consciousness and degree of dysfunction. The scores in each element of the GCS are summed to give the overall GCS score, which ranges from\xa03 (unresponsive in all domains) to\xa015 (no deficits in responsiveness):\n\nMild traumatic brain injury is a GCS score of 13\xa0to\xa015.\n\nModerate traumatic brain injury is a GCS score of 9\xa0to\xa012.\n\nSevere traumatic brain injury is a GCS score of 8\xa0or less.\n\n## High-energy head injury\n\nAn injury arising from, for example, a pedestrian being struck by a motor vehicle, an occupant being ejected from a motor vehicle, a fall from a height of more than 1\xa0m or more than 5 stairs, a diving accident, a high-speed motor vehicle collision, a rollover motor accident, an accident involving motorised recreational vehicles, a bicycle collision or any other potentially high-energy mechanism.\n\n## Hypopituitarism\n\nUnderactivity of the pituitary gland that can lead to:\n\nadrenocorticotropic hormone deficiency causing weakness, fatigue, weight loss, hypotension, hyponatraemia, hypoglycaemia, hypercalcaemia, anaemia and fatigue\n\ngrowth hormone deficiency causing decreased energy, low mood, neuropsychiatric and cognitive symptoms, decreased lean body mass, increased fat mass, altered metabolic profile and decreased exercise capacity\n\nlack of sex hormones that can cause later puberty, hot flushes, fatigue, tiredness, loss of body hair, reduced sex drive, irregular periods, erectile dysfunction and reduced fertility\n\nthyroid-stimulating hormone deficiency presenting with slow growth, fatigue, lethargy, cold intolerance and weight gain\n\nvasopressin deficiency causing polyuria, polydipsia, nocturia and incontinence.\n\n## Isolated simple linear non-displaced skull fracture\n\nA single or solitary linear fracture that does not exhibit any inward or outward displacement, does not consist of multiple fracture lines and does not involve or cross the normal sutures of the skull.\n\n## Paraesthesia\n\nPins and needles, or a prickling sensation, tingling or itching in any part of the body.\n\n## Post-concussion syndrome\n\nPost-concussion syndrome (or post-concussion symptoms) is seen in all severities of head injury and is under-recognised in mild head injuries. It is the term used in evidence review F: brain injury biomarkers and/or MRI for predicting post-concussion syndrome. The term 'concussion' is used in evidence review J: admission and observation of people with concussion symptoms.\n\nExamples of symptoms in these reviews include, but are not limited to:\n\nSensory and motor:\n\nheadache\n\ndizziness\n\nnausea\n\nchanges in vision, such as blurred vision, double vision, 'seeing stars' and 'looking through a haze'\n\nvisual processing problems, such as not taking in what you are seeing\n\ndifficulties staying awake, sleeping for many more hours than usual and chronic fatigue when awake\n\nunusual sensitivity to noise (hyperacusis)\n\nunusual sensitivity to bright lights (photophobia)\n\ndifficulties with balance, coordination and mobility, often resulting in falls, banging into objects and, at times, further traumatic brain injuries\n\nspeech problems.\n\nCognition:\n\ncognitive difficulties (as long as the GCS score is\xa015), sometimes described as 'brain fog', which may include problems finding words or numbers, difficulty speaking, slowed responsiveness, short-term memory problems, difficulty concentrating and problems with information processing, such as following conversations, digesting text and finding words\n\ndifficulties with executive functions, such as organising, planning and multitasking\n\namnesia\n\nproblems with spatial awareness and proprioception, including the sensation of touching something as if through a layer of numbness.\n\nEmotional:\n\nlability, such as unusual laughing or crying (because of being overwhelmed by sense impressions) or irritability\n\ndepression\n\nanxiety.\n\nAdditional symptoms that may present in children under\xa05:\n\nchanges in normal behaviour after a head injury, such as crying a lot or irritability\n\nchanges in feeding or sleeping habits\n\nloss of interest in people or objects\n\nlistlessness.\n\n## Traumatic brain injury\n\nAn alteration in brain function, or other evidence of brain pathology, caused by an external force.", 'Recommendations for research': "The guideline committee has made these recommendations for research.\n\n# Key recommendations for research\n\n## Indications for admission in people with a mild head injury and a confirmed abnormality on a CT scan\n\nWhat are the indications for admission using clinical decision rules in people with a Glasgow Coma Scale (GCS) score of 13\xa0to\xa015 (a mild head injury) and a confirmed abnormality on a CT scan? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on admission and observation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: hospital admission in people with small intracranial injuries.\n\nLoading. Please wait.\n\n## Using biomarkers for predicting acute post-traumatic brain injury complications\n\nWhat is the diagnostic accuracy of brain injury biomarkers for predicting acute complications after a traumatic brain injury? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on post-concussion syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: brain injury biomarkers for predicting acute post-brain injury complications.\n\nLoading. Please wait.\n\n## Indications for imaging for people with a history of recurrent head injuries\n\nWhat is the risk of intracranial injuries in people with a history of recurrent head injuries, including from sports and falls, and no other indications for a CT scan? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on criteria for doing a CT head scan\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups.\n\nLoading. Please wait.\n\n## Risk of bleeding for people with a pre-injury coagulopathy\n\nWhat is the risk of any intracranial bleeding or intracranial bleeding associated with clinical deterioration after head injury in people with a pre-injury coagulopathy? This includes medical conditions such as liver failure or haemophilia, or taking anticoagulants or antiplatelets in people who:\n\nhave a GCS score of\xa015 at 2\xa0hours after the head injury and medium risk factors for intracranial bleeding or\n\nloss of consciousness or amnesia with no additional risk factors (that is, they are under\xa065, had a low-energy transfer injury and any retrograde amnesia has lasted for less than\xa030 minutes) or\n\nthere is no loss of consciousness or amnesia \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on criteria for doing a CT head scan\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups.\n\nLoading. Please wait.\n\n## Indications for imaging for people with a pre-injury cognitive impairment\n\nWhat are the indications for selecting imaging in adults, young people, children and babies with a head injury sustained through a low-energy fall and with suspected pre-injury cognitive impairment when loss of consciousness or amnesia is difficult to assess or the pre-injury GCS score is not\xa015? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on criteria for doing a CT head scan\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Transport to a neuroscience centre\n\nWhat is the clinical and cost effectiveness of pre-hospital strategies to take people with a head injury to a distant specialist neuroscience centre instead of a closer non-specialist unit? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on transport to hospital\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: transfer to a distant specialist neuroscience centre.\n\nLoading. Please wait.\n\n## Tranexamic acid\n\nWhat is the clinical and cost effectiveness of tranexamic acid before imaging in people presenting within 2\xa0hours of a head injury with a GCS score of\xa013 to 15 and high-risk indications for intracranial bleeding? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on tranexamic acid\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: tranexamic acid.\n\nLoading. Please wait.\n\n## Indications for selecting people for imaging when they present more than 24\xa0hours after a head injury\n\nWhat are the indications for selecting people of any age who present more than 24\xa0hours after a head injury for a CT or MRI head scan? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on criteria for doing a CT head scan\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: selecting adults, children and infants with head injury for CT or MRI head scan in sub-groups.\n\nLoading. Please wait.\n\n## Using biomarkers and MRI for predicting post-concussion syndrome\n\nWhat is the prognostic accuracy of brain injury biomarkers or MRI for predicting post-concussion syndrome? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on post-concussion syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: brain injury biomarkers and/or MRI for predicting post-concussion syndrome.\n\nLoading. Please wait.\n\n## Timing of testing for hypopituitarism\n\nWhen should people with a head injury be investigated for hypopituitarism? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on early diagnosis of hypopituitarism\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review N: identification of hypopituitarism (when to investigate).\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice or services.\n\n# Decision making and mental capacity\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\nThe committee recognised the need to involve people with a head injury, and their family and carers, in decisions about their care, including referral to the emergency department. They also highlighted the importance of making decisions for people who may lack capacity now or in the future, and to follow any advance care plans.\n\n## How the recommendations might affect practice or services\n\nThere is not expected to be any change to practice or services.\n\nReturn to recommendations\n\n# Transport to hospital\n\nRecommendations 1.3.13 and 1.3.14\n\n## Why the committee made the recommendations\n\nEvidence from 1\xa0randomised controlled trial (RCT) and 1\xa0retrospective cohort study was identified. This compared transport for a head injury to a specialist neuroscience centre with transport to the nearest non-specialist acute hospital or general hospital emergency department. All the evidence was in people 16\xa0and over. No evidence was available for people under\xa016.\n\nThe evidence from the RCT suggested some benefit for transfer to a non-specialist general hospital for the outcome of mortality, but this was uncertain. The evidence from the retrospective cohort study suggested that there was no difference between the 2\xa0groups for the outcome of survival benefit. The committee agreed that there was limited evidence of a possible benefit for transfer to a specialist neuroscience centre for some outcomes but that this was uncertain. They agreed that there was no compelling evidence to change practice, and to cross refer to NICE's guideline on major trauma: service delivery.\n\nThe committee noted that the data collection for the RCT was in 2012. This was when trauma care was reorganised in the UK to enable rapid and safe transfer of people to major trauma centres. So, the evidence does not reflect the recent trauma care system, which includes more consultants, quicker CT scans and rehabilitation. So, the committee agreed that further research should be done in this area to determine the effectiveness of transport to specialist neuroscience centres in people with a head injury. They developed a recommendation for research on transport to a neuroscience centre.\n\n## How the recommendations might affect practice or services\n\nThere is not expected to be any change.\n\nReturn to recommendations\n\n# Tranexamic acid\n\nRecommendations 1.3.17 and 1.3.18\n\n## Why the committee made the recommendations\n\nThere was evidence from 2\xa0RCTs for tranexamic acid, both of which included adults with no suspicion of extracranial bleeding. One trial was in a pre-hospital (out-of-hospital) setting and the other was in a hospital setting. There was no evidence available for people under\xa016 (1\xa0trial included a few people aged 15\xa0and\xa016).\n\nIn the pre-hospital setting, a single 2\xa0g bolus dose of tranexamic acid was given within 2\xa0hours of a head injury. The evidence suggested that it reduced all-cause mortality at 28\xa0days and 6\xa0months in people with moderate or severe traumatic brain injury. But there was no clinically important difference between tranexamic acid and placebo for hospital-free days at 28\xa0days, degree of disability at discharge and after 6\xa0months (Glasgow Outcome Scale–Extended more than\xa04), and serious adverse events (that is, myocardial infarction, pulmonary embolism, deep vein thrombosis and stroke).\n\nIn the hospital setting, a 1\xa0g bolus dose of tranexamic acid was given within 3\xa0hours of injury, followed by an 8‑hour intravenous infusion of 1\xa0g of tranexamic acid. The evidence suggested that this reduced death from traumatic brain injury at 28\xa0days in groups with mild or moderate traumatic brain injury. Evidence suggested reduced mortality related to severe traumatic brain injury at 28\xa0days in high-income countries, but there was no difference in mortality related to traumatic brain injury in low- and middle-income countries. No evidence was available separating the mild from moderate severity groups for mortality related to traumatic brain injury and all-cause mortality, but communication with the study authors suggested significant uncertainty about tranexamic acid's effect in mild traumatic brain injury. There was no clinically important difference between tranexamic acid and placebo for serious adverse events (that is, myocardial infarction, pulmonary embolism, deep vein thrombosis and stroke) and disability rating scale scores in a mixed severity group (mild, moderate and severe) across all income groups.\n\nThe committee considered that, despite the uncertainty in the clinical evidence, there was a benefit with tranexamic acid in terms of reducing all-cause mortality and mortality from traumatic brain injury. They also considered that the evidence showed that it caused very few adverse events. Based on the evidence, they agreed that a 2\xa0g intravenous bolus dose of tranexamic acid, given within 2\xa0hours of a head injury and before imaging, could be considered for people 16 and over with moderate or severe traumatic brain injury. The committee recommended a 2\xa0g intravenous bolus injection of tranexamic acid because this dose was found to be the most safe and effective.\n\nAn economic model was developed that looked at each traumatic brain injury severity subgroup separately. It was based primarily on the pre-hospital clinical trial because:\n\nthat provided data for moderate traumatic brain injury separately from that for mild injury\n\nthe benefits of tranexamic acid were found to be greater when it was given earlier.\n\nFor moderate traumatic brain injury, the health benefits associated with a 2\xa0g bolus given in the pre-hospital setting outweighed the costs in all scenarios. For severe traumatic brain injury, the cost-effectiveness estimate was more borderline. But, when limitations in the modelling were taken into account, the committee concluded that the health benefits were likely to outweigh the costs in this group too.\n\nBecause of a lack of trial evidence for tranexamic use in people under 16, the committee used extrapolated evidence from the trials in adults, and their expertise and knowledge. In NHS clinical practice, a tranexamic acid dose of 15\xa0mg/kg is used in people under 16 with extracranial injuries. But, in this age group, tranexamic acid is not currently widely used for isolated head injury and dosing is variable (15\xa0mg/kg to 30\xa0mg/kg). Evidence for people 16 and over with a head injury from a pre-hospital setting suggested that a 2\xa0g dose of tranexamic acid reduced all-cause mortality (at 28\xa0days and 6\xa0months), with no evidence of negative effects. So, the committee concluded that it could recommend the equivalent of a 2\xa0g dose of tranexamic acid for people under 16. They discussed that, based on the average weight of people 16 and over being 70\xa0kg, a 2\xa0g dose of tranexamic acid for people 16 and over would equate to a 30\xa0mg/kg dose for people under 16. So, they concluded that a dose range of 15\xa0mg/kg to 30\xa0mg/kg was appropriate for people under 16.\n\nFor people with mild traumatic brain injury, it is less clear whether the benefits of tranexamic acid outweigh the potential risk of blood clots. So, the committee made a recommendation for research on tranexamic acid for this group.\n\n## How the recommendations might affect practice or services\n\nTranexamic acid is already used for people who have a head injury and other major trauma. NICE has not previously recommended it for people with an isolated head injury. It is expected that doing so will increase tranexamic acid use by paramedics. This should lead to improved survival for people with a head injury. More resources might be needed for treatment, rehabilitation and care for the people who would not have survived without tranexamic acid.\n\nReturn to recommendations\n\n# Direct access from the community to imaging\n\nRecommendation 1.3.19\n\n## Why the committee made the recommendation\n\nNo evidence was identified for direct access from the community for CT scans or MRI of the head compared with usual care for a suspected or confirmed head injury (including people with delayed presentation, and people in residential and care homes). The committee discussed that imaging ordered in the community setting is mainly used to exclude intracranial bleeding or provide reassurance. They noted that the timing of imaging depends on whether there is an acute injury or the person has post-concussion syndrome. Based on their experience, the committee agreed that people should go to hospital if:\n\nthere has been important traumatic brain injury within 24\xa0hours or\n\nthere is a reduced Glasgow Coma Scale (GCS) score.\n\nThe committee were aware that some trusts have referral pathways that allow for imaging to be requested directly from the community setting or primary care. But they noted the logistical challenges in the acute phase of a head injury in getting access to, and timely reporting of, imaging. They also noted the challenges faced in primary care and general practice in interpreting complex neuroradiology reports. The committee therefore agreed that people should not be referred to imaging directly from the community.\n\n## How the recommendation might affect practice or services\n\nThis is expected to be a change in practice for a few centres that will now have to send people for imaging by the emergency department route.\n\nReturn to recommendation\n\n# Assessment in the emergency department\n\nRecommendation 1.4.12\n\n## Why the committee made the recommendation\n\nThe committee highlighted the need to follow relevant guidance if abuse or other safeguarding issues may be factors in a head injury.\n\n## How the recommendation might affect practice or services\n\nThere is not expected to be any change to practice or services.\n\nReturn to recommendation\n\n# Criteria for doing a CT head scan\n\nRecommendations 1.5.8 to 1.5.14\n\n## Why the committee made the recommendations\n\nSeveral diagnostic accuracy studies were identified but there were no diagnostic RCTs. Most of the evidence was of low to very low quality and was in people with a mild head injury (defined as a GCS score of 13\xa0to\xa015 in many studies, but sometimes limited to a GCS score of 14\xa0to\xa015). The committee noted that the existing recommendations for clinical decision rules for head imaging in people 16\xa0and over were largely based on the Canadian CT Head Rule (CCHR). This involves identifying high and medium risk factors, with some modifications aimed at improving sensitivity. Updated evidence for this decision rule showed that it has good sensitivity when used as intended but that its specificity values are poor. The committee noted that specificity values of decision rules are often low because they prioritise very high sensitivity.\n\nEvidence identified for other decision rules showed sensitivity values similar to those of the CCHR. However, specificity values were lower compared with the CCHR high and medium risk rule. Limited evidence showed that the NEXUS\xa02 decision rule has specificity values similar to those of the CCHR.\n\nOnly 1\xa0study had assessed the performance of the 2014 update of NICE's head injury guideline recommendations for head imaging. This reported sensitivity values that were poorer than those for the CCHR. But the specificity values were better compared with other decision rules. The committee agreed that it was unclear why the sensitivity of the NICE recommendations would be worse than those of CCHR. They also agreed that it was unclear why the CCHR did not do as well in this study as in other studies. They thought that this possibly suggested some differences between study populations, which may have affected the results. The committee also agreed that, in their clinical experience, the sensitivity of the NICE recommendations was not as low as suggested in this study.\n\nThe committee agreed that there was insufficient evidence to support changing the clinical decision rule recommendations for head imaging in people 16\xa0and over. Because the NICE recommendations were largely based on the CCHR rule, this decision was further supported by cost-effectiveness evidence. This showed the CCHR rule to be the most cost effective of the multiple decision rules assessed.\n\nThe committee noted that the existing recommendations for clinical decision rules for head imaging in people under\xa016 were largely based on the CHALICE rules with some modifications. These modifications were based on current practice and experience allowing for the option of an observation period with imaging if the condition of some people deteriorated, rather than immediate imaging.\n\nUpdated evidence identified for this decision rule showed that it had good sensitivity when considering clinically important injuries or neurosurgical outcomes. In the 2014 update of this guideline, the committee stated that an improvement in specificity relative to the NICE recommendations would be needed to warrant switching to another decision rule for people under\xa016. They noted that PECARN and CATCH‑7 may have slightly better sensitivity values compared with CHALICE, but agreed that, overall:\n\nthe specificity values for CHALICE are much better than for other rules assessed\n\nthe sensitivity values for CHALICE are still over 90% for clinically important injuries and neurosurgical outcomes.\n\nThe committee noted that, in terms of the content of the rules, PECARN and the NICE guideline are not very different but that PECARN is vaguer and does not give timings. They thought this less useful. In addition, they noted that the PECARN and CATCH-7 rules apply to more specific populations than the NICE guideline recommendations.\n\nThe committee agreed that the recommendations in the NICE guideline are in widespread use in current practice, and used with little variation. Their opinion was that they are currently well-accepted and used with good effect. The committee therefore agreed that there was insufficient evidence to support changing the clinical decision rule recommendations for head imaging in people under\xa016.\n\nThe committee agreed to keep the existing recommendations in from the 2014 update of NICE's head injury guideline for people with bleeding and clotting disorders. This was because there was no new evidence to change practice in adults, and the committee agreed to extrapolate from an existing recommendation to make a new recommendation for people under 16. However, they changed the recommendation wording from 'history of bleeding or clotting disorders' to 'current bleeding or clotting disorders'. In children, some disorders are short-lived or resolve in a couple of months. In adults, a history of bleeding or clotting disorders is used to help screen people before surgery. However, this is a crude tool and may not be appropriate in this setting. So, the committee agreed to keep the changed wording for all age groups to help provide a consistent message.\n\nThere was conflicting evidence from cohort studies on whether people who are on anticoagulants or antiplatelets are at higher risk of intracranial haemorrhage than people not on anticoagulants or antiplatelets. CT scans could be limited to people with symptoms of traumatic brain injury such as loss of consciousness or amnesia. However, the committee thought that the new evidence was not strong enough to warrant stopping imaging in people with a head injury who are on anticoagulants but have no other indication for imaging. So, they decided CT scanning should be considered rather than automatically done in this group. They also agreed that antiplatelets other than aspirin monotherapy should be included in this. The review findings suggested that people on anticoagulants (including warfarin and direct-acting oral anticoagulants) or antiplatelets (excluding people on aspirin monotherapy) with low-risk factors (no loss of consciousness, amnesia, a GCS score of\xa015 and no other indications for CT brain scan) can be risk assessed (including for other injuries, supervision at home, cause of incident and risk of further falls). Then, if there are no risk factors and after shared decision making, they could be discharged safely without a CT scan, with the usual discharge advice (see the section on discharge and follow up). The committee highlighted that clinicians would either scan or admit someone for monitoring if any risks were identified. This might be, for example, if a person (with pre-existing cognitive impairment) may be less likely to return to the emergency department urgently if they have any signs of deterioration. The committee noted that, if an intracranial haemorrhage is not detected at initial presentation, delayed recovery is more likely rather than death. They also discussed that neurosurgical intervention for traumatic brain injury is less likely to be offered for people over\xa074 because risks outweigh the benefits.\n\nIn current practice, in accordance with the 2014 update of NICE's head injury guideline recommendations, a CT head scan is done within 8\xa0hours of a head injury in people with no other indications for a CT head scan who are having anticoagulant treatment. The 2014 update did not make specific recommendations for people on antiplatelets. The committee agreed that, in clinical practice, there is variation, with some services offering imaging to people on antiplatelets. Based on the evidence, they also agreed that antiplatelets other than aspirin monotherapy should be included but did not specify which antiplatelets. This was because they did not want to be prescriptive and exclude any newer antiplatelets in development. Based on their experience and extrapolation of evidence in people presenting within 8\xa0hours of injury, the committee agreed that these recommendations could be applicable to people presenting more than 8\xa0hours after their injury. However, they agreed that imaging should be done within an hour of confirming that the person with head injury is on anticoagulant or antiplatelet medication.\n\nThere was limited evidence on aspirin. From their knowledge and clinical experience, the committee highlighted that the risk of intracranial haemorrhage is low with aspirin. This is even so in people with neurological symptoms such as loss of consciousness or amnesia. So, they agreed that people on aspirin monotherapy could be discharged without a CT head scan after shared decision making if there is no other indication for a CT brain scan or hospital admission.\n\nThe committee made a recommendation for research on risk of bleeding for people with pre-injury coagulopathy.\n\nPeople with liver or coagulopathy disorders\n\nThere was no evidence for people with liver or coagulopathy disorders. Current practice is variable, with some services offering imaging to people with liver disease who have no symptoms. People with liver or coagulopathy disorders are at increased risk of bleeding, although some people will have a tendency for increased clotting. People with acquired coagulation defects can be a heterogenous and complex group. They can include people with acquired haemophilia through to people with other abnormalities such as disseminated intravascular coagulation.\n\nThe committee agreed to keep the existing recommendations from the 2014 update of NICE's head injury guideline for people with bleeding and clotting disorders. This was because there was no new evidence to change practice. But they changed the recommendation wording from 'history of bleeding or clotting disorders' to 'current bleeding or clotting disorders'. In people under\xa016, some disorders are short-lived or resolve in a couple of months. In adults, a history of bleeding or clotting disorders is used to help screen people before surgery. However, this may not be appropriate in the emergency department setting. So, the committee agreed to keep the changed wording for all age groups to help provide a consistent message.\n\nPeople with pre-injury cognitive impairment who have a head injury through low-energy impact or low-level falls\n\nLimited evidence from cohort studies suggested that, in people 16\xa0and over, falling from a standing position, being over\xa070, having a reduced GCS score compared with normal, taking antiplatelet medication including aspirin, and having neurological symptoms (loss of consciousness, vomiting after fall) were risk factors associated with the diagnosis of an intracranial bleed. Anticoagulant medication in this population was not associated with an intracranial bleed. It was not clear if people in the studies had pre-injury cognitive impairment, so the applicability of this evidence is limited.\n\nThe committee discussed the challenges in assessing risk in people with cognitive impairment. For example, people with dementia may under-report or may be unaware of symptoms such as loss of consciousness or amnesia. It is also difficult to differentiate head injury symptoms from the pre-existing dementia in these people. There was no evidence for people under\xa016.\n\nThe committee acknowledged the limited evidence for this group. They made a recommendation for research on indications for imaging for people with pre-injury cognitive impairment.\n\nPeople with recurrent head injuries\n\nThere was no evidence for recurrent head injuries in any age group. Recurrent head injuries could occur in people with epilepsy, people with mobility issues at high risk of falls and with some sports activities. Particularly in the context of sports injuries, these injuries can be repeated and lead to cumulative risks. Because of a lack of evidence, the committee decided to make a recommendation for research on indications for imaging for people with a history of recurrent traumatic head injuries.\n\nEvidence from 1\xa0observational\xa0study suggested that there was an increased risk of any traumatic brain injury or important traumatic brain injury on a CT head scan in babies and children under\xa02 years:\n\nthe younger their age\n\nif they have a GCS score of less than\xa015\n\nif they present more than 24\xa0hours after head injury.\n\nThere was no evidence for people 2\xa0years or over. The committee discussed that people 16\xa0and over presenting more than 24\xa0hours after injury have increased risk factors such as vomiting and loss of consciousness. This is because they would be attending because of worsening symptoms. The 2014 update of NICE's head injury guideline recommendations are for people presenting within 24\xa0hours of injury. But, because of a lack of evidence, the committee agreed that these could be extrapolated to people presenting more than 24\xa0hours after a head injury (see the recommendations on the criteria for doing a CT head scan). They also agreed that this was an important area, so proposed a recommendation for research on indications for selecting people for imaging when they present more than 24 hours after a head injury.\n\n## How the recommendations might affect practice or services\n\nWeakening the recommendation for people with a head injury who are on anticoagulants but have no other indication for imaging from 'offer' to 'consider' is expected to result in fewer scans. But expanding the recommendation to include people with a head injury who are on clopidogrel, prasugrel or ticagrelor is expected to result in more scans. It is uncertain whether this will lead to an overall increase or decrease in scanning.\n\nReturn to recommendations\n\n# Post-concussion syndrome\n\nRecommendation 1.5.15\n\n## Why the committee made the recommendation\n\nThe committee agreed that high specificity is needed for brain injury biomarkers for post-concussion syndrome. This was because the population with a mild head injury is large but only a small proportion go on to develop post-concussion syndrome. So, false positives would have a negative effect on resources if biomarkers were to be used to direct everyone towards interventions or monitoring.\n\nOverall, the committee agreed that the evidence was too limited to be able to make recommendations for using biomarkers (including fluid biomarkers or MRI) to predict post-concussion syndrome in people with mild traumatic brain injury. There was no evidence from prognostic test-and-treat studies comparing clinical outcomes, so the committee agreed to highlight the criteria for doing a CT head scan. They also made a recommendation for research on using biomarkers and MRI for predicting post-concussion syndrome.\n\nEvidence from diagnostic accuracy studies suggested that there were high sensitivity values for some biomarkers at certain thresholds for predicting acute complications after a traumatic brain injury, but the specificity values were not high enough across the evidence. Also, many biomarkers were only tested in small samples, which led to imprecise estimates. The committee noted that accuracy differed quite widely between different studies looking at the same biomarker test measured with different assays on different platforms. Also, the evidence was heterogenous, with variable thresholds and time points for different biomarkers. Most people with a head injury present to hospital within 3\xa0hours, and the manufacturers recommend this timeframe for optimal test results. Many of the studies assessed biomarkers beyond this time point.\n\nThe committee agreed that the specificity values were equally as important as the sensitivity values, given the consequences of unnecessary radiation from CT scans. They thought this was particularly important in people under\xa016. But, after considering the limitations of the evidence, the committee were unable to make recommendations for using biomarkers to predict acute complications after a mild traumatic brain injury. They did think that biomarker tests had promise, so they proposed a recommendation for research on using biomarkers for predicting acute post-traumatic brain injury complications.\n\n## How the recommendation might affect practice or services\n\nBiomarkers are not routinely used in people with acute head injury and the recommendation for MRI has not changed. So, there is not expected to be a change in practice.\n\nReturn to recommendation\n\n# Investigating injuries to the cervical spine\n\nRecommendations 1.6.1 to 1.6.11\n\n## Why the committee made the recommendations\n\nThe committee considered sensitivity to be the most important measure for types of investigation for cervical spine injuries in people with head injuries. This is to ensure the investigation does not miss important cervical spine injuries, which could result in subsequent negative consequences such as disability. The evidence was limited because the proportion of people with a confirmed head injury was not reported in the diagnostic accuracy studies, but it suggested that X‑rays have poor sensitivity compared with CT scans in people 16\xa0and over.\n\nBased on the evidence, and the committee's experience and knowledge of current practice, the committee agreed that X‑rays of the cervical spine should not be done initially in people 16\xa0and over with a head injury. They also agreed that CT scans of the cervical spine should be used in people 16\xa0and over in a way consistent with current clinical practice. There was limited evidence for MRI (less accurate at showing bony injuries, takes longer to do and younger people might need sedation). Also, MRI is rarely used as an initial imaging strategy. So, MRI is recommended as an additional form of imaging in certain circumstances (as in previous versions of the guideline). For people under\xa016, limitations in the evidence, and radiation exposure and risk of cancer, contributed to the committee's decision not to make any major changes to the recommendations.\n\n## How the recommendations might affect practice or services\n\nCT scanning of the neck in people 16\xa0and over with a head injury has already replaced X‑rays when there is at least a medium risk of serious spinal injury. So, there is not expected to be a change in practice.\n\nReturn to recommendations\n\n# Admission and observation\n\nRecommendations 1.9.1 to 1.9.5\n\n## Why the committee made the recommendations\n\nLimited evidence from cohort studies in people with intracranial injuries suggested that effect sizes for the clinical decision rules were larger overall than those for individual risk factors. So, the committee agreed that clinical decision rules were likely to be the way to identify people who should be admitted in the future. This was because they thought it would be difficult to make decisions based on individual risk factors in clinical practice. But the evidence for clinical decision rules was all retrospective. So, the committee did not think any specific clinical decision rules could be recommended, particularly because they would be new to clinical practice.\n\nFor individual risk factors, the committee noted that there was consistent evidence across all studies (including 1\xa0study in people under\xa016) that GCS scores of\xa013 and\xa014 were associated with a worse outcome than a GCS score of\xa015. But this is already an existing indication for admission (see recommendation 1.9.1).\n\nEvidence for specific thresholds and findings on CT (including thresholds for subdural or epidural haemorrhage size, or findings such as midline shift or mass effect on CT) also indicated larger effect sizes than for some other risk factors. But, for factors such as midline shift, the committee noted that a threshold for degree of shift would be more useful in practice. They also noted that the varying thresholds used for subdural and epidural haemorrhage across the different studies made the ideal threshold to use unclear.\n\nThe evidence also suggested that thresholds for age could be associated with a worse outcome in higher age groups. But the committee noted that older age would not solely be used in practice to make decisions about admission. This is particularly because admission in older age groups can also be associated with harms such as hospital-acquired infections. The committee agreed that age or frailty may be a concern but should not be a sole indicator for admission. Overall, the committee agreed that prospective studies are needed in people with a GCS score of\xa013, 14\xa0or\xa015 and a head injury of any size confirmed with CT to validate existing clinical decision rules for predicting deterioration. The aim would be to refine indications for admission in this group. So, the committee made a recommendation for research on indications for admission in people with a mild head injury and a confirmed abnormality on a CT scan.\n\nEvidence from several case series suggested that there was low risk of death, neurosurgery, admission to critical care, unplanned hospital admission and delayed intracranial injury in babies and children (age cut-off varied across studies) with an isolated skull fracture. The evidence suggested that there was a slightly higher risk of seizure (at presentation) and evaluation for suspected non-accidental injury in this group. According to current guidelines (recommendations 1.5.8 and 1.5.10), people with seizures and suspected non-accidental injuries will be admitted to hospital after a head injury.\n\nBased on the evidence, the committee agreed that simple linear non-displaced fractures are not likely to be a clinically important injury. So, they agreed that, after shared decision making, people under\xa016 with such fractures can be safely discharged if they have normal neurological status and there are no safeguarding concerns.\n\nThere was no direct evidence for people 16\xa0and over with an isolated skull fracture. Indirect evidence from cohort studies suggested that there was low risk of clinical deterioration from a simple skull fracture compared with:\n\na complex skull fracture\n\nto\xa02 bleeds\n\nbleeds less than 5\xa0mm in diameter\n\nno or minimal mass effect\n\nsignificant midline shift\n\na high- or mixed-density lesion\n\ncerebellar or brain stem injury.\n\nClinical deterioration was measured by a composite of death due to traumatic brain injury, neurosurgery, seizure, a fall in GCS score of more than\xa01, admission into intensive care for traumatic brain injury, intubation or hospital readmission for traumatic brain injury. The simple skull fracture group included both isolated and non-isolated skull fractures. But the committee agreed that the evidence is still likely to be broadly applicable for people 16\xa0and over with an isolated skull fracture. Based on the evidence and their collective experience, the committee agreed that, after shared decision making, people 16\xa0and over with an isolated skull fracture can be discharged safely (except for people on anticoagulants or antiplatelets) if there are no safety concerns.\n\nThe evidence was limited on admission to and observation in hospital of people who have a head injury and are on anticoagulants (warfarin and other vitamin\xa0K antagonists, and direct-acting oral anticoagulants) or antiplatelets (including aspirin, ticlopidine, clopidogrel, prasugrel and ticagrelor), and have normal brain imaging or no indication for early imaging.\n\nLimited evidence from non-randomised studies suggested that there was no clinically important difference between pre-injury anticoagulant or no anticoagulant treatment in terms of delayed bleeding. The evidence included at least 1\xa0propensity matched study including about 70,000 people.\n\nThe committee agreed that the evidence was not strong enough to recommend using anticoagulation status as a sole indicator for admission for people with a negative initial CT head scan. They highlighted that admission based solely on this could cause harm in people already vulnerable (because of, for example, frailty, an underlying condition such as delirium or risk of hospital-acquired infections). This is particularly so if there is not a large increase in risk of delayed bleeding. Also, when these events do occur, they are usually not clinically important.\n\nEvidence from non-randomised studies for antiplatelet comparisons was more limited than that for anticoagulants. There were no large studies, and all reported effects were based on a difference of only 1\xa0to\xa02 events between pre-injury antiplatelet and no-antiplatelet groups per study. The committee agreed that the evidence was not strong enough to recommend using antiplatelet status as a sole indicator for admission for people with a negative initial CT or no indication for a CT. The committee did not make a recommendation for research for this group because they did not consider it to be a priority for research.\n\nThere was no evidence on admission or discharge of people with concussion symptoms after normal imaging or no indication for imaging. The committee agreed that their discharge is based on clinical discretion, and admission is considered if non-accidental injury is suspected. From their experience, the committee also agreed that most people with concussion symptoms and normal imaging do not need further intervention and are safe to be discharged from the emergency department. They highlighted that current practice is to not admit people with concussion symptoms unless they have any of the indications in recommendation 1.9.1. The committee were unaware of any evidence indicating that current practice was causing harm (coroners reports, safety reports, patient group feedback). They also noted that someone's condition may worsen if they are admitted, for example, because of being in a noisy and unfamiliar environment, and because the risk of hospital-acquired infections could increase. When people with concussion symptoms are discharged, information is provided on when to return to hospital to seek further immediate care and ongoing support for persistent symptoms (see the recommendations on discharge advice). The committee agreed that this is important and did not think there was any evidence on which to base a change in practice.\n\n## How the recommendations might affect practice or services\n\nCurrently, most people with an isolated skull fracture are admitted for observation. It is expected that many of these people could be discharged from the emergency department without admission to hospital unless there are other indications for admission. For people on anticoagulants or antiplatelets, and people with concussion symptoms, there are no significant changes in practice recommended, and the recommendations are thought to reflect current practice.\n\nReturn to recommendations\n\n# Early diagnosis of hypopituitarism\n\nRecommendations 1.9.6 to 1.9.8\n\n## Why the committee made the recommendations\n\nThe committee highlighted that there is a higher risk of hypopituitarism with more severe head injuries, but noted that it can be caused by a mild head injury. Also, the condition can occur immediately after a head injury or in the weeks to months afterwards. This, and the wide variety of symptoms of hypopituitarism, can make the condition difficult to diagnose.\n\nThe committee supplemented the small amount of observational evidence (cohort studies) with their expertise. They discussed that why head injury causes hypopituitarism is not fully understood, and that there could be various reasons. Current practice for screening for hypopituitarism is variable, but it is not commonly identified on CT scanning in the emergency department. The clinician's familiarity and suspicion of hypopituitarism may affect diagnosis rates. Also, testing in the emergency department may not be useful because the acute injury phase stimulates cortisol secretion. This makes it difficult to tell if there is hypoadrenalism. So, the committee agreed that it would be better to investigate for hypopituitarism in people admitted to hospital with a head injury if they have clinical symptoms or biochemical findings such as hypotension or hyponatraemia. The committee suggested this would provide an opportunity for referral to a specialist.\n\nIn the absence of evidence on the timing of investigations, the committee also made a recommendation for research on timing of testing for hypopituitarism.\n\n## How the recommendations might affect practice or services\n\nHospital staff are advised to look out for symptoms of hypopituitarism in people admitted to hospital after a head injury. So, there might be an increase in testing for hypopituitarism in hospital. It is also intended that people will get referred for specialist care sooner.\n\nReturn to recommendations\n\n# Discharge and follow up\n\nRecommendation 1.10.6\n\n## Why the committee made the recommendation\n\nPre-existing cognitive impairment such as dementia, Parkinson's disease or stroke was reported in some studies in people taking anticoagulants and antiplatelets, but the studies did not report the effect of pre-injury cognitive impairment on the outcomes. Examples of pre-injury cognitive impairments and neurodivergence seen in people of any age include developmental delay, Down's syndrome, cerebral palsy, fetal alcohol syndrome, a learning disability, autism spectrum disorder and other conditions with altered sensation. Examples of pre-injury cognitive impairment seen only in adults include depression, dementia and medication side effects. The committee noted from their experience that people with pre-existing conditions affecting cognition are less likely to recognise and to raise an alarm about the early signs of a late intracranial bleed (such as a severe headache, drowsiness and vomiting) than people with no pre-existing cognitive impairment. So, in current practice, a short overnight admission for observation is arranged for people with a pre-existing cognitive impairment when no supervision at home is available. The committee agreed that people with a pre-existing cognitive impairment will need to be appropriately supervised and monitored to ensure that their symptoms are not worsening if they are discharged from the emergency department. Supervision and monitoring was also noted to be important for people discharged to custodial settings. The committee noted that, at discharge, it is important for people and their carers to be given a written copy of the head injury discharge advice.\n\n## How the recommendation might affect practice or services\n\nThere might be a small increase in overnight admissions for people with a pre-existing cognitive impairment when no supervision is available at home. This should lead to better outcomes for people who do deteriorate and reduced longer-term care costs.\n\nReturn to recommendation\n\n# Follow up\n\nRecommendations 1.10.13 and 1.10.14\n\n## Why the committee made the recommendations\n\nPeople with a head injury may need investigation for the causes of the injury or to manage contributing factors. People with a head injury may have persisting problems, including physical, sensory, motor, cognitive, emotional and hormonal (hypopituitarism). These can occur even in people who are not admitted to hospital or have normal imaging at the time of their injury. It is important that people know how to seek help and ongoing support for these symptoms. It is also important for healthcare professionals to make appropriate outpatient referrals to other healthcare professionals trained in managing these symptoms.\n\nSome people who have had a head injury will be at increased risk of further injury. It is important that these people can access relevant services.\n\n## How the recommendation might affect practice or services\n\nThere might be an increase in referrals from primary care to hospital outpatient clinics for people who were not admitted to hospital, or had a normal scan or no scan at the time of their head injury. This should mean that people get earlier access to effective treatment for persisting symptoms resulting from their head injury and prevention services.\n\nReturn to recommendation\n\n# Investigations for hypopituitarism\n\nRecommendation 1.10.15\n\n## Why the committee made the recommendation\n\nThe committee discussed further endocrinology investigations for suspected hypopituitarism in people who have been discharged after a head injury if symptoms persist or they are not recovering as expected. They noted that some of the symptoms of hypopituitarism may be non-specific and caused by other conditions, making diagnosis difficult. They agreed that investigation in endocrinology may be needed.\n\nIn people under\xa016, delayed symptoms may include slow growth, tiredness and late puberty. The committee emphasised that, if hypopituitarism is suspected, it is important to urgently refer the person under\xa016 to a paediatric endocrinologist.\n\n## How the recommendation might affect practice or services\n\nThe guideline raises awareness of the symptoms of hypopituitarism for people with a head injury, and their carers and clinicians. So, there might be an increase in testing for hypopituitarism in primary care. It is also intended that people will get referred for appropriate care sooner.\n\nReturn to recommendation", 'Context': 'Head injuries are a major cause of death and disability in people aged 1\xa0to 40\xa0in the UK. Each year, over 1\xa0million people attend emergency departments in England and Wales with a recent head injury. Between 33% and 50% of these people are aged under\xa015. About 200,000\xa0people are admitted to hospital with a head injury every year. Of these, about 40,000 have evidence of traumatic brain injury. Most people with a head injury recover without specific or specialist intervention. Others have long-term disability or even die from associated traumatic brain or other injuries. An increasing proportion of people presenting with head injury are over\xa065. Many people are injured through low-level falls, which can be sustained in the context of acute illness.\n\nThe incidence of death from head injuries is low. As few as 0.2% of people attending emergency departments with a head injury die because of their injury. Of people who have sustained a head injury, 95% present with a normal or minimally impaired conscious level, that is, a Glasgow Coma Scale (GCS) score of\xa013 or more. Most fatal outcomes are in the groups with a moderate (GCS score of 9\xa0to\xa012) or severe (GCS score of\xa08 or less) head injury, and account for only 5% of attenders. This means emergency departments need to identify the small number who will go on to have serious acute intracranial complications. It is estimated that, in 25% to 30% of children under\xa02 who are hospitalised with a head injury, it is caused by abuse. This guideline has updated some of the terminology used in relation to safeguarding people under\xa018 and vulnerable adults. This update addresses these areas, including in particular:\n\nindications for transporting people with a head injury from the scene of injury directly to the nearest neuroscience centre, bypassing the nearest emergency department\n\nindications for, and timing of, CT head scans and imaging of the cervical spine in the emergency department, with particular reference to anticoagulant treatment and levels of circulating brain injury biomarkers\n\nthe clinical and cost effectiveness of administering tranexamic acid to people who have sustained a head injury and have suspected intracranial bleeding\n\nconsideration of traumatic injury to the pituitary gland in people with a head injury\n\ninformation that should be provided to people with a head injury, and their family members and carers, on discharge from the emergency department or observation ward.'}	https://www.nice.org.uk/guidance/ng232	This guideline covers assessment and early management of head injury in babies, children, young people and adults. It aims to ensure that people have the right care for the severity of their head injury, including direct referral to specialist care if needed.
c76602ea3e6b94cf15779252950afc7081f201be	nice	Risankizumab for previously treated moderately to severely active Crohn's disease	Risankizumab for previously treated moderately to severely active Crohn's disease Evidence-based recommendations on risankizumab (Skyrizi) for previously treated moderately to severely active Crohn's disease in people 16 years and over. # Recommendations Risankizumab is recommended as an option for treating moderately to severely active Crohn's disease in people 16 years and over, only if: the disease has not responded well enough or lost response to a previous biological treatment, or a previous biological treatment was not tolerated, or tumour necrosis factor (TNF)-alpha inhibitors are not suitable.Risankizumab is only recommended if the company provides it according to the commercial arrangement. If people with the condition and their clinicians consider risankizumab to be 1 of a range of suitable treatments, after discussing the advantages and disadvantages of all the options, use the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements. These recommendations are not intended to affect treatment with risankizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by the clinician, the young person, and their parents or carers. Why the committee made these recommendations Standard treatments for moderately to severely active Crohn's disease when conventional treatments stop working are biological treatments (such as TNF-alpha inhibitors , ustekinumab and vedolizumab). Risankizumab is another biological treatment. Clinical trial evidence suggests that risankizumab reduces symptoms and increases the likelihood of disease remission compared with placebo. Results from indirect comparisons of risankizumab with other biological treatments are uncertain. But there is enough evidence to suggest it is as effective as vedolizumab, a treatment recommended by NICE for use after a TNF-alpha inhibitor or when TNF-alpha inhibitors are not suitable. A cost comparison of risankizumab with vedolizumab suggests that risankizumab has similar or lower costs than vedolizumab. NICE considers risankizumab an acceptable use of NHS resources. This is when it is used after a biological treatment has not worked well enough, has stopped working, or was not tolerated, or TNF-alpha inhibitors are unsuitable. So, risankizumab is recommended.# Information about risankizumab # Marketing authorisation indication Risankizumab (Skyrizi, AbbVie) is indicated for 'the treatment of patients 16 years and older with moderately to severely active Crohn's disease who have had an inadequate response to, lost response to, or were intolerant to conventional therapy or a biological therapy, or if such therapies are not advisable'. The CE mark for the on-body device that is used to deliver the 360‑mg risankizumab solution for injection has not been granted yet. Risankizumab will only be available in the UK for treating moderately to severely active Crohn's disease after this CE mark is granted. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for risankizumab 600-mg concentrate for solution for infusion and risankizumab 360-mg solution for injection in cartridge. # Price The company has stated that the list prices of the 600‑mg concentrate for solution for infusion (induction treatment) and the on-body device with 360‑mg solution for injection (maintenance treatment) are confidential until they are available, and cannot be reported here. The company has a commercial arrangement. This makes risankizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by AbbVie, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Crohn's disease Crohn's disease is a debilitating, chronic, relapsing systemic inflammatory bowel disease. It causes inflammation and mucosal ulceration anywhere in the digestive system. It is a lifelong condition. Symptoms include diarrhoea, abdominal pain, fatigue, loss of appetite, weight loss, blood or mucus in stool, and anaemia. Symptoms may vary over time and can last anywhere from a few days to several months. Persistent inflammation can lead to scarring of the bowel and further complications needing surgery. Treatments aim to relieve symptoms, promote mucosal healing, and maintain or improve quality of life by inducing disease remission while minimising drug-related toxicity. However, Crohn's disease often relapses and people can experience acute exacerbations (flares). Crohn's disease can present a major barrier to a person's ability to participate in daily life, severely affecting their self-esteem, social functioning, work, personal relationships, family life and other activities. One patient expert explained that treatments that induce remission are of great importance to people with the condition, because debilitating symptoms are not controlled unless the condition is in remission. Treatments which induce remission can also delay the need for surgery, which is also important to people with the condition. People with Crohn's disease fear the loss of remission and the arrival of flares because of the major impact these have on their life. The committee concluded that Crohn's disease can have a profound effect on people's quality of life and ability to do day-to-day activities. # Clinical management ## Treatment options The standard initial treatment for Crohn's disease is conventional treatment with corticosteroids and immunomodulators such as azathioprine, mercaptopurine and methotrexate. If these treatments fail, people are offered biological treatment. The clinical experts stated that tumour necrosis factor (TNF)-alpha inhibitors (infliximab or adalimumab, including biosimilars) are usually used first. Ustekinumab or vedolizumab are used when a TNF-alpha inhibitor has failed, is contraindicated or cannot be tolerated. These treatments are recommended in NICE's technology appraisal guidance on infliximab and adalimumab, ustekinumab and vedolizumab. A patient expert noted that NICE's recommendations on infliximab, adalimumab and ustekinumab specify that when more than 1 treatment is suitable the least expensive option should be used. NICE's recommendations also state that the benefit of continuing these treatments should be assessed at 1 year. The clinical experts explained that, when there is evidence of clinical benefit, treatment continues beyond 1 year and that stopping effective treatments would be very rare. They stated that if the treatment no longer works (including after a dose increase, if relevant), another biological treatment would be considered. The clinical experts stated that although there are several clinically effective biological treatments for Crohn's disease, these do not cause long-term disease remission for everyone. Some people may have a sequence of biological treatments followed by surgery. A patient expert stated that complications of surgery and the potential effect on fertility can have a large impact on people with the condition. The clinical and patient experts agreed that it is very important to have a range of treatment options to help more people gain and regain disease remission, and delay surgery. The committee concluded that people with Crohn's disease would value the availability of a further treatment option to improve symptoms and induce disease remission. ## Risankizumab and its comparators Risankizumab is a novel treatment with a different mechanism of action to existing treatments. The company proposed it can be used either after conventional treatment (conventional care failure population) or after a biological treatment (biological treatment failure population) as an additional biological option. The clinical experts explained that treatment is not dependent on disease location. They agreed with the company's positioning of risankizumab in the clinical pathway and that it was relevant to consider both the conventional care failure and biological treatment failure populations. However, they noted that it would probably be used more after biological treatment. This is because TNF-alpha inhibitors are an effective and less expensive treatment option (because biosimilars are available), so most people have them first. A patient expert highlighted the need for people with the condition to have access to the most effective treatment first. This is because it can take years before they find an effective treatment, and this process can delay finding a treatment that induces disease remission. The committee concluded that risankizumab could be an option for both the conventional care failure and biological treatment failure populations. It further concluded that the relevant comparators for the conventional care failure population are adalimumab, infliximab and ustekinumab. The relevant comparators for the biological treatment failure population are ustekinumab and vedolizumab. # Clinical trials The clinical evidence was from the phase 3 trials ADVANCE, MOTIVATE and FORTIFY. ADVANCE (n=931) and MOTIVATE (n=618) were multicentre, double-blind, placebo‑controlled randomised induction trials. These recruited people with moderately to severely active Crohn's disease that had an inadequate response to conventional treatments (ADVANCE) or biological treatments (ADVANCE and MOTIVATE). Moderately to severely active disease was defined by a Crohn's Disease Activity Index (CDAI) score of 220 to 450, average stool frequency of 4 or more, or abdominal pain score of 2 or more, and Simple Endoscopic Score for Crohn's Disease (SES‑CD) of 6 or more (4 or more for isolated ileal disease). People had intravenous risankizumab (600 mg or 1,200 mg) or placebo at week 0, week 4 and week 8. People whose disease did not respond at week 12 had a second induction treatment with risankizumab (1,200 mg intravenously, 360 mg subcutaneously or 180 mg subcutaneously). The company used data from ADVANCE or MOTIVATE for the subgroups who had the 600‑mg induction regimen covered by the marketing authorisation for risankizumab (for moderately to severely active Crohn's disease), or placebo. This included: in ADVANCE, 219 people in the conventional care failure subgroup and 292 people in the biological treatment failure subgroup in MOTIVATE, 378 people who had a previous biological treatment. People whose disease responded to treatment entered FORTIFY, a phase 3 multicentre, double-blind, placebo-controlled maintenance trial. FORTIFY sub‑study 1 (n=542) re-randomised people to subcutaneous 180 mg or 360 mg risankizumab or placebo (withdrawal) every 8 weeks for 52 weeks. The company included data from FORTIFY from 305 people who had 1 induction treatment with intravenous 360 mg risankizumab, the treatment regimen covered by the marketing authorisation for risankizumab, or placebo. Of these, 80 people were in the conventional care failure subgroup and 225 people were in the biological treatment failure subgroup. The committee concluded that the trials' results were generalisable to how risankizumab would be used in clinical practice. ## Primary outcomes The co-primary outcomes for all 3 trials were clinical remission and endoscopic response. Clinical remission was measured by either a CDAI score below 150 or patient-reported outcomes on stool frequency and abdominal pain, but both outcomes were collected in all trials. The SES‑CD was used to measure endoscopic response alongside either measure of clinical remission. The clinical experts explained that the CDAI is used primarily in clinical trials as a measure of remission but not in clinical practice because of the time needed to complete the measurements included in this index. The clinical experts stated that the Harvey‑Bradshaw Index is broadly comparable to the CDAI and is used in clinical practice. A clinical expert stated that the SES‑CD is used increasingly in clinical practice. The committee concluded that the measures of remission used in the trials would give applicable estimates of expected remission and endoscopic response rates in clinical practice. ## Results The results from the induction trials suggested that risankizumab is associated with higher rates of clinical remission and endoscopic response compared with placebo in the conventional care failure and biological treatment failure populations. The results from FORTIFY suggested that risankizumab is associated with higher rates of endoscopic response compared with placebo in the conventional care failure and biological treatment failure populations. The committee noted that the FORTIFY subgroup results in the conventional care failure and biological treatment failure populations were not statistically significant for clinical remission assessed by the CDAI. The committee concluded that risankizumab is associated with higher rates of clinical remission and endoscopic response compared with placebo (withdrawal) when used as a first biological treatment or after a previous biological treatment. # Clinical effectiveness ## Network meta-analyses Because of the lack of direct comparative evidence, the company's original submission included network meta-analyses for induction and maintenance treatment in the conventional care failure and biological treatment failure populations. The outcomes assessed were clinical remission and response (defined by the CDAI). In its original submission, the company used a Bayesian risk difference fixed-effects model. For the network meta-analyses for maintenance treatment, the company split the clinical trial evidence into 2 separate networks (risankizumab and ustekinumab, and adalimumab, infliximab and vedolizumab). It stated it chose this approach because: -f differences in drug mechanism of action, induction duration and half-life single network analyses lacked face validity (the estimated rates of remission were higher in people who had placebo) -f methodological challenges in accounting for the heterogeneity. The EAG disagreed with the company on: Splitting networks: The EAG noted that connections in network meta-analyses should be based on comparator connections, not drug characteristics. It also noted ustekinumab and vedolizumab, used in the different networks, have a similar half-life and are comparable treatment options. The EAG presented results using a single network. The committee agreed that a single network was more appropriate. Using a fixed-effects model rather than a random-effects model: The EAG agreed with the company that there were several differences between the trials that made doing network meta-analyses more challenging. This included differences in baseline risks, stratification by the conventional care failure and biological treatment failure populations, and an observed temporal effect in which remission rates in placebo groups appeared higher in more recent trials. Given these differences, using a random-effects model is more appropriate. The committee noted the company's concerns that its exploration of a random-effects model produced results with wide confidence intervals and included values which favoured placebo over biological treatments. However, the committee agreed with the EAG that a random-effects model was preferable. Lack of adjustment for baseline risks or temporal effect: The EAG noted that the company's risk difference approach was not an adjustment for heterogeneity. The committee agreed that there was no evidence that the company's approach minimised differences between placebo group results between trials in the network. The EAG preferred to include an adjustment for the temporal effect observed in placebo remission rates. The committee agreed an adjustment for temporal effect was needed.Overall, the committee concluded that it preferred the EAG's approach because it was more methodologically appropriate, but that the relative clinical effectiveness of risankizumab compared with other biological treatments was highly uncertain with either approach. The committee further noted that models using risk ratios rather than risk differences to compare risankizumab with the other biological treatments may be more informative, given the heterogeneity of studies in the network. This is because relative effect tends to be more stable across risk groups than absolute risk. It would also allow further, and more straightforward, exploration of data to improve the precision of the modelled comparative effectiveness estimates (by using an informative prior). At the first committee meeting, the committee concluded that updated analyses were needed: using a single maintenance network with an adjustment for temporal effect using risk ratios rather than risk difference and presenting the credible intervals around the estimates exploring both random-effects models and fixed-effects models. ## Clinical effectiveness similarity In response to draft guidance consultation, the company used the committee's preferred methods for its network meta-analyses. The company stated that the results suggested risankizumab and its comparators had similar clinical effectiveness, consistent with its previous analyses. The company noted that no statistically significant differences were observed. The committee noted that a lack of statistically significant differences between treatments did not mean that they were equally clinically effective. The exact point estimates for the comparisons and credible intervals are confidential and cannot be reported here. However, the committee noted that in all comparisons the point estimates of risk ratios for CDAI-measured clinical remission were below 1 for adalimumab, infliximab and ustekinumab compared with risankizumab, and around 1 for risankizumab compared with vedolizumab. In all comparisons, the 95% credible intervals were wide and included values above and below 1. In these analyses, a value below 1 suggests that clinical remission is more likely with the comparator than risankizumab, and a value above 1 suggests that clinical remission is more likely with risankizumab than the comparator. The EAG did not consider that the network meta-analyses supported equivalent clinical effectiveness across treatments. A clinical expert noted the difficulty in assessing clinical equivalence without clinical trials directly comparing the treatments. Based on experience in clinical practice and clinical trial evidence on risankizumab, the clinical expert considered that risankizumab is likely similarly effective to TNF-alpha inhibitors and ustekinumab, probably more effective than vedolizumab, and likely at least as effective as ustekinumab. They also cited a published meta-analysis suggesting that risankizumab's effectiveness is similar to other treatments (Barberio et al. 2022). The committee noted difficulties in doing network meta-analyses with the available trial data (for example, because of differences in treatments, trial designs or populations) and agreed that the results are uncertain. It stated that clinical equivalence or inferiority is usually assessed in specifically designed large-scale trials. The clinical expert also said that treatment response has been seen in people having risankizumab after previous biological treatment. The committee agreed that, based on the available evidence, there was only enough certainty that risankizumab had at least equivalent benefits to vedolizumab. # On-body device Risankizumab maintenance treatment will be delivered by a single-use on-body injector with a prefilled cartridge. However, in FORTIFY (see section 3.4) risankizumab was administered in 4 subcutaneous injections using a syringe. The committee was satisfied that results from other trials showed bioequivalence of risankizumab administered using the on-body device and using subcutaneous injections. However, it noted that the level of treatment adherence could differ from that observed in FORTIFY because of lack of experience with the device. The patient experts said that a new treatment option is needed regardless of the delivery method, noting that people with the condition are likely to prefer the on-body device to the 4 injections used in the trial. However, they explained that some drug delivery can be painful and they do not know whether it will be with the on-body device. They highlighted a need for a quiet and 'less-jarring' drug delivery mechanism than that associated with some other subcutaneous treatments for Crohn's disease. The EAG said that the implications for costs and patient outcomes are unknown. In particular, the cost of wastage if there were difficulties with self-administering or injection failure. A committee member also questioned the environmental impact of a single-use device that includes a battery and microchips. At the second committee meeting, the committee was reassured by clinical and patient experts that people with the condition and clinicians welcome this new delivery system. They said that injection failure wastage can happen with all self-administration systems, noting that pens for subcutaneous injection need coordination to hold and press a button at the correct pressure. They stated that all self-administration devices are single-use and highlighted that risankizumab is administered once every 12 weeks, while other treatments are administered more often giving more opportunities for wastage. The company stated that it will provide training and ongoing support for people using the on-body device free of charge to the NHS. The committee concluded that the on-body device is likely to be welcomed by people with Crohn's disease, although environmental concerns remained. # Company's first economic model ## Cost-utility model structure In its original submission, the company presented a cost-utility model comparing risankizumab with other biological treatments in the conventional care failure and biological treatment failure populations. It consisted of a short-term induction phase (decision tree) and a long-term maintenance phase (Markov state transition model). It assumed that people with moderately to severely active Crohn's disease have the same mortality as the general population. The maintenance phase modelled people having risankizumab or other biological treatments after a response to induction, or having conventional care if their Crohn's disease had not responded to induction treatment. After the first biological treatment, all people were modelled to have conventional care. With each maintenance treatment people were modelled to be in one of 4 health states: remission (CDAI score below 150), mild disease (CDAI score 150 to below 220), moderate to severe disease (CDAI score 220 to below 600), and surgery. It assumed that people with moderately to severely active disease could have surgery (constant rate across treatment arms based on NHS hospital episode statistics annual rates) and return to a CDAI-based health state after 8 weeks. The EAG explained that the CDAI used in the model to define clinical response and remission, and the severity of the disease, is not used in clinical practice. However, the clinical experts explained that the CDAI measure correlates with the Harvey-Bradshaw Index which is commonly used in clinical practice. The EAG further explained that the model does not reflect the lifelong relapsing–remitting nature of Crohn's disease because it does not allow people to have multiple biological treatments. Instead, it assumes all people have conventional treatment after a biological treatment. The company explained that a similar structure was used in previous NICE technology appraisals of treatments for Crohn's disease. The clinical experts agreed with the EAG that the model does not reflect the current clinical pathway. Overall, the committee concluded that although a CDAI-based model may be appropriate, the model is not suitable for decision making because it did not reflect the treatment pathway in which people can have more than 1 biological treatment. ## Treatment duration In the model, people could either stop treatment because of a lack of efficacy or once they had reached assumed maximum treatment duration. The company assumed a 1‑year maximum treatment duration. The EAG assumed a 20‑year maximum treatment duration and applied the company's rate of discontinuing treatment because of a lack of efficacy for 20 years. The company explained that a 1‑year maximum duration is consistent with modelling in previous NICE technology appraisals of treatments for Crohn's disease. The EAG noted that most people in FORTIFY were still having treatment at 1 year and that 1 year does not reflect the lifelong nature of Crohn's disease. The clinical and patient experts agreed with the EAG that a 1‑year maximum treatment duration does not reflect clinical practice and would not be fair for people with the condition. The company confirmed that it did not intend that there would be a 1‑year stopping rule for risankizumab in clinical practice. The committee concluded that the 1‑year maximum treatment duration assumption in the model was too short. It concluded that the EAG's 20‑year maximum treatment duration was more reflective of clinical practice and appropriate for use in the cost-utility model. # Company's second economic model At the first committee meeting, the committee noted the minimal quality-adjusted life-year gain for risankizumab in the company's cost-effectiveness analyses. The committee stated that cost-comparison analyses may be considered in NICE technology appraisals if it is shown that a technology has the same clinical effectiveness as a technology already recommended by NICE for the same indication. The committee outlined its preference for the network meta-analyses structure (see section 3.7). In response to draft guidance consultation, the company submitted a cost-comparison model because it considered that its updated network meta-analyses showed risankizumab was similarly clinically effective to its comparators. The committee concluded that it was appropriate to consider a cost-comparison model, but it would take into account both the evidence for clinical equivalence and whether risankizumab was cost saving in its decision making. ## Cost-comparison model structure The company developed a new model for cost comparison that had some different assumptions to its original cost-utility model: It used a 10‑year treatment duration rather than a maximum of 1 year (company's preference) or 20 years (EAG's preference) used in the cost-utility model (see section 3.11). It also did not account for some people stopping treatment before 10 years. A clinical expert stated that 10 years of treatment would be longer than expected and draft guidance consultation comments stated that 2 to 3 years is the reported median duration of treatment persistence with biologics. The EAG also provided a scenario analysis modelling treatment discontinuation. The committee considered that if using a cost-comparison analysis it was more appropriate to determine a time horizon sufficient to capture any differences in costs rather than to model treatment discontinuation. This is because treatments which are discontinued because of loss of effectiveness or tolerability may appear to be the cheapest option. It also agreed that a shorter time horizon than the company's 10 years may be appropriate. Infliximab and vedolizumab maintenance treatments can be delivered intravenously or subcutaneously. The company assumed that half of all people would have intravenous treatment and the other half subcutaneous. The model presented results that assumed 50% of vedolizumab and infliximab was administered subcutaneously and 50% intravenously. In the company's cost-utility model, a comparison of intravenous and subcutaneous vedolizumab and infliximab had been presented separately. A clinical expert agreed with the company, saying that the 50% split between intravenous and subcutaneous treatments, and the percentage of people having high doses assumed in the company's modelling, reflected clinical practice. Some maintenance treatments can be used at standard or high doses. The company assumed that 50% of people having adalimumab, 40% having infliximab, 92.5% having ustekinumab and 30% having intravenous vedolizumab start maintenance treatment with the high dose. A clinical expert stated that these assumptions were similar to what they had observed in their own centre. In the cost-utility model, an annual dose escalation using the same percentage was applied. They explained that although not everyone would start with a high dose, the dose would be increased soon after starting treatment, so the assumption reflects a simplification of clinical practice. The committee concluded that the company's modelling assumptions were appropriate, but a shorter time horizon should be considered in its decision making. # Cost-effectiveness results The committee considered only the cost-comparison model results because the cost-utility model was not suitable for decision making (see section 3.10). The company presented results for the whole population, although clinical-effectiveness evidence was presented separately for the conventional care failure and biological treatment failure populations. The committee already agreed that the relevant comparators for the conventional care failure population were adalimumab, infliximab and ustekinumab, and ustekinumab and vedolizumab for the biological treatment failure population (see section 3.3). The exact cost-effectiveness results cannot be reported here because of confidential prices for comparators. Using the company's assumptions, a 10‑year time horizon, and considering people with moderately to severely active Crohn's disease as a single population, risankizumab was: not cost saving compared with all comparators not cost saving compared with all adalimumab and infliximab comparators cost saving when compared with ustekinumab and vedolizumab in the biological treatment failure population. The company and the EAG did not consider that the total cost of treatments (dosing and administration costs) in the cost-comparison model would differ for the conventional care failure and biological treatment failure populations. The committee noted that the longer the treatment duration was in the cost-comparison model, the more cost saving risankizumab appeared. The committee considered the methods on decision making for cost comparisons. These state that to recommend a treatment there must be enough certainty that the technology has at least equivalent clinical or health and social care system benefits compared with current management, and overall uses fewer resources. The committee considered that, based on the available evidence, there was only enough certainty that risankizumab had at least equivalent benefits to vedolizumab. The committee considered that the cost saving of risankizumab compared with vedolizumab would be maintained over a 3‑year time horizon. In a cost-comparison analysis, a technology can be recommended if it is cost saving against a NICE-recommended technology. The committee concluded that it was appropriate to make a recommendation based on a cost comparison of risankizumab with vedolizumab and that in this comparison risankizumab was cost saving. The committee further concluded that because vedolizumab is recommended in clinical practice for use after a TNF-alpha inhibitor or if a TNF-alpha inhibitor is unsuitable, it was appropriate to recommend risankizumab as an option for people who have already had a biological treatment or for whom TNF-alpha inhibitors are unsuitable. # Other factors ## Equality issues No equality or social value judgement issues were identified. # Conclusion The committee agreed that although risankizumab may have similar clinical effectiveness to its comparators, there was uncertainty about its clinical equivalence to TNF-alpha inhibitors and ustekinumab in the conventional care failure population (see section 3.8). Risankizumab costs more than TNF-alpha inhibitors, which are typically the first biological treatments used in clinical practice after conventional care. However, the committee was satisfied that risankizumab was expected to have at least equivalent clinical effectiveness to vedolizumab and that risankizumab was cost saving when compared with vedolizumab in the biological treatment failure population (see section 3.14). The committee therefore recommended risankizumab for treating moderately to severely active Crohn's disease. It is recommended when the disease has not responded well enough or lost response to biological treatment, or this treatment was not tolerated, or when a TNF-alpha inhibitor is unsuitable.	{'Recommendations': "Risankizumab is recommended as an option for treating moderately to severely active Crohn's disease in people 16\xa0years and over, only if:\n\nthe disease has not responded well enough or lost response to a previous biological treatment, or\n\na previous biological treatment was not tolerated, or\n\ntumour necrosis factor (TNF)-alpha inhibitors are not suitable.Risankizumab is only recommended if the company provides it according to the commercial arrangement.\n\nIf people with the condition and their clinicians consider risankizumab to be 1\xa0of a range of suitable treatments, after discussing the advantages and disadvantages of all the options, use the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements.\n\nThese recommendations are not intended to affect treatment with risankizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by the clinician, the young person, and their parents or carers.\n\nWhy the committee made these recommendations\n\nStandard treatments for moderately to severely active Crohn's disease when conventional treatments stop working are biological treatments (such as TNF-alpha inhibitors [adalimumab and infliximab], ustekinumab and vedolizumab). Risankizumab is another biological treatment.\n\nClinical trial evidence suggests that risankizumab reduces symptoms and increases the likelihood of disease remission compared with placebo. Results from indirect comparisons of risankizumab with other biological treatments are uncertain. But there is enough evidence to suggest it is as effective as vedolizumab, a treatment recommended by NICE for use after a TNF-alpha inhibitor or when TNF-alpha inhibitors are not suitable.\n\nA cost comparison of risankizumab with vedolizumab suggests that risankizumab has similar or lower costs than vedolizumab. NICE considers risankizumab an acceptable use of NHS resources. This is when it is used after a biological treatment has not worked well enough, has stopped working, or was not tolerated, or TNF-alpha inhibitors are unsuitable. So, risankizumab is recommended.", 'Information about risankizumab': "# Marketing authorisation indication\n\nRisankizumab (Skyrizi, AbbVie) is indicated for 'the treatment of patients 16 years and older with moderately to severely active Crohn's disease who have had an inadequate response to, lost response to, or were intolerant to conventional therapy or a biological therapy, or if such therapies are not advisable'.\n\nThe CE mark for the on-body device that is used to deliver the 360‑mg risankizumab solution for injection has not been granted yet. Risankizumab will only be available in the UK for treating moderately to severely active Crohn's disease after this CE mark is granted.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for risankizumab 600-mg concentrate for solution for infusion and risankizumab 360-mg solution for injection in cartridge.\n\n# Price\n\nThe company has stated that the list prices of the 600‑mg concentrate for solution for infusion (induction treatment) and the on-body device with 360‑mg solution for injection (maintenance treatment) are confidential until they are available, and cannot be reported here.\n\nThe company has a commercial arrangement. This makes risankizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by AbbVie, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Crohn's disease\n\nCrohn's disease is a debilitating, chronic, relapsing systemic inflammatory bowel disease. It causes inflammation and mucosal ulceration anywhere in the digestive system. It is a lifelong condition. Symptoms include diarrhoea, abdominal pain, fatigue, loss of appetite, weight loss, blood or mucus in stool, and anaemia. Symptoms may vary over time and can last anywhere from a few days to several months. Persistent inflammation can lead to scarring of the bowel and further complications needing surgery. Treatments aim to relieve symptoms, promote mucosal healing, and maintain or improve quality of life by inducing disease remission while minimising drug-related toxicity. However, Crohn's disease often relapses and people can experience acute exacerbations (flares). Crohn's disease can present a major barrier to a person's ability to participate in daily life, severely affecting their self-esteem, social functioning, work, personal relationships, family life and other activities. One patient expert explained that treatments that induce remission are of great importance to people with the condition, because debilitating symptoms are not controlled unless the condition is in remission. Treatments which induce remission can also delay the need for surgery, which is also important to people with the condition. People with Crohn's disease fear the loss of remission and the arrival of flares because of the major impact these have on their life. The committee concluded that Crohn's disease can have a profound effect on people's quality of life and ability to do day-to-day activities.\n\n# Clinical management\n\n## Treatment options\n\nThe standard initial treatment for Crohn's disease is conventional treatment with corticosteroids and immunomodulators such as azathioprine, mercaptopurine and methotrexate. If these treatments fail, people are offered biological treatment. The clinical experts stated that tumour necrosis factor (TNF)-alpha inhibitors (infliximab or adalimumab, including biosimilars) are usually used first. Ustekinumab or vedolizumab are used when a TNF-alpha inhibitor has failed, is contraindicated or cannot be tolerated. These treatments are recommended in NICE's technology appraisal guidance on infliximab and adalimumab, ustekinumab and vedolizumab. A patient expert noted that NICE's recommendations on infliximab, adalimumab and ustekinumab specify that when more than 1 treatment is suitable the least expensive option should be used. NICE's recommendations also state that the benefit of continuing these treatments should be assessed at 1\xa0year. The clinical experts explained that, when there is evidence of clinical benefit, treatment continues beyond 1\xa0year and that stopping effective treatments would be very rare. They stated that if the treatment no longer works (including after a dose increase, if relevant), another biological treatment would be considered. The clinical experts stated that although there are several clinically effective biological treatments for Crohn's disease, these do not cause long-term disease remission for everyone. Some people may have a sequence of biological treatments followed by surgery. A patient expert stated that complications of surgery and the potential effect on fertility can have a large impact on people with the condition. The clinical and patient experts agreed that it is very important to have a range of treatment options to help more people gain and regain disease remission, and delay surgery. The committee concluded that people with Crohn's disease would value the availability of a further treatment option to improve symptoms and induce disease remission.\n\n## Risankizumab and its comparators\n\nRisankizumab is a novel treatment with a different mechanism of action to existing treatments. The company proposed it can be used either after conventional treatment (conventional care failure population) or after a biological treatment (biological treatment failure population) as an additional biological option. The clinical experts explained that treatment is not dependent on disease location. They agreed with the company's positioning of risankizumab in the clinical pathway and that it was relevant to consider both the conventional care failure and biological treatment failure populations. However, they noted that it would probably be used more after biological treatment. This is because TNF-alpha inhibitors are an effective and less expensive treatment option (because biosimilars are available), so most people have them first. A patient expert highlighted the need for people with the condition to have access to the most effective treatment first. This is because it can take years before they find an effective treatment, and this process can delay finding a treatment that induces disease remission. The committee concluded that risankizumab could be an option for both the conventional care failure and biological treatment failure populations. It further concluded that the relevant comparators for the conventional care failure population are adalimumab, infliximab and ustekinumab. The relevant comparators for the biological treatment failure population are ustekinumab and vedolizumab.\n\n# Clinical trials\n\nThe clinical evidence was from the phase\xa03 trials ADVANCE, MOTIVATE and FORTIFY. ADVANCE (n=931) and MOTIVATE (n=618) were multicentre, double-blind, placebo‑controlled randomised induction trials. These recruited people with moderately to severely active Crohn's disease that had an inadequate response to conventional treatments (ADVANCE) or biological treatments (ADVANCE and MOTIVATE). Moderately to severely active disease was defined by a Crohn's Disease Activity Index (CDAI) score of\xa0220 to\xa0450, average stool frequency of\xa04 or more, or abdominal pain score of\xa02 or more, and Simple Endoscopic Score for Crohn's Disease (SES‑CD) of\xa06 or more (4\xa0or more for isolated ileal disease). People had intravenous risankizumab (600\xa0mg or 1,200\xa0mg) or placebo at week\xa00, week\xa04 and week\xa08. People whose disease did not respond at week\xa012 had a second induction treatment with risankizumab (1,200\xa0mg intravenously, 360\xa0mg subcutaneously or 180\xa0mg subcutaneously). The company used data from ADVANCE or MOTIVATE for the subgroups who had the 600‑mg induction regimen covered by the marketing authorisation for risankizumab (for moderately to severely active Crohn's disease), or placebo. This included:\n\nin ADVANCE, 219\xa0people in the conventional care failure subgroup and 292\xa0people in the biological treatment failure subgroup\n\nin MOTIVATE, 378\xa0people who had a previous biological treatment. People whose disease responded to treatment entered FORTIFY, a phase\xa03 multicentre, double-blind, placebo-controlled maintenance trial. FORTIFY sub‑study\xa01 (n=542) re-randomised people to subcutaneous 180\xa0mg or 360\xa0mg risankizumab or placebo (withdrawal) every 8\xa0weeks for 52\xa0weeks. The company included data from FORTIFY from 305\xa0people who had 1\xa0induction treatment with intravenous 360\xa0mg risankizumab, the treatment regimen covered by the marketing authorisation for risankizumab, or placebo. Of these, 80\xa0people were in the conventional care failure subgroup and 225\xa0people were in the biological treatment failure subgroup. The committee concluded that the trials' results were generalisable to how risankizumab would be used in clinical practice.\n\n## Primary outcomes\n\nThe co-primary outcomes for all 3\xa0trials were clinical remission and endoscopic response. Clinical remission was measured by either a CDAI score below\xa0150 or patient-reported outcomes on stool frequency and abdominal pain, but both outcomes were collected in all trials. The SES‑CD was used to measure endoscopic response alongside either measure of clinical remission. The clinical experts explained that the CDAI is used primarily in clinical trials as a measure of remission but not in clinical practice because of the time needed to complete the measurements included in this index. The clinical experts stated that the Harvey‑Bradshaw Index is broadly comparable to the CDAI and is used in clinical practice. A clinical expert stated that the SES‑CD is used increasingly in clinical practice. The committee concluded that the measures of remission used in the trials would give applicable estimates of expected remission and endoscopic response rates in clinical practice.\n\n## Results\n\nThe results from the induction trials suggested that risankizumab is associated with higher rates of clinical remission and endoscopic response compared with placebo in the conventional care failure and biological treatment failure populations. The results from FORTIFY suggested that risankizumab is associated with higher rates of endoscopic response compared with placebo in the conventional care failure and biological treatment failure populations. The committee noted that the FORTIFY subgroup results in the conventional care failure and biological treatment failure populations were not statistically significant for clinical remission assessed by the CDAI. The committee concluded that risankizumab is associated with higher rates of clinical remission and endoscopic response compared with placebo (withdrawal) when used as a first biological treatment or after a previous biological treatment.\n\n# Clinical effectiveness\n\n## Network meta-analyses\n\nBecause of the lack of direct comparative evidence, the company's original submission included network meta-analyses for induction and maintenance treatment in the conventional care failure and biological treatment failure populations. The outcomes assessed were clinical remission and response (defined by the CDAI). In its original submission, the company used a Bayesian risk difference fixed-effects model. For the network meta-analyses for maintenance treatment, the company split the clinical trial evidence into 2\xa0separate networks (risankizumab and ustekinumab, and adalimumab, infliximab and vedolizumab). It stated it chose this approach because:\n\nof differences in drug mechanism of action, induction duration and half-life\n\nsingle network analyses lacked face validity (the estimated rates of remission were higher in people who had placebo)\n\nof methodological challenges in accounting for the heterogeneity. The EAG disagreed with the company on:\n\nSplitting networks: The EAG noted that connections in network meta-analyses should be based on comparator connections, not drug characteristics. It also noted ustekinumab and vedolizumab, used in the different networks, have a similar half-life and are comparable treatment options. The EAG presented results using a single network. The committee agreed that a single network was more appropriate.\n\nUsing a fixed-effects model rather than a random-effects model: The EAG agreed with the company that there were several differences between the trials that made doing network meta-analyses more challenging. This included differences in baseline risks, stratification by the conventional care failure and biological treatment failure populations, and an observed temporal effect in which remission rates in placebo groups appeared higher in more recent trials. Given these differences, using a random-effects model is more appropriate. The committee noted the company's concerns that its exploration of a random-effects model produced results with wide confidence intervals and included values which favoured placebo over biological treatments. However, the committee agreed with the EAG that a random-effects model was preferable.\n\nLack of adjustment for baseline risks or temporal effect: The EAG noted that the company's risk difference approach was not an adjustment for heterogeneity. The committee agreed that there was no evidence that the company's approach minimised differences between placebo group results between trials in the network. The EAG preferred to include an adjustment for the temporal effect observed in placebo remission rates. The committee agreed an adjustment for temporal effect was needed.Overall, the committee concluded that it preferred the EAG's approach because it was more methodologically appropriate, but that the relative clinical effectiveness of risankizumab compared with other biological treatments was highly uncertain with either approach. The committee further noted that models using risk ratios rather than risk differences to compare risankizumab with the other biological treatments may be more informative, given the heterogeneity of studies in the network. This is because relative effect tends to be more stable across risk groups than absolute risk. It would also allow further, and more straightforward, exploration of data to improve the precision of the modelled comparative effectiveness estimates (by using an informative prior). At the first committee meeting, the committee concluded that updated analyses were needed:\n\nusing a single maintenance network with an adjustment for temporal effect\n\nusing risk ratios rather than risk difference and presenting the credible intervals around the estimates\n\nexploring both random-effects models and fixed-effects models.\n\n## Clinical effectiveness similarity\n\nIn response to draft guidance consultation, the company used the committee's preferred methods for its network meta-analyses. The company stated that the results suggested risankizumab and its comparators had similar clinical effectiveness, consistent with its previous analyses. The company noted that no statistically significant differences were observed. The committee noted that a lack of statistically significant differences between treatments did not mean that they were equally clinically effective. The exact point estimates for the comparisons and credible intervals are confidential and cannot be reported here. However, the committee noted that in all comparisons the point estimates of risk ratios for CDAI-measured clinical remission were below\xa01 for adalimumab, infliximab and ustekinumab compared with risankizumab, and around\xa01 for risankizumab compared with vedolizumab. In all comparisons, the 95% credible intervals were wide and included values above and below\xa01. In these analyses, a value below\xa01 suggests that clinical remission is more likely with the comparator than risankizumab, and a value above\xa01 suggests that clinical remission is more likely with risankizumab than the comparator. The EAG did not consider that the network meta-analyses supported equivalent clinical effectiveness across treatments. A clinical expert noted the difficulty in assessing clinical equivalence without clinical trials directly comparing the treatments. Based on experience in clinical practice and clinical trial evidence on risankizumab, the clinical expert considered that risankizumab is likely similarly effective to TNF-alpha inhibitors and ustekinumab, probably more effective than vedolizumab, and likely at least as effective as ustekinumab. They also cited a published meta-analysis suggesting that risankizumab's effectiveness is similar to other treatments (Barberio et al. 2022). The committee noted difficulties in doing network meta-analyses with the available trial data (for example, because of differences in treatments, trial designs or populations) and agreed that the results are uncertain. It stated that clinical equivalence or inferiority is usually assessed in specifically designed large-scale trials. The clinical expert also said that treatment response has been seen in people having risankizumab after previous biological treatment. The committee agreed that, based on the available evidence, there was only enough certainty that risankizumab had at least equivalent benefits to vedolizumab.\n\n# On-body device\n\nRisankizumab maintenance treatment will be delivered by a single-use on-body injector with a prefilled cartridge. However, in FORTIFY (see section\xa03.4) risankizumab was administered in 4\xa0subcutaneous injections using a syringe. The committee was satisfied that results from other trials showed bioequivalence of risankizumab administered using the on-body device and using subcutaneous injections. However, it noted that the level of treatment adherence could differ from that observed in FORTIFY because of lack of experience with the device. The patient experts said that a new treatment option is needed regardless of the delivery method, noting that people with the condition are likely to prefer the on-body device to the 4\xa0injections used in the trial. However, they explained that some drug delivery can be painful and they do not know whether it will be with the on-body device. They highlighted a need for a quiet and 'less-jarring' drug delivery mechanism than that associated with some other subcutaneous treatments for Crohn's disease. The EAG said that the implications for costs and patient outcomes are unknown. In particular, the cost of wastage if there were difficulties with self-administering or injection failure. A committee member also questioned the environmental impact of a single-use device that includes a battery and microchips. At the second committee meeting, the committee was reassured by clinical and patient experts that people with the condition and clinicians welcome this new delivery system. They said that injection failure wastage can happen with all self-administration systems, noting that pens for subcutaneous injection need coordination to hold and press a button at the correct pressure. They stated that all self-administration devices are single-use and highlighted that risankizumab is administered once every 12\xa0weeks, while other treatments are administered more often giving more opportunities for wastage. The company stated that it will provide training and ongoing support for people using the on-body device free of charge to the NHS. The committee concluded that the on-body device is likely to be welcomed by people with Crohn's disease, although environmental concerns remained.\n\n# Company's first economic model\n\n## Cost-utility model structure\n\nIn its original submission, the company presented a cost-utility model comparing risankizumab with other biological treatments in the conventional care failure and biological treatment failure populations. It consisted of a short-term induction phase (decision tree) and a long-term maintenance phase (Markov state transition model). It assumed that people with moderately to severely active Crohn's disease have the same mortality as the general population. The maintenance phase modelled people having risankizumab or other biological treatments after a response to induction, or having conventional care if their Crohn's disease had not responded to induction treatment. After the first biological treatment, all people were modelled to have conventional care. With each maintenance treatment people were modelled to be in one of 4\xa0health states: remission (CDAI score below\xa0150), mild disease (CDAI score\xa0150 to below\xa0220), moderate to severe disease (CDAI score\xa0220 to below\xa0600), and surgery. It assumed that people with moderately to severely active disease could have surgery (constant rate across treatment arms based on NHS hospital episode statistics annual rates) and return to a CDAI-based health state after 8\xa0weeks. The EAG explained that the CDAI used in the model to define clinical response and remission, and the severity of the disease, is not used in clinical practice. However, the clinical experts explained that the CDAI measure correlates with the Harvey-Bradshaw Index which is commonly used in clinical practice. The EAG further explained that the model does not reflect the lifelong relapsing–remitting nature of Crohn's disease because it does not allow people to have multiple biological treatments. Instead, it assumes all people have conventional treatment after a biological treatment. The company explained that a similar structure was used in previous NICE technology appraisals of treatments for Crohn's disease. The clinical experts agreed with the EAG that the model does not reflect the current clinical pathway. Overall, the committee concluded that although a CDAI-based model may be appropriate, the model is not suitable for decision making because it did not reflect the treatment pathway in which people can have more than 1\xa0biological treatment.\n\n## Treatment duration\n\nIn the model, people could either stop treatment because of a lack of efficacy or once they had reached assumed maximum treatment duration. The company assumed a 1‑year maximum treatment duration. The EAG assumed a 20‑year maximum treatment duration and applied the company's rate of discontinuing treatment because of a lack of efficacy for 20\xa0years. The company explained that a 1‑year maximum duration is consistent with modelling in previous NICE technology appraisals of treatments for Crohn's disease. The EAG noted that most people in FORTIFY were still having treatment at 1\xa0year and that 1\xa0year does not reflect the lifelong nature of Crohn's disease. The clinical and patient experts agreed with the EAG that a 1‑year maximum treatment duration does not reflect clinical practice and would not be fair for people with the condition. The company confirmed that it did not intend that there would be a 1‑year stopping rule for risankizumab in clinical practice. The committee concluded that the 1‑year maximum treatment duration assumption in the model was too short. It concluded that the EAG's 20‑year maximum treatment duration was more reflective of clinical practice and appropriate for use in the cost-utility model.\n\n# Company's second economic model\n\nAt the first committee meeting, the committee noted the minimal quality-adjusted life-year gain for risankizumab in the company's cost-effectiveness analyses. The committee stated that cost-comparison analyses may be considered in NICE technology appraisals if it is shown that a technology has the same clinical effectiveness as a technology already recommended by NICE for the same indication. The committee outlined its preference for the network meta-analyses structure (see section\xa03.7). In response to draft guidance consultation, the company submitted a cost-comparison model because it considered that its updated network meta-analyses showed risankizumab was similarly clinically effective to its comparators. The committee concluded that it was appropriate to consider a cost-comparison model, but it would take into account both the evidence for clinical equivalence and whether risankizumab was cost saving in its decision making.\n\n## Cost-comparison model structure\n\nThe company developed a new model for cost comparison that had some different assumptions to its original cost-utility model:\n\nIt used a 10‑year treatment duration rather than a maximum of 1\xa0year (company's preference) or 20\xa0years (EAG's preference) used in the cost-utility model (see section\xa03.11). It also did not account for some people stopping treatment before 10\xa0years. A clinical expert stated that 10\xa0years of treatment would be longer than expected and draft guidance consultation comments stated that 2\xa0to 3\xa0years is the reported median duration of treatment persistence with biologics. The EAG also provided a scenario analysis modelling treatment discontinuation. The committee considered that if using a cost-comparison analysis it was more appropriate to determine a time horizon sufficient to capture any differences in costs rather than to model treatment discontinuation. This is because treatments which are discontinued because of loss of effectiveness or tolerability may appear to be the cheapest option. It also agreed that a shorter time horizon than the company's 10\xa0years may be appropriate.\n\nInfliximab and vedolizumab maintenance treatments can be delivered intravenously or subcutaneously. The company assumed that half of all people would have intravenous treatment and the other half subcutaneous. The model presented results that assumed 50% of vedolizumab and infliximab was administered subcutaneously and 50% intravenously. In the company's cost-utility model, a comparison of intravenous and subcutaneous vedolizumab and infliximab had been presented separately. A clinical expert agreed with the company, saying that the 50% split between intravenous and subcutaneous treatments, and the percentage of people having high doses assumed in the company's modelling, reflected clinical practice.\n\nSome maintenance treatments can be used at standard or high doses. The company assumed that 50% of people having adalimumab, 40% having infliximab, 92.5% having ustekinumab and 30% having intravenous vedolizumab start maintenance treatment with the high dose. A clinical expert stated that these assumptions were similar to what they had observed in their own centre. In the cost-utility model, an annual dose escalation using the same percentage was applied. They explained that although not everyone would start with a high dose, the dose would be increased soon after starting treatment, so the assumption reflects a simplification of clinical practice. The committee concluded that the company's modelling assumptions were appropriate, but a shorter time horizon should be considered in its decision making.\n\n# Cost-effectiveness results\n\nThe committee considered only the cost-comparison model results because the cost-utility model was not suitable for decision making (see section\xa03.10). The company presented results for the whole population, although clinical-effectiveness evidence was presented separately for the conventional care failure and biological treatment failure populations. The committee already agreed that the relevant comparators for the conventional care failure population were adalimumab, infliximab and ustekinumab, and ustekinumab and vedolizumab for the biological treatment failure population (see section\xa03.3). The exact cost-effectiveness results cannot be reported here because of confidential prices for comparators. Using the company's assumptions, a 10‑year time horizon, and considering people with moderately to severely active Crohn's disease as a single population, risankizumab was:\n\nnot cost saving compared with all comparators\n\nnot cost saving compared with all adalimumab and infliximab comparators\n\ncost saving when compared with ustekinumab and vedolizumab in the biological treatment failure population. The company and the EAG did not consider that the total cost of treatments (dosing and administration costs) in the cost-comparison model would differ for the conventional care failure and biological treatment failure populations. The committee noted that the longer the treatment duration was in the cost-comparison model, the more cost saving risankizumab appeared. The committee considered the methods on decision making for cost comparisons. These state that to recommend a treatment there must be enough certainty that the technology has at least equivalent clinical or health and social care system benefits compared with current management, and overall uses fewer resources. The committee considered that, based on the available evidence, there was only enough certainty that risankizumab had at least equivalent benefits to vedolizumab. The committee considered that the cost saving of risankizumab compared with vedolizumab would be maintained over a 3‑year time horizon. In a cost-comparison analysis, a technology can be recommended if it is cost saving against a NICE-recommended technology. The committee concluded that it was appropriate to make a recommendation based on a cost comparison of risankizumab with vedolizumab and that in this comparison risankizumab was cost saving. The committee further concluded that because vedolizumab is recommended in clinical practice for use after a TNF-alpha inhibitor or if a TNF-alpha inhibitor is unsuitable, it was appropriate to recommend risankizumab as an option for people who have already had a biological treatment or for whom TNF-alpha inhibitors are unsuitable.\n\n# Other factors\n\n## Equality issues\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\nThe committee agreed that although risankizumab may have similar clinical effectiveness to its comparators, there was uncertainty about its clinical equivalence to TNF-alpha inhibitors and ustekinumab in the conventional care failure population (see section\xa03.8). Risankizumab costs more than TNF-alpha inhibitors, which are typically the first biological treatments used in clinical practice after conventional care. However, the committee was satisfied that risankizumab was expected to have at least equivalent clinical effectiveness to vedolizumab and that risankizumab was cost saving when compared with vedolizumab in the biological treatment failure population (see section\xa03.14). The committee therefore recommended risankizumab for treating moderately to severely active Crohn's disease. It is recommended when the disease has not responded well enough or lost response to biological treatment, or this treatment was not tolerated, or when a TNF-alpha inhibitor is unsuitable."}	https://www.nice.org.uk/guidance/ta888	Evidence-based recommendations on risankizumab (Skyrizi) for previously treated moderately to severely active Crohn's disease in people 16 years and over.
09c85e5aa1e9bc1382d1302871f3ec33616bc9c4	nice	Difelikefalin for treating pruritus in people having haemodialysis	Difelikefalin for treating pruritus in people having haemodialysis Evidence-based recommendations on difelikefalin (Kapruvia) for pruritus in adults with chronic kidney disease having haemodialysis. # Recommendations Difelikefalin is recommended, within its marketing authorisation, for treating moderate to severe pruritus in adults with chronic kidney disease (CKD) having in-centre haemodialysis. Difelikefalin is only recommended if the company provides it according to the commercial arrangement. Why the committee made this recommendation Usual treatment for pruritus (itching) in people with CKD having haemodialysis includes creams and emollients, antihistamines and gabapentin. Difelikefalin would be offered if usual treatments do not work well enough. Evidence from clinical trials shows that difelikefalin reduces itching compared with usual treatment, despite some uncertainty about how long it works for and whether it improves people's quality of life. The cost-effectiveness estimates for difelikefalin are within the range that NICE usually considers an acceptable use of NHS resources. So, it is recommended.# Information about difelikefalin # Marketing authorisation indication Difelikefalin (Kapruvia, Vifor Pharma) is indicated for 'the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adult patients on haemodialysis'. Difelikefalin should be restricted to in‑centre haemodialysis use only. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for difelikefalin. # Price The list price of 50‑microgram 1‑ml vials of difelikefalin is £420 for 12 vials (excluding VAT; BNF online accessed February 2023). The company has a commercial arrangement. This makes difelikefalin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Vifor Pharma, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Details of the condition Chronic kidney disease (CKD) is a common and progressive disease. It is characterised by abnormalities of kidney function or structure for more than 3 months. CKD-associated pruritus (CKD‑aP) is a systemic itch that occurs in people with CKD, especially those having dialysis. The itch can affect the skin over the entire body, or only specific areas such as the scalp, face, upper back, arms or buttocks. Severity can change over time but can affect quality of life, and cause sleep disturbance, anxiety and depression. The patient experts explained that people with CKD‑aP will often have an additional treatment burden that can be physically and emotionally exhausting. They can have increased risks of infection, hospitalisation and mortality compared with people with normal renal function. CKD‑aP can affect daily activities, and people may have visible signs of scratching, which can have a negative emotional impact. The committee agreed there is an unmet need for treatment in people with moderate to severe CKD‑aP having haemodialysis. # Clinical management ## Treatment pathway There is no established standard care for CKD‑aP. The company stated that treatment would only be started when dialysis has normalised the calcium–phosphate balance and controlled parathyroid hormones to acceptable levels. Best supportive care could include anti-itch medicines such as creams and emollients, antihistamines and gabapentin. But these are currently unlicensed for this condition. If a person still has pruritus after having best supportive care, difelikefalin would then be offered. But the clinical experts explained that difelikefalin may be used earlier in the treatment pathway. It would be an intravenous in-centre treatment at the same time as having dialysis. It would continue for the duration of dialysis, as long as there is a sufficient reduction in itch score in the first 12 weeks of treatment. The committee agreed that the positioning of difelikefalin in the treatment pathway was appropriate. ## Comparators The company's submission compared difelikefalin plus anti-itch medicines used in established clinical practice with placebo plus anti-itch medicines used in established clinical practice. The EAG noted that this comparison was different from that in the NICE scope, which only listed difelikefalin compared with placebo. At technical engagement, the company clarified that the key clinical evidence considered the effect of difelikefalin compared with placebo including people who were both having and not having additional anti-itch medication. Considering the vast array of anti‑itch medicines used in established clinical practice, the EAG thought that it would be hard to identify whether there was a possible interaction between difelikefalin and specific anti-itch treatments when taken together. Any interaction might increase the benefit of difelikefalin compared with the benefits from anti-itch treatments being used alongside placebo. A clinical expert stated that there is a lack of empirical evidence on the efficacy of commonly used anti-itch treatments for pruritus, so the magnitude of any interactive effect is unknown. Pruritus treatment varies across the UK because there is no established standard care. Difelikefalin would be given at the same time as in-centre dialysis. So it was not unreasonable to expect that people would also be using other anti-itch medicines at the same time. The patient experts explained that people with CKD‑aP might be having multiple treatments to relieve their itch, as well as controlling their CKD symptoms. The committee agreed that difelikefalin would be used in addition to other anti-itch medicines to treat pruritus, so the comparison presented by the company was appropriate. It also acknowledged that the impact of these other treatments on the efficacy of difelikefalin is unknown. # Clinical effectiveness ## KALM trials The main clinical evidence came from two phase 3, randomised, multicentre, double-blind, placebo-controlled studies: KALM‑1 (n=378) and KALM‑2 (n=473). These investigated the safety and efficacy of difelikefalin in adults with end-stage renal disease who had been having haemodialysis at least 3 times per week for at least 3 months, and who had moderate to severe CKD‑aP. Difelikefalin was administered after each haemodialysis session (usually 3 times per week). Both studies included a 12‑week double-blind phase in which people were randomised to have intravenous difelikefalin (0.5 microgram/kg) or placebo. Each trial had a 7‑day run-in period during the week before randomisation, to identify the baseline itch intensity and whether the pruritus was moderate to severe. Treatment with other anti-itch medicines and presence of other medical conditions were recorded in the run-in period. A 52‑week open‑label extension period followed, in which difelikefalin was provided. In KALM‑1, there was a 2‑week discontinuation period at 12 weeks, between the double-blind and open-label phases, in which participants were evaluated for signs of physical dependence. The committee considered that this might influence the efficacy results, but this was unknown. It concluded that the trials were appropriate for evaluating the efficacy of difelikefalin in people with moderate to severe pruritus, but that some aspects of the trial design might influence results. ## Itch severity The primary efficacy outcome in both KALM trials was the percentage of people who had an improvement of at least 3 points from baseline at week 12 in the weekly mean score on the daily worst itching intensity numerical rating scale (WI‑NRS). In KALM‑1, the mean percentage of people with at least a 3‑point improvement from baseline in the WI‑NRS was 51% in the difelikefalin group and 27.6% in the placebo group. The estimated odds ratio for an improvement of at least 3 points from baseline with difelikefalin compared with placebo was 2.72 (95% confidence interval 1.72 to 4.30; p<0.001). In KALM‑2, the mean percentage of people with at least a 3‑point improvement from baseline in the WI‑NRS was 54% in the difelikefalin group and 42.2% in the placebo group. The estimated odds ratio for an improvement of at least 3 points from baseline with difelikefalin compared with placebo was in favour of difelikefalin at 1.61 (95% CI 1.08 to 2.41). The company provided further evidence on the efficacy of difelikefalin from a pooled analysis of results from the KALM trials (Topf et al. 2022). The odds of having at least a 3‑point reduction in WI‑NRS score at week 12 with difelikefalin compared with placebo was 1.93 (95% CI 1.44 to 2.57). The EAG was concerned about the company's method of doing the pooled analysis. It had included all randomised participants from the pooled KALM‑1 and KALM‑2 studies. The EAG suggested that the individual patient data from both trials was simply added together rather than doing a meta-analysis. It considered that pooling data in this way might lead to over-precise results and might bias the results. It did its own meta-analysis of the results from the KALM studies. This resulted in the odds of at least a 3‑point reduction in WI‑NRS score at week 12 with difelikefalin compared with placebo being 2.07 (95% CI 1.24 to 3.45). The committee concluded that the evidence suggested that difelikefalin reduces itch severity compared with placebo, but that there was uncertainty in the pooled data. ## Measures of itch intensity In the KALM trials, itch severity was measured using the WI‑NRS and the 5‑D itch scale. The WI‑NRS is a single-item patient-reported outcome that assesses the intensity of the worst itching experienced in the past 24 hours. The company considered that the WI‑NRS was a reliable, reproducible and valid measure of itch intensity in people with moderate to severe CKD‑aP. The 5‑D itch score is a multidimensional questionnaire that assesses itch severity and itch-related quality of life in the previous 2 weeks. The dimensions of itch assessed are degree, duration, direction, disability and distribution. Each domain is scored from 1 to 5 (1 suggesting no pruritus, and 5 for the most severe pruritus) and has a total score range of 5 to 25. A 5‑point change is considered clinically significant. The committee considered how appropriate the WI‑NRS and 5‑D itch scores are for measuring itch intensity in CKD‑aP. The clinical expert explained that a multidimensional scale is less likely to be used in clinical practice, because it is time consuming and relies on people retaining information over a longer time than a daily single-item scale. In practice, healthcare professionals are unlikely to use a questionnaire and would usually rely simply on people verbally reporting their itch severity. The committee accepted that both scales would inform itch severity, but in clinical practice neither is likely to be used. # Generalisability ## Concomitant medicines The company clarified that the participants in the KALM trials were allowed anti-itch medicines other than difelikefalin throughout the trial. This was restricted to the medicine they were taking before the trial, and changes in dosage were not allowed. The EAG considered whether the overall array of anti-itch medicines allowed in the KALM trials was comparable to UK standard care. The company had provided data from KALM‑1 and KALM‑2, grouped by 5 key anti-itch medicines. This showed that, based on WI‑NRS improvement, there was a trend for greater benefits with difelikefalin compared with placebo when used with anti-itch medicines, antihistamines, opioids or steroids. Used with gabapentin or pregabalin, the benefits of difelikefalin compared with placebo were reduced. Whether the anti-itch medicines used in the KALM trials were applicable to UK practice was unclear. The committee recalled that there is variation in practice across the UK (see section 3.2 and section 3.6). One clinical expert said that it is difficult to compare UK practice to the anti-itch medicines used in the KALM trials, but that topical therapies, antihistamines (mainly non-sedating medicines like cetirizine) and gabapentin are likely to be the most commonly used. Differences between the anti-itch medicines included in the trials and those used in UK clinical practice could limit the generalisability of the clinical-effectiveness evidence from the trials. The committee concluded that the impact of the various anti-itch medicines used in the KALM trials could affect the efficacy of difelikefalin. But there is currently no established standard care, and there is too little evidence for commonly used anti-itch medicines to allow the interaction of these medicines with difelikefalin to be explored. ## Family background The company considered that the KALM trial data was representative of a UK population with CKD‑aP. It provided data from the UK Renal Registry which showed that the data from UK participants in the KALM trials aligned reasonably well with the UK population. But the EAG noted that the overall population in the KALM trials and the UK target population were not comparable. The KALM trials had recruited a larger proportion of Black participants (29.2%) than is seen in the UK target population (12.8%). The company provided subgroup analyses of family background, sex and age for the primary efficacy results of each trial. The results suggested that people reported as being Black or African American in the trial had better outcomes with difelikefalin than people from other family backgrounds. The EAG questioned whether family background may be an effect modifier, which meant the overall efficacy from the KALM trials would overestimate the efficacy in the UK population. The company said that the KALM trials had been carried out in 5 treatment centres in the UK and included 20 UK participants. It considered that this represented the UK population well. The company stated that the effect of difelikefalin was not statistically significantly different in Black participants compared with people from other family backgrounds in the KALM trials. The committee noted that the trials were not powered to detect statistically significant differences in treatment effect by family background. One clinical expert explained that because the KALM trials had recruited participants in a large number of UK clinical centres, the populations were broadly generalisable to the UK population. There are large health inequalities in CKD. People from Black and Asian family backgrounds may have faster progression to renal failure and have haemodialysis for longer, so there would be a high proportion of people with CKD from Black and Asian family backgrounds in UK clinical practice. The committee concluded that the KALM data was representative of the UK clinical population. ## Handling missing data in the KALM trials The company used multiple imputation to handle missing data in the double-blind phases of KALM‑1 and KALM‑2. At technical engagement, the company clarified that it had chosen this approach because single imputation methods would have overestimated a treatment effect but underestimated the variability caused by the missing data. The company stated that it had done 20 imputations, but the EAG was not clear how all of the transition matrices were identified based on the company's methods of accounting for the missing data. It was unsure whether the company's transition probabilities were based on averages over the 20 different probabilities, or if each came from a different complete dataset to create an overall estimated dataset. The company had not directly tested the variability of the between-arm datasets. It had used several covariates in KALM‑1 and KALM‑2. These were baseline WI‑NRS score, use of anti‑itch medication during the week before randomisation, presence of a specific medical condition and the patient-reported numerical rating scale scores for each week. It also considered region to be a covariate, for KALM‑2 only, but had not considered all regions that had participated in the trial. The variables used in the logistic regression model were trial group, baseline WI‑NRS score, baseline use of antipruritic medication and history of prespecified medical conditions. The EAG explained that, when imputing data, it is important to explore how uncertainty was estimated. This should account for both within-dataset and between-dataset variation. So, it is usual to include as many variables as possible rather than only exploring covariates that might influence effectiveness. The EAG queried the company's rationale for choosing specific covariates over other potential prognostic variables that may be correlated with the outcome of interest. Because there were 279 missing observations throughout the KALM trials, the committee considered that using an imputed approach to missing clinical data in the KALM trials was more appropriate than relying on direct observations. But it noted that the company had provided insufficient information about the methodology of the multiple imputation. # Economic model ## Company's model The company developed a Markov model to assess the cost effectiveness of difelikefalin for adults with moderate to severe CKD‑aP who are having haemodialysis. The model had 5 core health states, which were defined by itch severity (none, mild, moderate, severe and very severe). It had 2 additional health states of renal transplant and death. The 5 core health states used in the model were defined using the outcome measures of WI‑NRS and 5‑D itch scale scores, as these were collected in the KALM trials. The committee had some concerns about the company's modelling of treatment efficacy, and the fact that the 'severe' and 'very severe' health states had identical costs and utility values. The company used the 5‑D itch scores to model treatment efficacy in its base-case analysis, but the WI‑NRS had been the primary outcome in KALM‑1 and KALM‑2. The company explained that the 5‑D itch scale had been used for up to 64 weeks in the KALM open-label phases, whereas the WI‑NRS was only used for the first 12 weeks. The EAG felt that the model structure adequately reflected clinical issues for people with moderate to severe CKD‑aP who are having haemodialysis. The committee accepted this, but considered there was still some uncertainty in using the 5‑D itch scores to model treatment efficacy. # Assumptions in the economic model ## Waning of treatment effect In the company's original base case, the comparator arm was modelled as having a 5% waning of treatment effect per year. The company assumed no waning in the difelikefalin arm. It did not provide evidence to support these waning assumptions, so the EAG considered that they were uncertain. At technical engagement, the company presented evidence based on an economic literature review that identified 3 NICE highly specialised technologies appraisals in which itching was important, and treatment waning had been accepted in the comparator arm. Based on this, the company carried out 2 scenario analyses to explore the impact of a waning effect in the comparator arm of its model. This showed that waning rates were much higher than the 5% waning per year that was assumed in its original base case. So, the company increased the waning for the comparator arm in its revised base case to 10%. The EAG considered this to be a reasonable approach and accepted 10% waning per year in the comparator arm, and updated its base case in line with this. One clinical expert explained that in people having established standard care, there is likely to be a placebo effect and so waning would occur. The committee recognised that the 10% waning applied in the comparator arm was a conservative estimate, and accepted this. It was less certain that no waning would occur in the difelikefalin group, and considered it plausible that there would be a waning of treatment effect for difelikefalin. The committee welcomed the scenarios exploring the impact of different waning assumptions for difelikefalin. It considered that the scenario analysis assuming 5% waning in the treatment arm and 10% waning in the control arm was useful. ## Health state utility values No generic health state measures of quality of life were collected in the KALM trials. So, the company carried out a separate primary data collection study across UK dialysis centres to map the WI‑NRS and 5‑D itch scale to the EQ‑5D‑3L. These utility values were used to reflect the CKD‑aP health states in its base case. In the mapping study, the severe and very severe populations were merged, so the utility scores for these populations were equal and had the same measures of utility, quality of life and costs. The company explained that the populations were merged because of the small numbers of observations in each group. The committee noted that most observations were populated by the severe health state, and queried whether it was appropriate to include the very severe health state in the model. The company stated that the model had been developed to represent the 5 core health states of CKD‑aP severity and it considered this was appropriate. One clinical expert stated that in practice, severe CKD‑aP would be different to very severe CKD‑aP. The committee agreed the mapping study was robust and accepted that the model should include all 5 health states of CKD‑aP severity. ## Transition probabilities To account for the missing data in the KALM trials, the company used multiple imputation (see section 3.9). In its base case, transition probabilities were estimated using a simulated approach that considered the mean change from baseline in itch scores by CKD‑aP severity for the moderate, severe and very severe health states at baseline. The simulated approach only allowed for a person's condition to improve, whereas the observed data showed people's conditions could improve or deteriorate up to 3 health states at a time. One clinical expert explained that in clinical practice, people's conditions would likely improve or deteriorate, rather than only improving. The EAG preferred to estimate transition probabilities from directly observed data. The committee agreed that the observed data better reflected clinical practice. It considered that the company had provided little justification for how, in its base case, it had estimated and simulated the transition probabilities from aggregate data. It preferred the EAG's approach of estimating transitions using observed patient-level data, as this better reflected transitions in clinical practice. The committee was aware of the uncertainties in using this simulated approach (see section 3.9). The company provided a histogram plot showing the frequency of observations for each 5‑D itch scale total score at week 12 using the observed patient-level dataset and simulated dataset. The committee felt that a longer-term exploration of the observed data, compared with data drawn from the simulated dataset, might address these uncertainties. A comparison showing the health state occupancy from the simulated data used in the company's model against the directly observed health state occupancy from the KALM trials would have been helpful to the committee's decision making. # Cost-effectiveness estimates ## Acceptable ICER The NICE health technology evaluations manual notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of the technology as an effective use of NHS resources will specifically consider: the degree of certainty and uncertainty around the ICER uncaptured benefits and non-health factors.The committee noted several points when it considered the uncertainty around the cost-effectiveness estimates, specifically: waning of treatment effect of difelikefalin in the economic model (see section 3.11) estimation of transition probabilities from the observed patient data (see section 3.13) modelling of itch severity using the 5-D itch scale (see section 3.10).The committee concluded that these uncertainties would have to be reflected in the maximum ICER it would be willing to accept, which would need to be well below £30,000 per QALY gained. ## The committee's preferred cost-effectiveness estimate The committee recalled its preference to use transition probabilities directly from the trial, and that the EAG's base case more closely matched its preferred assumptions. The committee noted that when taking into account the confidential discount for difelikefalin, the EAG's base-case ICER was £22,000 per QALY gained for difelikefalin compared with established standard care. The committee was satisfied that the most likely cost-effectiveness estimates were within what NICE considers an acceptable use of NHS resources. # Other factors ## Uncaptured benefits One clinical expert pointed out that in clinical practice, difelikefalin would be administered at the same time as having dialysis. The committee recognised this would reduce the treatment burden for people with CKD‑aP. It noted that this benefit had not been captured in the cost‑effectiveness analysis. ## Equality issues The company submission noted several groups of people who are at greater risk of developing CKD‑aP and having symptoms for longer while on dialysis. These include: people with lower socioeconomic status, who are more likely to develop CKD, whose condition is more likely to progress towards kidney failure, and who die earlier because of CKD people from Black, Asian and other minority ethnic family backgrounds, whose condition is more likely to progress to kidney failure faster, and who are less likely to receive a transplant women, who are more likely to be diagnosed with CKD, but less likely to start dialysis -lder people with CKD, who are less likely to have a kidney transplant than younger people. The company noted that difelikefalin is restricted for in-centre haemodialysis use, which may be considered a barrier for people who find in-centre haemodialysis less accessible. The committee recalled the treatment burden of having CKD‑aP (see section 3.1). It considered that 1 advantage of difelikefalin might be to lessen that burden and therefore help reduce health inequalities. The committee further concluded that a recommendation for difelikefalin would be unlikely to result in any direct or indirect discrimination. NICE's advice about conditions with a high degree of severity did not apply. ## Innovation The committee considered if difelikefalin was an innovative treatment for CKD‑aP. It recalled that the reduced treatment burden had not been captured in the modelling, and that it would take this into account in its decision making. # Conclusion ## Recommendation The committee noted its preference for the EAG's base-case results, the uncaptured benefits, and the need for uncertainty to be taken into account in its decision. The committee concluded that difelikefalin would be a cost‑effective use of NHS resources. So, it recommended difelikefalin, within its marketing authorisation, for treating moderate to severe pruritus in adults with CKD having in-centre haemodialysis.	{'Recommendations': "Difelikefalin is recommended, within its marketing authorisation, for treating moderate to severe pruritus in adults with chronic kidney disease (CKD) having in-centre haemodialysis. Difelikefalin is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nUsual treatment for pruritus (itching) in people with CKD having haemodialysis includes creams and emollients, antihistamines and gabapentin. Difelikefalin would be offered if usual treatments do not work well enough.\n\nEvidence from clinical trials shows that difelikefalin reduces itching compared with usual treatment, despite some uncertainty about how long it works for and whether it improves people's quality of life.\n\nThe cost-effectiveness estimates for difelikefalin are within the range that NICE usually considers an acceptable use of NHS resources. So, it is recommended.", 'Information about difelikefalin': "# Marketing authorisation indication\n\nDifelikefalin (Kapruvia, Vifor Pharma) is indicated for 'the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adult patients on haemodialysis'. Difelikefalin should be restricted to in‑centre haemodialysis use only.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for difelikefalin.\n\n# Price\n\nThe list price of 50‑microgram 1‑ml vials of difelikefalin is £420 for 12\xa0vials (excluding VAT; BNF online accessed February\xa02023).\n\nThe company has a commercial arrangement. This makes difelikefalin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Vifor Pharma, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Details of the condition\n\nChronic kidney disease (CKD) is a common and progressive disease. It is characterised by abnormalities of kidney function or structure for more than 3\xa0months. CKD-associated pruritus (CKD‑aP) is a systemic itch that occurs in people with CKD, especially those having dialysis. The itch can affect the skin over the entire body, or only specific areas such as the scalp, face, upper back, arms or buttocks. Severity can change over time but can affect quality of life, and cause sleep disturbance, anxiety and depression. The patient experts explained that people with CKD‑aP will often have an additional treatment burden that can be physically and emotionally exhausting. They can have increased risks of infection, hospitalisation and mortality compared with people with normal renal function. CKD‑aP can affect daily activities, and people may have visible signs of scratching, which can have a negative emotional impact. The committee agreed there is an unmet need for treatment in people with moderate to severe CKD‑aP having haemodialysis.\n\n# Clinical management\n\n## Treatment pathway\n\nThere is no established standard care for CKD‑aP. The company stated that treatment would only be started when dialysis has normalised the calcium–phosphate balance and controlled parathyroid hormones to acceptable levels. Best supportive care could include anti-itch medicines such as creams and emollients, antihistamines and gabapentin. But these are currently unlicensed for this condition. If a person still has pruritus after having best supportive care, difelikefalin would then be offered. But the clinical experts explained that difelikefalin may be used earlier in the treatment pathway. It would be an intravenous in-centre treatment at the same time as having dialysis. It would continue for the duration of dialysis, as long as there is a sufficient reduction in itch score in the first 12\xa0weeks of treatment. The committee agreed that the positioning of difelikefalin in the treatment pathway was appropriate.\n\n## Comparators\n\nThe company's submission compared difelikefalin plus anti-itch medicines used in established clinical practice with placebo plus anti-itch medicines used in established clinical practice. The EAG noted that this comparison was different from that in the NICE scope, which only listed difelikefalin compared with placebo. At technical engagement, the company clarified that the key clinical evidence considered the effect of difelikefalin compared with placebo including people who were both having and not having additional anti-itch medication. Considering the vast array of anti‑itch medicines used in established clinical practice, the EAG thought that it would be hard to identify whether there was a possible interaction between difelikefalin and specific anti-itch treatments when taken together. Any interaction might increase the benefit of difelikefalin compared with the benefits from anti-itch treatments being used alongside placebo. A clinical expert stated that there is a lack of empirical evidence on the efficacy of commonly used anti-itch treatments for pruritus, so the magnitude of any interactive effect is unknown. Pruritus treatment varies across the UK because there is no established standard care. Difelikefalin would be given at the same time as in-centre dialysis. So it was not unreasonable to expect that people would also be using other anti-itch medicines at the same time. The patient experts explained that people with CKD‑aP might be having multiple treatments to relieve their itch, as well as controlling their CKD symptoms. The committee agreed that difelikefalin would be used in addition to other anti-itch medicines to treat pruritus, so the comparison presented by the company was appropriate. It also acknowledged that the impact of these other treatments on the efficacy of difelikefalin is unknown.\n\n# Clinical effectiveness\n\n## KALM trials\n\nThe main clinical evidence came from two phase\xa03, randomised, multicentre, double-blind, placebo-controlled studies: KALM‑1 (n=378) and KALM‑2 (n=473). These investigated the safety and efficacy of difelikefalin in adults with end-stage renal disease who had been having haemodialysis at least 3\xa0times per week for at least 3\xa0months, and who had moderate to severe CKD‑aP. Difelikefalin was administered after each haemodialysis session (usually 3\xa0times per week). Both studies included a 12‑week double-blind phase in which people were randomised to have intravenous difelikefalin (0.5\xa0microgram/kg) or placebo. Each trial had a 7‑day run-in period during the week before randomisation, to identify the baseline itch intensity and whether the pruritus was moderate to severe. Treatment with other anti-itch medicines and presence of other medical conditions were recorded in the run-in period. A 52‑week open‑label extension period followed, in which difelikefalin was provided. In KALM‑1, there was a 2‑week discontinuation period at 12\xa0weeks, between the double-blind and open-label phases, in which participants were evaluated for signs of physical dependence. The committee considered that this might influence the efficacy results, but this was unknown. It concluded that the trials were appropriate for evaluating the efficacy of difelikefalin in people with moderate to severe pruritus, but that some aspects of the trial design might influence results.\n\n## Itch severity\n\nThe primary efficacy outcome in both KALM trials was the percentage of people who had an improvement of at least 3\xa0points from baseline at week\xa012 in the weekly mean score on the daily worst itching intensity numerical rating scale (WI‑NRS). In KALM‑1, the mean percentage of people with at least a 3‑point improvement from baseline in the WI‑NRS was 51% in the difelikefalin group and 27.6% in the placebo group. The estimated odds ratio for an improvement of at least 3\xa0points from baseline with difelikefalin compared with placebo was 2.72 (95% confidence interval [CI] 1.72\xa0to\xa04.30; p<0.001). In KALM‑2, the mean percentage of people with at least a 3‑point improvement from baseline in the WI‑NRS was 54% in the difelikefalin group and 42.2% in the placebo group. The estimated odds ratio for an improvement of at least 3\xa0points from baseline with difelikefalin compared with placebo was in favour of difelikefalin at 1.61 (95% CI 1.08\xa0to\xa02.41). The company provided further evidence on the efficacy of difelikefalin from a pooled analysis of results from the KALM trials (Topf et al. 2022). The odds of having at least a 3‑point reduction in WI‑NRS score at week\xa012 with difelikefalin compared with placebo was 1.93 (95% CI 1.44 to 2.57). The EAG was concerned about the company's method of doing the pooled analysis. It had included all randomised participants from the pooled KALM‑1 and KALM‑2 studies. The EAG suggested that the individual patient data from both trials was simply added together rather than doing a meta-analysis. It considered that pooling data in this way might lead to over-precise results and might bias the results. It did its own meta-analysis of the results from the KALM studies. This resulted in the odds of at least a 3‑point reduction in WI‑NRS score at week\xa012 with difelikefalin compared with placebo being 2.07 (95% CI 1.24\xa0to\xa03.45). The committee concluded that the evidence suggested that difelikefalin reduces itch severity compared with placebo, but that there was uncertainty in the pooled data.\n\n## Measures of itch intensity\n\nIn the KALM trials, itch severity was measured using the WI‑NRS and the 5‑D itch scale. The WI‑NRS is a single-item patient-reported outcome that assesses the intensity of the worst itching experienced in the past 24\xa0hours. The company considered that the WI‑NRS was a reliable, reproducible and valid measure of itch intensity in people with moderate to severe CKD‑aP. The 5‑D itch score is a multidimensional questionnaire that assesses itch severity and itch-related quality of life in the previous 2\xa0weeks. The dimensions of itch assessed are degree, duration, direction, disability and distribution. Each domain is scored from 1 to 5 (1\xa0suggesting no pruritus, and 5 for the most severe pruritus) and has a total score range of 5\xa0to\xa025. A 5‑point change is considered clinically significant. The committee considered how appropriate the WI‑NRS and 5‑D itch scores are for measuring itch intensity in CKD‑aP. The clinical expert explained that a multidimensional scale is less likely to be used in clinical practice, because it is time consuming and relies on people retaining information over a longer time than a daily single-item scale. In practice, healthcare professionals are unlikely to use a questionnaire and would usually rely simply on people verbally reporting their itch severity. The committee accepted that both scales would inform itch severity, but in clinical practice neither is likely to be used.\n\n# Generalisability\n\n## Concomitant medicines\n\nThe company clarified that the participants in the KALM trials were allowed anti-itch medicines other than difelikefalin throughout the trial. This was restricted to the medicine they were taking before the trial, and changes in dosage were not allowed. The EAG considered whether the overall array of anti-itch medicines allowed in the KALM trials was comparable to UK standard care. The company had provided data from KALM‑1 and KALM‑2, grouped by 5\xa0key anti-itch medicines. This showed that, based on WI‑NRS improvement, there was a trend for greater benefits with difelikefalin compared with placebo when used with anti-itch medicines, antihistamines, opioids or steroids. Used with gabapentin or pregabalin, the benefits of difelikefalin compared with placebo were reduced. Whether the anti-itch medicines used in the KALM trials were applicable to UK practice was unclear. The committee recalled that there is variation in practice across the UK (see section\xa03.2 and section\xa03.6). One clinical expert said that it is difficult to compare UK practice to the anti-itch medicines used in the KALM trials, but that topical therapies, antihistamines (mainly non-sedating medicines like cetirizine) and gabapentin are likely to be the most commonly used. Differences between the anti-itch medicines included in the trials and those used in UK clinical practice could limit the generalisability of the clinical-effectiveness evidence from the trials. The committee concluded that the impact of the various anti-itch medicines used in the KALM trials could affect the efficacy of difelikefalin. But there is currently no established standard care, and there is too little evidence for commonly used anti-itch medicines to allow the interaction of these medicines with difelikefalin to be explored.\n\n## Family background\n\nThe company considered that the KALM trial data was representative of a UK population with CKD‑aP. It provided data from the UK Renal Registry which showed that the data from UK participants in the KALM trials aligned reasonably well with the UK population. But the EAG noted that the overall population in the KALM trials and the UK target population were not comparable. The KALM trials had recruited a larger proportion of Black participants (29.2%) than is seen in the UK target population (12.8%). The company provided subgroup analyses of family background, sex and age for the primary efficacy results of each trial. The results suggested that people reported as being Black or African American in the trial had better outcomes with difelikefalin than people from other family backgrounds. The EAG questioned whether family background may be an effect modifier, which meant the overall efficacy from the KALM trials would overestimate the efficacy in the UK population. The company said that the KALM trials had been carried out in 5\xa0treatment centres in the UK and included 20\xa0UK participants. It considered that this represented the UK population well. The company stated that the effect of difelikefalin was not statistically significantly different in Black participants compared with people from other family backgrounds in the KALM trials. The committee noted that the trials were not powered to detect statistically significant differences in treatment effect by family background. One clinical expert explained that because the KALM trials had recruited participants in a large number of UK clinical centres, the populations were broadly generalisable to the UK population. There are large health inequalities in CKD. People from Black and Asian family backgrounds may have faster progression to renal failure and have haemodialysis for longer, so there would be a high proportion of people with CKD from Black and Asian family backgrounds in UK clinical practice. The committee concluded that the KALM data was representative of the UK clinical population.\n\n## Handling missing data in the KALM trials\n\nThe company used multiple imputation to handle missing data in the double-blind phases of KALM‑1 and KALM‑2. At technical engagement, the company clarified that it had chosen this approach because single imputation methods would have overestimated a treatment effect but underestimated the variability caused by the missing data. The company stated that it had done 20\xa0imputations, but the EAG was not clear how all of the transition matrices were identified based on the company's methods of accounting for the missing data. It was unsure whether the company's transition probabilities were based on averages over the 20 different probabilities, or if each came from a different complete dataset to create an overall estimated dataset. The company had not directly tested the variability of the between-arm datasets. It had used several covariates in KALM‑1 and KALM‑2. These were baseline WI‑NRS score, use of anti‑itch medication during the week before randomisation, presence of a specific medical condition and the patient-reported numerical rating scale scores for each week. It also considered region to be a covariate, for KALM‑2 only, but had not considered all regions that had participated in the trial. The variables used in the logistic regression model were trial group, baseline WI‑NRS score, baseline use of antipruritic medication and history of prespecified medical conditions. The EAG explained that, when imputing data, it is important to explore how uncertainty was estimated. This should account for both within-dataset and between-dataset variation. So, it is usual to include as many variables as possible rather than only exploring covariates that might influence effectiveness. The EAG queried the company's rationale for choosing specific covariates over other potential prognostic variables that may be correlated with the outcome of interest. Because there were 279\xa0missing observations throughout the KALM trials, the committee considered that using an imputed approach to missing clinical data in the KALM trials was more appropriate than relying on direct observations. But it noted that the company had provided insufficient information about the methodology of the multiple imputation.\n\n# Economic model\n\n## Company's model\n\nThe company developed a Markov model to assess the cost effectiveness of difelikefalin for adults with moderate to severe CKD‑aP who are having haemodialysis. The model had 5\xa0core health states, which were defined by itch severity (none, mild, moderate, severe and very severe). It had 2\xa0additional health states of renal transplant and death. The 5\xa0core health states used in the model were defined using the outcome measures of WI‑NRS and 5‑D itch scale scores, as these were collected in the KALM trials. The committee had some concerns about the company's modelling of treatment efficacy, and the fact that the 'severe' and 'very severe' health states had identical costs and utility values. The company used the 5‑D itch scores to model treatment efficacy in its base-case analysis, but the WI‑NRS had been the primary outcome in KALM‑1 and KALM‑2. The company explained that the 5‑D itch scale had been used for up to 64\xa0weeks in the KALM open-label phases, whereas the WI‑NRS was only used for the first 12\xa0weeks. The EAG felt that the model structure adequately reflected clinical issues for people with moderate to severe CKD‑aP who are having haemodialysis. The committee accepted this, but considered there was still some uncertainty in using the 5‑D itch scores to model treatment efficacy.\n\n# Assumptions in the economic model\n\n## Waning of treatment effect\n\nIn the company's original base case, the comparator arm was modelled as having a 5% waning of treatment effect per year. The company assumed no waning in the difelikefalin arm. It did not provide evidence to support these waning assumptions, so the EAG considered that they were uncertain. At technical engagement, the company presented evidence based on an economic literature review that identified 3\xa0NICE highly specialised technologies appraisals in which itching was important, and treatment waning had been accepted in the comparator arm. Based on this, the company carried out 2\xa0scenario analyses to explore the impact of a waning effect in the comparator arm of its model. This showed that waning rates were much higher than the 5% waning per year that was assumed in its original base case. So, the company increased the waning for the comparator arm in its revised base case to 10%. The EAG considered this to be a reasonable approach and accepted 10% waning per year in the comparator arm, and updated its base case in line with this. One clinical expert explained that in people having established standard care, there is likely to be a placebo effect and so waning would occur. The committee recognised that the 10% waning applied in the comparator arm was a conservative estimate, and accepted this. It was less certain that no waning would occur in the difelikefalin group, and considered it plausible that there would be a waning of treatment effect for difelikefalin. The committee welcomed the scenarios exploring the impact of different waning assumptions for difelikefalin. It considered that the scenario analysis assuming 5% waning in the treatment arm and 10% waning in the control arm was useful.\n\n## Health state utility values\n\nNo generic health state measures of quality of life were collected in the KALM trials. So, the company carried out a separate primary data collection study across UK dialysis centres to map the WI‑NRS and 5‑D itch scale to the EQ‑5D‑3L. These utility values were used to reflect the CKD‑aP health states in its base case. In the mapping study, the severe and very severe populations were merged, so the utility scores for these populations were equal and had the same measures of utility, quality of life and costs. The company explained that the populations were merged because of the small numbers of observations in each group. The committee noted that most observations were populated by the severe health state, and queried whether it was appropriate to include the very severe health state in the model. The company stated that the model had been developed to represent the 5\xa0core health states of CKD‑aP severity and it considered this was appropriate. One clinical expert stated that in practice, severe CKD‑aP would be different to very severe CKD‑aP. The committee agreed the mapping study was robust and accepted that the model should include all 5\xa0health states of CKD‑aP severity.\n\n## Transition probabilities\n\nTo account for the missing data in the KALM trials, the company used multiple imputation (see section\xa03.9). In its base case, transition probabilities were estimated using a simulated approach that considered the mean change from baseline in itch scores by CKD‑aP severity for the moderate, severe and very severe health states at baseline. The simulated approach only allowed for a person's condition to improve, whereas the observed data showed people's conditions could improve or deteriorate up to 3\xa0health states at a time. One clinical expert explained that in clinical practice, people's conditions would likely improve or deteriorate, rather than only improving. The EAG preferred to estimate transition probabilities from directly observed data. The committee agreed that the observed data better reflected clinical practice. It considered that the company had provided little justification for how, in its base case, it had estimated and simulated the transition probabilities from aggregate data. It preferred the EAG's approach of estimating transitions using observed patient-level data, as this better reflected transitions in clinical practice. The committee was aware of the uncertainties in using this simulated approach (see section\xa03.9). The company provided a histogram plot showing the frequency of observations for each 5‑D itch scale total score at week\xa012 using the observed patient-level dataset and simulated dataset. The committee felt that a longer-term exploration of the observed data, compared with data drawn from the simulated dataset, might address these uncertainties. A comparison showing the health state occupancy from the simulated data used in the company's model against the directly observed health state occupancy from the KALM trials would have been helpful to the committee's decision making.\n\n# Cost-effectiveness estimates\n\n## Acceptable ICER\n\nThe NICE health technology evaluations manual notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of the technology as an effective use of NHS resources will specifically consider:\n\nthe degree of certainty and uncertainty around the ICER\n\nuncaptured benefits and non-health factors.The committee noted several points when it considered the uncertainty around the cost-effectiveness estimates, specifically:\n\nwaning of treatment effect of difelikefalin in the economic model (see section\xa03.11)\n\nestimation of transition probabilities from the observed patient data (see section\xa03.13)\n\nmodelling of itch severity using the 5-D itch scale (see section\xa03.10).The committee concluded that these uncertainties would have to be reflected in the maximum ICER it would be willing to accept, which would need to be well below £30,000 per QALY gained.\n\n## The committee's preferred cost-effectiveness estimate\n\nThe committee recalled its preference to use transition probabilities directly from the trial, and that the EAG's base case more closely matched its preferred assumptions. The committee noted that when taking into account the confidential discount for difelikefalin, the EAG's base-case ICER was £22,000 per QALY gained for difelikefalin compared with established standard care. The committee was satisfied that the most likely cost-effectiveness estimates were within what NICE considers an acceptable use of NHS resources.\n\n# Other factors\n\n## Uncaptured benefits\n\nOne clinical expert pointed out that in clinical practice, difelikefalin would be administered at the same time as having dialysis. The committee recognised this would reduce the treatment burden for people with CKD‑aP. It noted that this benefit had not been captured in the cost‑effectiveness analysis.\n\n## Equality issues\n\nThe company submission noted several groups of people who are at greater risk of developing CKD‑aP and having symptoms for longer while on dialysis. These include:\n\npeople with lower socioeconomic status, who are more likely to develop CKD, whose condition is more likely to progress towards kidney failure, and who die earlier because of CKD\n\npeople from Black, Asian and other minority ethnic family backgrounds, whose condition is more likely to progress to kidney failure faster, and who are less likely to receive a transplant\n\nwomen, who are more likely to be diagnosed with CKD, but less likely to start dialysis\n\nolder people with CKD, who are less likely to have a kidney transplant than younger people. The company noted that difelikefalin is restricted for in-centre haemodialysis use, which may be considered a barrier for people who find in-centre haemodialysis less accessible. The committee recalled the treatment burden of having CKD‑aP (see section\xa03.1). It considered that 1 advantage of difelikefalin might be to lessen that burden and therefore help reduce health inequalities. The committee further concluded that a recommendation for difelikefalin would be unlikely to result in any direct or indirect discrimination.\n\nNICE's advice about conditions with a high degree of severity did not apply.\n\n## Innovation\n\nThe committee considered if difelikefalin was an innovative treatment for CKD‑aP. It recalled that the reduced treatment burden had not been captured in the modelling, and that it would take this into account in its decision making.\n\n# Conclusion\n\n## Recommendation\n\nThe committee noted its preference for the EAG's base-case results, the uncaptured benefits, and the need for uncertainty to be taken into account in its decision. The committee concluded that difelikefalin would be a cost‑effective use of NHS resources. So, it recommended difelikefalin, within its marketing authorisation, for treating moderate to severe pruritus in adults with CKD having in-centre haemodialysis."}	https://www.nice.org.uk/guidance/ta890	Evidence-based recommendations on difelikefalin (Kapruvia) for pruritus in adults with chronic kidney disease having haemodialysis.
0150f4971d6cd1325cdecdb7991b799e4aef53f5	nice	Acne vulgaris: management	Acne vulgaris: management This guideline covers management of acne vulgaris in primary and specialist care. It includes advice on topical and oral treatments (including antibiotics and retinoids), treatment using physical modalities, and the impact of acne vulgaris on mental health and wellbeing. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Throughout this guideline, 'acne' in recommendations refers to 'acne vulgaris' unless otherwise stated. # Information and support for people with acne vulgaris Give people with acne clear information tailored to their needs and concerns. Topics to cover include: the possible reasons for their acne treatment options, including over the counter treatments if appropriate the benefits and drawbacks associated with treatments the potential impact of acne the importance of adhering to treatment (see also the section on providing information in the NICE guideline on medicines adherence) relapses during or after treatment, including: when and how to obtain further advice treatment options should a relapse occur.See also the NICE guideline on patient experience in adult NHS services (particularly recommendations 1.5.11 to 1.5.19) for advice on how to tailor information and communication based on the person's needs. Include parents and carers in discussions if the person with acne would like them to be involved, or when support is needed (for example, for a person with cognitive impairment). For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on information and support for people with acne vulgaris . Full details of the evidence and the committee's discussion are in evidence review A: information and support. Loading. Please wait. # Skin care advice Advise people with acne to use a non-alkaline (skin pH neutral or slightly acidic) synthetic detergent (syndet) cleansing product twice daily on acne-prone skin. Advise people with acne who use skin care products (for example, moisturisers) and sunscreens to avoid oil-based and comedogenic preparations. Advise people with acne who use make-up to avoid oil-based and comedogenic products, and to remove make-up at the end of the day. Advise people that persistent picking or scratching of acne lesions can increase the risk of scarring. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on skin care advice . Full details of the evidence and the committee's discussion are in evidence review B: skin care advice for people with acne vulgaris and evidence review L: risk factors for scarring due to acne vulgaris. Loading. Please wait. # Diet Advise people that there is not enough evidence to support specific diets for treating acne.For general advice about a balanced diet and how it could contribute to wellbeing see Public Health England's Eatwell Guide. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on diet . Full details of the evidence and the committee's discussion are in evidence review C: dietary interventions for the treatment of acne vulgaris. Loading. Please wait. # Referral to specialist care Urgently refer people with acne fulminans on the same day to the on-call hospital dermatology team, to be assessed within 24 hours. Refer people to a consultant dermatologist-led team if any of the following apply: there is diagnostic uncertainty about their acne they have acne conglobata they have nodulo-cystic acne. Consider referring people to a consultant dermatologist-led team if they have: mild to moderate acne that has not responded to 2 completed courses of treatment (see table 1) moderate to severe acne which has not responded to previous treatment that contains an oral antibiotic (see table 1) acne with scarring acne with persistent pigmentary changes. Consider referring people to a consultant dermatologist-led team if their acne of any severity, or acne-related scarring, is causing or contributing to persistent psychological distress or a mental health disorder. Consider referral to mental health services if a person with acne experiences significant psychological distress or a mental health disorder, including those with a current or past history of: suicidal ideation or self-harm a severe depressive or anxiety disorder body dysmorphic disorder.When considering referral, take into account the person's potential treatment options (for example, oral isotretinoin). Also see the NICE guidelines on depression in children and young people for advice on recognition, depression in adults for advice on recognition and assessment, and self-harm for advice on self-harm. Consider condition-specific management or referral to a specialist (for example a reproductive endocrinologist), if a medical disorder or medication (including self-administered anabolic steroids) is likely to be contributing to a person's acne. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral to specialist care . Full details of the evidence and the committee's discussion are in evidence review D: referral to specialist care. Loading. Please wait. # Managing acne vulgaris The recommendations in this section cover mild to moderate and moderate to severe acne. ## First-line treatment options Offer people with acne a 12-week course of 1 of the following first-line treatment options, taking account of the severity of their acne and the person's preferences, and after a discussion of the advantages and disadvantages of each option (see table 1): a fixed combination of topical adapalene with topical benzoyl peroxide for any acne severity a fixed combination of topical tretinoin with topical clindamycin for any acne severity a fixed combination of topical benzoyl peroxide with topical clindamycin for mild to moderate acne a fixed combination of topical adapalene with topical benzoyl peroxide, together with either oral lymecycline or oral doxycycline for moderate to severe acne topical azelaic acid with either oral lymecycline or oral doxycycline for moderate to severe acne. Acne severity Treatment Advantages Disadvantages Any severity Fixed combination of topical adapalene with topical benzoyl peroxide, applied once daily in the evening Topical Does not contain antibiotics Not for use during pregnancy Use with caution during breastfeeding (see recommendation 1.5.8) Can cause skin irritation (see recommendation 1.5.7), photosensitivity, and bleaching of hair and fabrics Any severity Fixed combination of topical tretinoin with topical clindamycin, applied once daily in the evening Topical Not for use during pregnancy or breastfeeding (see recommendation 1.5.8) Can cause skin irritation (see recommendation 1.5.7), and photosensitivity Mild to moderate Fixed combination of topical benzoyl peroxide with topical clindamycin, applied once daily in the evening Topical Can be used with caution during pregnancy and breastfeeding. Can cause skin irritation (see recommendation 1.5.7), photosensitivity, and bleaching of hair and fabrics Moderate to severe Fixed combination of topical adapalene with topical benzoyl peroxide, applied once daily in the evening, plus either oral lymecycline or oral doxycycline taken once daily Oral component may be effective in treating affected areas that are difficult to reach with topical treatment (such as the back) Treatment with adequate courses of standard therapy with systemic antibiotics and topical therapy is a Medicines and Healthcare products Regulatory Agency (MHRA) requirement for subsequent oral isotretinoin, which is only recommended for severe acne (see recommendation 1.5.10 and the MHRA guidance on important risks and precautions for isotretinoin) Not for use in pregnancy, during breastfeeding (see recommendation 1.5.8), or under the age of 12 Topical adapalene and topical benzoyl peroxide can cause skin irritation (see recommendation 1.5.7), photosensitivity, and bleaching of hair and fabrics Oral antibiotics may cause systemic side effects and antimicrobial resistance Oral tetracyclines can cause photosensitivity Moderate to severe Topical azelaic acid applied twice daily, plus either oral lymecycline or oral doxycycline taken once daily Oral component may be effective in treating affected areas that are difficult to reach with topical treatment (such as the back) Treatment with adequate courses of standard therapy with systemic antibiotics and topical therapy is an MHRA requirement for subsequent oral isotretinoin, which is only recommended for severe acne (see recommendation 1.5.10 and the MHRA guidance on important risks and precautions for isotretinoin) Not for use in pregnancy, during breastfeeding (see recommendation 1.5.8), or under the age of 12 Oral antibiotics may cause systemic side effects and resistance Oral tetracyclines can cause photosensitivity Consider topical benzoyl peroxide monotherapy as an alternative treatment to the options in table 1, if: these treatments are contraindicated, or the person wishes to avoid using a topical retinoid, or an antibiotic (topical or oral). For people with moderate to severe acne who cannot tolerate or have contraindications to oral lymecycline or oral doxycycline, consider replacing these medicines in the combination treatments in table 1 with trimethoprim or with an oral macrolide (for example, erythromycin). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on first-line treatment options . Full details of the evidence and the committee's discussion are in: evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses evidence review E2: management options for mild to moderate acne – pairwise comparisons evidence review F2: management options for moderate to severe acne – pairwise comparisons. Loading. Please wait. ## Factors to take into account during consultations Take into account that acne of any severity can cause psychological distress and mental health disorders. Discuss the importance of completing the course of treatment, because positive effects can take 6 to 8 weeks to become noticeable (see also the section on supporting adherence in the NICE guideline on medicines adherence). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on factors to take into account during consultations . Full details of the committee's discussion are in: evidence review D: referral to specialist care evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses. Loading. Please wait. ## Factors to take into account when choosing a treatment option Take into account that the risk of scarring increases with the severity and duration of acne. To reduce the risk of skin irritation associated with topical treatments, such as benzoyl peroxide or retinoids, start with alternate-day or short-contact application (for example washing off after an hour). If tolerated, progress to using a standard application. When discussing treatment choices with a person with childbearing potential, cover: that topical retinoids and oral tetracyclines are contraindicated during pregnancy and when planning a pregnancy and that they will need to use effective contraception, or choose an alternative treatment to these options. If a person receiving treatment for acne wishes to use hormonal contraception, consider using the combined oral contraceptive pill in preference to the progestogen-only pill (if oral isotretinoin treatment is likely to be used, also see recommendations 1.5.19 and 1.5.20). If clinical judgement indicates a person may need treatment with oral isotretinoin for their acne in future: be aware that oral isotretinoin should not be used unless adequate courses of standard therapy with systemic antibiotics and topical therapy have been tried, in line with the Medicines and Healthcare products Regulatory Agency (MHRA) guidance on important risks and precautions for isotretinoin and take this into account when choosing any initial treatment option. Do not use the following to treat acne: monotherapy with a topical antibiotic monotherapy with an oral antibiotic a combination of a topical antibiotic and an oral antibiotic. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on factors to take into account when choosing a treatment option . Full details of the evidence and the committee's discussion are in: evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses evidence review E2: management options for mild to moderate acne – pairwise comparisons evidence review F2: management options for moderate to severe acne – pairwise comparisons evidence review L: risk factors for scarring due to acne vulgaris. Loading. Please wait. ## Factors to take into account at review Review first-line treatment at 12 weeks and: assess whether the person's acne has improved, and whether they have any side effects in people whose treatment includes an oral antibiotic, if their acne has completely cleared consider stopping the antibiotic but continuing the topical treatment in people whose treatment includes an oral antibiotic, if their acne has improved but not completely cleared, consider continuing the oral antibiotic, alongside the topical treatment, for up to 12 more weeks. Only continue a treatment option that includes an antibiotic (topical or oral) for more than 6 months in exceptional circumstances. Review at 3‑monthly intervals, and stop the antibiotic as soon as possible. Be aware that the use of antibiotic treatments is associated with a risk of antimicrobial resistance (see the NICE guideline on antimicrobial stewardship). If a person's acne has cleared, consider maintenance options (also see the section on maintenance). If acne fails to respond adequately to a 12‑week course of a first-line treatment option and at review the severity is: mild to moderate: offer another option from the table of treatment choices (see table 1) moderate to severe, and the treatment did not include an oral antibiotic: offer another option which includes an oral antibiotic from the table of treatment choices (see table 1) moderate to severe, and the treatment included an oral antibiotic: consider referral to a consultant dermatologist-led team. If mild to moderate acne fails to respond adequately to 2 different 12‑week courses of treatment options, consider referral to a consultant dermatologist-led team. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on factors to take into account at review . Full details of the evidence and the committee's discussion are in: evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses evidence review E2: management options for mild to moderate acne – pairwise comparisons evidence review F2: management options for moderate to severe acne – pairwise comparisons evidence review H: management options for refractory acne. Loading. Please wait. ## Oral isotretinoin treatment Consider oral isotretinoin for people older than 12 years who have a severe form of acne that is resistant to adequate courses of standard therapy with systemic antibiotics and topical therapy (table 1). For example: nodulo-cystic acne acne conglobata acne fulminans acne at risk of permanent scarring. If a person with acne is likely to benefit from oral isotretinoin treatment: Follow the MHRA guidance on important risks and precautions for isotretinoin. This includes: prescribing only by a consultant dermatologist-led team assessing and monitoring mental health assessing and monitoring sexual function. Fully inform the person (and their family and carers as appropriate) about the potential risks of isotretinoin treatment as well as the expected benefits before referral to the consultant-dermatologist-led team, and again before prescribing isotretinoin if that is the chosen treatment. When considering oral isotretinoin for acne take into account the person's psychological wellbeing (see recommendation 1.4.5), and refer them to mental health services before starting treatment if appropriate. If a person for whom oral isotretinoin treatment is being considered has the potential to become pregnant: explain that isotretinoin can cause serious harm to a developing baby if taken during pregnancy and inform them that they will need to follow the MHRA pregnancy prevention programme. Prescribe oral isotretinoin for acne treatment (see recommendation 1.5.18) at a standard daily dose of 0.5 to 1 mg/kg. Consider a reduced daily dose of isotretinoin (less than 0.5 mg/kg) for people at increased risk of, or experiencing, adverse effects. When giving isotretinoin as a course of treatment for acne: continue until a total cumulative dose of 120 to 150 mg/kg is reached, but if there has been an adequate response and no new acne lesions for 4 to 8 weeks, consider discontinuing treatment sooner. If a person is taking oral isotretinoin for acne: review their psychological wellbeing during treatment, and monitor them regularly for symptoms or signs of developing or worsening mental health problems or sexual dysfunction tell them to seek medical advice if they feel their mental health or sexual function is affected or is worsening, and to stop their treatment and seek urgent medical advice if these problems are severe. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on oral isotretinoin treatment . Full details of the evidence and the committee's discussion are in evidence review F1: management options for moderate to severe acne – network meta-analyses and evidence review F2: management options for moderate to severe acne – pairwise comparisons. Loading. Please wait. ## Use of oral corticosteroids in addition to oral isotretinoin If an acne flare (acute significant worsening of acne) occurs after starting oral isotretinoin, consider adding a course of oral prednisolone. When a person with acne fulminans is started on oral isotretinoin, consider adding a course of oral prednisolone to prevent an acne flare. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on use of oral corticosteroids in addition to oral isotretinoin . Full details of the evidence and the committee's discussion are in evidence review J: addition of oral corticosteroids to oral isotretinoin for the treatment of severe inflammatory acne vulgaris. Loading. Please wait. ## Physical treatments Consider photodynamic therapy for people aged 18 and over with moderate to severe acne if other treatments are ineffective, not tolerated or contraindicated. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on physical treatments . Full details of the evidence and the committee's discussion are in evidence review F1: management options for moderate to severe acne – network meta-analyses and evidence review F2: management options for moderate to severe acne – pairwise comparisons. Loading. Please wait. ## Use of intralesional corticosteroids Consider treating severe inflammatory cysts with intralesional injection of triamcinolone acetonide (0.1 ml of triamcinolone acetonide per cm of cyst diameter, at 0.6 mg/ml diluted in 0.9% sodium chloride). This should be done by a member of a consultant dermatologist-led team.In June 2021 this was an off-label use for triamcinolone acetonide. See NICE's information on prescribing medicines for more information. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on use of intralesional corticosteroids . Full details of the evidence and the committee's discussion are in evidence review K: intralesional corticosteroids for the treatment of individual acne vulgaris lesions. Loading. Please wait. ## Treatment options for people with polycystic ovary syndrome For people with polycystic ovary syndrome and acne: treat their acne using a first-line treatment option (see recommendation 1.5.1 and table 1) if the chosen first-line treatment is not effective, consider adding ethinylestradiol with cyproterone acetate (co-cyprindiol) or an alternative combined oral contraceptive pill to their treatment for those using co-cyprindiol, review at 6 months and discuss continuation or alternative treatment options. Consider referring people with acne and polycystic ovary syndrome with additional features of hyperandrogenism to an appropriate specialist (for example, a reproductive endocrinologist). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment options for people with polycystic ovary syndrome . Full details of the evidence and the committee's discussion are in evidence review G: management options for people with acne vulgaris and polycystic ovary syndrome. Loading. Please wait. # Relapse If acne responds adequately to a course of an appropriate first-line treatment (see recommendation 1.5.3 and table 1) but then relapses, consider either: another 12‑week course of the same treatment, or an alternative 12‑week treatment (see table 1). If acne relapses after an adequate response to oral isotretinoin and is currently mild to moderate, offer an appropriate treatment option (see table 1). If acne relapses after an adequate response to oral isotretinoin and is currently moderate to severe, offer either: a 12-week course of an appropriate treatment option (see table 1), or re-referral, if the person is no longer under the care of the consultant dermatologist-led team. If acne relapses after a second course of oral isotretinoin and is currently moderate to severe, further care should be decided by the consultant dermatologist-led team. If the person is no longer under the care of the consultant dermatologist-led team, offer re-referral. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on relapse . Full details of the evidence and the committee's discussion are in evidence review H: management options for refractory acne. Loading. Please wait. # Maintenance Encourage continued appropriate skin care (see recommendations 1.2.1 to 1.2.4). Explain to the person with acne that, after completion of treatment, maintenance treatment is not always necessary. Consider maintenance treatment in people with a history of frequent relapse after treatment. Consider a fixed combination of topical adapalene and topical benzoyl peroxide as maintenance treatment for acne. If this is not tolerated, or if 1 component of the combination is contraindicated, consider topical monotherapy with adapalene, azelaic acid, or benzoyl peroxide (see also recommendation 1.5.7 on starting topical treatment). Review maintenance treatments for acne after 12 weeks to decide if they should continue. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on maintenance . Full details of the evidence and the committee's discussion are in evidence review I: maintenance treatment for acne vulgaris. Loading. Please wait. # Management of acne-related scarring If a person has acne-related scarring, discuss their concerns and provide information in a way that suits their needs. Topics to cover include: possible reasons for their scars treatment of ongoing acne to help prevent further scarring (see recommendations 1.5.1 to 1.5.3 and recommendation 1.5.18) possible treatment options for acne-related scarring the way their acne scars may change over time psychological distress. If a person's acne-related scarring is severe and persists a year after their acne has cleared: refer the person to a consultant dermatologist-led team with expertise in scarring management in a consultant dermatologist-led team setting, consider CO2 laser treatment (alone or after a session of punch elevation) or glycolic acid peel. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing acne-related scarring . Full details of the evidence and the committee's discussion are in evidence review M: management of acne vulgaris-associated scarring. Loading. Please wait. # Terms used in this guideline ## Acne conglobata A severe form of nodulo-cystic acne with interconnecting sinuses and abscesses. ## Acne fulminans A very serious form of acne conglobata associated with systemic symptoms. ## Comedogenic An ingredient that is likely to block skin pores. ## Consultant dermatologist-led team This team may include associate specialists and healthcare professionals accredited for extended roles for dermatology under consultant supervision. ## Fixed combination of topical adapalene with topical benzoyl peroxide Formulation with either of these 2 concentrations: % adapalene with 2.5% benzoyl peroxide % adapalene with 2.5% benzoyl peroxide. ## Fixed combination of topical benzoyl peroxide with topical clindamycin Formulation with either of these 2 concentrations: % benzoyl peroxide with 1% clindamycin % benzoyl peroxide with 1% clindamycin. ## Fixed combination of topical tretinoin with topical clindamycin Formulation with: % tretinoin with 1% clindamycin. ## Mild to moderate acne Acne severity varies along a continuum. For mild to moderate acne, this includes people who have 1 or more of: any number of non-inflammatory lesions (comedones) up to 34 inflammatory lesions (with or without non-inflammatory lesions) up to 2 nodules. ## Moderate to severe acne Acne severity varies along a continuum. For moderate to severe acne this includes people who have either or both of: -r more inflammatory lesions (with or without non-inflammatory lesions) -r more nodules. ## Oral lymecycline or oral doxycycline Formulation of either: mg lymecycline daily mg doxycycline daily. ## Synthetic detergent (syndet) A synthetic detergent (syndet) is a blend of synthetic surfactants and is formulated to have neutral to slightly acidic pH similar to the skin. It is widely available in both solid and liquid forms as a skin cleansing product. ## Topical adapalene Formulation with: % adapalene. ## Topical azelaic acid Formulation with either of these 2 concentrations: % azelaic acid % azelaic acid. ## Topical benzoyl peroxide Formulation with: % benzoyl peroxide.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Oral isotretinoin treatment What is the efficacy of reduced dose oral isotretinoin in the management of acne vulgaris? For a short explanation of why the committee made the recommendation for research, see the rationale section on oral isotretinoin treatment . Full details of the evidence and the committee's discussion are in evidence review F1: management options for moderate to severe acne – network meta-analyses. Loading. Please wait. ## Treatment options for people with polycystic ovary syndrome What is the most effective first-line treatment option for any severity of acne vulgaris for people with polycystic ovary syndrome? For a short explanation of why the committee made the recommendation for research, see the rationale section on treatment options for people with polycystic ovary syndrome . Full details of the evidence and the committee's discussion are in evidence review G: management options for people with acne vulgaris and polycystic ovary syndrome. Loading. Please wait. ## Diet What is the effect of dietary interventions or dietary changes on acne? For a short explanation of why the committee made the recommendation for research, see the rationale section on diet . Full details of the evidence and the committee's discussion are in evidence review C: dietary interventions for the treatment of acne vulgaris. Loading. Please wait. ## Skin care advice What skin care advice is appropriate for people with acne? For a short explanation of why the committee made the recommendation for research, see the rationale section on skin care advice . Full details of the evidence and the committee's discussion are in evidence review L: risk factors for scarring due to acne vulgaris. Loading. Please wait. ## Physical treatments for acne vulgaris and acne vulgaris-related scarring What is the effectiveness of physical treatments (such as light devices) in the treatment of acne vulgaris or persistent acne vulgaris-related scarring? For a short explanation of why the committee made the recommendation for research, see the rationale section on physical treatments . Full details of the evidence and the committee's discussion are in evidence review F1: management options for moderate to severe acne – network meta-analyses and evidence review M: management of acne vulgaris-associated scarring. Loading. Please wait. # Other recommendations for research ## Acne-related scarring What are the risk factors for acne vulgaris-related scarring? For a short explanation of why the committee made the recommendation for research, see the rationale section on managing acne-related scarring . Full details of the evidence and the committee's discussion are in evidence review L: risk factors for scarring due to acne vulgaris. Loading. Please wait. ## Physical treatments for acne vulgaris and acne vulgaris-related scarring What is the effectiveness of chemical peels for the treatment of acne vulgaris or persistent acne vulgaris-related scarring? For a short explanation of why the committee made the recommendation for research, see the rationale section on physical treatments . Full details of the evidence and the committee's discussion are in: evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses evidence review M: management of acne-vulgaris-associated scarring. Loading. Please wait. ## Hormonal and hormone-modifying treatment option What is the effectiveness of hormone-modifying agents in the treatment of acne vulgaris? For a short explanation of why the committee made the recommendation for research, see the rationale section on first-line treatment options . Full details of the evidence and the committee's discussion are in evidence review E1: management of mild to moderate acne – network meta-analyses and evidence review F1: management of moderate to severe acne – network meta-analyses. Loading. Please wait. ## Information and support What information and support is valued by people with acne vulgaris? For a short explanation of why the committee made the recommendation for research, see the rationale section on information and support for people with acne vulgaris . Full details of the evidence and the committee's discussion are in evidence review A: information and support. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion. # Information and support for people with acne vulgaris Recommendations 1.1.1 and 1.1.2 ## Why the committee made the recommendation No evidence was found on what information and support is valued by people with acne vulgaris, and their parents or carers. Therefore, the committee made recommendations based on their knowledge and experience. The committee listed some topics that they thought most people with acne vulgaris would find useful in relation to the condition and their care. Among these topics, the committee noted that there were some drawbacks of treatments and that it is important to encourage people to adhere to treatment, because improvement may not be seen immediately. The committee acknowledged that general information about adherence is covered in the NICE guideline on medicines adherence to which they cross-referred. The committee were aware that general principles about tailoring information to people's needs and circumstance are set out in the NICE guideline on patient experience in adult NHS services and agreed that this would also be relevant to young people, the age group that acne is most common in. Based on their experience, the committee agreed that some people may need support from parents or carers during treatment discussions, but noted that outside of these situations parents and carers should only be involved if the person requests it. Because of the lack of evidence the committee made a recommendation for research on what information people with acne vulgaris would value, and what impact this would have on their satisfaction with services and shared decision making. ## How the recommendations might affect practice The recommendation aims to standardise what information is provided, and how it is given. No impact on resources is expected. Full details of the evidence and the committee's discussion are in evidence review A: information and support. Return to recommendations # Skin care advice Recommendations 1.2.1 to 1.2.4 ## Why the committee made the recommendations Overall, the evidence on skin care products was very limited, but what evidence was available suggested that syndet skin cleansing products used twice daily reduce inflammatory and non-inflammatory acne vulgaris lesion counts. Compared to traditional soap bars, non-alkaline (skin pH neutral or slightly acidic) syndet products are less irritant and do not form a residue layer, so they rinse off easily. Syndet cleansing products have a relatively high free fatty acid content which helps to maintain skin hydration. Although the research was carried out using a syndet bar, many syndets are now available in different formulations such as liquid or foam. The committee agreed that different formulations are probably similarly effective, so it would be reasonable to try the cheapest syndet cleansing product in the first instance. Because of the limited evidence they recommended this as general skin care advice rather than as a treatment. Although there was some limited evidence on the use of acidic skin cleansers and benzoyl peroxide-based face washes, the committee agreed that this was not sufficient to make a recommendation. No relevant evidence was identified on the use of other skin care products, such as oil-free and non-comedogenic products or make-up. Based on the committee's knowledge, oil-based and comedogenic products can make acne vulgaris worse because acne is typified by excessively oily skin and the blocking of skin pores. The committee noted that make-up should be removed at the end of the day, but because of the lack of evidence they decided they could not be prescriptive about the products that should be used for make-up removal. The committee discussed how people often pick or scratch their acne lesions. In the committee's experience this can lead to scarring, so they recommended that people are advised to avoid these behaviours. Given that the evidence on risk factors for scarring was limited the committee decided that further information was needed, and made a research recommendation on the risk factors for acne vulgaris-related scarring. Clinicians are frequently asked for skin care advice and it is therefore an important topic for people with acne. Because of the limited evidence the committee decided to prioritise a recommendation for research on what skin care advice is appropriate for people with acne. ## How the recommendations might affect practice The committee noted that there is currently variation in the type of advice that is provided to people with acne and therefore recommendations are aimed at standardising practice. Full details of the evidence and the committee's discussion are in evidence review B: skin care advice for people with acne vulgaris and evidence review L: risk factors for scarring due to acne vulgaris. Return to recommendations # Diet Recommendation 1.3.1 ## Why the committee made the recommendation The committee reviewed the evidence from limited randomised controlled trials that examined the effectiveness of a low-glycaemic load diet in people with acne vulgaris. Although there was some evidence that a low-glycaemic load diet may improve acne vulgaris, the committee discussed the evidence of weight loss and also noted the effort needed to work out glycaemic load. Loss of weight and attention to the details of food raised concerns about eating disorders, especially as most people with acne vulgaris are young and the onset of eating disorders is most common in adolescence. Because of this, the committee decided that they did not want to recommend a specific diet as a potential treatment option, as the limited evidence of benefit did not outweigh the risk. However, the committee thought that it is generally useful to promote a healthy balanced diet so they added a recommendation linking to Public Health England's advice about this topic. Given the limited evidence the committee decided that further research is needed in this area and made a recommendation for research on the effect of dietary interventions or dietary changes on acne to encourage this. ## How the recommendation might affect practice The recommendation will not have a substantial impact on current practice. Full details of the evidence and the committee's discussion are in evidence review C: dietary interventions for the treatment of acne vulgaris. Return to recommendation # Referral to specialist care Recommendations 1.4.1 to 1.4.6 ## Why the committee made the recommendations No evidence was identified comparing different criteria of referral to specialist care. The committee therefore made recommendations based on their expertise and experience. When discussing referral related to scarring the committee also considered evidence related to risk factors for scarring. The committee discussed what would constitute 'specialist care' and who the referral would be made to. They agreed that, in line with current advice (see the Medicines and Healthcare products Regulatory Agency safety advice on isotretinoin for severe acne: uses and effects), people who may go on to have treatment with isotretinoin should be referred to a consultant dermatologist-led team to ensure the person's safety and wellbeing. The committee decided that people with acne fulminans have to be urgently referred in order to be assessed within 24 hours because this condition could make people seriously unwell, potentially needing them to be admitted to hospital. The committee agreed that referral should take place when the diagnosis is unclear, for example when the lesion is potentially caused by another condition, or when people have severe forms of acne. Such referrals should be made so that progression of acne symptoms (such as pigmentary changes or scarring) or other issues (such as mental health) can be addressed as soon as possible, and outcomes improved. Because of the psychological impact that acne or acne-related scarring can have, the committee recommended that people who are persistently psychologically distressed by this could be referred. As levels of psychological distress can be interpreted in many different ways, and what may or may not count as persistent can also vary, the committee recommended that this should be judged on a case-by-case basis. The committee discussed the importance of the identification of risk factors for scarring so that these can be addressed to prevent this. They therefore made a recommendation for research on the risk factors for acne vulgaris-related scarring. The committee recognised that acne vulgaris can have a psychological and social impact on people, potentially causing anxiety or depression. It can also exacerbate pre-existing mental health conditions. They discussed that it is important to refer people to mental health services if there are serious mental health concerns to ensure people's safety. In line with the MHRA advice related to mental health adverse events related to oral isotretinoin use, the committee highlighted that awareness of possible mental health disorders or psychological distress, resulting in a need for referral to mental health services, is particularly important when considering this treatment. The committee agreed that it was important to raise awareness that people with an underlying condition should have their acne treated, but in addition the healthcare professional should provide condition-specific management if possible, or referral should be considered if the healthcare professional does not have expertise in management of the specific condition. ## How the recommendations might affect practice The recommendations aim to reduce the variability in referral for people with acne to specialist care. Having standard criteria would also encourage more timely referrals. Timely referrals will improve outcomes and reduce the potential risk of scarring through appropriate implementation of treatment or management strategies for people with acne. There may be increased resources needed for urgent referral; however the population with acne fulminans is very small and therefore the resource impact is unlikely to be substantial. Full details of the evidence and the committee's discussion are in evidence review D: referral to specialist care. Return to recommendations # First-line treatment options Recommendations 1.5.1 to 1.5.3 ## Why the committee made the recommendations Based on the evidence, the committee concluded that there were a number of pharmacological treatment options that were clinically and cost effective. For each of the 2 examined levels of acne severity (mild to moderate acne and moderate to severe acne), the identified evidence showed that a range of treatments had similar clinical and cost effectiveness. The committee recommended 5 treatments (2 treatment options for both levels of severity, 1 option specifically for mild to moderate acne and 2 options specifically for moderate to severe acne, all according to relevant evidence), with the advantages and disadvantages of each given in a table to help shared decision making. The committee decided that all of these options would be given as a 12‑week course, as this was consistent with current practice and also the most common course length in the evidence. The committee noted that the evidence showed that combinations of topical treatments that included benzoyl peroxide, clindamycin and/or a retinoid (adapalene) were overall more effective than any of these interventions used as topical monotherapies, and this was the case for any severity of acne. The committee agreed that this was consistent with their clinical experience. The evidence also showed that a combination of 3 topical agents was less or similarly effective compared with a combination of any 2 agents, so triple therapy was not recommended. Topical treatments in combination with an oral tetracycline (either lymecycline or doxycycline) were recommended for moderate to severe acne, as the evidence indicated that oral tetracycline combined with a fixed combination of topical benzoyl peroxide and topical retinoid, and oral tetracycline with topical azelaic acid, were among the most clinically and cost-effective pharmacological options. The committee chose to recommend the option of azelaic acid combined with oral tetracycline because, despite its more limited evidence base, it was shown to be clinically and cost effective. It was therefore considered to be a good alternative for people who have irritation to topical retinoids, since all other options for moderate to severe acne contain a topical retinoid. The committee recommended either lymecycline or doxycycline because both are usually taken only once a day, which may improve adherence to the oral antibiotic treatment component compared to tetracycline and oxytetracycline which are taken twice a day. Lymecycline or doxycycline have a lower risk of side effects than minocycline (which may, for example, be associated with lupus erythematosus, hepatitis and pigmentation), and are preferred to oxytetracycline because they can be taken with food. Of the 5 options, 4 contain either a topical retinoid or oral tetracycline (lymecycline or doxycycline), so they should not be used during pregnancy. There was evidence that monotherapy with benzoyl peroxide was clinically and cost effective at any level of severity, albeit less so than the other 5 treatments recommended, and so this was recommended as an alternative for people when topical retinoids or oral tetracyclines are contraindicated (for example, for use during pregnancy). For people who have contraindications or who do not wish to use the treatment options in table 1 or topical benzoyl peroxide, other treatments may be suitable based on individual circumstances and clinical expertise. The committee also noted that some people with moderate to severe acne cannot tolerate, or have contraindications to, oral tetracyclines. These people would be at risk of complications if only topical treatment is used, so based on experience and expertise the committee recommended some alternatives that can be used. The committee noted that the evidence for some treatment options such as physical treatments, chemical peels and hormone-modifying treatments was limited, and therefore they made a research recommendation on the effectiveness of physical treatments (such as light devices) and on the effectiveness of chemical peels for the treatment of acne vulgaris or persistent acne vulgaris-related scarring ## How the recommendations might affect practice While the recommendations largely reflect current practice, the committee felt that treatment options including the advantages and disadvantages should be discussed with the person, which may mean additional resource use (for example, if longer or more consultations are needed). This will, however, likely lead to later benefits and reductions in resource use from better understanding and compliance with medication. The committee recognised that some currently available treatment options are not in the recommended list. The evidence related to this, and a detailed discussion of why some specific treatment options were not recommended, can be found in: evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses evidence review E2: management options for mild to moderate acne – pairwise comparisons evidence review F2: management options for moderate to severe acne – pairwise comparisons. Return to recommendations # Factors to take into account during consultations Recommendations 1.5.4 and 1.5.5 ## Why the committee made the recommendations Based on experience and expertise the committee discussed that there were some general points that should be taken into account and discussed at consultation. The committee recognised that acne vulgaris can be the cause of psychological distress and agreed that this can be the case even if acne is mild. They decided to make a recommendation to raise the awareness of this so that the impact of acne on the person's psychological health will be taken into account during consultations. The committee also agreed that it is important to encourage adherence and therefore discuss the need for continued treatment with the person, because usually the positive effects of treatments only become visible after 6 to 8 weeks. ## How the recommendations might affect practice Even though the recommendations are consistent with current practice, they emphasise psychological aspects and adhering to treatment regimens because both of these are important factors in the management of acne. Full details of the committee's discussion are in: evidence review D: referral to specialist care evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses. Return to recommendations # Factors to take into account when choosing a treatment option Recommendations 1.5.6 to 1.5.11 ## Why the committee made the recommendations Based on their experience and expertise, as well as some evidence, the committee agreed that some factors related to treatments should be highlighted. The committee looked at evidence related to risk of scarring, which suggests that the severity and duration of acne may be risk factors for scarring. The committee noted that there is substantial uncertainty, as the studies did not control for the influence of other factors. However, they agreed that the risk factors were consistent with their knowledge and experience, so recommended that healthcare practitioners be made aware so that they can take this into account during discussions with the person. The evidence indicated that topical agents such as benzoyl peroxide and retinoids often cause skin irritation. Therefore, based on this and clinical experience, the committee recommended an initial alternate-day or short-contact application to help reduce skin irritation, and in doing so encourage adherence to treatment. Since some of the options include a topical retinoid or oral tetracyclines, the committee highlighted that these are contraindicated during pregnancy and when planning a pregnancy. Therefore use of effective contraception should be discussed with people with the potential to become pregnant. Even though evidence for the combined oral contraceptive pill did not show clear effectiveness, based on consensus and clinical experience the committee decided that women who need hormonal contraceptives could be given the combined oral contraceptive pill in addition to a first-line treatment option. This would be preferable to the progestogen-only pill, which, based on the expertise and experience of the committee, is known to potentially cause acne. The committee also recognised that making recommendations about contraceptive methods is outside the scope of this guideline, and that the most reliable contraceptive is the one which the person would prefer to use after shared decision making looking at all options. They therefore only recommended this for people who had already chosen hormonal contraception. Due to specific considerations related to contraception when taking oral isotretinoin treatment, the committee added a cross reference to the relevant recommendation in the oral isotretinoin section. The committee discussed that in clinical practice it may be anticipated that oral isotretinoin treatment will be needed in future, for example based on severity. A healthcare professional may then want to choose a first-line option with an oral antibiotic, as this is a prerequisite for oral isotretinoin treatment and may also successfully treat the acne. The evidence showed lower clinical and cost effectiveness of oral antibiotics when used as monotherapy compared with the recommended treatment options in moderate to severe acne, and no clinical effectiveness in mild to moderate acne, and because of this as well as antibiotic stewardship the committee decided not to recommend oral antibiotics as monotherapy. They also agreed that combined topical antibiotics and oral antibiotics should not be used. There was no evidence on this, but based on experience and expertise the committee noted that such combinations are not used in current practice and agreed that without evidence this should not be introduced as an option. ## How the recommendations might affect practice The advice related to antibiotics may lead to a significant change in clinical practice: currently, topical and oral antibiotics can be prescribed as long-term treatments for acne either as monotherapy or in combination with each other. The recommendation not to offer either of these forms of treatment should lead to lower antibiotic prescribing for acne, and reduce the risk of antimicrobial resistance. Full details of the evidence and the committee's discussion are in: evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses evidence review E2: management options for mild to moderate acne – pairwise comparisons evidence review F2: management options for moderate to severe acne – pairwise comparisons evidence review L: risk factors for scarring due to acne vulgaris. Return to recommendations # Factors to take into account at review Recommendations 1.5.12 to 1.5.17 ## Why the committee made the recommendations No evidence was identified for how long a treatment should be used. The committee agreed, based on their clinical experience, that first-line treatment should be continued for 12 weeks to determine if it is effective and to allow it to have the optimum effect, and then reviewed. The committee noted that an adequate response to treatment would be jointly determined by the healthcare professional and the person. The committee supported review at 12 weeks because their experience indicated people often stay on an ineffective treatment for too long, and having a review would prevent this. The committee also agreed that to help prevent the development of antimicrobial resistance, treatment with an oral antibiotic (as part of combined oral antibiotic and topical treatment) could be stopped at 12 weeks, while continuing with the topical treatment, if the person's acne is completely clear. If not completely cleared the antibiotic can be continued for up to a further 12 weeks (alongside the topical treatment). There was a lack of evidence on the comparative effectiveness of antibiotic use according to different length of treatment times. Therefore, the committee used their knowledge and experience to recommend that treatments including topical or oral antibiotics should only last longer than 6 months in exceptional circumstances, with review at 3‑monthly intervals: the aim being to discontinue the antibiotic as soon as possible. The committee agreed that providing examples of exceptional circumstances would be of limited use, as these are rare and complex cases that should be assessed on an individual basis. The committee acknowledged that factors to take into account at review would also include discussions related to potential maintenance treatments. This would be relevant if acne has cleared, and so a cross referral was added to the maintenance section for further guidance on this. The committee noted that 6 months of antibiotic treatment is longer than the 12‑week course of antibiotic treatments that are currently commonly used. However, they decided that if the treatment is found to improve the acne at the 12‑week review it would be useful to continue. They also noted that recommendation 1.5.11 against antibiotic monotherapy and against combined topical antibiotic with an oral antibiotic treatment would lead to substantially lower prescribing of antibiotic treatments for acne vulgaris overall. The committee also took into account the principles of antimicrobial guidance and policy, as outlined in the NICE guideline on antimicrobial stewardship, as well as the World Health Organization Global action plan on antimicrobial resistance. All of these antibiotic treatments increase the risk of antimicrobial resistance, and the committee noted that healthcare professionals should be aware of the principles of antimicrobial stewardship when considering treatments for acne. No evidence was identified for the best further treatment option when there has been no or only a partial response at review. The committee therefore agreed that inadequate response to treatment should be dealt with in a stepwise approach, taking into account the number of treatment courses and severity of acne after the first treatment. If mild to moderate acne fails to respond to a 12‑week course of a topical first-line treatment, the committee decided that another option should be offered. For unresponsive moderate to severe acne, further treatment depends on whether or not the first choice was an option that contained an oral antibiotic. If it did not then this should be considered next, but if the option included an oral antibiotic then referral to a consultant dermatologist-led team can be considered. The committee discussed that in these cases a timely referral could prevent scarring. When mild to moderate acne vulgaris fails to respond to a second 12‑week course of treatment, the committee agreed that the person should be referred to a consultant dermatologist-led team rather than continuing courses of treatment in primary care. ## How the recommendations might affect practice The recommendation of 12‑week review and a maximum 6‑month duration of antibiotic treatment for most people will lead to standardisation of practice, reducing repeated long-term antibiotic prescription and the risk of antimicrobial resistance. This in turn may result in positive associated cost savings and improved clinical outcomes. With regard to further treatment when there was no or only partial improvement, the committee noted that these recommendations are consistent with other parts of the guideline and therefore will help standardise practice. Full details of the evidence and the committee's discussion are in: evidence review E1: management options for mild to moderate acne – network meta-analyses evidence review F1: management options for moderate to severe acne – network meta-analyses evidence review E2: management options for mild to moderate acne – pairwise comparisons evidence review F2: management options for moderate to severe acne – pairwise comparisons evidence review H: management options for refractory acne. Return to recommendations # Oral isotretinoin treatment Recommendations 1.5.18 to 1.5.26 ## Why the committee made the recommendations The committee noted that the evidence on this topic was uncertain because of the small number of participants, and agreed that results should be interpreted with some caution. The evidence indicated that oral isotretinoin was an effective and cost-effective treatment for moderate to severe acne. However, taking into account the MHRA safety advice on isotretinoin for severe acne: uses and effects, and specifically the possibility of psychiatric side effects, the committee recommended oral isotretinoin only in situations when they agreed the benefits outweighed the risks. The committee noted the need to follow MHRA guidance before oral isotretinoin is started, and to ensure that those who are taking it are advised about the important safety issues associated with this medicine, and are monitored as needed. They also emphasised that when starting oral isotretinoin, people of childbearing potential have to use contraception and need to follow the recommended MHRA pregnancy prevention programme. The committee noted from the evidence that results were almost exclusively derived from trials testing oral isotretinoin in dosages of at least 0.5 mg/kg/day, and that total cumulative doses of at least 120 mg/kg in a single course were more effective compared with total cumulative doses lower than 120 mg/kg in a single course. After reviewing the evidence, and based on their clinical experience, the committee decided to recommend a standard daily dose of 0.5 to 1 mg/kg. Based on expertise and clinical experience, the committee agreed that people who have an intolerance or are at risk of significant adverse effects may need a reduced daily dose of oral isotretinoin. The committee discussed that the risk of adverse events is multifactorial, and so assessment of risk would be dependent on the person's circumstances and could not be quantified as part of the recommendation. The evidence suggested that a cumulative dose of 120 to 150 mg/kg is effective, but it was known from the committee's experience that sometimes an adequate response with skin clearance can occur before this has been reached. They decided after balancing the potential adverse events and effectiveness, that for some people (based on clinical judgement), treatment can be complete before a total cumulative dose of 120 to 150 mg/kg is reached if there is sustained clear skin for 4 to 8 weeks. When people take oral isotretinoin the committee emphasised, because of MHRA safety concerns, that their psychological wellbeing has to be reviewed and monitored, and that people need to know that it is important to seek help if they need it. The committee noted that the evidence for lower dose oral isotretinoin was scarce, and therefore prioritised this for a research recommendation on the efficacy of reduced dose oral isotretinoin in the management of acne vulgaris. May 2023: the recommendations on oral isotretinoin have been amended in line with new MHRA guidance. ## How the recommendations might affect practice The recommendations reinforce current practice and MHRA guidance. There may be additional resource use, for example, referral to mental health services or if longer or more consultations are needed. This will likely to lead to later benefits and cost savings, with reduction in potential adverse outcomes and shorter overall duration of treatment. Full details of the evidence and the committee's discussion are in evidence review F1: management options for moderate to severe acne – network meta-analyses and evidence review F2: management options for moderate to severe acne – pairwise comparisons. Return to recommendations # Use of oral corticosteroids in addition to oral isotretinoin Recommendations 1.5.27 and 1.5.28 ## Why the committee made the recommendations No evidence was found on this topic, so the committee made recommendations based on their clinical knowledge and experience. The committee noted that oral corticosteroid can be used to treat acne flare occurring after the start of treatment with oral isotretinoin, and that this would apply to anyone on oral isotretinoin and not just people with acne fulminans. The committee also agreed that it is known that oral isotretinoin may cause acne flare, so it is accepted practice to also give oral corticosteroids to people with acne fulminans who are starting oral isotretinoin to prevent an acne flare from occurring. ## How the recommendations might affect practice The recommendation aims to standardise the use of oral corticosteroids in addition to oral isotretinoin when treating acne fulminans. This reflects current clinical practice and is not likely to have resource implications. Full details of the evidence and the committee's discussion are in evidence review J: addition of oral corticosteroids to oral isotretinoin for the treatment of severe inflammatory acne vulgaris. Return to recommendations # Physical treatments Recommendation 1.5.29 ## Why the committee made the recommendation Based on modest evidence that photodynamic therapy is moderately clinically and cost effective in the treatment of moderate to severe acne vulgaris compared with other treatments, the committee decided that it could be recommended as an alternative for treating this severity of acne when other treatments are ineffective, not tolerated or contraindicated. The evidence for physical treatments for mild to moderate acne was very limited. Therefore, the committee noted that the use of photodynamic therapy would depend upon the consultant dermatologist's clinical expertise and judgement on a case-by-case basis. Because of the limited evidence, the committee decided to prioritise a research recommendation on the effectiveness of physical treatments (such as light devices) in the treatment of acne vulgaris or persistent acne vulgaris-related scarring. ## How the recommendation might affect practice Physical treatments for the management of acne are not part of current practice in the NHS. Therefore, the recommendation is expected to result in a change in current practice and to have some impact on resources and training. The impact is not expected to be substantial, as many hospitals across the country already have photodynamic therapy facilities and the proportion of people with acne fulfilling the criteria is not expected to be high. Full details of the evidence and the committee's discussion are in: evidence review F1: management options for moderate to severe acne – network meta-analyses evidence review F2: management options for moderate to severe acne – pairwise comparisons evidence review M: management of acne-vulgaris-associated scarring. Return to recommendation # Use of intralesional corticosteroids Recommendation 1.5.30 ## Why the committee made the recommendation Severe inflammatory acne vulgaris cysts can be painful and unsightly, so even though the evidence was limited the committee agreed it was important to make a recommendation on this based on their knowledge and experience together with the available evidence. From the limited evidence there were sufficiently positive results to recommend the use of intralesional triamcinolone acetonide, which agreed with the committee's experience. The committee chose to recommend a concentration of 0.6 mg/ml as this is in line with the effective concentrations used in the available evidence. The committee also discussed that there are some possible side effects of triamcinolone acetonide injections, for example hypopigmentation (especially in people with darker skin). Because of this, the committee recommended a lower dose than is used for other inflammatory conditions, noting that the recommended dose is small and is less likely to cause side effects. The committee also agreed that, usually, inflammatory acne cysts respond well to low concentrations of triamcinolone acetonide, so the higher doses often used for other treatments are not needed. ## How the recommendation might affect practice At present there is variation in the use of intralesional corticosteroids for people with inflammatory cysts, in terms of indication, time point and dosage. The recommendation aims to standardise practice and is likely to have a low impact on resources as intralesional corticosteroids are readily available and the procedure can be done during the clinic consultation. Full details of the evidence and the committee's discussion are in evidence review K: intralesional corticosteroids for the treatment of individual acne vulgaris lesions. Return to recommendation # Treatment options for people with polycystic ovary syndrome Recommendations 1.5.31 and 1.5.32 ## Why the committee made the recommendations There was insufficient evidence to identify the most effective treatment for acne vulgaris in people with polycystic ovary syndrome, so the committee agreed that the usual first-line treatment options are appropriate in the first instance. This enables treatment for acne in people with polycystic ovary syndrome to be started without delay. If the first-line treatment options do not work, adding a hormonal treatment could be effective because of hyperandrogenism in people with polycystic ovary syndrome. The committee agreed that either the combined oral contraceptive pill (which is an established and widely available hormonal treatment for the symptoms of polycystic ovary syndrome) or ethinylestradiol with cyproterone acetate (co-cyprindiol) could be used, as they have different mechanisms of action from one another. The committee agreed that a 6‑month review for co-cyprindiol should take place to discuss the benefits and risks of continuing the treatment or the use of an alternative option. The committee also agreed that the standard first-line treatment options as well as the combined contraceptive pill or co-cyprindiol could be delivered in primary care, but some people with acne vulgaris and polycystic ovary syndrome who have additional features of hyperandrogenism would need more specialist treatment and may benefit from referral to a specialist, such as a reproductive endocrinologist. Because of the insufficient evidence for this review the committee prioritised a research recommendation on the most effective first-line treatment option for any severity of acne vulgaris for people with polycystic ovary syndrome. ## How the recommendations might affect practice The committee considered that the recommendations largely reflect current practice, although there may be an increase in the use of first-line treatment options instead of hormonal treatments as initial care for acne in people with polycystic ovary syndrome which could be cost saving. Full details of the evidence and the committee's discussion are in evidence review G: management options for people with acne vulgaris and polycystic ovary syndrome. Return to recommendations # Relapse Recommendations 1.6.1 to 1.6.4 ## Why the committee made the recommendations No evidence was identified, so the recommendations were based on the committee's experience and expertise. The committee agreed that relapse after treatment should be dealt with in a stepwise approach, taking into account the number of treatment courses and severity of acne at the time of relapse. For people with acne that relapses after adequate response to first-line treatment, the committee agreed either the same treatment should be tried again if it was well tolerated and the person was happy with the outcome, or a different option could be tried if preferred. In a situation when acne has adequately responded to oral isotretinoin but has relapsed to mild to moderate severity, the committee recommended offering a new 12‑week course of one of the first-line treatments for mild to moderate severity. This would most likely achieve adequate results while avoiding the side effects of oral antibiotics or another course of oral isotretinoin. In a situation when acne has adequately responded to oral isotretinoin but has relapsed to moderate to severe severity, the committee agreed to recommend 2 options: either a new 12‑week course of one of the first-line treatment options, as this may adequately treat the relapse, or re-referral to a consultant dermatologist-led team for alternative treatment options (which may include a further course of isotretinoin). The committee agreed that people whose acne vulgaris has relapsed after treatment with 2 separate courses of oral isotretinoin, and who currently have moderate to severe acne, should be offered a re-referral if they are no longer under the care of a consultant dermatologist-led team. They discussed that these people may need a tailored approach to their acne treatment, including a change in dose or duration of oral isotretinoin or other alternative treatment options. ## How the recommendations might affect practice The committee noted that these recommendations are consistent with other parts of the guideline and therefore will help standardise practice. They acknowledged that referral of a person to a consultant dermatologist-led team after acne vulgaris relapsed twice with 2 separate courses of oral isotretinoin, may lead to a change in current clinical practice. However, they agreed that this approach will lead to better outcomes because it is using a specialist tailored approach to treatment. Full details of the evidence and the committee's discussion are in evidence review H: management options for refractory acne. Return to recommendations # Maintenance Recommendations 1.7.1 to 1.7.5 ## Why the committee made the recommendations There was some evidence on this topic, and the committee used this together with their experience and expertise to make recommendations. The committee noted that appropriate skin care, as described in section 1.2, should be encouraged to maintain the skin improvements achieved by acne treatment. The committee discussed that people whose acne has cleared are often concerned that not having further treatment will mean their acne will relapse, which is often not the case. The committee therefore recommended that healthcare professionals should explain that maintenance treatment is not always needed. Based on clinical experience, the group that the committee thought may benefit from maintenance treatment were those whose acne had previously returned after treatment. There was some evidence of limited quality suggesting that topical retinoids such as adapalene and tretinoin, topical benzoyl peroxide or topical azelaic acid, could reduce lesion count with few adverse effects for maintenance treatment. The committee agreed that the combination treatment of adapalene and benzoyl peroxide demonstrated the best clinical effect, but discussed that other options should be available for those who have contraindications or who are unable to tolerate the treatment. They agreed that topical adapalene, topical azelaic acid or topical benzoyl peroxide could be used. Based on experience, the committee agreed that a 12‑week review was suitable to decide whether or not continued maintenance treatment is necessary because by 12 weeks any effects of the maintenance treatments should have become apparent. ## How the recommendations might affect practice Although the recommendations do not largely deviate from current practice, there is currently variation on what types of maintenance treatments are given. The recommendations would therefore standardise practice. Full details of the evidence and the committee's discussion are in evidence review I: maintenance treatment for acne vulgaris. Return to recommendations # Managing acne-related scarring Recommendations 1.8.1 and 1.8.2 ## Why the committee made the recommendations A considerable amount of evidence was identified on this topic. However, the types of comparisons made interpretation of the effectiveness of treatments difficult. The committee acknowledged that any treatment should be preceded by a discussion of treatment options (for ongoing acne as well as acne-associated scarring) and other issues relevant to the person, to help with shared decision making. The committee noted that referral to a consultant dermatologist-led team with expertise in the management of scarring is important to prevent potential skin damage caused by treatment. They were aware that the evidence was not strong enough to recommend referral for everyone with acne scarring, which would also lead to a significant impact on resources. The committee therefore specified, based on the available evidence and clinical expertise, that those with persistent severe scarring are likely to have the greatest benefit. The committee discussed that in their experience, the tissue remodelling and healing process occurs for up to about a year after the acne has cleared and management of acne scarring should be considered after this timeframe. There was evidence that 3 types of treatment showed some efficacy in improving the appearance of scars. These were glycolic acid peels, or CO2 laser treatment either alone or after a session of punch elevation. The choice of option would depend on the type of scarring, but the committee chose to allow for clinical judgement as people may present with a number of different types of scars. Additionally, the committee agreed that the uncertainties in the evidence needed further research to clarify. The committee therefore prioritised recommendations for research on the effectiveness of physical treatments (such as light devices) and on the effectiveness of chemical peels for the treatment of acne vulgaris or persistent acne vulgaris-related scarring. ## How the recommendations might affect practice The availability of treatments for acne scarring in NHS centres varies across the country. The recommendations are expected to result in a change in current practice, with referral to a consultant dermatologist-led team and standardised options of glycolic acid peel or CO2 laser treatment with punch elevation where needed. The impact is not expected to be substantive, as only a small number of people will fulfil the criteria. Additional resources and training may be needed in centres offering these treatment options. Full details of the evidence and the committee's discussion are in evidence review L: risk factors for scarring due to acne vulgaris. Return to recommendations# Context Acne vulgaris is a common condition that can affect the face, chest and back. It is most prevalent among young people and younger adults, affecting approximately 80% of people at some time between 11 and 30 years. When treating acne vulgaris its severity, distribution, and the views of the affected person need to be taken into account. The aim of treatment is to reduce the severity of skin lesions and to prevent recurrence and scarring. There is variation in how acne vulgaris is treated in clinical practice, and there is therefore a need to standardise treatment. There is also a need when prescribing antibiotic therapy for acne vulgaris to take into account the principles of antimicrobial guidance and policy, as outlined in the NICE guideline on antimicrobial stewardship, as well as the World Health Organization Global action plan on antimicrobial resistance.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThroughout this guideline, 'acne' in recommendations refers to 'acne vulgaris' unless otherwise stated.\n\n# Information and support for people with acne vulgaris\n\nGive people with acne clear information tailored to their needs and concerns. Topics to cover include:\n\nthe possible reasons for their acne\n\ntreatment options, including over the counter treatments if appropriate\n\nthe benefits and drawbacks associated with treatments\n\nthe potential impact of acne\n\nthe importance of adhering to treatment (see also the section on providing information in the NICE guideline on medicines adherence)\n\nrelapses during or after treatment, including:\n\n\n\nwhen and how to obtain further advice\n\ntreatment options should a relapse occur.See also the NICE guideline on patient experience in adult NHS services (particularly recommendations 1.5.11 to 1.5.19) for advice on how to tailor information and communication based on the person's needs.\n\n\n\nInclude parents and carers in discussions if the person with acne would like them to be involved, or when support is needed (for example, for a person with cognitive impairment).\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on information and support for people with acne vulgaris\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information and support.\n\nLoading. Please wait.\n\n# Skin care advice\n\nAdvise people with acne to use a non-alkaline (skin pH neutral or slightly acidic) synthetic detergent (syndet) cleansing product twice daily on acne-prone skin.\n\nAdvise people with acne who use skin care products (for example, moisturisers) and sunscreens to avoid oil-based and comedogenic preparations.\n\nAdvise people with acne who use make-up to avoid oil-based and comedogenic products, and to remove make-up at the end of the day.\n\nAdvise people that persistent picking or scratching of acne lesions can increase the risk of scarring.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on skin care advice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: skin care advice for people with acne vulgaris and evidence review\xa0L: risk factors for scarring due to acne vulgaris.\n\nLoading. Please wait.\n\n# Diet\n\nAdvise people that there is not enough evidence to support specific diets for treating acne.For general advice about a balanced diet and how it could contribute to wellbeing see Public Health England's Eatwell Guide.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on diet\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: dietary interventions for the treatment of acne vulgaris.\n\nLoading. Please wait.\n\n# Referral to specialist care\n\nUrgently refer people with acne fulminans on the same day to the on-call hospital dermatology team, to be assessed within 24\xa0hours.\n\nRefer people to a consultant dermatologist-led team if any of the following apply:\n\nthere is diagnostic uncertainty about their acne\n\nthey have acne conglobata\n\nthey have nodulo-cystic acne.\n\nConsider referring people to a consultant dermatologist-led team if they have:\n\nmild to moderate acne that has not responded to 2 completed courses of treatment (see table\xa01)\n\nmoderate to severe acne which has not responded to previous treatment that contains an oral antibiotic (see table\xa01)\n\nacne with scarring\n\nacne with persistent pigmentary changes.\n\nConsider referring people to a consultant dermatologist-led team if their acne of any severity, or acne-related scarring, is causing or contributing to persistent psychological distress or a mental health disorder.\n\nConsider referral to mental health services if a person with acne experiences significant psychological distress or a mental health disorder, including those with a current or past history of:\n\nsuicidal ideation or self-harm\n\na severe depressive or anxiety disorder\n\nbody dysmorphic disorder.When considering referral, take into account the person's potential treatment options (for example, oral isotretinoin). Also see the NICE guidelines on depression in children and young people for advice on recognition, depression in adults for advice on recognition and assessment, and self-harm for advice on self-harm.\n\nConsider condition-specific management or referral to a specialist (for example a reproductive endocrinologist), if a medical disorder or medication (including self-administered anabolic steroids) is likely to be contributing to a person's acne.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral to specialist care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: referral to specialist care.\n\nLoading. Please wait.\n\n# Managing acne vulgaris\n\nThe recommendations in this section cover mild to moderate and moderate to severe acne.\n\n## First-line treatment options\n\nOffer people with acne a 12-week course of 1 of the following first-line treatment options, taking account of the severity of their acne and the person's preferences, and after a discussion of the advantages and disadvantages of each option (see table\xa01):\n\na fixed combination of topical adapalene with topical benzoyl peroxide for any acne severity\n\na fixed combination of topical tretinoin with topical clindamycin for any acne severity\n\na fixed combination of topical benzoyl peroxide with topical clindamycin for mild to moderate acne\n\na fixed combination of topical adapalene with topical benzoyl peroxide, together with either oral lymecycline or oral doxycycline for moderate to severe acne\n\ntopical azelaic acid with either oral lymecycline or oral doxycycline for moderate to severe acne.\n\nAcne severity\n\nTreatment\n\nAdvantages\n\nDisadvantages\n\nAny severity\n\nFixed combination of topical adapalene with topical benzoyl peroxide, applied once daily in the evening\n\nTopical\n\nDoes not contain antibiotics\n\nNot for use during pregnancy\n\nUse with caution during breastfeeding (see recommendation\xa01.5.8)\n\nCan cause skin irritation (see recommendation 1.5.7), photosensitivity, and bleaching of hair and fabrics\n\nAny severity\n\nFixed combination of topical tretinoin with topical clindamycin, applied once daily in the evening\n\nTopical\n\nNot for use during pregnancy or breastfeeding (see recommendation 1.5.8)\n\nCan cause skin irritation (see recommendation\xa01.5.7), and photosensitivity\n\nMild to moderate\n\nFixed combination of topical benzoyl peroxide with topical clindamycin, applied once daily in the evening\n\nTopical\n\nCan be used with caution during pregnancy and breastfeeding.\n\nCan cause skin irritation (see recommendation\xa01.5.7), photosensitivity, and bleaching of hair and fabrics\n\nModerate to severe\n\nFixed combination of topical adapalene with topical benzoyl peroxide, applied once daily in the evening, plus either oral lymecycline or oral doxycycline taken once daily\n\nOral component may be effective in treating affected areas that are difficult to reach with topical treatment (such as the back)\n\nTreatment with adequate courses of standard therapy with systemic antibiotics and topical therapy is a Medicines and Healthcare products Regulatory Agency (MHRA) requirement for subsequent oral isotretinoin, which is only recommended for severe acne (see recommendation 1.5.10 and the MHRA guidance on important risks and precautions for isotretinoin)\n\nNot for use in pregnancy, during breastfeeding (see recommendation\xa01.5.8), or under the age of 12\n\nTopical adapalene and topical benzoyl peroxide can cause skin irritation (see recommendation\xa01.5.7), photosensitivity, and bleaching of hair and fabrics\n\nOral antibiotics may cause systemic side effects and antimicrobial resistance\n\nOral tetracyclines can cause photosensitivity\n\nModerate to severe\n\nTopical azelaic acid applied twice daily, plus either oral lymecycline or oral doxycycline taken once daily\n\nOral component may be effective in treating affected areas that are difficult to reach with topical treatment (such as the back)\n\nTreatment with adequate courses of standard therapy with systemic antibiotics and topical therapy is an MHRA requirement for subsequent oral isotretinoin, which is only recommended for severe acne (see recommendation 1.5.10 and the MHRA guidance on important risks and precautions for isotretinoin)\n\nNot for use in pregnancy, during breastfeeding (see recommendation\xa01.5.8), or under the age of 12\n\nOral antibiotics may cause systemic side effects and resistance\n\nOral tetracyclines can cause photosensitivity\n\nConsider topical benzoyl peroxide monotherapy as an alternative treatment to the options in table\xa01, if:\n\nthese treatments are contraindicated, or\n\nthe person wishes to avoid using a topical retinoid, or an antibiotic (topical or oral).\n\nFor people with moderate to severe acne who cannot tolerate or have contraindications to oral lymecycline or oral doxycycline, consider replacing these medicines in the combination treatments in table\xa01 with trimethoprim or with an oral macrolide (for example, erythromycin).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on first-line treatment options\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review F1: management options for moderate to severe acne – network meta-analyses\n\nevidence review E2: management options for mild to moderate acne – pairwise comparisons\n\nevidence review F2: management options for moderate to severe acne – pairwise comparisons.\n\nLoading. Please wait.\n\n## Factors to take into account during consultations\n\nTake into account that acne of any severity can cause psychological distress and mental health disorders.\n\nDiscuss the importance of completing the course of treatment, because positive effects can take 6 to 8\xa0weeks to become noticeable (see also the section on supporting adherence in the NICE guideline on medicines adherence).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on factors to take into account during consultations\xa0.\n\nFull details of the committee's discussion are in:\n\nevidence review\xa0D: referral to specialist care\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review F1: management options for moderate to severe acne – network meta-analyses.\n\nLoading. Please wait.\n\n## Factors to take into account when choosing a treatment option\n\nTake into account that the risk of scarring increases with the severity and duration of acne.\n\nTo reduce the risk of skin irritation associated with topical treatments, such as benzoyl peroxide or retinoids, start with alternate-day or short-contact application (for example washing off after an hour). If tolerated, progress to using a standard application.\n\nWhen discussing treatment choices with a person with childbearing potential, cover:\n\nthat topical retinoids and oral tetracyclines are contraindicated during pregnancy and when planning a pregnancy and\n\nthat they will need to use effective contraception, or choose an alternative treatment to these options.\n\nIf a person receiving treatment for acne wishes to use hormonal contraception, consider using the combined oral contraceptive pill in preference to the progestogen-only pill (if oral isotretinoin treatment is likely to be used, also see recommendations 1.5.19 and 1.5.20).\n\nIf clinical judgement indicates a person may need treatment with oral isotretinoin for their acne in future:\n\nbe aware that oral isotretinoin should not be used unless adequate courses of standard therapy with systemic antibiotics and topical therapy have been tried, in line with the Medicines and Healthcare products Regulatory Agency (MHRA) guidance on important risks and precautions for isotretinoin\xa0and\n\ntake this into account when choosing any initial treatment option.\n\nDo not use the following to treat acne:\n\nmonotherapy with a topical antibiotic\n\nmonotherapy with an oral antibiotic\n\na combination of a topical antibiotic and an oral antibiotic.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on factors to take into account when choosing a treatment option\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review\xa0F1: management options for moderate to severe acne – network meta-analyses\n\nevidence review\xa0E2: management options for mild to moderate acne – pairwise comparisons\n\nevidence review\xa0F2: management options for moderate to severe acne – pairwise comparisons\n\nevidence review\xa0L: risk factors for scarring due to acne vulgaris.\n\nLoading. Please wait.\n\n## Factors to take into account at review\n\nReview first-line treatment at 12\xa0weeks and:\n\nassess whether the person's acne has improved, and whether they have any side effects\n\nin people whose treatment includes an oral antibiotic, if their acne has completely cleared consider stopping the antibiotic but continuing the topical treatment\n\nin people whose treatment includes an oral antibiotic, if their acne has improved but not completely cleared, consider continuing the oral antibiotic, alongside the topical treatment, for up to 12 more weeks.\n\nOnly continue a treatment option that includes an antibiotic (topical or oral) for more than 6\xa0months in exceptional circumstances. Review at 3‑monthly intervals, and stop the antibiotic as soon as possible.\n\nBe aware that the use of antibiotic treatments is associated with a risk of antimicrobial resistance (see the NICE guideline on antimicrobial stewardship).\n\nIf a person's acne has cleared, consider maintenance options (also see the section on maintenance).\n\nIf acne fails to respond adequately to a 12‑week course of a first-line treatment option and at review the severity is:\n\nmild to moderate: offer another option from the table of treatment choices (see table\xa01)\n\nmoderate to severe, and the treatment did not include an oral antibiotic: offer another option which includes an oral antibiotic from the table of treatment choices (see table 1)\n\nmoderate to severe, and the treatment included an oral antibiotic: consider referral to a consultant dermatologist-led team.\n\nIf mild to moderate acne fails to respond adequately to 2 different 12‑week courses of treatment options, consider referral to a consultant dermatologist-led team.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on factors to take into account at review\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review\xa0F1: management options for moderate to severe acne – network meta-analyses\n\nevidence review\xa0E2: management options for mild to moderate acne – pairwise comparisons\n\nevidence review\xa0F2: management options for moderate to severe acne – pairwise comparisons\n\nevidence review\xa0H: management options for refractory acne.\n\nLoading. Please wait.\n\n## Oral isotretinoin treatment\n\nConsider oral isotretinoin for people older than 12\xa0years who have a severe form of acne that is resistant to adequate courses of standard therapy with systemic antibiotics and topical therapy (table\xa01). For example:\n\nnodulo-cystic acne\n\nacne conglobata\n\nacne fulminans\n\nacne at risk of permanent scarring.\n\nIf a person with acne is likely to benefit from oral isotretinoin treatment:\n\nFollow the MHRA guidance on important risks and precautions for isotretinoin. This includes:\n\n\n\nprescribing only by a consultant dermatologist-led team\n\nassessing and monitoring mental health\n\nassessing and monitoring sexual function. \n\n\n\nFully inform the person (and their family and carers as appropriate) about the potential risks of isotretinoin treatment as well as the expected benefits before referral to the consultant-dermatologist-led team, and again before prescribing isotretinoin if that is the chosen treatment. \n\nWhen considering oral isotretinoin for acne take into account the person's psychological wellbeing (see recommendation\xa01.4.5), and refer them to mental health services before starting treatment if appropriate.\n\nIf a person for whom oral isotretinoin treatment is being considered has the potential to become pregnant:\n\nexplain that isotretinoin can cause serious harm to a developing baby if taken during pregnancy and\n\ninform them that they will need to follow the MHRA pregnancy prevention programme.\n\nPrescribe oral isotretinoin for acne treatment (see recommendation\xa01.5.18) at a standard daily dose of 0.5 to 1\xa0mg/kg.\n\nConsider a reduced daily dose of isotretinoin (less than 0.5\xa0mg/kg) for people at increased risk of, or experiencing, adverse effects.\n\nWhen giving isotretinoin as a course of treatment for acne:\n\ncontinue until a total cumulative dose of 120 to 150\xa0mg/kg is reached, but\n\nif there has been an adequate response and no new acne lesions for 4 to 8\xa0weeks, consider discontinuing treatment sooner.\n\nIf a person is taking oral isotretinoin for acne:\n\nreview their psychological wellbeing during treatment, and monitor them regularly for symptoms or signs of developing or worsening mental health problems or sexual dysfunction\n\ntell them to seek medical advice if they feel their mental health or sexual function is affected or is worsening, and to stop their treatment and seek urgent medical advice if these problems are severe. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on oral isotretinoin treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F1: management options for moderate to severe acne – network meta-analyses and evidence review F2: management options for moderate to severe acne – pairwise comparisons.\n\nLoading. Please wait.\n\n## Use of oral corticosteroids in addition to oral isotretinoin\n\nIf an acne flare (acute significant worsening of acne) occurs after starting oral isotretinoin, consider adding a course of oral prednisolone.\n\nWhen a person with acne fulminans is started on oral isotretinoin, consider adding a course of oral prednisolone to prevent an acne flare.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on use of oral corticosteroids in addition to oral isotretinoin\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: addition of oral corticosteroids to oral isotretinoin for the treatment of severe inflammatory acne vulgaris.\n\nLoading. Please wait.\n\n## Physical treatments\n\nConsider photodynamic therapy for people aged 18 and over with moderate to severe acne if other treatments are ineffective, not tolerated or contraindicated.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on physical treatments\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F1: management options for moderate to severe acne – network meta-analyses and evidence review F2: management options for moderate to severe acne – pairwise comparisons.\n\nLoading. Please wait.\n\n## Use of intralesional corticosteroids\n\nConsider treating severe inflammatory cysts with intralesional injection of triamcinolone acetonide (0.1\xa0ml of triamcinolone acetonide per cm of cyst diameter, at 0.6\xa0mg/ml diluted in 0.9% sodium chloride). This should be done by a member of a consultant dermatologist-led team.In June 2021 this was an off-label use for triamcinolone acetonide. See NICE's information on prescribing medicines for more information.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on use of intralesional corticosteroids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: intralesional corticosteroids for the treatment of individual acne vulgaris lesions.\n\nLoading. Please wait.\n\n## Treatment options for people with polycystic ovary syndrome\n\nFor people with polycystic ovary syndrome and acne:\n\ntreat their acne using a first-line treatment option (see recommendation\xa01.5.1 and table\xa01)\n\nif the chosen first-line treatment is not effective, consider adding ethinylestradiol with cyproterone acetate (co-cyprindiol) or an alternative combined oral contraceptive pill to their treatment\n\nfor those using co-cyprindiol, review at 6\xa0months and discuss continuation or alternative treatment options.\n\nConsider referring people with acne and polycystic ovary syndrome with additional features of hyperandrogenism to an appropriate specialist (for example, a reproductive endocrinologist).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment options for people with polycystic ovary syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: management options for people with acne vulgaris and polycystic ovary syndrome.\n\nLoading. Please wait.\n\n# Relapse\n\nIf acne responds adequately to a course of an appropriate first-line treatment (see recommendation\xa01.5.3 and table\xa01) but then relapses, consider either:\n\nanother 12‑week course of the same treatment, or\n\nan alternative 12‑week treatment (see table\xa01).\n\nIf acne relapses after an adequate response to oral isotretinoin and is currently mild to moderate, offer an appropriate treatment option (see table\xa01).\n\nIf acne relapses after an adequate response to oral isotretinoin and is currently moderate to severe, offer either:\n\na 12-week course of an appropriate treatment option (see table\xa01), or\n\nre-referral, if the person is no longer under the care of the consultant dermatologist-led team.\n\nIf acne relapses after a second course of oral isotretinoin and is currently moderate to severe, further care should be decided by the consultant dermatologist-led team. If the person is no longer under the care of the consultant dermatologist-led team, offer re-referral.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on relapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: management options for refractory acne.\n\nLoading. Please wait.\n\n# Maintenance\n\nEncourage continued appropriate skin care (see recommendations\xa01.2.1 to 1.2.4).\n\nExplain to the person with acne that, after completion of treatment, maintenance treatment is not always necessary.\n\nConsider maintenance treatment in people with a history of frequent relapse after treatment.\n\nConsider a fixed combination of topical adapalene and topical benzoyl peroxide as maintenance treatment for acne. If this is not tolerated, or if 1\xa0component of the combination is contraindicated, consider topical monotherapy with adapalene, azelaic acid, or benzoyl peroxide (see also recommendation 1.5.7 on starting topical treatment).\n\nReview maintenance treatments for acne after 12\xa0weeks to decide if they should continue.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on maintenance\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: maintenance treatment for acne vulgaris.\n\nLoading. Please wait.\n\n# Management of acne-related scarring\n\nIf a person has acne-related scarring, discuss their concerns and provide information in a way that suits their needs. Topics to cover include:\n\npossible reasons for their scars\n\ntreatment of ongoing acne to help prevent further scarring (see recommendations 1.5.1 to 1.5.3 and recommendation 1.5.18)\n\npossible treatment options for acne-related scarring\n\nthe way their acne scars may change over time\n\npsychological distress.\n\nIf a person's acne-related scarring is severe and persists a year after their acne has cleared:\n\nrefer the person to a consultant dermatologist-led team with expertise in scarring management\n\nin a consultant dermatologist-led team setting, consider CO2 laser treatment (alone or after a session of punch elevation) or glycolic acid peel.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing acne-related scarring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: management of acne vulgaris-associated scarring.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Acne conglobata\n\nA severe form of nodulo-cystic acne with interconnecting sinuses and abscesses.\n\n## Acne fulminans\n\nA very serious form of acne conglobata associated with systemic symptoms.\n\n## Comedogenic\n\nAn ingredient that is likely to block skin pores.\n\n## Consultant dermatologist-led team\n\nThis team may include associate specialists and healthcare professionals accredited for extended roles for dermatology under consultant supervision.\n\n## Fixed combination of topical adapalene with topical benzoyl peroxide\n\nFormulation with either of these 2 concentrations:\n\n% adapalene with 2.5% benzoyl peroxide\n\n% adapalene with 2.5% benzoyl peroxide.\n\n## Fixed combination of topical benzoyl peroxide with topical clindamycin\n\nFormulation with either of these 2 concentrations:\n\n% benzoyl peroxide with 1% clindamycin\n\n% benzoyl peroxide with 1% clindamycin.\n\n## Fixed combination of topical tretinoin with topical clindamycin\n\nFormulation with:\n\n% tretinoin with 1% clindamycin.\n\n## Mild to moderate acne\n\nAcne severity varies along a continuum. For mild to moderate acne, this includes people who have 1 or more of:\n\nany number of non-inflammatory lesions (comedones)\n\nup to 34 inflammatory lesions (with or without non-inflammatory lesions)\n\nup to 2 nodules.\n\n## Moderate to severe acne\n\nAcne severity varies along a continuum. For moderate to severe acne this includes people who have either or both of:\n\nor more inflammatory lesions (with or without non-inflammatory lesions)\n\nor more nodules.\n\n## Oral lymecycline or oral doxycycline\n\nFormulation of either:\n\nmg lymecycline daily\n\nmg doxycycline daily.\n\n## Synthetic detergent (syndet)\n\nA synthetic detergent (syndet) is a blend of synthetic surfactants and is formulated to have neutral to slightly acidic pH similar to the skin. It is widely available in both solid and liquid forms as a skin cleansing product.\n\n## Topical adapalene\n\nFormulation with:\n\n% adapalene.\n\n## Topical azelaic acid\n\nFormulation with either of these 2 concentrations:\n\n% azelaic acid\n\n% azelaic acid.\n\n## Topical benzoyl peroxide\n\nFormulation with:\n\n% benzoyl peroxide.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Oral isotretinoin treatment\n\nWhat is the efficacy of reduced dose oral isotretinoin in the management of acne vulgaris?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on oral isotretinoin treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F1: management options for moderate to severe acne – network meta-analyses.\n\nLoading. Please wait.\n\n## Treatment options for people with polycystic ovary syndrome\n\nWhat is the most effective first-line treatment option for any severity of acne vulgaris for people with polycystic ovary syndrome?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on treatment options for people with polycystic ovary syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: management options for people with acne vulgaris and polycystic ovary syndrome.\n\nLoading. Please wait.\n\n## Diet\n\nWhat is the effect of dietary interventions or dietary changes on acne?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on diet\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: dietary interventions for the treatment of acne vulgaris.\n\nLoading. Please wait.\n\n## Skin care advice\n\nWhat skin care advice is appropriate for people with acne?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on skin care advice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: risk factors for scarring due to acne vulgaris.\n\nLoading. Please wait.\n\n## Physical treatments for acne vulgaris and acne vulgaris-related scarring\n\nWhat is the effectiveness of physical treatments (such as light devices) in the treatment of acne vulgaris or persistent acne vulgaris-related scarring?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical treatments\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F1: management options for moderate to severe acne – network meta-analyses and evidence review M: management of acne vulgaris-associated scarring.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Acne-related scarring\n\nWhat are the risk factors for acne vulgaris-related scarring?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on managing acne-related scarring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: risk factors for scarring due to acne vulgaris.\n\nLoading. Please wait.\n\n## Physical treatments for acne vulgaris and acne vulgaris-related scarring\n\nWhat is the effectiveness of chemical peels for the treatment of acne vulgaris or persistent acne vulgaris-related scarring?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical treatments\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review F1: management options for moderate to severe acne – network meta-analyses\n\nevidence review M: management of acne-vulgaris-associated scarring.\n\nLoading. Please wait.\n\n## Hormonal and hormone-modifying treatment option\n\nWhat is the effectiveness of hormone-modifying agents in the treatment of acne vulgaris?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on first-line treatment options\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E1: management of mild to moderate acne – network meta-analyses and evidence review F1: management of moderate to severe acne – network meta-analyses.\n\nLoading. Please wait.\n\n## Information and support\n\nWhat information and support is valued by people with acne vulgaris?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on information and support for people with acne vulgaris\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information and support.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Information and support for people with acne vulgaris\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendation\n\nNo evidence was found on what information and support is valued by people with acne vulgaris, and their parents or carers. Therefore, the committee made recommendations based on their knowledge and experience.\n\nThe committee listed some topics that they thought most people with acne vulgaris would find useful in relation to the condition and their care. Among these topics, the committee noted that there were some drawbacks of treatments and that it is important to encourage people to adhere to treatment, because improvement may not be seen immediately. The committee acknowledged that general information about adherence is covered in the NICE guideline on medicines adherence to which they cross-referred.\n\nThe committee were aware that general principles about tailoring information to people's needs and circumstance are set out in the NICE guideline on patient experience in adult NHS services and agreed that this would also be relevant to young people, the age group that acne is most common in.\n\nBased on their experience, the committee agreed that some people may need support from parents or carers during treatment discussions, but noted that outside of these situations parents and carers should only be involved if the person requests it.\n\nBecause of the lack of evidence the committee made a recommendation for research on what information people with acne vulgaris would value, and what impact this would have on their satisfaction with services and shared decision making.\n\n## How the recommendations might affect practice\n\nThe recommendation aims to standardise what information is provided, and how it is given. No impact on resources is expected.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information and support.\n\nReturn to recommendations\n\n# Skin care advice\n\nRecommendations 1.2.1 to 1.2.4\n\n## Why the committee made the recommendations\n\nOverall, the evidence on skin care products was very limited, but what evidence was available suggested that syndet skin cleansing products used twice daily reduce inflammatory and non-inflammatory acne vulgaris lesion counts. Compared to traditional soap bars, non-alkaline (skin pH neutral or slightly acidic) syndet products are less irritant and do not form a residue layer, so they rinse off easily. Syndet cleansing products have a relatively high free fatty acid content which helps to maintain skin hydration. Although the research was carried out using a syndet bar, many syndets are now available in different formulations such as liquid or foam. The committee agreed that different formulations are probably similarly effective, so it would be reasonable to try the cheapest syndet cleansing product in the first instance. Because of the limited evidence they recommended this as general skin care advice rather than as a treatment.\n\nAlthough there was some limited evidence on the use of acidic skin cleansers and benzoyl peroxide-based face washes, the committee agreed that this was not sufficient to make a recommendation.\n\nNo relevant evidence was identified on the use of other skin care products, such as oil-free and non-comedogenic products or make-up. Based on the committee's knowledge, oil-based and comedogenic products can make acne vulgaris worse because acne is typified by excessively oily skin and the blocking of skin pores. The committee noted that make-up should be removed at the end of the day, but because of the lack of evidence they decided they could not be prescriptive about the products that should be used for make-up removal. The committee discussed how people often pick or scratch their acne lesions. In the committee's experience this can lead to scarring, so they recommended that people are advised to avoid these behaviours. Given that the evidence on risk factors for scarring was limited the committee decided that further information was needed, and made a research recommendation on the risk factors for acne vulgaris-related scarring.\n\nClinicians are frequently asked for skin care advice and it is therefore an important topic for people with acne. Because of the limited evidence the committee decided to prioritise a recommendation for research on what skin care advice is appropriate for people with acne.\n\n## How the recommendations might affect practice\n\nThe committee noted that there is currently variation in the type of advice that is provided to people with acne and therefore recommendations are aimed at standardising practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: skin care advice for people with acne vulgaris and evidence review\xa0L: risk factors for scarring due to acne vulgaris.\n\nReturn to recommendations\n\n# Diet\n\nRecommendation 1.3.1\n\n## Why the committee made the recommendation\n\nThe committee reviewed the evidence from limited randomised controlled trials that examined the effectiveness of a low-glycaemic load diet in people with acne vulgaris.\n\nAlthough there was some evidence that a low-glycaemic load diet may improve acne vulgaris, the committee discussed the evidence of weight loss and also noted the effort needed to work out glycaemic load. Loss of weight and attention to the details of food raised concerns about eating disorders, especially as most people with acne vulgaris are young and the onset of eating disorders is most common in adolescence. Because of this, the committee decided that they did not want to recommend a specific diet as a potential treatment option, as the limited evidence of benefit did not outweigh the risk. However, the committee thought that it is generally useful to promote a healthy balanced diet so they added a recommendation linking to Public Health England's advice about this topic.\n\nGiven the limited evidence the committee decided that further research is needed in this area and made a recommendation for research on the effect of dietary interventions or dietary changes on acne to encourage this.\n\n## How the recommendation might affect practice\n\nThe recommendation will not have a substantial impact on current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: dietary interventions for the treatment of acne vulgaris.\n\nReturn to recommendation\n\n# Referral to specialist care\n\nRecommendations 1.4.1 to 1.4.6\n\n## Why the committee made the recommendations\n\nNo evidence was identified comparing different criteria of referral to specialist care. The committee therefore made recommendations based on their expertise and experience. When discussing referral related to scarring the committee also considered evidence related to risk factors for scarring.\n\nThe committee discussed what would constitute 'specialist care' and who the referral would be made to. They agreed that, in line with current advice (see the Medicines and Healthcare products Regulatory Agency [MHRA] safety advice on isotretinoin for severe acne: uses and effects), people who may go on to have treatment with isotretinoin should be referred to a consultant dermatologist-led team to ensure the person's safety and wellbeing.\n\nThe committee decided that people with acne fulminans have to be urgently referred in order to be assessed within 24\xa0hours because this condition could make people seriously unwell, potentially needing them to be admitted to hospital.\n\nThe committee agreed that referral should take place when the diagnosis is unclear, for example when the lesion is potentially caused by another condition, or when people have severe forms of acne. Such referrals should be made so that progression of acne symptoms (such as pigmentary changes or scarring) or other issues (such as mental health) can be addressed as soon as possible, and outcomes improved.\n\nBecause of the psychological impact that acne or acne-related scarring can have, the committee recommended that people who are persistently psychologically distressed by this could be referred. As levels of psychological distress can be interpreted in many different ways, and what may or may not count as persistent can also vary, the committee recommended that this should be judged on a case-by-case basis.\n\nThe committee discussed the importance of the identification of risk factors for scarring so that these can be addressed to prevent this. They therefore made a recommendation for research on the risk factors for acne vulgaris-related scarring.\n\nThe committee recognised that acne vulgaris can have a psychological and social impact on people, potentially causing anxiety or depression. It can also exacerbate pre-existing mental health conditions. They discussed that it is important to refer people to mental health services if there are serious mental health concerns to ensure people's safety. In line with the MHRA advice related to mental health adverse events related to oral isotretinoin use, the committee highlighted that awareness of possible mental health disorders or psychological distress, resulting in a need for referral to mental health services, is particularly important when considering this treatment.\n\nThe committee agreed that it was important to raise awareness that people with an underlying condition should have their acne treated, but in addition the healthcare professional should provide condition-specific management if possible, or referral should be considered if the healthcare professional does not have expertise in management of the specific condition.\n\n## How the recommendations might affect practice\n\nThe recommendations aim to reduce the variability in referral for people with acne to specialist care. Having standard criteria would also encourage more timely referrals. Timely referrals will improve outcomes and reduce the potential risk of scarring through appropriate implementation of treatment or management strategies for people with acne. There may be increased resources needed for urgent referral; however the population with acne fulminans is very small and therefore the resource impact is unlikely to be substantial.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: referral to specialist care.\n\nReturn to recommendations\n\n# First-line treatment options\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nBased on the evidence, the committee concluded that there were a number of pharmacological treatment options that were clinically and cost effective. For each of the 2 examined levels of acne severity (mild to moderate acne and moderate to severe acne), the identified evidence showed that a range of treatments had similar clinical and cost effectiveness. The committee recommended 5\xa0treatments (2\xa0treatment options for both levels of severity, 1 option specifically for mild to moderate acne and 2 options specifically for moderate to severe acne, all according to relevant evidence), with the advantages and disadvantages of each given in a table to help shared decision making. The committee decided that all of these options would be given as a 12‑week course, as this was consistent with current practice and also the most common course length in the evidence.\n\nThe committee noted that the evidence showed that combinations of topical treatments that included benzoyl peroxide, clindamycin and/or a retinoid (adapalene) were overall more effective than any of these interventions used as topical monotherapies, and this was the case for any severity of acne. The committee agreed that this was consistent with their clinical experience. The evidence also showed that a combination of 3 topical agents was less or similarly effective compared with a combination of any 2 agents, so triple therapy was not recommended.\n\nTopical treatments in combination with an oral tetracycline (either lymecycline or doxycycline) were recommended for moderate to severe acne, as the evidence indicated that oral tetracycline combined with a fixed combination of topical benzoyl peroxide and topical retinoid, and oral tetracycline with topical azelaic acid, were among the most clinically and cost-effective pharmacological options. The committee chose to recommend the option of azelaic acid combined with oral tetracycline because, despite its more limited evidence base, it was shown to be clinically and cost effective. It was therefore considered to be a good alternative for people who have irritation to topical retinoids, since all other options for moderate to severe acne contain a topical retinoid.\n\nThe committee recommended either lymecycline or doxycycline because both are usually taken only once a day, which may improve adherence to the oral antibiotic treatment component compared to tetracycline and oxytetracycline which are taken twice a day. Lymecycline or doxycycline have a lower risk of side effects than minocycline (which may, for example, be associated with lupus erythematosus, hepatitis and pigmentation), and are preferred to oxytetracycline because they can be taken with food.\n\nOf the 5 options, 4 contain either a topical retinoid or oral tetracycline (lymecycline or doxycycline), so they should not be used during pregnancy. There was evidence that monotherapy with benzoyl peroxide was clinically and cost effective at any level of severity, albeit less so than the other 5 treatments recommended, and so this was recommended as an alternative for people when topical retinoids or oral tetracyclines are contraindicated (for example, for use during pregnancy). For people who have contraindications or who do not wish to use the treatment options in table\xa01 or topical benzoyl peroxide, other treatments may be suitable based on individual circumstances and clinical expertise.\n\nThe committee also noted that some people with moderate to severe acne cannot tolerate, or have contraindications to, oral tetracyclines. These people would be at risk of complications if only topical treatment is used, so based on experience and expertise the committee recommended some alternatives that can be used.\n\nThe committee noted that the evidence for some treatment options such as physical treatments, chemical peels and hormone-modifying treatments was limited, and therefore they made a research recommendation on the effectiveness of physical treatments (such as light devices) and on the effectiveness of chemical peels for the treatment of acne vulgaris or persistent acne vulgaris-related scarring\n\n## How the recommendations might affect practice\n\nWhile the recommendations largely reflect current practice, the committee felt that treatment options including the advantages and disadvantages should be discussed with the person, which may mean additional resource use (for example, if longer or more consultations are needed). This will, however, likely lead to later benefits and reductions in resource use from better understanding and compliance with medication.\n\nThe committee recognised that some currently available treatment options are not in the recommended list. The evidence related to this, and a detailed discussion of why some specific treatment options were not recommended, can be found in:\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review F1: management options for moderate to severe acne – network meta-analyses\n\nevidence review E2: management options for mild to moderate acne – pairwise comparisons\n\nevidence review F2: management options for moderate to severe acne – pairwise comparisons.\n\nReturn to recommendations\n\n# Factors to take into account during consultations\n\nRecommendations 1.5.4 and 1.5.5\n\n## Why the committee made the recommendations\n\nBased on experience and expertise the committee discussed that there were some general points that should be taken into account and discussed at consultation.\n\nThe committee recognised that acne vulgaris can be the cause of psychological distress and agreed that this can be the case even if acne is mild. They decided to make a recommendation to raise the awareness of this so that the impact of acne on the person's psychological health will be taken into account during consultations.\n\nThe committee also agreed that it is important to encourage adherence and therefore discuss the need for continued treatment with the person, because usually the positive effects of treatments only become visible after 6 to 8\xa0weeks.\n\n## How the recommendations might affect practice\n\nEven though the recommendations are consistent with current practice, they emphasise psychological aspects and adhering to treatment regimens because both of these are important factors in the management of acne.\n\nFull details of the committee's discussion are in:\n\nevidence review\xa0D: referral to specialist care\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review F1: management options for moderate to severe acne – network meta-analyses.\n\nReturn to recommendations\n\n# Factors to take into account when choosing a treatment option\n\nRecommendations 1.5.6 to 1.5.11\n\n## Why the committee made the recommendations\n\nBased on their experience and expertise, as well as some evidence, the committee agreed that some factors related to treatments should be highlighted.\n\nThe committee looked at evidence related to risk of scarring, which suggests that the severity and duration of acne may be risk factors for scarring. The committee noted that there is substantial uncertainty, as the studies did not control for the influence of other factors. However, they agreed that the risk factors were consistent with their knowledge and experience, so recommended that healthcare practitioners be made aware so that they can take this into account during discussions with the person.\n\nThe evidence indicated that topical agents such as benzoyl peroxide and retinoids often cause skin irritation. Therefore, based on this and clinical experience, the committee recommended an initial alternate-day or short-contact application to help reduce skin irritation, and in doing so encourage adherence to treatment.\n\nSince some of the options include a topical retinoid or oral tetracyclines, the committee highlighted that these are contraindicated during pregnancy and when planning a pregnancy. Therefore use of effective contraception should be discussed with people with the potential to become pregnant.\n\nEven though evidence for the combined oral contraceptive pill did not show clear effectiveness, based on consensus and clinical experience the committee decided that women who need hormonal contraceptives could be given the combined oral contraceptive pill in addition to a first-line treatment option. This would be preferable to the progestogen-only pill, which, based on the expertise and experience of the committee, is known to potentially cause acne. The committee also recognised that making recommendations about contraceptive methods is outside the scope of this guideline, and that the most reliable contraceptive is the one which the person would prefer to use after shared decision making looking at all options. They therefore only recommended this for people who had already chosen hormonal contraception. Due to specific considerations related to contraception when taking oral isotretinoin treatment, the committee added a cross reference to the relevant recommendation in the oral isotretinoin section.\n\nThe committee discussed that in clinical practice it may be anticipated that oral isotretinoin treatment will be needed in future, for example based on severity. A healthcare professional may then want to choose a first-line option with an oral antibiotic, as this is a prerequisite for oral isotretinoin treatment and may also successfully treat the acne.\n\nThe evidence showed lower clinical and cost effectiveness of oral antibiotics when used as monotherapy compared with the recommended treatment options in moderate to severe acne, and no clinical effectiveness in mild to moderate acne, and because of this as well as antibiotic stewardship the committee decided not to recommend oral antibiotics as monotherapy. They also agreed that combined topical antibiotics and oral antibiotics should not be used. There was no evidence on this, but based on experience and expertise the committee noted that such combinations are not used in current practice and agreed that without evidence this should not be introduced as an option.\n\n## How the recommendations might affect practice\n\nThe advice related to antibiotics may lead to a significant change in clinical practice: currently, topical and oral antibiotics can be prescribed as long-term treatments for acne either as monotherapy or in combination with each other. The recommendation not to offer either of these forms of treatment should lead to lower antibiotic prescribing for acne, and reduce the risk of antimicrobial resistance.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review F1: management options for moderate to severe acne – network meta-analyses\n\nevidence review E2: management options for mild to moderate acne – pairwise comparisons\n\nevidence review F2: management options for moderate to severe acne – pairwise comparisons\n\nevidence review\xa0L: risk factors for scarring due to acne vulgaris.\n\nReturn to recommendations\n\n# Factors to take into account at review\n\nRecommendations 1.5.12 to 1.5.17\n\n## Why the committee made the recommendations\n\nNo evidence was identified for how long a treatment should be used. The committee agreed, based on their clinical experience, that first-line treatment should be continued for 12\xa0weeks to determine if it is effective and to allow it to have the optimum effect, and then reviewed. The committee noted that an adequate response to treatment would be jointly determined by the healthcare professional and the person.\n\nThe committee supported review at 12\xa0weeks because their experience indicated people often stay on an ineffective treatment for too long, and having a review would prevent this. The committee also agreed that to help prevent the development of antimicrobial resistance, treatment with an oral antibiotic (as part of combined oral antibiotic and topical treatment) could be stopped at 12\xa0weeks, while continuing with the topical treatment, if the person's acne is completely clear. If not completely cleared the antibiotic can be continued for up to a further 12\xa0weeks (alongside the topical treatment).\n\nThere was a lack of evidence on the comparative effectiveness of antibiotic use according to different length of treatment times. Therefore, the committee used their knowledge and experience to recommend that treatments including topical or oral antibiotics should only last longer than 6\xa0months in exceptional circumstances, with review at 3‑monthly intervals: the aim being to discontinue the antibiotic as soon as possible.\n\nThe committee agreed that providing examples of exceptional circumstances would be of limited use, as these are rare and complex cases that should be assessed on an individual basis.\n\nThe committee acknowledged that factors to take into account at review would also include discussions related to potential maintenance treatments. This would be relevant if acne has cleared, and so a cross referral was added to the maintenance section for further guidance on this.\n\nThe committee noted that 6\xa0months of antibiotic treatment is longer than the 12‑week course of antibiotic treatments that are currently commonly used. However, they decided that if the treatment is found to improve the acne at the 12‑week review it would be useful to continue. They also noted that recommendation 1.5.11 against antibiotic monotherapy and against combined topical antibiotic with an oral antibiotic treatment would lead to substantially lower prescribing of antibiotic treatments for acne vulgaris overall.\n\nThe committee also took into account the principles of antimicrobial guidance and policy, as outlined in the NICE guideline on antimicrobial stewardship, as well as the World Health Organization Global action plan on antimicrobial resistance. All of these antibiotic treatments increase the risk of antimicrobial resistance, and the committee noted that healthcare professionals should be aware of the principles of antimicrobial stewardship when considering treatments for acne.\n\nNo evidence was identified for the best further treatment option when there has been no or only a partial response at review.\n\nThe committee therefore agreed that inadequate response to treatment should be dealt with in a stepwise approach, taking into account the number of treatment courses and severity of acne after the first treatment. If mild to moderate acne fails to respond to a 12‑week course of a topical first-line treatment, the committee decided that another option should be offered. For unresponsive moderate to severe acne, further treatment depends on whether or not the first choice was an option that contained an oral antibiotic. If it did not then this should be considered next, but if the option included an oral antibiotic then referral to a consultant dermatologist-led team can be considered. The committee discussed that in these cases a timely referral could prevent scarring.\n\nWhen mild to moderate acne vulgaris fails to respond to a second 12‑week course of treatment, the committee agreed that the person should be referred to a consultant dermatologist-led team rather than continuing courses of treatment in primary care.\n\n## How the recommendations might affect practice\n\nThe recommendation of 12‑week review and a maximum 6‑month duration of antibiotic treatment for most people will lead to standardisation of practice, reducing repeated long-term antibiotic prescription and the risk of antimicrobial resistance. This in turn may result in positive associated cost savings and improved clinical outcomes. With regard to further treatment when there was no or only partial improvement, the committee noted that these recommendations are consistent with other parts of the guideline and therefore will help standardise practice.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0E1: management options for mild to moderate acne – network meta-analyses\n\nevidence review F1: management options for moderate to severe acne – network meta-analyses\n\nevidence review E2: management options for mild to moderate acne – pairwise comparisons\n\nevidence review F2: management options for moderate to severe acne – pairwise comparisons\n\nevidence review\xa0H: management options for refractory acne.\n\nReturn to recommendations\n\n# Oral isotretinoin treatment\n\nRecommendations 1.5.18 to 1.5.26\n\n## Why the committee made the recommendations\n\nThe committee noted that the evidence on this topic was uncertain because of the small number of participants, and agreed that results should be interpreted with some caution. The evidence indicated that oral isotretinoin was an effective and cost-effective treatment for moderate to severe acne. However, taking into account the MHRA safety advice on isotretinoin for severe acne: uses and effects, and specifically the possibility of psychiatric side effects, the committee recommended oral isotretinoin only in situations when they agreed the benefits outweighed the risks.\n\nThe committee noted the need to follow MHRA guidance before oral isotretinoin is started, and to ensure that those who are taking it are advised about the important safety issues associated with this medicine, and are monitored as needed. They also emphasised that when starting oral isotretinoin, people of childbearing potential have to use contraception and need to follow the recommended MHRA pregnancy prevention programme.\n\nThe committee noted from the evidence that results were almost exclusively derived from trials testing oral isotretinoin in dosages of at least 0.5\xa0mg/kg/day, and that total cumulative doses of at least 120\xa0mg/kg in a single course were more effective compared with total cumulative doses lower than 120\xa0mg/kg in a single course. After reviewing the evidence, and based on their clinical experience, the committee decided to recommend a standard daily dose of 0.5 to 1\xa0mg/kg. Based on expertise and clinical experience, the committee agreed that people who have an intolerance or are at risk of significant adverse effects may need a reduced daily dose of oral isotretinoin. The committee discussed that the risk of adverse events is multifactorial, and so assessment of risk would be dependent on the person's circumstances and could not be quantified as part of the recommendation.\n\nThe evidence suggested that a cumulative dose of 120 to 150\xa0mg/kg is effective, but it was known from the committee's experience that sometimes an adequate response with skin clearance can occur before this has been reached. They decided after balancing the potential adverse events and effectiveness, that for some people (based on clinical judgement), treatment can be complete before a total cumulative dose of 120 to 150\xa0mg/kg is reached if there is sustained clear skin for 4 to 8\xa0weeks.\n\nWhen people take oral isotretinoin the committee emphasised, because of MHRA safety concerns, that their psychological wellbeing has to be reviewed and monitored, and that people need to know that it is important to seek help if they need it.\n\nThe committee noted that the evidence for lower dose oral isotretinoin was scarce, and therefore prioritised this for a research recommendation on the efficacy of reduced dose oral isotretinoin in the management of acne vulgaris.\n\nMay 2023: the recommendations on oral isotretinoin have been amended in line with new MHRA guidance.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current practice and MHRA guidance. There may be additional resource use, for example, referral to mental health services or if longer or more consultations are needed. This will likely to lead to later benefits and cost savings, with reduction in potential adverse outcomes and shorter overall duration of treatment.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F1: management options for moderate to severe acne – network meta-analyses and evidence review\xa0F2: management options for moderate to severe acne – pairwise comparisons.\n\nReturn to recommendations\n\n# Use of oral corticosteroids in addition to oral isotretinoin\n\nRecommendations 1.5.27 and 1.5.28\n\n## Why the committee made the recommendations\n\nNo evidence was found on this topic, so the committee made recommendations based on their clinical knowledge and experience.\n\nThe committee noted that oral corticosteroid can be used to treat acne flare occurring after the start of treatment with oral isotretinoin, and that this would apply to anyone on oral isotretinoin and not just people with acne fulminans.\n\nThe committee also agreed that it is known that oral isotretinoin may cause acne flare, so it is accepted practice to also give oral corticosteroids to people with acne fulminans who are starting oral isotretinoin to prevent an acne flare from occurring.\n\n## How the recommendations might affect practice\n\nThe recommendation aims to standardise the use of oral corticosteroids in addition to oral isotretinoin when treating acne fulminans. This reflects current clinical practice and is not likely to have resource implications.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: addition of oral corticosteroids to oral isotretinoin for the treatment of severe inflammatory acne vulgaris.\n\nReturn to recommendations\n\n# Physical treatments\n\nRecommendation 1.5.29\n\n## Why the committee made the recommendation\n\nBased on modest evidence that photodynamic therapy is moderately clinically and cost effective in the treatment of moderate to severe acne vulgaris compared with other treatments, the committee decided that it could be recommended as an alternative for treating this severity of acne when other treatments are ineffective, not tolerated or contraindicated. The evidence for physical treatments for mild to moderate acne was very limited. Therefore, the committee noted that the use of photodynamic therapy would depend upon the consultant dermatologist's clinical expertise and judgement on a case-by-case basis.\n\nBecause of the limited evidence, the committee decided to prioritise a research recommendation on the effectiveness of physical treatments (such as light devices) in the treatment of acne vulgaris or persistent acne vulgaris-related scarring.\n\n## How the recommendation might affect practice\n\nPhysical treatments for the management of acne are not part of current practice in the NHS. Therefore, the recommendation is expected to result in a change in current practice and to have some impact on resources and training. The impact is not expected to be substantial, as many hospitals across the country already have photodynamic therapy facilities and the proportion of people with acne fulfilling the criteria is not expected to be high.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0F1: management options for moderate to severe acne – network meta-analyses\n\nevidence review\xa0F2: management options for moderate to severe acne – pairwise comparisons\n\nevidence review M: management of acne-vulgaris-associated scarring.\n\nReturn to recommendation\n\n# Use of intralesional corticosteroids\n\nRecommendation 1.5.30\n\n## Why the committee made the recommendation\n\nSevere inflammatory acne vulgaris cysts can be painful and unsightly, so even though the evidence was limited the committee agreed it was important to make a recommendation on this based on their knowledge and experience together with the available evidence.\n\nFrom the limited evidence there were sufficiently positive results to recommend the use of intralesional triamcinolone acetonide, which agreed with the committee's experience. The committee chose to recommend a concentration of 0.6\xa0mg/ml as this is in line with the effective concentrations used in the available evidence.\n\nThe committee also discussed that there are some possible side effects of triamcinolone acetonide injections, for example hypopigmentation (especially in people with darker skin). Because of this, the committee recommended a lower dose than is used for other inflammatory conditions, noting that the recommended dose is small and is less likely to cause side effects. The committee also agreed that, usually, inflammatory acne cysts respond well to low concentrations of triamcinolone acetonide, so the higher doses often used for other treatments are not needed.\n\n## How the recommendation might affect practice\n\nAt present there is variation in the use of intralesional corticosteroids for people with inflammatory cysts, in terms of indication, time point and dosage. The recommendation aims to standardise practice and is likely to have a low impact on resources as intralesional corticosteroids are readily available and the procedure can be done during the clinic consultation.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: intralesional corticosteroids for the treatment of individual acne vulgaris lesions.\n\nReturn to recommendation\n\n# Treatment options for people with polycystic ovary syndrome\n\nRecommendations 1.5.31 and 1.5.32\n\n## Why the committee made the recommendations\n\nThere was insufficient evidence to identify the most effective treatment for acne vulgaris in people with polycystic ovary syndrome, so the committee agreed that the usual first-line treatment options are appropriate in the first instance. This enables treatment for acne in people with polycystic ovary syndrome to be started without delay.\n\nIf the first-line treatment options do not work, adding a hormonal treatment could be effective because of hyperandrogenism in people with polycystic ovary syndrome. The committee agreed that either the combined oral contraceptive pill (which is an established and widely available hormonal treatment for the symptoms of polycystic ovary syndrome) or ethinylestradiol with cyproterone acetate (co-cyprindiol) could be used, as they have different mechanisms of action from one another. The committee agreed that a 6‑month review for co-cyprindiol should take place to discuss the benefits and risks of continuing the treatment or the use of an alternative option.\n\nThe committee also agreed that the standard first-line treatment options as well as the combined contraceptive pill or co-cyprindiol could be delivered in primary care, but some people with acne vulgaris and polycystic ovary syndrome who have additional features of hyperandrogenism would need more specialist treatment and may benefit from referral to a specialist, such as a reproductive endocrinologist.\n\nBecause of the insufficient evidence for this review the committee prioritised a research recommendation on the most effective first-line treatment option for any severity of acne vulgaris for people with polycystic ovary syndrome.\n\n## How the recommendations might affect practice\n\nThe committee considered that the recommendations largely reflect current practice, although there may be an increase in the use of first-line treatment options instead of hormonal treatments as initial care for acne in people with polycystic ovary syndrome which could be cost saving.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: management options for people with acne vulgaris and polycystic ovary syndrome.\n\nReturn to recommendations\n\n# Relapse\n\nRecommendations 1.6.1 to 1.6.4\n\n## Why the committee made the recommendations\n\nNo evidence was identified, so the recommendations were based on the committee's experience and expertise. The committee agreed that relapse after treatment should be dealt with in a stepwise approach, taking into account the number of treatment courses and severity of acne at the time of relapse.\n\nFor people with acne that relapses after adequate response to first-line treatment, the committee agreed either the same treatment should be tried again if it was well tolerated and the person was happy with the outcome, or a different option could be tried if preferred.\n\nIn a situation when acne has adequately responded to oral isotretinoin but has relapsed to mild to moderate severity, the committee recommended offering a new 12‑week course of one of the first-line treatments for mild to moderate severity. This would most likely achieve adequate results while avoiding the side effects of oral antibiotics or another course of oral isotretinoin.\n\nIn a situation when acne has adequately responded to oral isotretinoin but has relapsed to moderate to severe severity, the committee agreed to recommend 2\xa0options: either a new 12‑week course of one of the first-line treatment options, as this may adequately treat the relapse, or re-referral to a consultant dermatologist-led team for alternative treatment options (which may include a further course of isotretinoin).\n\nThe committee agreed that people whose acne vulgaris has relapsed after treatment with 2 separate courses of oral isotretinoin, and who currently have moderate to severe acne, should be offered a re-referral if they are no longer under the care of a consultant dermatologist-led team. They discussed that these people may need a tailored approach to their acne treatment, including a change in dose or duration of oral isotretinoin or other alternative treatment options.\n\n## How the recommendations might affect practice\n\nThe committee noted that these recommendations are consistent with other parts of the guideline and therefore will help standardise practice. They acknowledged that referral of a person to a consultant dermatologist-led team after acne vulgaris relapsed twice with 2 separate courses of oral isotretinoin, may lead to a change in current clinical practice. However, they agreed that this approach will lead to better outcomes because it is using a specialist tailored approach to treatment.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: management options for refractory acne.\n\nReturn to recommendations\n\n# Maintenance\n\nRecommendations 1.7.1 to 1.7.5\n\n## Why the committee made the recommendations\n\nThere was some evidence on this topic, and the committee used this together with their experience and expertise to make recommendations.\n\nThe committee noted that appropriate skin care, as described in section 1.2, should be encouraged to maintain the skin improvements achieved by acne treatment.\n\nThe committee discussed that people whose acne has cleared are often concerned that not having further treatment will mean their acne will relapse, which is often not the case. The committee therefore recommended that healthcare professionals should explain that maintenance treatment is not always needed.\n\nBased on clinical experience, the group that the committee thought may benefit from maintenance treatment were those whose acne had previously returned after treatment.\n\nThere was some evidence of limited quality suggesting that topical retinoids such as adapalene and tretinoin, topical benzoyl peroxide or topical azelaic acid, could reduce lesion count with few adverse effects for maintenance treatment. The committee agreed that the combination treatment of adapalene and benzoyl peroxide demonstrated the best clinical effect, but discussed that other options should be available for those who have contraindications or who are unable to tolerate the treatment. They agreed that topical adapalene, topical azelaic acid or topical benzoyl peroxide could be used.\n\nBased on experience, the committee agreed that a 12‑week review was suitable to decide whether or not continued maintenance treatment is necessary because by 12\xa0weeks any effects of the maintenance treatments should have become apparent.\n\n## How the recommendations might affect practice\n\nAlthough the recommendations do not largely deviate from current practice, there is currently variation on what types of maintenance treatments are given. The recommendations would therefore standardise practice.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: maintenance treatment for acne vulgaris.\n\nReturn to recommendations\n\n# Managing acne-related scarring\n\nRecommendations 1.8.1 and 1.8.2\n\n## Why the committee made the recommendations\n\nA considerable amount of evidence was identified on this topic. However, the types of comparisons made interpretation of the effectiveness of treatments difficult. The committee acknowledged that any treatment should be preceded by a discussion of treatment options (for ongoing acne as well as acne-associated scarring) and other issues relevant to the person, to help with shared decision making. The committee noted that referral to a consultant dermatologist-led team with expertise in the management of scarring is important to prevent potential skin damage caused by treatment. They were aware that the evidence was not strong enough to recommend referral for everyone with acne scarring, which would also lead to a significant impact on resources. The committee therefore specified, based on the available evidence and clinical expertise, that those with persistent severe scarring are likely to have the greatest benefit. The committee discussed that in their experience, the tissue remodelling and healing process occurs for up to about a year after the acne has cleared and management of acne scarring should be considered after this timeframe.\n\nThere was evidence that 3 types of treatment showed some efficacy in improving the appearance of scars. These were glycolic acid peels, or CO2 laser treatment either alone or after a session of punch elevation. The choice of option would depend on the type of scarring, but the committee chose to allow for clinical judgement as people may present with a number of different types of scars.\n\nAdditionally, the committee agreed that the uncertainties in the evidence needed further research to clarify. The committee therefore prioritised recommendations for research on the effectiveness of physical treatments (such as light devices) and on the effectiveness of chemical peels for the treatment of acne vulgaris or persistent acne vulgaris-related scarring.\n\n## How the recommendations might affect practice\n\nThe availability of treatments for acne scarring in NHS centres varies across the country. The recommendations are expected to result in a change in current practice, with referral to a consultant dermatologist-led team and standardised options of glycolic acid peel or CO2 laser treatment with punch elevation where needed. The impact is not expected to be substantive, as only a small number of people will fulfil the criteria. Additional resources and training may be needed in centres offering these treatment options.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: risk factors for scarring due to acne vulgaris.\n\nReturn to recommendations", 'Context': 'Acne vulgaris is a common condition that can affect the face, chest and back. It is most prevalent among young people and younger adults, affecting approximately 80% of people at some time between 11 and 30\xa0years.\n\nWhen treating acne vulgaris its severity, distribution, and the views of the affected person need to be taken into account. The aim of treatment is to reduce the severity of skin lesions and to prevent recurrence and scarring.\n\nThere is variation in how acne vulgaris is treated in clinical practice, and there is therefore a need to standardise treatment. There is also a need when prescribing antibiotic therapy for acne vulgaris to take into account the principles of antimicrobial guidance and policy, as outlined in the NICE guideline on antimicrobial stewardship, as well as the World Health Organization Global action plan on antimicrobial resistance.'}	https://www.nice.org.uk/guidance/ng198	This guideline covers management of acne vulgaris in primary and specialist care. It includes advice on topical and oral treatments (including antibiotics and retinoids), treatment using physical modalities, and the impact of acne vulgaris on mental health and wellbeing.
55e4da313e87cdd076e76602a856ee75d73dcc02	nice	Diabetes (type 1 and type 2) in children and young people: diagnosis and management	Diabetes (type 1 and type 2) in children and young people: diagnosis and management This guideline covers the diagnosis and management of type 1 and type 2 diabetes in children and young people aged under 18. The guideline recommends how to support children and young people and their families and carers to maintain tight control of blood glucose to reduce the long-term risks associated with diabetes. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Blood glucose and plasma glucose 'Blood glucose' is the more commonly used term. However, a lot of the evidence this guideline is based on uses 'plasma' rather than 'blood' glucose, and patient‑held glucose meters and monitoring systems are calibrated to plasma glucose equivalents. Because of this, in this guideline we use the term 'blood glucose', except when referring to specific concentration values. # Diagnosis Be aware that signs of type 1 diabetes in children and young people include: hyperglycaemia (random plasma glucose more than 11 mmol/litre) polyuria polydipsia weight loss excessive tiredness. Refer children and young people with suspected type 1 diabetes immediately (on the same day) to a multidisciplinary paediatric diabetes team with the competencies needed to confirm diagnosis and provide immediate care. Confirm type 1 diabetes in children and young people using the plasma glucose criteria in the World Health Organization's 2006 report on the diagnosis and classification of diabetes mellitus. When diagnosing diabetes in a child or young person, assume type 1 diabetes unless there are strong indications of type 2 diabetes, monogenic or mitochondrial diabetes. Think about the possibility of type 2 diabetes in children and young people with suspected diabetes who: have a strong family history of type 2 diabetes are obese are from a Black or Asian family background do not need insulin, or need less than 0.5 units/kg body weight/day after the partial remission phase show evidence of insulin resistance (for example, acanthosis nigricans). Think about the possibility of other types of diabetes (not type 1 or 2), such as other insulin-resistance syndromes, or monogenic or mitochondrial diabetes, in children and young people with suspected diabetes who have any of the following: diabetes in the first year of life rarely or never develop ketones in the blood (ketonaemia) during episodes of hyperglycaemia associated features, such as optic atrophy, retinitis pigmentosa, deafness, or another systemic illness or syndrome. Do not measure C‑peptide or diabetes‑specific autoantibody titres at initial presentation to distinguish type 1 diabetes from type 2 diabetes. Consider measuring C‑peptide after initial presentation if needed to distinguish between type 1 diabetes and other types of diabetes. Be aware that C‑peptide concentrations have better discriminative value the longer the interval between initial presentation and the test. Perform genetic testing if atypical disease behaviour, clinical characteristics or family history suggest monogenic diabetes. # Type 1 diabetes ## Education and information Offer children and young people with type 1 diabetes and their families or carers a continuing programme of education from diagnosis. Include the following core topics: insulin therapy (including its aims and how it works), insulin delivery (including rotating injection sites within the same body region) and dosage adjustment blood glucose monitoring, including blood glucose and HbA1c targets how diet, physical activity and intercurrent illness affect blood glucose levels managing intercurrent illness ('sick‑day rules', including monitoring of blood ketones ) detecting and managing hypoglycaemia, hyperglycaemia and ketosis the importance of good oral hygiene and regular oral health reviews for preventing periodontitis. Tailor the education programme to each child or young person with type 1 diabetes and their families or carers, taking account of issues such as: personal preferences emotional wellbeing age and maturity cultural considerations existing knowledge current and future social circumstances life goals. Encourage young people with type 1 diabetes to attend clinic 4 times a year, and explain that regular contact with the diabetes team will help them maintain optimal blood glucose levels. Explain to children and young people with type 1 diabetes and their families or carers that, like people without diabetes, they should have: regular dental examinations (see the NICE guideline on dental checks: intervals between oral health reviews) an eye examination by an optician at least every 2 years. Encourage children and young people with type 1 diabetes and their families or carers to discuss any concerns and raise any questions they have with their diabetes team. Give children and young people with type 1 diabetes and their families or carers information about diabetes support groups and organisations, and the potential benefits of membership. Give this information after diagnosis and regularly afterwards. Encourage children and young people with type 1 diabetes to wear or carry something that tells people they have type 1 diabetes (for example, a bracelet). Explain to children and young people with type 1 diabetes and their families or carers how to find out about government disability benefits. Take particular care when communicating with children and young people with type 1 diabetes if they or their families or carers have physical or sensory disabilities, or difficulties speaking or reading English. Diabetes teams should offer comprehensive advice to children and young people with type 1 diabetes who want to play sports that have particular risks for people with diabetes. Support groups and organisations (including sports organisations) may be able to provide more information. Offer education for children and young people with type 1 diabetes and their families or carers on the practical issues around long‑distance travel, such as when best to eat and inject insulin when travelling across time zones. Encourage children and young people with type 1 diabetes not to start smoking. Explain the general health problems smoking causes, in particular the risks of vascular complications. For more guidance on preventing smoking, see also the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. Offer smoking cessation programmes to children and young people with type 1 diabetes who smoke. See also the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. Explain to children and young people with type 1 diabetes and their families or carers about the general dangers of substance misuse and the possible effects on blood glucose levels. Explain to children and young people with type 1 diabetes and their families or carers that the Public Health England Green Book recommends they have: annual immunisation against influenza, starting when they are 6 months old immunisation against pneumococcal infection if they are taking insulin or oral hypoglycaemic medicines. ## Insulin therapy Discuss the choice of insulin regimen with the child or young person and their family: explain the advantages and disadvantages of the different options discuss their personal circumstances and preferences help them to make an informed decision between the options that are available to them. Offer children and young people with type 1 diabetes a multiple daily injection basal-bolus insulin regimen from diagnosis. If multiple daily insulin injections are not appropriate for a particular child or young person, consider an insulin pump, as recommended in the NICE technology appraisal guidance on continuous subcutaneous insulin infusion for the treatment of diabetes mellitus. Encourage children and young people with type 1 diabetes who are having multiple daily insulin injections to adjust the insulin dose if appropriate after each blood glucose measurement. Tell children and young people with type 1 diabetes who are having multiple daily insulin injections to inject rapid‑acting insulin analogues before eating. Explain that this reduces blood glucose levels after meals and will help them optimise their blood glucose levels. When children and young people start on an insulin pump, train them and their families and carers how to use it. A specialist team should provide ongoing support. Specialist teams should agree a common core of advice to give insulin pump users. For children and young people with type 1 diabetes who are using twice-daily injection regimens, encourage them to adjust the insulin dose according to the general trend in their pre‑meal, bedtime and occasional night‑time blood glucose. Explain to children and young people with newly diagnosed type 1 diabetes and their families or carers that: they may have a partial remission phase (a 'honeymoon period') when they start using insulin during this time, they may only need a low dosage of insulin (0.5 units/kg body weight/day) to maintain an HbA1c level of less than 48 mmol/mol (6.5%). Offer children and young people with type 1 diabetes a choice of insulin delivery systems. Provide children and young people with type 1 diabetes insulin injection needles that are the right length for their body fat. Provide children and young people with type 1 diabetes and their families or carers: suitable containers for collecting used needles and other sharps a way to safely get rid of these containers.See also the section on safe use and disposal of sharps in the NICE guideline on healthcare-associated infections. Offer children and young people with type 1 diabetes a review of injection sites at each clinic visit. Provide children and young people with type 1 diabetes rapid‑acting insulin analogues to use during intercurrent illness or episodes of hyperglycaemia. If a child or young person with type 1 diabetes does not have optimal blood glucose levels (see recommendation 1.2.55 and recommendation 1.2.76): -ffer additional support, such as more contact with their diabetes team and if necessary, offer an alternative insulin regimen (multiple daily injections, an insulin pump, or once‑, twice‑ or three‑times daily mixed insulin injections). ## Oral medicines Only use metformin in combination with insulin within research studies because it is uncertain whether this combination improves blood glucose management. Do not offer children and young people with type 1 diabetes acarbose or sulfonylureas (glibenclamide, gliclazide, glipizide, tolbutamide) in combination with insulin, because they may increase the risk of hypoglycaemia without improving blood glucose management. ## Dietary management Support children and young people with type 1 diabetes and their families or carers to develop a good working knowledge of nutrition and how it affects their diabetes. Discuss healthy eating regularly with children and young people with type 1 diabetes and their families or carers. Explain that this means eating foods with a low glycaemic index, fruit and vegetables, and appropriate types and amounts of fats. Explain that healthy eating can reduce their risk of cardiovascular disease. Support them to adjust their food choices accordingly. Take into account social and cultural considerations when providing advice on diet to children and young people with type 1 diabetes. Explain that children and young people with type 1 diabetes have the same basic nutritional requirements as other children and young people. Their food should provide enough energy and nutrients for their growth and development. For children and young people who are using a multiple daily insulin injection regimen or an insulin pump, offer level 3 carbohydrate counting education from diagnosis to them and their families or carers. Repeat this offer regularly. When children and young people with type 1 diabetes change their insulin regimen, offer them and their families or carers dietary advice tailored to the new treatment. Offer children and young people with type 1 diabetes and their families or carers education about the practical problems associated with fasting and feasting. Encourage children and young people with type 1 diabetes and their families or carers to discuss the nutritional composition and timing of snacks with their diabetes team. Encourage children and young people with type 1 diabetes to eat at least 5 portions of fruit and vegetables each day. Explain to children and young people with type 1 diabetes and their families or carers that a low glycaemic index diet may help to improve blood glucose management and reduce the risk of hyperglycaemic episodes. Offer children and young people with type 1 diabetes and their families or carers advice and education to help them follow a low glycaemic index diet. Offer children and young people with type 1 diabetes dietetic support to help optimise body weight and blood glucose levels. At each clinic visit for children and young people with type 1 diabetes, measure their height and weight and plot on an appropriate growth chart. Check for normal growth or significant changes in weight because these may reflect changes in blood glucose levels. Provide arrangements for weighing children and young people with type 1 diabetes that respect their privacy. ## Exercise Encourage children and young people with type 1 diabetes to exercise on a regular basis, and explain that this reduces their long-term risk of developing cardiovascular disease. Explain to children and young people with type 1 diabetes and their families or carers that they can take part in all forms of exercise, provided that appropriate attention is given to changes in insulin and dietary management. Explain to children and young people with type 1 diabetes and their families or carers about: the effects of exercise on blood glucose levels and how to avoid hypo‑ or hyperglycaemia during or after physical activity. Encourage children and young people with type 1 diabetes and their families or carers to monitor blood glucose levels before and after exercise so that they can: identify when changes in insulin or food intake are needed learn how their blood glucose responds to different levels of exercise watch out for exercise‑induced hypoglycaemia see how hypoglycaemia can occur several hours after prolonged exercise. Explain to children and young people with type 1 diabetes and their families or carers that: they should have extra carbohydrates as needed to avoid hypoglycaemia and they should have carbohydrate‑based foods available during and after exercise. Explain to children and young people with type 1 diabetes and their families or carers that they should have extra carbohydrates if their plasma glucose levels are less than 7 mmol/litre before they exercise. Explain to children and young people with type 1 diabetes and their families or carers that they may need to alter their insulin dose or carbohydrate intake if they change their daily exercise patterns. ## Blood glucose and HbA1c targets and monitoring Explain to children and young people with type 1 diabetes and their families or carers that the optimal target ranges for short‑term plasma glucose management are: fasting plasma glucose level of 4 mmol/litre to 7 mmol/litre on waking a plasma glucose level of 4 mmol/litre to 7 mmol/litre before meals at other times of the day a plasma glucose level of 5 mmol/litre to 9 mmol/litre after meals a plasma glucose level of at least 5 mmol/litre when driving (see the Driver and Vehicle Licensing Agency guidance for people with diabetes for further details about driving). Explain to children and young people with type 1 diabetes and their families or carers that maintaining blood glucose levels at the lower end of the target ranges will help them achieve the lowest possible HbA1c. If children and young people with type 1 diabetes experience problematic hypoglycaemia or undue emotional distress while attempting to achieve blood glucose and HbA1c targets, discuss changing the targets with them and their families and carers. Be aware that blood glucose and HbA1c targets can cause conflict between children and young people with type 1 diabetes and their families or carers, and they may need to agree a compromise. Explain to children and young people with type 1 diabetes and their families or carers that blood glucose levels should be interpreted in the 'whole child' context, which includes the social, emotional and physical environment. Offer real-time continuous glucose monitoring (rtCGM) to all children and young people with type 1 diabetes, alongside education to support children and young people, and their families and carers, to use it (see recommendation 1.2.67). Offer intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') to children and young people with type 1 diabetes aged 4 years and over who are unable to use rtCGM or who express a clear preference for isCGM. In March 2022, isCGM was licensed for children aged 4 years and over. Offer children and young people with type 1 diabetes a choice of rtCGM device, based on their individual preferences, needs, characteristics, and the functionality of the devices available. See box 1 for examples of factors to consider as part of this discussion. When choosing a continuous glucose monitoring (CGM) device: use shared decision making to identify the child or young person's needs and preferences and offer them an appropriate device if multiple devices meet their needs and preferences, offer the device with the lowest cost. Accuracy of the device. Whether the device provides predictive alerts or alarms and if these need to be shared with anyone else, for example a parent or carer. Whether using the device requires access to particular technologies (such as a smartphone and up-to-date phone software). How easy the device is to use and take readings from, including for people with limited dexterity (taking into account the age and abilities of the child or young person and whether the device needs to be used by others). Fear, frequency, awareness and severity of hypoglycaemia. Psychosocial factors. The child or young person's insulin regimen or type of insulin pump, if relevant (taking into account whether a particular device integrates with their pump as part of a hybrid closed loop or insulin suspend function). Whether, how often and how the device needs to be calibrated, and how easy it is for the person to do this themselves. How data can be collected, compatibility of the device with other technology, and whether data can be shared with the person's healthcare provider to help inform treatment. How unpredictable the child or young person's activity and blood glucose levels are and whether erratic blood glucose is affecting their quality of life. Whether the choice of device will impact on the child or young person's ability to attend school or education, or to do their job. Whether the child or young person takes part in sports or exercise when glucose levels will need additional management. Whether the child or young person has situations when symptoms of hypoglycaemia cannot be communicated or can be confused, for example during exercise. Clinical factors that may make devices easier or harder to use. Frequency of sensor replacement. Sensitivities to the device, for example local skin reactions. Body image concerns. CGM should be provided by a team with expertise in its use, as part of supporting children and young people to self-manage their diabetes. Advise children and young people with type 1 diabetes who are using CGM (and their families or carers) that they will still need to take capillary blood glucose measurements (although they can do this less often). Explain that this is because: they will need to use capillary blood glucose measurements to check the accuracy of their CGM device they will need capillary blood glucose monitoring as a back-up (for example, when their blood glucose levels are changing quickly or if the device stops working).Provide them with enough test strips to take capillary blood glucose measurements as needed. If a person cannot use or does not want rtCGM or isCGM, offer capillary blood glucose monitoring. Include CGM in the continuing programme of education provided to all children and young people with type 1 diabetes and their families or carers (see the section on education and information). Monitor and review the child or young person's use of CGM as part of reviewing their diabetes care plan, and explain to them the importance of continuously wearing the device. If the child or young person is not using their CGM device at least 70% of the time: ask if they are having problems with their device look at ways to address any problems or concerns to improve their use of the device, including further education and emotional and psychological support. Commissioners, providers and healthcare professionals should address inequalities in CGM access and uptake by: monitoring who is using CGM identifying groups who are eligible but who have a lower uptake making plans to engage with these groups to encourage them to consider CGM. For a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on continuous glucose monitoring . Full details of the evidence and the committee's discussion are in evidence review B: continuous glucose monitoring in children and young people with type 1 diabetes. Loading. Please wait. Advise children and young people with type 1 diabetes who are using capillary blood glucose monitoring (and their families or carers) to routinely perform at least 5 capillary blood glucose tests per day. Advise children and young people with type 1 diabetes who are using capillary blood glucose monitoring (and their families or carers) that more frequent testing is often needed (for example, with physical activity and during intercurrent illness). Ensure they have enough test strips for this. Offer children and young people with type 1 diabetes who are using capillary blood glucose monitoring (and their families or carers) a choice of equipment for monitoring, so they can optimise their blood glucose management in response to changes in their insulin, diet and exercise. Measure HbA1c using methods that have been calibrated according to International Federation of Clinical Chemistry standardisation. Explain the benefits of safely achieving and maintaining the lowest attainable HbA1c to children and young people with type 1 diabetes and their families or carers. Explain to children and young people with type 1 diabetes and their families or carers that an HbA1c target level of 48 mmol/mol (6.5%) or lower will minimise their risk of long‑term complications. Explain to children and young people with type 1 diabetes who have an HbA1c level above 48 mmol/mol (6.5%) that any reduction in HbA1c level reduces their risk of long‑term complications. Agree an individualised lowest achievable HbA1c target with each child or young person with type 1 diabetes and their families or carers. Take into account factors such as their daily activities, individual life goals, complications, comorbidities and the risk of hypoglycaemia. Support children and young people with type 1 diabetes and their families or carers to safely achieve and maintain their individual agreed HbA1c target level. Measure HbA1c level 4 times a year in children and young people with type 1 diabetes. Think about more frequent testing if they are having difficulty with blood glucose management. Diabetes services should document the proportion of children and young people with type 1 diabetes who achieve an HbA1c level of 53 mmol/mol (7%) or lower. ## Hyperglycaemia, blood ketone monitoring and intercurrent illness Provide children and young people with type 1 diabetes and their families or carers with individualised oral and written advice ('sick‑day rules') about managing type 1 diabetes during intercurrent illness or episodes of hyperglycaemia, including: monitoring blood glucose monitoring and interpreting blood ketones (beta‑hydroxybutyrate) adjusting their insulin regimen food and fluid intake when and where to get further advice or help.Revisit the advice at least annually. Offer children and young people with type 1 diabetes blood ketone testing strips and a meter. Advise them and their families or carers to test for ketonaemia if they are ill or have hyperglycaemia. Explain to children and young people with type 1 diabetes and their families or carers that they should not use blood ketone testing strips after the use‑by date. ## Hypoglycaemia Explain to children and young people with type 1 diabetes and their families or carers how they can avoid and manage hypoglycaemia. Offer education for children and young people with type 1 diabetes and their families, carers, and teachers about recognising and managing hypoglycaemia. Explain to children and young people with type 1 diabetes and their families or carers that they should always have access to an immediate source of fast‑acting glucose and blood glucose monitoring equipment, so that they can check for hypoglycaemia and manage it safely. Train and equip families, carers, and (if appropriate) school nurses and other carers to give intramuscular glucagon for severe hypoglycaemia in an emergency. Immediately treat mild-to-moderate hypoglycaemia in children and young people with type 1 diabetes as follows: Give oral fast‑acting glucose (for example, 10 g to 20 g; liquid carbohydrate may be easier to swallow than solid). Be aware that fast‑acting glucose may need to be given in frequent small amounts because hypoglycaemia can cause vomiting. Recheck blood glucose levels within 15 minutes (fast‑acting glucose should raise blood glucose levels within 5 to 15 minutes), and give more fast‑acting glucose if they still have hypoglycaemia. As symptoms improve or blood glucose levels return to normal, give oral complex long-acting carbohydrate to maintain blood glucose levels, unless the child or young person is: about to have a snack or meal having a continuous subcutaneous insulin infusion. For children and young people with type 1 diabetes who are in hospital, treat severe hypoglycaemia with 10% intravenous glucose if rapid intravenous access is possible. Give a maximum dose of 500 mg/kg body weight (equivalent to a maximum of 5 ml/kg). For children and young people with type 1 diabetes who are not in hospital, or if rapid intravenous access is not possible, treat severe hypoglycaemia as follows: Use intramuscular glucagon or a concentrated oral glucose solution (for example, Glucogel). Do not use oral glucose solution if they have reduced consciousness because this could be dangerous. If using intramuscular glucagon: give 1 mg glucagon to children and young people who are over 8 years old, or who weigh 25 kg or more give 500 micrograms of glucagon to children who are under 8 years old, or who weigh less than 25 kg. Seek medical assistance if blood glucose levels do not respond or symptoms continue for more than 10 minutes. As symptoms improve or blood glucose levels return to normal, and once the child or young person is sufficiently awake, give oral complex long‑acting carbohydrate to maintain normal blood glucose levels. Recheck blood glucose repeatedly in children and young people who have persistently reduced consciousness after a severe hypoglycaemic episode to determine whether further glucose is needed. Explain to young people with type 1 diabetes how alcohol affects blood glucose levels, and in particular the increased risk of hypoglycaemia (including hypoglycaemia while sleeping). Explain to young people with type 1 diabetes who drink alcohol that they should: eat food containing carbohydrates before and after drinking monitor their blood glucose levels regularly and aim to keep the levels within the recommended range by eating food containing carbohydrates. Explain to children and young people with type 1 diabetes and their families or carers that when alcohol causes or contributes to hypoglycaemia, glucagon may be ineffective and they may need intravenous glucose. Diabetes teams should consider referring children and young people with type 1 diabetes for assessment of cognitive function if they have frequent hypoglycaemia or recurrent seizures, particularly if these occur at a young age. ## Difficulties with maintaining optimal blood glucose levels Think about the possibility of non‑adherence to therapy in children and young people with type 1 diabetes who have difficulty with blood glucose management, especially in adolescence. Be aware that young people with type 1 diabetes can have difficulty with blood glucose management during adolescence, and this may in part be due to non‑adherence to therapy. Raise the issue of non‑adherence to therapy with children and young people with type 1 diabetes and their families or carers in a sensitive manner. Be aware of the possible negative psychological impact of setting targets that may be difficult for a child or young person with type 1 diabetes to achieve and maintain. ## Surgery Only offer surgery in centres that have dedicated paediatric facilities for children and young people with diabetes. All centres caring for children and young people with type 1 diabetes should have written protocols on safe surgery for children and young people. The protocols should be agreed between surgical and anaesthetic staff and the diabetes team. Surgical, anaesthetic and diabetes teams should discuss care for children and young people with type 1 diabetes before they are admitted to hospital for elective surgery, and as soon as possible after they are admitted for emergency surgery. ## Psychological and social issues Be aware that children and young people with type 1 diabetes have a greater risk of emotional and behavioural difficulties. Offer children and young people with type 1 diabetes and their families or carers emotional support after diagnosis, and tailor this to their emotional, social, cultural and age‑dependent needs. Assess the emotional and psychological wellbeing of young people with type 1 diabetes who have frequent episodes of diabetic ketoacidosis (DKA). Be aware that a lack of adequate psychosocial support for children and young people with type 1 diabetes has a negative effect on various outcomes (including blood glucose management) and can also reduce their self‑esteem. Offer children and young people with type 1 diabetes and their families or carers timely and ongoing access to mental health professionals with an understanding of diabetes. This is because they may experience psychological problems (such as anxiety, depression, behavioural and conduct disorders, and family conflict) or psychosocial difficulties that can impact on the management of diabetes and wellbeing. See the NICE guidelines on depression in children and young people and antisocial behaviour and conduct disorders in children and young people for guidance on managing these conditions. Diabetes teams should have access to mental health professionals to support them in psychological assessment and providing psychosocial support. Offer children and young people with type 1 diabetes who have behavioural or conduct disorders, and their families or carers, access to mental health professionals. Offer specific family‑based behavioural interventions, such as behavioural family systems therapy, if there are difficulties with diabetes‑related family conflict. Consider a programme of behavioural intervention therapy or behavioural techniques for children and young people with type 1 diabetes if there are concerns about their psychological wellbeing. Choose a type of therapy based on what the child or young person needs help with: health‑related quality of life – for example, counselling or cognitive behavioural therapy (CBT), including CBT focused on quality of life adherence to diabetes treatment – for example, motivational interviewing or multisystemic therapy blood glucose management if they have high HbA1c levels (above 69 mmol/mol ) – for example, multisystemic therapy. Offer screening for anxiety and depression to children and young people with type 1 diabetes who have persistent difficulty with blood glucose management. Be aware that children and young people with type 1 diabetes may develop anxiety or depression, particularly when they have difficulty with self-management when they have had diabetes for a long time. Refer children and young people with type 1 diabetes and suspected anxiety or depression promptly to child mental health professionals. Be aware that children and young people with type 1 diabetes (in particular, young women) have an increased risk of eating disorders. For more guidance on assessing and managing eating disorders, see the NICE guideline on eating disorders. Be aware that children and young people with type 1 diabetes and an eating disorder may have associated difficulties with: blood glucose management (both hyperglycaemia and hypoglycaemia) symptoms of gastroparesis. For children and young people with type 1 diabetes and an eating disorder, offer joint management involving their diabetes team and child mental health professionals. ## Monitoring for complications and associated conditions of type 1 diabetes Offer children and young people with type 1 diabetes monitoring for: thyroid disease, at diagnosis and then annually until transfer to adult services moderately increased albuminuria (albumin to creatinine ratio 3 mg/mmol to 30 mg/mmol) to detect diabetic kidney disease, annually from 12 years hypertension, annually from 12 years. Refer children and young people with type 1 diabetes for diabetic retinopathy screening from 12 years, in line with Public Health England's diabetic eye screening programme. For guidance on monitoring for coeliac disease in children and young people with type 1 diabetes, see the NICE guideline on coeliac disease. For guidance on managing foot problems in children and young people with type 1 diabetes, see the NICE guideline on diabetic foot problems. Be aware of the following rare complications and associated conditions when children and young people with type 1 diabetes attend clinic visits: juvenile cataracts necrobiosis lipoidica Addison's disease. Explain to children and young people with type 1 diabetes and their families or carers the importance of annual monitoring from 12 years for diabetic kidney disease. For children and young people with type 1 diabetes who are having eye screening, explain to them and their families or carers that: monitoring for diabetic retinopathy begins at 12 years (see recommendation 1.2.120) because diabetic retinopathy that needs treatment is extremely rare in children and young people under 12 annual monitoring from age 12 is important because if significant diabetic retinopathy is found, early treatment will improve the outcome (for more information, see Public Health England's diabetic eye screening programme) it will help them keep their eyes healthy and help prevent problems with their vision the screening service is effective at identifying problems so that they can be treated early. Explain to children and young people with type 1 diabetes and their families or carers that: monitoring for moderately increased albuminuria (ACR 3 mg/mmol to 30 mg/mmol) to detect diabetic kidney disease begins at 12 years because diabetic kidney disease in children and young people under 12 is extremely rare using the first urine sample of the day ('early morning urine') to screen for moderately increased albuminuria is important, as this reduces the risk of false positive results if moderately increased albuminuria is detected, improving blood glucose management will reduce the risk of this progressing to significant diabetic kidney disease annual monitoring from 12 years is important because if they have diabetic kidney disease, early treatment will improve the outcome. Use the first urine sample of the day ('early morning urine') to measure the ACR. If the first urine sample of the day is not available, use a random sample, but be aware that this is associated with an increased risk of false positive results. If the initial ACR is above 3 mg/mmol but below 30 mg/mmol, confirm the result by repeating the test on 2 further occasions using the first urine samples of the day ('early morning urine') before starting further investigation and therapy. Investigate further if the initial ACR is 30 mg/mmol or more (proteinuria). Advise children and young people with type 1 diabetes and their families and carers at their regular diabetes reviews that: they are at higher risk of periodontitis if they get periodontitis, managing it can improve their blood glucose control and can reduce their risk of hyperglycaemia. Advise children and young people with type 1 diabetes to have regular oral health reviews (their oral healthcare or dental team will tell them how often, in line with the NICE guideline on dental checks: intervals between oral health reviews). For guidance for oral healthcare and dental teams on how to provide oral health advice, see the NICE guideline on oral health promotion. For a short explanation of why the committee made these recommendations, see the rationale and impact section on periodontitis . Full details of the evidence and the committee's discussion are in evidence review C: periodontitis. Loading. Please wait. # Type 2 diabetes ## Education and information When giving children and young people, or their families or carers, information about type 2 diabetes: tailor the timing, content and delivery of information to their needs and preferences, paying particular attention to people with additional needs such as autistic people or those with learning disabilities, people who have physical or sensory disabilities and people who have difficulties speaking or reading English ensure that the information given supports shared decision making between the child or young person and the multidisciplinary diabetes team.Follow the recommendation in NICE's guideline on shared decision making and babies, children and young people's experience of healthcare. Offer children and young people with type 2 diabetes and their families or carers a continuing programme of education from diagnosis. Include the following core topics: the importance of managing glucose levels, including achieving and maintaining glucose and HbA1c targets how and when to take capillary blood glucose measurements (self-monitoring) how diet, increasing physical activity and reducing body weight can reduce the symptoms of type 2 diabetes and lead to remission how diet, physical activity, body weight and intercurrent illness affects blood glucose levels how metformin can help, and its possible adverse effects the complications of type 2 diabetes and how to prevent them.See also the recommendations for children and young people in NICE's guideline on identifying, assessing and managing obesity, lifestyle interventions, behavioural interventions, physical activity and dietary approaches for weight management, and recommendations 1.3.68 to 1.3.70 on psychological and social issues in this guideline. Tailor the education programme to each child or young person with type 2 diabetes and their families or carers, taking account of issues such as: personal preferences emotional wellbeing age and maturity cultural considerations existing knowledge current and future social circumstances life goals. Give children and young people with type 2 diabetes who are taking insulin, and their families or carers, information and education about: insulin therapy (including its aims and how it works) insulin delivery (including rotating injection sites within the same body region) dosage adjustment the recognition and management of hypoglycaemia the importance of monitoring their glucose levels. Give children and young people with type 2 diabetes who are offered continuous glucose monitoring (CGM), and their families and carers, information about how to use their chosen device, as part of their continuing programme of education. Explain to children and young people with type 2 diabetes and their families or carers that, like people without diabetes, they should have: regular dental examinations (see the NICE guideline on dental checks: intervals between oral health reviews) an eye examination by an optician every 2 years. Encourage children and young people with type 2 diabetes and their families or carers to discuss any concerns and raise any questions they have with their diabetes team. Give children and young people with type 2 diabetes and their families or carers information about diabetes support groups and organisations, and the potential benefits of membership. Give this information after diagnosis and regularly afterwards. Explain to children and young people with type 2 diabetes and their families or carers how to find out about possible government disability benefits. For a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on education and information for children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. Encourage children and young people with type 2 diabetes not to start smoking. Explain the general health problems smoking causes, in particular the risks of vascular complications. For more guidance on preventing smoking, see also the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. Offer smoking cessation programmes to children and young people with type 2 diabetes who smoke. See also the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. Explain to children and young people with type 2 diabetes and their families or carers about the general dangers of substance misuse and the possible effects on blood glucose levels. Explain to children and young people with type 2 diabetes and their families or carers that the Public Health England Green Book recommends they have: annual immunisation against influenza immunisation against pneumococcal infection if they are taking insulin or oral hypoglycaemic medicines. ## Dietary management At each contact with a child or young person with type 2 diabetes who is overweight or obese, advise them and their families or carers about the benefits of exercise and weight loss, and provide support towards achieving this. See also the NICE guidelines on preventing excess weight gain and managing obesity. Offer children and young people with type 2 diabetes dietetic support to help optimise body weight and blood glucose levels. At each contact with a child or young person with type 2 diabetes, explain to them and their families or carers how healthy eating can help to: reduce hyperglycaemia reduce cardiovascular risk promote weight loss (see recommendation 1.3.15). Provide dietary advice to children and young people with type 2 diabetes and their families or carers in a sensitive manner. Take into account the difficulties that many people have with losing weight, and how healthy eating can also help with blood glucose levels and avoiding complications. Take into account social and cultural considerations when providing dietary advice to children and young people with type 2 diabetes. Encourage children and young people with type 2 diabetes to eat at least 5 portions of fruit and vegetables each day. At each clinic visit for children and young people with type 2 diabetes: measure height and weight and plot on an appropriate growth chart calculate body mass index.Check for normal growth or significant changes in weight because these may reflect changes in blood glucose levels. Provide arrangements for weighing children and young people with type 2 diabetes that respect their privacy. ## At diagnosis Refer children and young people with suspected type 2 diabetes to a multidisciplinary paediatric diabetes team for specialist review to: confirm diagnosis and provide immediate and continuing care. Offer children and young people with type 2 diabetes: advice and support on dietary management (see recommendations 1.3.15 to 1.3.22) a metformin monotherapy formulation in line with their own preferences equipment for capillary blood glucose monitoring.See also recommendation 1.3.84 on screening for diabetic retinopathy. In May 2023, the use of formulations other than standard-release metformin was off-label. See NICE's information on prescribing medicines. (2015, updated 2023) In addition, offer children and young people with type 2 diabetes: insulin if their HbA1c level is 69 mmol/mol (8.5%) or more basal-bolus insulin if they have ketosis but not diabetic ketoacidosis (DKA). If the child or young person with type 2 diabetes exhibits signs and symptoms of DKA, see section 1.4 on DKA. For a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on what to do at diagnosis for children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. ## Monitoring blood glucose levels and reviewing treatment Four weeks after diagnosing type 2 diabetes and starting metformin in a child or young person, review data from glucose monitoring and, if needed, change treatment (see recommendations on adding liraglutide, dulaglutide, or empagliflozin for people on metformin only or for people on metformin and insulin). Review treatment for children and young people with type 2 diabetes, as needed, at least every 3 months. Assess glucose trends using available data from glucose monitoring and HbA1c measurements. If HbA1c monitoring cannot be used because of disturbed erythrocyte turnover or abnormal haemoglobin type, estimate trends in blood glucose levels using one of the following: glucose profiles total glycated haemoglobin estimation (if abnormal haemoglobins) fructosamine estimation. Adjust the frequency of capillary blood glucose monitoring based on the person's treatment and whether they are using CGM. Ensure they have enough test strips for capillary blood glucose monitoring. For a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on monitoring blood glucose levels and reviewing treatment for children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. Measure HbA1c using methods that have been calibrated according to the International Federation of Clinical Chemistry standardisation. Explain to children and young people with type 2 diabetes and their families or carers that an HbA1c target level of 48 mmol/mol (6.5%) or lower will minimise their risk of long‑term complications. Explain to children and young people with type 2 diabetes who have an HbA1c level above 48 mmol/mol (6.5%) that any reduction in HbA1c level reduces their risk of long‑term complications. Explain the benefits of safely achieving and maintaining the lowest attainable HbA1c to children and young people with type 2 diabetes and their families or carers. Agree an individualised lowest achievable HbA1c target with each child or young person with type 2 diabetes and their families or carers. Take into account factors such as their daily activities, individual life goals, complications and comorbidities. Measure HbA1c levels every 3 months in children and young people with type 2 diabetes. Support children and young people with type 2 diabetes and their families or carers to safely achieve and maintain their individual agreed HbA1c target level. Diabetes services should document the proportion of children and young people with type 2 diabetes who achieve an HbA1c level of 53 mmol/mol (7%) or lower. Offer real-time continuous glucose monitoring (rtCGM) to children and young people with type 2 diabetes if any of the following apply. They: have a need, condition or disability (including a mental health need, learning disability or cognitive impairment) that means they cannot engage in monitoring their glucose levels by capillary blood glucose monitoring would otherwise be advised to self-monitor at least 8 times a day have recurrent or severe hypoglycaemia. Consider rtCGM for children and young people with type 2 diabetes who are on insulin therapy. Consider intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') for children and young people with type 2 diabetes aged 4 years and over who are on insulin therapy if: rtCGM is contraindicated for them or they express a clear preference for isCGM. In May 2023, use of isCGM for children aged 3 years and under was off-licence. When offering CGM to children and young people with type 2 diabetes, choose the appropriate device with them, based on their individual preferences, needs, characteristics, and the functionality of the devices available. See box 1 for factors to consider as part of this discussion. When choosing a CGM device, if multiple devices meet the person's needs and preferences, offer the device with the lowest cost. CGM should be provided by a team with expertise in its use to support children and young people to self-manage their type 2 diabetes. Advise children and young people with type 2 diabetes who are using CGM, and their families or carers, that they will still need to take capillary blood glucose measurements, but they can do this less often. Explain that this is because they will need the capillary blood glucose measurements: to check the accuracy of their CGM device as a back-up (for example, if the device stops working). Monitor and review the child or young person's use of CGM when reviewing their diabetes care plan and explain to them the importance of continuously wearing the device. If the child or young person is not using their CGM device at least 70% of the time: ask if they are having problems with their device look at ways to address any problems or concerns to improve their use of the device, including further education and emotional and psychological support. Commissioners, providers and healthcare professionals should address inequalities in CGM access and uptake by: monitoring who is using CGM identifying groups who are eligible but have a lower uptake making plans to engage with these groups to encourage them to consider CGM. For a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on continuous glucose monitoring for children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. ## When to reduce insulin for people who have been on it from diagnosis For children and young people with type 2 diabetes who have been on insulin therapy from diagnosis, gradually reduce with the aim of stopping insulin therapy if they have achieved: an HbA1c level of 48 mmol/mol (6.5%) or less or a plasma glucose level of 4 mmol/litre to 7 mmol/litre, on 4 or more days a week, when fasting or before meals or a plasma glucose level of 5 mmol/litre to 9 mmol/litre, on 4 or more days a week, 2 hours after meals.See also recommendations on insulin therapy for children and young people with type 2 diabetes in this guideline. For a short explanation of why the committee made the 2023 recommendation, see the rationale and impact section on when to reduce insulin for children and young people with type 2 diabetes who have been on insulin since diagnosis . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. ## Adding liraglutide, dulaglutide, or empagliflozin Offer liraglutide or dulaglutide, depending on the person's preference, in addition to metformin, to children and young people aged 10 or over with type 2 diabetes if they have: an HbA1c level of more than 48 mmol/mol (6.5%) or a plasma glucose level of more than 7 mmol/litre, on 4 or more days a week, when fasting or before meals or a plasma glucose level of more than 9 mmol/litre, on 4 or more days a week, 2 hours after meals.In May 2023, this was an off-label use of dulaglutide. See NICE's information on prescribing medicines. Consider empagliflozin, in addition to metformin, for children and young people aged 10 or over with type 2 diabetes who: meet any of the criteria listed in recommendation 1.3.49 are not able to tolerate liraglutide or dulaglutide or have a clear preference for empagliflozin.In May 2023, this was an off-label use of empagliflozin. See NICE's information on prescribing medicines. Offer insulin to children and young people with type 2 diabetes in whom an HbA1c level of 48 mmol/mol (6.5%) or less cannot be achieved using metformin with one medicine among liraglutide, dulaglutide or empagliflozin. Offer liraglutide or dulaglutide in addition to current treatment, rather than increasing insulin, for a child or young person aged 10 or over with type 2 diabetes if: they are already on insulin therapy and their HbA1c or glucose levels do not meet the conditions in recommendation 1.3.48 to safely reduce and stop insulin.See also recommendation 1.3.15 on dietary management. In May 2023, this was an off-label use of dulaglutide. See NICE's information on prescribing medicines. Consider empagliflozin in addition to current treatment, rather than increasing insulin, for a child or young person aged 10 or over with type 2 diabetes if: they are already on insulin therapy and their HbA1c or glucose levels do not meet the conditions in recommendation 1.3.48 to safely reduce and stop insulin and they are not able to tolerate liraglutide or dulaglutide or have a clear preference for empagliflozin.See also recommendation 1.3.15 on dietary management. In May 2023, this was an off-label use of empagliflozin. See NICE's information on prescribing medicines. Only increase insulin for a child or young person aged 10 or over with type 2 diabetes who is on metformin and insulin if their HbA1c or glucose levels are not in the target ranges listed in recommendation 1.3.48 and: they are already also taking liraglutide, dulaglutide or empagliflozin, or a combination of them or liraglutide, dulaglutide and empagliflozin are not tolerated or contraindicated. For children and young people aged 10 or over with type 2 diabetes who are on liraglutide, dulaglutide or empagliflozin, maintain the lowest dose that enables them to achieve the target ranges specified in recommendation 1.3.48. See relevant Medicines and Healthcare products Regulatory Agency (MHRA) advice on the use of SGLT2 inhibitors and specific BNF advice on the use of empagliflozin. For a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on adding liraglutide, dulaglutide or empagliflozin to current treatment for children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. ## Insulin therapy When insulin therapy is appropriate (as per the recommendations about prescribing insulin at diagnosis or when to subsequently add insulin in this guideline), discuss the choice of insulin regimen with the child or young person and their family: explain the advantages and disadvantages of the different options and whether only basal or a combination of basal and meal-time insulin is required discuss their personal circumstances and preferences help them make an informed decision between the options that are available to them. Provide children and young people with type 2 diabetes insulin injection needles that are the right length for their body fat. Provide children and young people with type 2 diabetes and their families or carers with: suitable containers for collecting used needles and other sharps a way to safely get rid of these containers.See also the section on safe use and disposal of sharps in the NICE guideline on healthcare-associated infections. Offer children and young people with type 2 diabetes a review of injection sites at each clinic visit. If a child or young person with type 2 diabetes does not have optimal blood glucose levels (see recommendations 1.3.31 on HbA1c target and 1.3.48 for HbA1c and plasma glucose targets), offer additional support, such as more contact with their diabetes team. For a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on insulin therapy for children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. ## Changing treatments and updating healthcare plans Ensure that the paediatric diabetes team updates the child or young person's school healthcare plan as soon as treatment changes in a way that affects the school's involvement, and annually. For recommendations about involving children and young people, and their family and carers, in making decisions about treatment, see: recommendation 1.5.4 (2015) on service provision in this guideline sections 1.2 to 1.4 in NICE's guideline on shared decision making. For a short explanation of why the committee made the 2023 recommendation, see the rationale and impact section on changing treatment and updating school healthcare plans for children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. ## Surgery Only offer surgery in centres that have dedicated paediatric facilities for children and young people with diabetes. All centres caring for children and young people with type 2 diabetes should have written protocols on safe surgery for children and young people. The protocols should be agreed between surgical and anaesthetic staff and the diabetes team. ## Psychological and social issues Be aware that children and young people with type 2 diabetes have a greater risk of emotional and behavioural difficulties. Offer children and young people with type 2 diabetes and their families or carers emotional support after diagnosis, and tailor this to their emotional, social, cultural and age‑dependent needs. Be aware that children and young people with type 2 diabetes have an increased risk of psychological conditions (for example, anxiety, depression, and behavioural and conduct disorders) and complex social factors (for example, family conflict), and these can affect their wellbeing and diabetes management. Be aware that a lack of adequate psychosocial support for children and young people with type 2 diabetes has a negative effect on various outcomes (including blood glucose management) and can also reduce their self‑esteem. Offer children and young people with type 2 diabetes and their families or carers timely and ongoing access to mental health professionals with an understanding of diabetes. This is because they may experience psychological problems (such as anxiety, depression, behavioural and conduct disorders, and family conflict) or psychosocial difficulties that can impact on the management of diabetes and wellbeing. See the NICE guidelines on depression in children and young people and antisocial behaviour and conduct disorders in children and young people for guidance on managing these conditions. Diabetes teams should have access to mental health professionals to support them in psychological assessment and providing psychosocial support. Offer assessment for anxiety and depression to children and young people with type 2 diabetes who have persistent difficulty with blood glucose management. Refer children and young people with type 2 diabetes and suspected anxiety or depression promptly to child mental health professionals. Ensure that children and young people with type 2 diabetes and their families or carers have timely and ongoing access to mental health services when needed. ## Monitoring for complications and associated conditions of type 2 diabetes Offer children and young people with type 2 diabetes annual monitoring for: hypertension, starting at diagnosis dyslipidaemia, starting at diagnosis moderately increased albuminuria (albumin to creatinine ratio 3 mg/mmol to 30 mg/mmol) to detect diabetic kidney disease, starting at diagnosis. Explain to children and young people with type 2 diabetes and their families or carers the importance of annual monitoring for hypertension, dyslipidaemia and diabetic kidney disease. Refer children and young people with type 2 diabetes for diabetic retinopathy screening from 12 years, in line with Public Health England's diabetic eye screening programme. For guidance on managing foot problems in children and young people with type 2 diabetes, see the NICE guideline on diabetic foot problems. Explain to children and young people with type 2 diabetes and their families or carers that monitoring (see recommendation 1.3.74) is important because if they have hypertension, early treatment will reduce their risk of complications. Use a cuff large enough for the child or young person with type 2 diabetes when measuring blood pressure. If repeated resting measurements are greater than the 95th percentile for age and sex, confirm hypertension using 24‑hour ambulatory blood pressure monitoring before starting antihypertensive therapy. Explain to children and young people with type 2 diabetes and their families or carers that monitoring (see recommendation 1.3.74) is important because if they have dyslipidaemia, early treatment will reduce their risk of complications. When monitoring for dyslipidaemia in children and young people with type 2 diabetes, measure total cholesterol, high‑density lipoprotein (HDL) cholesterol, non‑HDL cholesterol and triglyceride concentrations. Confirm dyslipidaemia using a repeat sample (fasting or non‑fasting) before deciding on further management. For children and young people with type 2 diabetes who are having eye screening, explain to them and their families or carers that: background retinopathy is often found through screening (see recommendation 1.3.76), and improved blood glucose management will reduce the risk of this progressing to significant diabetic retinopathy it will help them keep their eyes healthy and prevent problems with their vision the screening service is effective at identifying problems so that they can be treated early at least annual monitoring from 12 years is important because, if significant diabetic retinopathy is found, early treatment will improve the outcome. Consider referring children and young people with type 2 diabetes who are younger than 12 years to an ophthalmologist for retinal examination if they have difficulty with blood glucose management. Explain to children and young people with type 2 diabetes and their families or carers that: using the first urine sample of the day ('early morning urine') to screen for moderately increased albuminuria (ACR 3 mg/mmol to 30 mg/mmol) is important as this reduces the risk of false positive results if moderately increased albuminuria is detected, improving blood glucose management will reduce the risk of this progressing to significant diabetic kidney disease annual monitoring (see recommendation 1.3.74) is important because, if they have diabetic kidney disease, early treatment will improve the outcome. Use the first urine sample of the day ('early morning urine') to measure the ACR. If the first urine sample of the day is not available, use a random sample, but be aware that this is associated with an increased risk of false positive results. If the initial ACR is above 3 mg/mmol but below 30 mg/mmol, confirm the result by repeating the test on 2 further occasions using the first urine samples of the day ('early morning urine') before starting further investigation and therapy. Investigate further if the initial ACR is 30 mg/mmol or more (proteinuria). Advise children and young people with type 2 diabetes and their families and carers at their regular diabetes reviews that: they are at higher risk of periodontitis if they get periodontitis, managing it can improve their blood glucose control and can reduce their risk of hyperglycaemia. Advise children and young people with type 2 diabetes to have regular oral health reviews (their oral healthcare or dental team will tell them how often, in line with the NICE guideline on dental checks: intervals between oral health reviews). For guidance for oral healthcare and dental teams on how to provide oral health advice, see the NICE guideline on oral health promotion. For a short explanation of why the committee made these recommendations, see the rationale and impact section on periodontitis . Full details of the evidence and the committee's discussion are in evidence review C: periodontitis. Loading. Please wait. # Diabetic ketoacidosis ## Recognition, referral and diagnosis Measure capillary blood glucose at presentation in children and young people without known diabetes who have: increased thirst, polyuria, recent unexplained weight loss or excessive tiredness and any of nausea, vomiting, abdominal pain, hyperventilation, dehydration or reduced level of consciousness. For children or young people without known diabetes who have a plasma glucose level above 11 mmol/litre and symptoms that suggest diabetic ketoacidosis (DKA; see recommendation 1.4.1), suspect DKA and immediately send them to a hospital with acute paediatric facilities. Be aware that children and young people taking insulin for diabetes may develop DKA with normal blood glucose levels. Suspect DKA even if the blood glucose is normal in a child or young person with known diabetes and any of the following: nausea or vomiting abdominal pain hyperventilation dehydration reduced level of consciousness. When DKA is suspected in a child or young person with known diabetes, measure their blood ketones (beta‑hydroxybutyrate), using a near‑patient method if available. Immediately send them to a hospital with acute paediatric facilities if: their blood ketones are elevated a near-patient method for measuring their blood ketones is not available. If DKA is suspected or confirmed in a child or young person, explain to them and to their families or carers that DKA is serious and that they need urgent hospital assessment. When a child or young person with suspected or known DKA arrives at hospital, measure their: capillary blood glucose capillary blood ketones (beta‑hydroxybutyrate) if near‑patient testing is available, or urine ketones if it is not capillary or venous pH and bicarbonate. Diagnose DKA in children and young people with diabetes who have: hyperglycaemia (plasma glucose more than 11 mmol/litre) and acidosis (indicated by blood pH below 7.3 or plasma bicarbonate below 15 mmol/litre) and ketonaemia (indicated by blood beta‑hydroxybutyrate above 3 mmol/litre) or ketonuria (++ and above on the standard strip marking scale). Diagnose DKA severity as follows: mild DKA if blood pH is below 7.3 or plasma bicarbonate is below 15 mmol/litre moderate DKA if blood pH is below 7.2 or plasma bicarbonate is below 10 mmol/litre severe DKA if blood pH is below 7.1 or plasma bicarbonate is below 5 mmol/litre. ## Initial management of diabetic ketoacidosis Inform the responsible senior clinician when a child or young person is diagnosed with DKA. Explain to the child or young person and their families or carers what DKA is, and what care that they may need. When DKA is diagnosed in a child or young person in hospital, record their: level of consciousness heart rate, blood pressure, temperature, respiratory rate (look for Kussmaul breathing) history of nausea or vomiting clinical evidence of dehydration body weight. When DKA is diagnosed in a child or young person in hospital, measure and record the capillary or venous: pH and pCO2 plasma sodium, potassium, urea and creatinine plasma bicarbonate. Consider a near‑patient blood ketone (beta‑hydroxybutyrate) testing method for rapid diagnosis and monitoring of DKA in children and young people in hospital. Children and young people with DKA should be cared for in a facility that can provide the level of monitoring and care for DKA specified in section 1.4 of this guideline. Children and young people with DKA should be cared for with one‑to‑one nursing either on a high‑dependency unit (preferably a paediatric unit) or on a general paediatric ward, if: they are younger than 2 years or they have severe DKA (blood pH below 7.1). Think about inserting a nasogastric tube if a child or young person with DKA has a reduced level of consciousness and is vomiting. Seek urgent anaesthetic review and discuss with a paediatric critical care specialist if a child or young person with DKA cannot protect their airway because they have a reduced level of consciousness. Discuss the use of inotropes with a paediatric critical care specialist if a child or young person with DKA is in hypotensive shock. Think about sepsis in a child or young person with DKA who has any of the following: fever or hypothermia hypotension refractory acidosis lactic acidosis. ## Fluid and insulin therapy Treat DKA with intravenous fluids and intravenous insulin if the child or young person is not alert, is nauseated or vomiting, or is clinically dehydrated. Do not give oral fluids to a child or young person who is receiving intravenous fluids for DKA unless ketosis is resolving, they are alert, and they are not nauseated or vomiting. For children and young people with DKA who are clinically dehydrated but not in shock: give an initial intravenous bolus of 10 ml/kg 0.9% sodium chloride over 30 minutes discuss with the responsible senior paediatrician before giving more than one intravenous bolus of 10 ml/kg 0.9% sodium chloride -nly consider giving a second 10 ml/kg 0.9% sodium chloride intravenous bolus if needed to improve tissue perfusion, and only after reassessing their clinical status when calculating the total fluid requirement, subtract these initial bolus volumes from the total fluid deficit. For children and young people who have signs of shock, that is weak, thready (low-volume) pulse and hypotension, give an initial intravenous bolus of 10 ml/kg 0.9% sodium chloride as soon as possible. When calculating the total fluid requirement, do not subtract this fluid bolus from the total fluid deficit. Be aware that: shock is rare in children and young people with DKA prolonged capillary refill, tachycardia and tachypnoea are common in children with moderate-to-severe DKA, but this does not mean the child or young person is in shock (these are signs of vasoconstriction caused by metabolic acidosis and hypocapnia). Calculate the total fluid requirement for the first 48 hours in children and young people with DKA by adding the estimated fluid deficit to the fluid maintenance requirement: For the fluid deficit: in mild-to-moderate DKA (blood pH 7.1 or above), assume 5% dehydration (so a 10 kg child needs 500 ml) in severe DKA (blood pH below 7.1), assume 10% dehydration aim to replace the deficit evenly over the first 48 hours, but in critically ill children and young people, discuss the fluid regimen early with the senior paediatrician or paediatric intensivist (or both) because the risk of cerebral oedema is higher. For the fluid maintenance requirement, use the Holliday–Segar formula: give 100 ml/kg for the first 10 kg of weight give 50 ml/kg for the second 10 kg of weight give 20 ml/kg for every kg after this use a maximum weight of 75 kg in the calculation. When calculating the total fluid requirement, subtract any initial bolus volumes from the total fluid deficit (unless the child or young person is in shock). Use 0.9% sodium chloride without added glucose for both rehydration and maintenance fluid in children and young people with DKA, until the plasma glucose concentration is below 14 mmol/litre. Be aware that some children and young people with DKA may develop hyperchloremic acidosis, but this resolves on its own over time and specific management is not needed. Include 40 mmol/litre (or 20 mmol/500 ml) potassium chloride in all fluids (except the initial intravenous boluses) given to children and young people with DKA, unless they have anuria or their potassium level is above the normal range. Do not delay potassium replacement, because hypokalaemia can occur once the insulin infusion starts. For children and young people with potassium levels above the normal range, only add 40 mmol/litre (or 20 mmol/500 ml) potassium chloride to their intravenous fluids if: their potassium is less than 5.5 mmol/litre or they have a history of passing urine. For children and young people with DKA who have hypokalaemia at presentation, include potassium chloride in intravenous fluids before starting the insulin infusion. Monitor sodium levels throughout DKA treatment and calculate the corrected sodium initially to identify if the child or young person has hyponatraemia. When monitoring serum sodium levels in children and young people with DKA, be aware that: serum sodium should rise as DKA is treated as blood glucose falls falling serum sodium is a sign of possible cerebral oedema a rapid and ongoing rise in serum sodium concentration may also be a sign of cerebral oedema, caused by the loss of free water in the urine. Do not give intravenous sodium bicarbonate to children and young people with DKA unless: they have compromised cardiac contractility, caused by life-threatening hyperkalaemia or severe acidosis and you have discussed with the paediatric intensivist. Do not give children and young people with DKA additional intravenous fluid to replace urinary losses. Start an intravenous insulin infusion 1 to 2 hours after beginning intravenous fluid therapy in children and young people with DKA. If a child or young person with DKA is using an insulin pump, disconnect the pump when starting intravenous insulin therapy. When treating DKA with intravenous insulin in children and young people, use a soluble insulin infusion at a dosage between 0.05 units/kg/hour and 0.1 units/kg/hour. Do not give bolus doses of intravenous insulin. In discussion with a diabetes specialist, think about continuing subcutaneous basal insulin in a child or young person who was using a basal insulin before DKA started. When the plasma glucose concentration falls below 14 mmol/litre in children and young people with DKA, change fluids to 0.9% sodium chloride with 5% glucose and 40 mmol/litre (or 20 mmol/500 ml) potassium chloride. If a child or young person's plasma glucose falls below 6 mmol/litre during DKA treatment: increase the glucose concentration of the intravenous fluid infusion and if they have persisting ketosis, continue to give insulin at a dosage of least 0.05 units/kg/hour. If the blood beta‑hydroxybutyrate level is not falling within 6 to 8 hours in a child or young person with DKA, think about increasing the insulin dosage to 0.1 units/kg/hour or more. Think about stopping intravenous fluid therapy for DKA in a child or young person if: ketosis is resolving and their blood pH has reached 7.3 and they are alert and they can take oral fluids without nausea or vomiting.Discuss with the responsible senior paediatrician before stopping intravenous fluid therapy and changing to oral fluids for DKA in a child or young person if they still have mild acidosis or ketosis. Do not change from intravenous insulin to subcutaneous insulin in a child or young person with DKA until ketosis is resolving, they are alert, and they can take oral fluids without nausea or vomiting. Start subcutaneous insulin in a child or young person with DKA at least 30 minutes before stopping intravenous insulin. For a child or young person with DKA who is using an insulin pump, restart the pump at least 60 minutes before stopping intravenous insulin. Change the insulin cartridge and infusion set and insert the cannula into a new subcutaneous site. For a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on fluid therapy . Full details of the evidence and the committee's discussion are in evidence review A: fluid therapy for the management of diabetic ketoacidosis. Loading. Please wait. ## Monitoring during therapy Monitor and record the following at least hourly in children and young people with DKA: capillary blood glucose heart rate, blood pressure, temperature, respiratory rate (look for Kussmaul breathing) fluid balance, with fluid input and output charts level of consciousness (using the modified Glasgow Coma Scale). Monitor and record the level of consciousness (using the modified Glasgow Coma Scale) and heart rate (to detect bradycardia) every 30 minutes in: children under 2 years with DKA children and young people with severe DKA (blood pH below 7.1).This is because these children and young people are at an increased risk of cerebral oedema. Monitor children and young people having intravenous therapy for DKA using continuous electrocardiogram (ECG) to detect signs of hypokalaemia (including ST‑segment depression and prominent U‑waves). Ensure that healthcare professionals performing the monitoring described in recommendations 1.4.46, 1.4.47 and 1.4.48 know what to look for and when to seek advice. At 2 hours after starting treatment, and then at least every 4 hours, carry out and record the results of the following blood tests in children and young people with DKA: glucose (laboratory measurement) blood pH and pCO2 plasma sodium, potassium and urea beta‑hydroxybutyrate. A doctor involved in the care of the child or young person with DKA should review them face‑to‑face at diagnosis and then at least every 4 hours, and more frequently if: they are aged under 2 years they have severe DKA (blood pH below 7.1) there are any other reasons for special concern. At each face‑to‑face review of children and young people with DKA, assess the following: clinical status, including vital signs and neurological status results of blood investigations ECG trace cumulative fluid balance record. Update the child and young person with DKA and their families or carers regularly about their progress. ## Complications of diabetic ketoacidosis Immediately assess children and young people with DKA for suspected cerebral oedema if they have any of these early manifestations: headache agitation or irritability unexpected fall in heart rate increased blood pressure. If cerebral oedema is suspected in a child or young person with DKA, start treatment immediately. Start treatment for cerebral oedema immediately in children and young people with DKA and any of these signs: deterioration in level of consciousness abnormalities of breathing pattern, such as respiratory pauses -culomotor palsies pupillary inequality or dilatation. When treating cerebral oedema in children and young people with DKA, use the most readily available of: mannitol (20%, 0.5 g/kg to 1 g/kg over 10 to 15 minutes) or hypertonic sodium chloride (2.7% or 3%, 2.5 ml/kg to 5 ml/kg over 10 to 15 minutes). After starting treatment for cerebral oedema with mannitol or hypertonic sodium chloride in a child or young person with DKA, immediately seek specialist advice on further management, including which care setting would be best. If a child or young person with DKA develops hypokalaemia (potassium below 3 mmol/litre): think about temporarily suspending the insulin infusion discuss hypokalaemia management urgently with a paediatric critical care specialist because a central venous catheter is needed to give intravenous potassium solutions above 40 mmol/litre. Be aware of the increased risk of venous thromboembolism in children and young people with DKA, especially if they have a central venous catheter. ## Avoiding future episodes of diabetic ketoacidosis After a child or young person with known diabetes has recovered from an episode of DKA, discuss what may have led to the episode with them and their families or carers. Think about the possibility of non‑adherence to therapy in children and young people with established type 1 diabetes who present with DKA, especially if they have had multiple episodes of DKA. Advise children and young people who have had DKA and their families or carers how to reduce the risk of future episodes. In particular, explain the importance of managing intercurrent illnesses. # Service provision Offer children and young people with diabetes an ongoing integrated package of care, provided by a multidisciplinary paediatric diabetes team. The diabetes team should include members with training in clinical, educational, dietetic, lifestyle, mental health and foot care aspects of diabetes for children and young people. Offer children and young people with diabetes and their families or carers 24‑hour access to advice from their diabetes team. Involve children and young people with diabetes and their families or carers in making decisions about the package of care provided by their diabetes team. At diagnosis, offer children and young people with diabetes either home‑based or inpatient management, depending on their clinical need, family circumstances and preferences. Explain that home‑based care with support from the local paediatric diabetes team (including 24‑hour telephone access) is safe, and is as effective as initial inpatient management. Offer initial inpatient management to children with diabetes who are under 2 years old. Think about initial inpatient management for children and young people with diabetes if there are social or emotional factors that would make home‑based management inappropriate, or if they live a long way from the hospital. Diabetes teams should speak regularly with school staff who look after children and young people with type 1 diabetes, to provide diabetes education and practical information. Record the details of children and young people with diabetes on a population‑based, practice‑based or clinic‑based diabetes register. ## Transition from paediatric to adult care Give young people with diabetes enough time to understand how transition from paediatric to adult services will work, because this improves clinic attendance. Agree specific local protocols for transferring young people with diabetes from paediatric to adult services. Base the decision on when a young person should transfer to the adult service on their physical development and emotional maturity, and on local circumstances. Ensure that transition from the paediatric service occurs at a time of relative stability in the young person's health, and that it is coordinated with other life transitions. Explain to young people with type 1 diabetes who are preparing for transition to adult services that some aspects of diabetes care will change. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## Continuous glucose monitoring This covers both real-time (rtCGM) and intermittently scanned (isCGM, commonly referred to as 'flash') continuous glucose monitoring. A continuous glucose monitor is a device that measures blood glucose levels and sends the readings to a display device or smartphone. ## Hyperchloremic acidosis A persisting base deficit or low bicarbonate concentration, despite evidence of resolving ketosis and clinical improvement. ## Insulin pump Continuous subcutaneous insulin infusion. A programmable pump and insulin storage device that gives a regular or continuous amount of insulin (usually a rapid‑acting insulin analogue or short‑acting insulin) through a subcutaneous needle or cannula. ## Level 3 carbohydrate counting Carbohydrate counting with adjustment of insulin dosage according to an insulin to carbohydrate ratio. ## Multiple daily injection basal-bolus regimen Injections of short‑acting insulin or rapid‑acting insulin analogue before meals, together with 1 or more separate daily injections of intermediate‑acting insulin or long‑acting insulin analogue. ## Periodontitis A chronic inflammatory gum disease that destroys the supporting tissues of the teeth (the periodontium). Gingivitis is a milder form of periodontal disease than periodontitis. However, gingivitis still causes inflammation in the gum, and if not treated it can lead to periodontitis. ## Once-, twice-, or three‑times daily mixed insulin injections These are usually injections of short‑acting insulin or rapid‑acting insulin analogue mixed with intermediate‑acting insulin.# Recommendations for research The guideline committee has made the following recommendations for research. # Use of routinely collected real-world data to examine the effectiveness and cost effectiveness of continuous glucose monitoring Based on routinely collected real-world data, what is the effectiveness and cost effectiveness of continuous glucose monitoring devices to improve glycaemic control in children and young people? For a short explanation of why the committee made this recommendation for research, see the rationale section on continuous glucose monitoring . Full details of the evidence and the committee's discussion are in evidence review B: continuous glucose monitoring in children and young people with type 1 diabetes. Loading. Please wait. # Effectiveness of glucose-lowering agents used to manage blood glucose levels in children and young people with type 2 diabetes In children and young people with type 2 diabetes, what is the effectiveness of glucose-lowering agents used to manage blood glucose levels in adults with type 2 diabetes? For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale section on glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. # Weekly treatment with glucose-lowering agents for managing blood glucose levels In children and young people with type 2 diabetes, what is the effectiveness of weekly treatment with glucose-lowering agents for managing blood glucose levels compared to daily treatment? For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale section on glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes . Full details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes. Loading. Please wait. # Continuous glucose monitor sensor adhesive to prevent sensitivities What is the best continuous glucose monitor sensor adhesive to prevent sensitivities to the device, for example local skin reactions? For a short explanation of why the committee made this recommendation for research, see the rationale section on continuous glucose monitoring . Full details of the evidence and the committee's discussion are in evidence review B: continuous glucose monitoring in children and young people with type 1 diabetes. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Continuous glucose monitoring in children with type 1 diabetes Recommendations 1.2.60 to 1.2.70 ## Why the committee made the recommendations The evidence on real-time continuous glucose monitoring (rtCGM) showed it leads to: a decrease in HbA1c and an increase in time in range. This reflected the committee's experience in clinical practice. They highlighted that the continuous nature of rtCGM, and the fact that it can be connected to the phone or device of a parent or carer so they can track the data, were particularly important components for children and young people. Because the evidence showed similar benefits of rtCGM for children and young people as for adults, the committee extrapolated the cost-effectiveness results from adults, concluding that rtCGM was cost effective in this population. The committee agreed that children and young people needed support to understand how continuous glucose monitoring (CGM) works, the accuracy of devices and the benefits it can provide, so they emphasised that rtCGM should be provided along with education on how to use it. Intermittently scanned CGM (isCGM) had no clinically meaningful effect on any of the outcomes that were looked at in the evidence. In the committee's experience, the intermittent nature of isCGM can affect adherence in children and young people. Since the same clinical benefits were not found for isCGM in children and young people as in adults, the committee agreed those cost-effectiveness findings could not be extrapolated, so they could not conclude that isCGM is a cost-effective technology for the full population of children and young people. They therefore agreed that isCGM should be restricted to children and young people who are unable or do not want to use rtCGM, or who would prefer isCGM. Children and young people who prefer isCGM are likely to have better adherence with this type of device, so it would provide more benefit. The recommendation limits isCGM to children aged 4 and over because no isCGM devices are licensed in children under 4. The committee did not make a recommendation on using specific devices because CGM technologies are changing very quickly and this recommendation would soon be out of date. Local healthcare services are better placed to assess which devices are evidence-based and suitable for use at any given time. The committee wanted to highlight the importance of providing choice between the different CGM devices because the best device for each person would vary, so they produced a list of what to consider when discussing this with children and young people. The committee recommended keeping capillary blood glucose monitoring as a back-up for situations such as when blood glucose levels are changing quickly or when technology fails. CGM should also be included in the continuing programme of education that children and young people with type 1 diabetes are offered. This will increase the likelihood that people will scan and report the results frequently, allowing them to understand and manage their diabetes effectively. In addition, children and young people should be supported by a team with expertise in using CGM. This will help them to use the technology effectively to manage their diabetes. The committee made the recommendation about discussing possible problems with children and young people who are not using their device 70% of the time because it is important that the CGM device is used for a significant proportion of time for it to have a positive effect. They wanted to avoid a child or young person feeling 'punished' for using it less than that, but agreed that less than 70% use should trigger a discussion to find out if extra support is needed. While they did not make recommendations on stopping CGM, the committee acknowledged that it may not be offered as a permanent solution and that it can be stopped if it is not being used effectively or not perceived to be providing enough benefit. Despite the positive recommendations on CGM, the committee were concerned that existing health inequalities may still lead to lower uptake of CGM in some groups of people. To address this, the committee made a recommendation outlining actions for commissioners, providers and healthcare professionals. One of the known factors determining the use of CGM devices among children and young people with type 1 diabetes is sensitivities to the device, such as local skin reactions to the adhesive used in the sensor. The committee agreed that research is needed to investigate strategies to reduce local skin reactions to promote ease of use and adherence of these devices, so they made a recommendation for research on continuous glucose monitor sensor adhesive to prevent sensitivities. The committee also made a recommendation for research using routinely collected real-world data to examine the effectiveness and cost effectiveness of CGM. They agreed that this has the potential to show the direct effects of implemented technology in children and young people instead of interpreting it through the results of clinical trials. Increased monitoring of routine healthcare data including registries and audits would ensure the findings from a broader population is captured. ## How the recommendations might affect practice These recommendations are likely to result in broader access to rtCGM and isCGM devices for children and young people. This will increase costs but should reduce inequalities and enable more people to access the technology. Currently, children and young people, and their parents and carers, who have more time and knowledge to advocate or self-advocate are often more likely to gain access to these devices. Some children and young people have insulin insufficiency because of other conditions. The committee noted that these children and young people would get the same care as children and young people with type 1 diabetes, so they should have access to CGM. Return to recommendations # Periodontitis Recommendations 1.2.1, 1.2.130 to 1.2.132, and 1.3.90 to 1.3.92 ## Why the committee made the recommendations There was no evidence for children and young people, so the committee extrapolated from the evidence for adults with type 1 and type 2 diabetes. There was a lot of consistent evidence showing that adults with diabetes are at increased risk of periodontitis and that non-surgical treatment can improve diabetic control. The clinical and cost effectiveness of periodontal treatment in adults were sufficient to justify the recommendations for children and young people with diabetes. Children and young people with diabetes are at increased risk of developing periodontitis. However, in the committee's experience, they are often unaware of this and may not be having regular oral health reviews. To address this, the committee recommended routinely discussing the risk of periodontitis at the child or young person's regular diabetes reviews, alongside eye disease and foot problems. Oral hygiene and the need for regular oral health reviews has been added to the standard education children and young people with diabetes should receive, because this will help them prevent periodontitis. ## How the recommendations might affect practice For oral healthcare professionals, the long-term impact of the recommendations is uncertain. The recommendations specify that people should follow existing NICE guidelines on oral health. However, the recommendations may also increase awareness of periodontitis, leading to a possible short-term increase in the number of oral health reviews. Any increase in the number of oral health reviews will potentially impact on services as NHS dental services already have capacity issues. A short-term increase in the number of oral health reviews will also lead to a short-term increase in costs. However, there is likely to be a larger long-term reduction in costs from the improvement to oral health and diabetes control. Oral healthcare and dental teams will need clear advice on what they need to do for people with diabetes. They will need clear care pathways to improve quality of care and service delivery, in line with the NHS England commissioning standard on dental care for people with diabetes. NHS dental services are free for children and young people under 18, although not everyone makes use of this. The recommendations may encourage more children and young people with diabetes to have regular oral health reviews. Combined with proactive engagement and enhanced support for children and young people with diabetes, this may broaden access to dental and oral healthcare and help to reduce oral health inequalities. Return to recommendations # Glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes ## Education and information Recommendations 1.3.1, 1.3.2, 1.3.4 and 1.3.5 Type 2 diabetes in children and young people can be effectively managed through a combination of: lifestyle changes (for example, diet and exercise) blood glucose monitoring and glucose-lowering agents. The committee made recommendations to provide information and education to support all 3. They also made 3 further recommendations about education and information. They agreed that: Insulin therapy to manage blood glucose levels is a complicated and demanding treatment. Children and young people with type 2 diabetes should be given the opportunity to learn about it so that they can more effectively manage their disease. Information should be provided in a way that takes the specific needs and preferences of children and young people with type 2 diabetes into account and supports shared decision making. Information and education about CGM for those receiving insulin or who are in specific groups should be part of a continuing programme of education because it is likely that they will use it at least once during the course of their lives. The recommendations are not expected to substantially affect practice. Return to recommendations ## At diagnosis Recommendations 1.3.23 to 1.3.25 In the committee's experience, children and young people with type 2 diabetes are sometimes not cared for by a multidisciplinary team, in a specialist paediatric diabetes clinic. When this is the case, the child or young person is not able to access additional essential services such as telephone or mental health support. The committee therefore made a recommendation to ensure equal access to paediatric diabetes services for all children and young people with type 2 diabetes. Various formulations of metformin are available, but only the standard-release tablets are licensed for use in a paediatric population. As of April 2023, use of other formulations would be off-label. However, the committee left the choice of metformin monotherapy formulation open on the basis that: alternative formulations may be more acceptable or better tolerated, and it is common practice for these to be used off-label in such cases the unit cost per day of modified-release tablets is the same as that of standard-release tablets. The committee also recommended, using their knowledge and experience, that children and young people with type 2 diabetes should be offered capillary blood glucose monitoring equipment to allow them to monitor their own glucose levels. The committee agreed, based on their knowledge and experience, that a high HbA1c level at diagnosis justifies adding insulin therapy to metformin to reduce: blood glucose levels, and therefore reduce the risk of hyperglycaemia the risk of developing diabetic ketoacidosis (DKA) the risk of hyperglycaemia-related complications in the long term. They did not specify which insulin therapy should be used (for example, short-, long-, or intermediate-acting) because they agreed that this choice should be left to the relevant healthcare professional to allow flexibility of treatment. They also agreed that the presence of ketosis indicates a current insulin deficiency, so a multiple daily (basal-bolus) insulin injection is needed to ensure, as a matter of safety, that DKA does not develop. The recommendations are not expected to substantially affect practice because dietary management is standard practice. It is also common for different metformin formulations to be used because some children and young people prefer formulations other than the standard-release tablet. Given the relatively small number of children and young people with type 2 diabetes in England and Wales (1,560 in all NHS settings as of 2019/20, according to the NHS Digital report on Young People with type 2 diabetes, 2019-20), the provision of equipment for both capillary blood glucose monitoring and insulin is not expected to have a significant resource impact. Return to recommendations ## Monitoring blood glucose levels and reviewing treatment Recommendations 1.3.26 to 1.3.29 The committee agreed that, for children and young people with type 2 diabetes, it is important to: achieve an HbA1c level of 48 mmol/mol (6.5%) or lower as early as possible in the treatment pathway to avoid later complications (such as cardiovascular, kidney and liver disease) and avoid staying on the same treatment for too long without reassessing its effectiveness. As a result, they also agreed that current guidance to measure HbA1c levels every 3 months should be retained but supplemented with new recommendations, to make provision for an initial visit earlier than 3 months after diagnosis and for the use of data from capillary blood glucose monitoring or CGM. This is because combining HbA1c and glucose monitoring data will allow seeing trends quicker than changes in HbA1c levels alone. The target HbA1c level of 48 mmol/mol (6.5%) or lower was chosen because: it can be used to diagnose type 2 diabetes and staying below this level is recommended to minimise the risk of long-term complications (see recommendation 1.3.31). The committee agreed, using their knowledge and experience, that a first visit to review glucose data should take place after 4 weeks of metformin monotherapy. A period of 4 weeks was agreed because: at least 4 weeks of glucose monitoring data is needed to assess whether glucose levels are improving or whether treatment needs to be escalated although current guidance is for the first clinical visit to take place 3 months after diagnosis, in practice, this occurs earlier because newly diagnosed children and young people with type 2 diabetes often need more support than those whose glucose levels have already stabilised for children and young people with type 2 diabetes who are also on insulin therapy, safely reducing and stopping insulin typically takes 2 to 6 weeks, so a review of additional CGM data at 4 weeks will help. Given the above considerations and the many differences between individual children and young people with type 2 diabetes, the committee agreed that healthcare professionals should carry out subsequent reviews at least every 3 months (the recommended frequency of HbA1c measurements). However, they recognised and allowed for the fact that reviews may be required more often (especially if the child or young person is on insulin therapy). The committee acknowledged that there are rare cases in which HbA1c measurements cannot be used (for example, when the child or young person has abnormal haemoglobin). Using their knowledge and experience, they recommended 3 alternative methods of estimating average glycaemia for use in such cases. They also agreed that the frequency of monitoring should be based on several factors: the type of treatment the duration of the child or young person's type 2 diabetes and their general ability to maintain blood glucose within the target range. For example, children and young people with type 2 diabetes who are on insulin but not using CGM will need to test their capillary blood glucose 4 to 5 times a day while those using insulin and CGM will not need to test it so often. As blood glucose levels stabilise, frequency of capillary blood glucose monitoring can be reduced. Given these considerations, enough test strips should be prescribed to enable the person to self-monitor as required by their treatment until the next review. The recommendations on capillary blood glucose monitoring and an initial review 4 weeks after diagnosis reflect current practice in England and therefore are not expected to have a significant impact. Return to recommendations ## Continuous glucose monitoring Recommendations 1.3.38 to 1.3.47 CGM is already recommended for everyone with type 1 diabetes and in some adults with type 2 diabetes, and the committee agreed that children and young people with type 2 diabetes should be offered the same. The committee's decision to include these recommendations was also based on the following: Type 2 diabetes in children and young people is the most aggressive form of the disease, and this population will live with the condition for longer than adults with type 2 diabetes, so timely intervention is important to reduce the risk of developing severe long-term (and possibly life-threatening) complications, such as peripheral neuropathy. Many children and young people experience health inequalities because of comorbidities (for example, special educational needs or learning disabilities), which can make it difficult for them to conduct capillary blood glucose measurements. Capillary blood glucose monitoring often requires several finger-prick tests a day, which can be tiring, stressful and have a negative psychological impact on the person. CGM provides another, less invasive way for children and young people with diabetes to manage their blood glucose levels. Some CGM devices allow glucose data to be shared electronically. Using CGM, even in the short term, is likely to improve the child or young person's understanding of their own blood glucose patterns because of the continuous and visual way CGM allows glucose data to be presented. The evidence base for the effectiveness of CGM in this population is limited, mostly because of the small number of children and young people with type 2 diabetes. As a result, the committee based recommendations on CGM for this population on the recommendations about CGM for children and young people with type 1 diabetes, in this guideline, and on the recommendations about CGM for adults in NICE's guideline on type 2 diabetes in adults. The 2022 evidence review on the effectiveness of CGM to improve blood glucose level management in children and young people with type 1 diabetes concluded that: rtCGM is more effective than capillary blood glucose monitoring isCGM is no more effective than capillary blood glucose monitoring. Therefore, the committee agreed that rtCGM should be considered when children and young people with type 2 diabetes are on insulin therapy because of: the increased risk of hypoglycaemia comorbidities associated with type 2 diabetes in children and young people and the decreasing costs over time of available and appropriate devices. As for adults, the committee agreed that CGM should not be considered for all children and young people with type 2 diabetes because some will be able to maintain their blood glucose levels within the target range using glucose-lowering agents that do not increase the risk of hypoglycaemia (such as metformin monotherapy). The option to consider isCGM for people over 4 years old was provided because: some children and young people with type 2 diabetes have difficulties using rtCGM or may prefer isCGM to rtCGM in May 2023, isCGM was licensed for children aged 4 years and over. The committee agreed that a stronger recommendation to offer rtCGM to 3 specific groups was justified, regardless of whether they are having insulin therapy, because of the child or young person's individual needs and the treatment burden associated with capillary blood glucose monitoring. Regardless of the reason the child or young person with type 2 diabetes is offered CGM, the committee agreed that it should be provided by a team with expertise in its use, so that support can be provided and any issues with it can be quickly resolved. The committee agreed that CGM should not replace capillary blood glucose monitoring because it is still needed both for checking the CGM device and as a back-up. They made some further recommendations about choosing and using a CGM device to encourage adherence and provide support. Finally, the committee agreed, in line with the recommendations for children and young people with type 1 diabetes, that inequalities in access and uptake of CGM may still occur for those with type 2 diabetes, so they added a recommendation to address this. For example, obesity and type 2 diabetes are also closely associated, as are childhood obesity and socioeconomic status (it is highest among children living in the most deprived areas). The availability of devices for rtCGM or isCGM that allow remote sharing of data is increasing, although there can be wide variation in their cost. Some children or young people will also not have access to a mobile phone or compatible electronic device, which the CGM devices may require, so some provision for this may be needed. However, the number of children and young people with type 2 diabetes who will be eligible for CGM will also be relatively low. So, the recommendations to consider or offer CGM is unlikely to have a significant resource impact. Return to recommendations ## When to reduce insulin for people who have been on it from diagnosis Recommendation 1.3.48 The committee recognised that insulin use substantively increases the risk of hypoglycaemia and weight gain and that it should be gradually reduced and stopped when the person's HbA1c levels is under the 48 mmol/mol (6.5%) threshold. They agreed 3 criteria for when to reduce insulin use, based on those recommended for type 1 diabetes (see recommendation 1.2.55). The committee also recognised that the choice of how often glucose levels could exceed the target ranges was somewhat arbitrary, but they were keen to avoid basing decisions on single events and agreed that having low glucose levels more often than not (for example, on 4 or more days a week) would certainly indicate that insulin can be reduced. The recommendation is not expected to substantially affect practice. Return to recommendation ## Adding liraglutide, dulaglutide, or empagliflozin Recommendations 1.3.49 to 1.3.55 The committee made separate recommendations about combining metformin with other glucose-lowering agents for children and young people with type 2 diabetes who are or are not on insulin therapy because insulin therapy is associated with specific risks (such as hypoglycaemia) not associated with metformin monotherapy. However, the overall rationale for these recommendations remains broadly the same and any differences relating to insulin therapy will be noted below. Three thresholds were chosen for when to initiate metformin therapy with liraglutide, dulaglutide, or empagliflozin (rather than insulin) for children and young people with type 2 diabetes. These thresholds reflect the chosen HbA1c threshold and upper limits of the blood glucose target ranges in recommendation 1.3.48. Overall, the evidence showed that 2 GLP-1 receptor agonists, liraglutide and dulaglutide, and one SGLT2 inhibitor, empagliflozin, were generally effective in the short term at reducing glucose levels in children and young people with type 2 diabetes. Liraglutide and dulaglutide had significant effects on the majority of critical outcomes, including change in HbA1c level, mean fasting plasma glucose level, and use of insulin rescue medication. Empagliflozin also had significant effects on change in HbA1c percentage level and mean fasting plasma glucose level. No difference on the important outcomes (serious adverse events, gastrointestinal symptoms) was found in the short term. Only one trial reported long-term data, comparing liraglutide to placebo, which showed that its effectiveness for managing blood glucose levels was maintained after 52 weeks. However, there was an increased risk of nausea and vomiting. Though the recommendations mean potentially combining dulaglutide, liraglutide or empagliflozin with metformin earlier than it would be combined for an adult, the committee agreed it is justified by the relatively small number of available treatments for the paediatric population and the risks associated with: not achieving an HbA1c level of 48 mmol/mol (6.5%) or lower, and developing complications related to diabetes. The committee agreed that this should be done in preference to offering insulin because of the risks of hypoglycaemia and weight gain associated with insulin use. The restriction to children and young people aged 10 years or over reflects the licensing conditions for liraglutide. The weaker strength of recommendation for empagliflozin reflects the evidence, suggesting that it is slightly less effective at managing blood glucose levels than liraglutide and dulaglutide, although there was no direct evidence comparing any of these agents to each other. The committee also agreed that the lowest dose of liraglutide, dulaglutide, and empagliflozin needed to maintain the target ranges specified in recommendation 1.3.48 should be maintained. This is because higher doses can lead to side effects and poorer treatment adherence. The committee also agreed, using their experience, that a specific warning about the use of empagliflozin was needed because its use as a glucose-lowering agent in the paediatric population is relatively recent. Insulin use is associated with an increased risk of hypoglycaemia and weight gain. Given this, the committee recommended that, for children and young people with type 2 diabetes on metformin only, insulin should only be offered when other treatments have failed to stabilise glucose levels. Similarly, the committee agreed that, for children and young people with type 2 diabetes who are on both metformin and insulin, insulin should only be increased when adding other treatments has failed to stabilise glucose levels. However, the committee recognised that there may be some children and young people with type 2 diabetes in whom other treatments (that is, liraglutide, dulaglutide or empagliflozin) may be contraindicated or not tolerated. The committee agreed that this should not prevent increasing their insulin dose and added a specific provision in the criteria to account for this. The committee also discussed whether body mass index should be a criterion for starting treatment with glucose-lowering agents – as it is for adults – but decided that this was not needed because a small proportion of children and young people with type 2 diabetes are not overweight and specifying such a criterion would exclude this group from treatment. Dulaglutide is administered as a weekly injection, whereas liraglutide requires daily injections. Empagliflozin is an oral (tablet) treatment. Because some children and young people may prefer 1 treatment regimen over the other, the committee agreed to recommend both liraglutide and dulaglutide injections and, if contraindicated, oral empagliflozin, even though: There is an increased risk of nausea and vomiting associated with long-term use of liraglutide. There was no long-term comparative data for dulaglutide or empagliflozin. Dulaglutide, liraglutide or both may be contraindicated in some children and young people with type 2 diabetes. The committee recognised that they did not have direct evidence comparing the effectiveness of weekly treatments compared to daily treatments with glucose-lowering agents for managing blood glucose levels. So, they made a research recommendation to: address this gap assess whether weekly injections could help reduce stigma and treatment burden for children and young people with type 2 diabetes. There are a lot of medicines that can be used to manage blood glucose levels in adults with type 2 diabetes. In contrast, there are very few licensed, effective and safe medicines to manage blood glucose levels for children and young people with type 2 diabetes. The committee thus made a research recommendation for further clinical trials in children and young people of medicines used for adults. As of April 2023, there are 4 other medicines that are licensed for use in the UK in a paediatric population: exenatide (a GLP-1 receptor agonist) dapagliflozin (an SGLT2 inhibitor) insulin detemir (a long-acting insulin) neutral protamine Hagedorn (NPH) insulin (an intermediate-acting insulin). The committee agreed that the evidence was not sufficient for either of the first 2 licensed medicines to be recommended, nor for one insulin to be recommended over the other. Liraglutide and dulaglutide are relatively expensive compared to other possible treatments but recommending them is unlikely to surpass NICE's £1 million threshold for significant resource impact. Empagliflozin is approximately half the price of both liraglutide and dulaglutide. However, there was insufficient evidence to construct a full cost-effectiveness model. The committee indicated that the difference in unit cost per dose is relatively small, especially when considering the low prevalence of type 2 diabetes in children and young people. Similar considerations apply to using insulin at diagnosis where the prevalence of type 2 diabetes combined with a high HbA1c level or high blood ketones is even lower. Increased support from a paediatric diabetic nurse and consultant will be needed when the child or young person starts on liraglutide, dulaglutide or empagliflozin. However, once the child or young person's HbA1c levels are stabilised, this will no longer be required because repeat prescriptions can be made by the GP. Insulin is a last resort in the management of type 2 diabetes in children and young people and the recommendations are not expected to substantially affect practice. Return to recommendations ## Insulin therapy Recommendations 1.3.56 to 1.3.60 The committee based their recommendations on insulin therapy on those for children and young people with type 1 diabetes. Overall, the committee agreed that the choice of insulin therapy should be left to the child or young person with type 2 diabetes (or their families or carers), in consultation with the specialist diabetes paediatric team. The committee made some general recommendations about choosing an insulin regimen, providing appropriate equipment for injections, reviewing injection sites, and providing additional support when their glucose levels are not optimal. Insulin is a last resort in the management of type 2 diabetes in children and young people and the recommendations are not expected to substantially affect practice. Return to recommendations ## Changing treatments and updating school healthcare plans Recommendation 1.3.61 The committee agreed that the paediatric diabetes team should update the child or young person's school healthcare plan annually, and when treatment changes in a way that affects the child or young person while they are at school. This will enable coordination of care with the child's or young person's school. The recommendation is not expected to substantially affect practice. Return to recommendation # Fluid therapy for diabetic ketoacidosis Recommendations 1.4.21 to 1.4.34, 1.4.39, 1.4.40 and 1.4.42 ## Why the committee made the recommendations The 2015 recommendations caused some confusion around when to use oral or intravenous fluids. To address this, the committee looked for research evidence that would help them make clearer recommendations. There was no evidence that compared different routes of administration or different oral fluids for hydration, so the committee updated the recommendations based on their experience and expertise. In the 2015 guideline, the rate of fluid administration in DKA was restricted because rapid fluid administration was believed to cause cerebral oedema. However, for the 2020 update there was some randomised controlled trial evidence (particularly the PECARN FLUID trial) comparing the effect of different DKA protocols on outcomes such as mortality or clinically apparent brain injury. This evidence showed no significant difference between the 2 protocols, and it demonstrated that the restrictions on the rate of fluid administration were not needed. In response to this evidence, and applying their clinical expertise, the committee updated the recommendations to use more rapid fluid administration (including fluid boluses). They also made a separate recommendation for children and young people who are in shock, as this group need a higher volume of fluids and they need these fluids to be given more rapidly. When the 2015 recommendations were made, rapid fluid administration was believed to cause cerebral oedema. However, more recent randomised controlled trial evidence (particularly the PECARN FLUID trial) has shown that brain injury in this group may be caused by DKA itself because of the resulting cerebral hypoperfusion, reperfusion and neuro-inflammation. If DKA is the cause of brain injury, children and young people would benefit from receiving more fluids in the first 48 hours than was recommended in the 2015 guideline. To address this, the committee updated the recommendation on calculating the fluid maintenance requirement, based on their clinical knowledge and on evidence from the PECARN FLUID trial. The Holliday–Segar formula that they recommended is commonly used in practice and has not been shown to cause any adverse events. No evidence was identified on the use of potassium. The committee used their expertise and their understanding of the evidence on the pathophysiology of DKA to update the recommendation. They added more detail about how to care for children and young people with anuria or potassium levels above the normal range. It is essential to not delay adding potassium to fluids because insulin can cause hypokalaemia in this population, which can lead to cardiac arrhythmias and death. The committee also used their expertise to make recommendations highlighting complications such as hyperchloremic acidosis. The committee used their expertise to make recommendations on monitoring serum sodium levels and identifying children and young people with hyponatraemia. ## How the recommendations might affect practice There is variation in practice due to the different beliefs on the causes of cerebral oedema. The new recommendations will be a change in practice in some areas, but they are in line with randomised trial evidence and with other clinical guidance (such as chapter 11 in the 2018 International Society for Paediatric and Adolescent Diabetes DKA guideline). Return to recommendations# Context Diabetes is a long‑term condition that can have a major impact on the life of a child or young person, as well as their family or carers. In addition to glucose-lowering agents for managing blood glucose levels, diabetes management should include education, support and access to psychological services, as detailed in this guideline. Preparations should also be made for the transition from paediatric to adult services, which have a somewhat different model of care and evidence base. Type 1 diabetes is becoming more common in the UK, and since 2004 type 2 diabetes is also being diagnosed with increasing frequency. The 2020/21 National Paediatric Diabetes Audit identified 29,000 children and young people with type 1 diabetes and 973 with type 2 being managed within a paediatric diabetes unit. Much of the general care for type 2 diabetes is the same as for type 1 diabetes, although the initial management is different. In addition, overweight and obesity associated with type 2 diabetes bring an increased risk of renal complications and problems such as hypertension and dyslipidaemia. These differences in management and complications need guidance specific to type 2 diabetes. A variety of genetic conditions (such as maturity‑onset diabetes in the young) and other conditions (such as cystic fibrosis‑related diabetes) may also lead to diabetes in children and young people, but the care of these diverse conditions is beyond the scope of this guideline. This guideline recommends attempting to reach a glycated haemoglobin (HbA1c) level near the normal range and near normoglycaemia. This is to further reduce the long-term risks associated with diabetes. Newer technology such as continuous subcutaneous glucose monitoring may also help children and young people to have better blood glucose management, although this is not currently recommended for all children and young people with type 2 diabetes. By implementing the strict blood glucose management recommended in this guideline, improvements can be made to diabetes care that reduce the impact of the condition on the future health of children and young people.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Blood glucose and plasma glucose\n\n'Blood glucose' is the more commonly used term. However, a lot of the evidence this guideline is based on uses 'plasma' rather than 'blood' glucose, and patient‑held glucose meters and monitoring systems are calibrated to plasma glucose equivalents. Because of this, in this guideline we use the term 'blood glucose', except when referring to specific concentration values.\n\n# Diagnosis\n\nBe aware that signs of type\xa01\xa0diabetes in children and young people include:\n\nhyperglycaemia (random plasma glucose more than 11\xa0mmol/litre)\n\npolyuria\n\npolydipsia\n\nweight loss\n\nexcessive tiredness. [2004, amended 2015]\n\nRefer children and young people with suspected type\xa01\xa0diabetes immediately (on the same day) to a multidisciplinary paediatric diabetes team with the competencies needed to confirm diagnosis and provide immediate care. [2004, amended 2015]\n\nConfirm type\xa01\xa0diabetes in children and young people using the plasma glucose criteria in the World Health Organization's 2006 report on the diagnosis and classification of diabetes mellitus. [2004, amended 2015]\n\nWhen diagnosing diabetes in a child or young person, assume type\xa01\xa0diabetes unless there are strong indications of type\xa02\xa0diabetes, monogenic or mitochondrial diabetes. \n\nThink about the possibility of type\xa02\xa0diabetes in children and young people with suspected diabetes who:\n\nhave a strong family history of type\xa02\xa0diabetes\n\nare obese\n\nare from a Black or Asian family background\n\ndo not need insulin, or need less than 0.5\xa0units/kg body weight/day after the partial remission phase\n\nshow evidence of insulin resistance (for example, acanthosis nigricans). [2004, amended 2015]\n\nThink about the possibility of other types of diabetes (not type\xa01 or 2), such as other insulin-resistance syndromes, or monogenic or mitochondrial diabetes, in children and young people with suspected diabetes who have any of the following:\n\ndiabetes in the first year of life\n\nrarely or never develop ketones in the blood (ketonaemia) during episodes of hyperglycaemia\n\nassociated features, such as optic atrophy, retinitis pigmentosa, deafness, or another systemic illness or syndrome. [2004, amended 2015]\n\nDo not measure C‑peptide or diabetes‑specific autoantibody titres at initial presentation to distinguish type\xa01\xa0diabetes from type\xa02\xa0diabetes. \n\nConsider measuring C‑peptide after initial presentation if needed to distinguish between type\xa01\xa0diabetes and other types of diabetes. Be aware that C‑peptide concentrations have better discriminative value the longer the interval between initial presentation and the test. \n\nPerform genetic testing if atypical disease behaviour, clinical characteristics or family history suggest monogenic diabetes. \n\n# Type 1 diabetes\n\n## Education and information\n\nOffer children and young people with type\xa01\xa0diabetes and their families or carers a continuing programme of education from diagnosis. Include the following core topics:\n\ninsulin therapy (including its aims and how it works), insulin delivery (including rotating injection sites within the same body region) and dosage adjustment \n\nblood glucose monitoring, including blood glucose and HbA1c targets \n\nhow diet, physical activity and intercurrent illness affect blood glucose levels \n\nmanaging intercurrent illness ('sick‑day rules', including monitoring of blood ketones [beta‑hydroxybutyrate]) \n\ndetecting and managing hypoglycaemia, hyperglycaemia and ketosis \n\nthe importance of good oral hygiene and regular oral health reviews for preventing periodontitis. \n\nTailor the education programme to each child or young person with type\xa01\xa0diabetes and their families or carers, taking account of issues such as:\n\npersonal preferences\n\nemotional wellbeing\n\nage and maturity\n\ncultural considerations\n\nexisting knowledge\n\ncurrent and future social circumstances\n\nlife goals. \n\nEncourage young people with type\xa01\xa0diabetes to attend clinic 4\xa0times a year, and explain that regular contact with the diabetes team will help them maintain optimal blood glucose levels. [2004, amended 2015]\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that, like people without diabetes, they should have:\n\nregular dental examinations (see the NICE guideline on dental checks: intervals between oral health reviews)\n\nan eye examination by an optician at least every 2 years. [2015, amended 2020]\n\nEncourage children and young people with type\xa01\xa0diabetes and their families or carers to discuss any concerns and raise any questions they have with their diabetes team. \n\nGive children and young people with type\xa01\xa0diabetes and their families or carers information about diabetes support groups and organisations, and the potential benefits of membership. Give this information after diagnosis and regularly afterwards. [2004, amended 2015]\n\nEncourage children and young people with type\xa01\xa0diabetes to wear or carry something that tells people they have type\xa01\xa0diabetes (for example, a bracelet). \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers how to find out about government disability benefits. [2004, amended 2015]\n\nTake particular care when communicating with children and young people with type\xa01\xa0diabetes if they or their families or carers have physical or sensory disabilities, or difficulties speaking or reading English. \n\nDiabetes teams should offer comprehensive advice to children and young people with type\xa01\xa0diabetes who want to play sports that have particular risks for people with diabetes. Support groups and organisations (including sports organisations) may be able to provide more information. [2004, amended 2015]\n\nOffer education for children and young people with type\xa01\xa0diabetes and their families or carers on the practical issues around long‑distance travel, such as when best to eat and inject insulin when travelling across time zones. \n\nEncourage children and young people with type\xa01\xa0diabetes not to start smoking. Explain the general health problems smoking causes, in particular the risks of vascular complications. [2004, amended 2015]\n\nFor more guidance on preventing smoking, see also the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. [2004, amended 2015]\n\nOffer smoking cessation programmes to children and young people with type\xa01\xa0diabetes who smoke. See also the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. [2004, amended 2015]\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers about the general dangers of substance misuse and the possible effects on blood glucose levels. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that the Public Health England Green Book recommends they have:\n\nannual immunisation against influenza, starting when they are 6\xa0months old\n\nimmunisation against pneumococcal infection if they are taking insulin or oral hypoglycaemic medicines. [2004, amended 2015]\n\n## Insulin therapy\n\nDiscuss the choice of insulin regimen with the child or young person and their family:\n\nexplain the advantages and disadvantages of the different options\n\ndiscuss their personal circumstances and preferences\n\nhelp them to make an informed decision between the options that are available to them. \n\nOffer children and young people with type\xa01\xa0diabetes a multiple daily injection basal-bolus insulin regimen from diagnosis. \n\nIf multiple daily insulin injections are not appropriate for a particular child or young person, consider an insulin pump, as recommended in the NICE technology appraisal guidance on continuous subcutaneous insulin infusion for the treatment of diabetes mellitus. \n\nEncourage children and young people with type\xa01\xa0diabetes who are having multiple daily insulin injections to adjust the insulin dose if appropriate after each blood glucose measurement. [2004, amended 2015]\n\nTell children and young people with type\xa01\xa0diabetes who are having multiple daily insulin injections to inject rapid‑acting insulin analogues before eating. Explain that this reduces blood glucose levels after meals and will help them optimise their blood glucose levels. [2004, amended 2015]\n\nWhen children and young people start on an insulin pump, train them and their families and carers how to use it. A specialist team should provide ongoing support. [2004, amended 2015]\n\nSpecialist teams should agree a common core of advice to give insulin pump users. [2004, amended 2015]\n\nFor children and young people with type\xa01\xa0diabetes who are using twice-daily injection regimens, encourage them to adjust the insulin dose according to the general trend in their pre‑meal, bedtime and occasional night‑time blood glucose. [2004, amended 2015]\n\nExplain to children and young people with newly diagnosed type\xa01\xa0diabetes and their families or carers that:\n\nthey may have a partial remission phase (a 'honeymoon period') when they start using insulin\n\nduring this time, they may only need a low dosage of insulin (0.5\xa0units/kg body weight/day) to maintain an HbA1c level of less than 48\xa0mmol/mol (6.5%). [2004, amended 2015]\n\nOffer children and young people with type\xa01\xa0diabetes a choice of insulin delivery systems. \n\nProvide children and young people with type\xa01\xa0diabetes insulin injection needles that are the right length for their body fat. [2004, amended 2015]\n\nProvide children and young people with type\xa01\xa0diabetes and their families or carers:\n\nsuitable containers for collecting used needles and other sharps\n\na way to safely get rid of these containers.See also the section on safe use and disposal of sharps in the NICE guideline on healthcare-associated infections. \n\nOffer children and young people with type\xa01\xa0diabetes a review of injection sites at each clinic visit. [2004, amended 2015]\n\nProvide children and young people with type\xa01\xa0diabetes rapid‑acting insulin analogues to use during intercurrent illness or episodes of hyperglycaemia. \n\nIf a child or young person with type\xa01\xa0diabetes does not have optimal blood glucose levels (see recommendation 1.2.55 and recommendation 1.2.76):\n\noffer additional support, such as more contact with their diabetes team and\n\nif necessary, offer an alternative insulin regimen (multiple daily injections, an insulin pump, or once‑, twice‑ or three‑times daily mixed insulin injections). \n\n## Oral medicines\n\nOnly use metformin in combination with insulin within research studies because it is uncertain whether this combination improves blood glucose management. \n\nDo not offer children and young people with type\xa01\xa0diabetes acarbose or sulfonylureas (glibenclamide, gliclazide, glipizide, tolbutamide) in combination with insulin, because they may increase the risk of hypoglycaemia without improving blood glucose management. [2004, amended 2015]\n\n## Dietary management\n\nSupport children and young people with type\xa01\xa0diabetes and their families or carers to develop a good working knowledge of nutrition and how it affects their diabetes. \n\nDiscuss healthy eating regularly with children and young people with type\xa01\xa0diabetes and their families or carers.\n\nExplain that this means eating foods with a low glycaemic index, fruit and vegetables, and appropriate types and amounts of fats.\n\nExplain that healthy eating can reduce their risk of cardiovascular disease.\n\nSupport them to adjust their food choices accordingly. \n\nTake into account social and cultural considerations when providing advice on diet to children and young people with type\xa01\xa0diabetes. \n\nExplain that children and young people with type\xa01\xa0diabetes have the same basic nutritional requirements as other children and young people. Their food should provide enough energy and nutrients for their growth and development. [2004, amended 2015]\n\nFor children and young people who are using a multiple daily insulin injection regimen or an insulin pump, offer level 3 carbohydrate counting education from diagnosis to them and their families or carers. Repeat this offer regularly. \n\nWhen children and young people with type\xa01\xa0diabetes change their insulin regimen, offer them and their families or carers dietary advice tailored to the new treatment. \n\nOffer children and young people with type\xa01\xa0diabetes and their families or carers education about the practical problems associated with fasting and feasting. [2004, amended 2015]\n\nEncourage children and young people with type\xa01\xa0diabetes and their families or carers to discuss the nutritional composition and timing of snacks with their diabetes team. \n\nEncourage children and young people with type\xa01\xa0diabetes to eat at least 5\xa0portions of fruit and vegetables each day. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that a low glycaemic index diet may help to improve blood glucose management and reduce the risk of hyperglycaemic episodes. \n\nOffer children and young people with type\xa01\xa0diabetes and their families or carers advice and education to help them follow a low glycaemic index diet. \n\nOffer children and young people with type\xa01\xa0diabetes dietetic support to help optimise body weight and blood glucose levels. \n\nAt each clinic visit for children and young people with type\xa01\xa0diabetes, measure their height and weight and plot on an appropriate growth chart. Check for normal growth or significant changes in weight because these may reflect changes in blood glucose levels. [2004, amended 2015]\n\nProvide arrangements for weighing children and young people with type\xa01\xa0diabetes that respect their privacy. \n\n## Exercise\n\nEncourage children and young people with type\xa01\xa0diabetes to exercise on a regular basis, and explain that this reduces their long-term risk of developing cardiovascular disease. [2004, amended 2015]\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that they can take part in all forms of exercise, provided that appropriate attention is given to changes in insulin and dietary management. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers about:\n\nthe effects of exercise on blood glucose levels and\n\nhow to avoid hypo‑ or hyperglycaemia during or after physical activity. [2004, amended 2015]\n\nEncourage children and young people with type\xa01\xa0diabetes and their families or carers to monitor blood glucose levels before and after exercise so that they can:\n\nidentify when changes in insulin or food intake are needed\n\nlearn how their blood glucose responds to different levels of exercise\n\nwatch out for exercise‑induced hypoglycaemia\n\nsee how hypoglycaemia can occur several hours after prolonged exercise. [2004, amended 2015]\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that:\n\nthey should have extra carbohydrates as needed to avoid hypoglycaemia and\n\nthey should have carbohydrate‑based foods available during and after exercise. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that they should have extra carbohydrates if their plasma glucose levels are less than 7\xa0mmol/litre before they exercise. [2004, amended 2015]\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that they may need to alter their insulin dose or carbohydrate intake if they change their daily exercise patterns. \n\n## Blood glucose and HbA1c targets and monitoring\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that the optimal target ranges for short‑term plasma glucose management are:\n\nfasting plasma glucose level of 4\xa0mmol/litre to 7\xa0mmol/litre on waking\n\na plasma glucose level of 4\xa0mmol/litre to 7\xa0mmol/litre before meals at other times of the day\n\na plasma glucose level of 5\xa0mmol/litre to 9\xa0mmol/litre after meals\n\na plasma glucose level of at least 5\xa0mmol/litre when driving (see the Driver and Vehicle Licensing Agency [DVLA] guidance for people with diabetes for further details about driving). \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that maintaining blood glucose levels at the lower end of the target ranges will help them achieve the lowest possible HbA1c. \n\nIf children and young people with type\xa01 diabetes experience problematic hypoglycaemia or undue emotional distress while attempting to achieve blood glucose and HbA1c targets, discuss changing the targets with them and their families and carers. \n\nBe aware that blood glucose and HbA1c targets can cause conflict between children and young people with type\xa01\xa0diabetes and their families or carers, and they may need to agree a compromise. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that blood glucose levels should be interpreted in the 'whole child' context, which includes the social, emotional and physical environment. \n\nOffer real-time continuous glucose monitoring (rtCGM) to all children and young people with type\xa01 diabetes, alongside education to support children and young people, and their families and carers, to use it (see recommendation 1.2.67). \n\nOffer intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') to children and young people with type\xa01 diabetes aged 4 years and over who are unable to use rtCGM or who express a clear preference for isCGM. In March 2022, isCGM was licensed for children aged 4 years and over.\n\nOffer children and young people with type\xa01 diabetes a choice of rtCGM device, based on their individual preferences, needs, characteristics, and the functionality of the devices available. See box 1 for examples of factors to consider as part of this discussion. \n\nWhen choosing a continuous glucose monitoring (CGM) device:\n\nuse shared decision making to identify the child or young person's needs and preferences and offer them an appropriate device\n\nif multiple devices meet their needs and preferences, offer the device with the lowest cost. \n\nAccuracy of the device.\n\nWhether the device provides predictive alerts or alarms and if these need to be shared with anyone else, for example a parent or carer.\n\nWhether using the device requires access to particular technologies (such as a smartphone and up-to-date phone software).\n\nHow easy the device is to use and take readings from, including for people with limited dexterity (taking into account the age and abilities of the child or young person and whether the device needs to be used by others).\n\nFear, frequency, awareness and severity of hypoglycaemia.\n\nPsychosocial factors.\n\nThe child or young person's insulin regimen or type of insulin pump, if relevant (taking into account whether a particular device integrates with their pump as part of a hybrid closed loop or insulin suspend function).\n\nWhether, how often and how the device needs to be calibrated, and how easy it is for the person to do this themselves.\n\nHow data can be collected, compatibility of the device with other technology, and whether data can be shared with the person's healthcare provider to help inform treatment.\n\nHow unpredictable the child or young person's activity and blood glucose levels are and whether erratic blood glucose is affecting their quality of life.\n\nWhether the choice of device will impact on the child or young person's ability to attend school or education, or to do their job.\n\nWhether the child or young person takes part in sports or exercise when glucose levels will need additional management.\n\nWhether the child or young person has situations when symptoms of hypoglycaemia cannot be communicated or can be confused, for example during exercise.\n\nClinical factors that may make devices easier or harder to use.\n\nFrequency of sensor replacement.\n\nSensitivities to the device, for example local skin reactions.\n\nBody image concerns.\n\nCGM should be provided by a team with expertise in its use, as part of supporting children and young people to self-manage their diabetes. \n\nAdvise children and young people with type 1 diabetes who are using CGM (and their families or carers) that they will still need to take capillary blood glucose measurements (although they can do this less often). Explain that this is because:\n\nthey will need to use capillary blood glucose measurements to check the accuracy of their CGM device\n\nthey will need capillary blood glucose monitoring as a back-up (for example, when their blood glucose levels are changing quickly or if the device stops working).Provide them with enough test strips to take capillary blood glucose measurements as needed. \n\nIf a person cannot use or does not want rtCGM or isCGM, offer capillary blood glucose monitoring. \n\nInclude CGM in the continuing programme of education provided to all children and young people with type\xa01 diabetes and their families or carers (see the section on education and information). \n\nMonitor and review the child or young person's use of CGM as part of reviewing their diabetes care plan, and explain to them the importance of continuously wearing the device. \n\nIf the child or young person is not using their CGM device at least 70% of the time:\n\nask if they are having problems with their device\n\nlook at ways to address any problems or concerns to improve their use of the device, including further education and emotional and psychological support. \n\nCommissioners, providers and healthcare professionals should address inequalities in CGM access and uptake by:\n\nmonitoring who is using CGM\n\nidentifying groups who are eligible but who have a lower uptake\n\nmaking plans to engage with these groups to encourage them to consider CGM. \n\nFor a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on continuous glucose monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: continuous glucose monitoring in children and young people with type\xa01 diabetes.\n\nLoading. Please wait.\n\nAdvise children and young people with type\xa01\xa0diabetes who are using capillary blood glucose monitoring (and their families or carers) to routinely perform at least 5\xa0capillary blood glucose tests per day. [2015, amended 2022]\n\nAdvise children and young people with type\xa01\xa0diabetes who are using capillary blood glucose monitoring (and their families or carers) that more frequent testing is often needed (for example, with physical activity and during intercurrent illness). Ensure they have enough test strips for this. [2015, amended 2022]\n\nOffer children and young people with type\xa01\xa0diabetes who are using capillary blood glucose monitoring (and their families or carers) a choice of equipment for monitoring, so they can optimise their blood glucose management in response to changes in their insulin, diet and exercise. [2004, amended 2022]\n\nMeasure HbA1c using methods that have been calibrated according to International Federation of Clinical Chemistry standardisation. \n\nExplain the benefits of safely achieving and maintaining the lowest attainable HbA1c to children and young people with type\xa01\xa0diabetes and their families or carers. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that an HbA1c target level of 48\xa0mmol/mol (6.5%) or lower will minimise their risk of long‑term complications. \n\nExplain to children and young people with type\xa01\xa0diabetes who have an HbA1c level above 48\xa0mmol/mol (6.5%) that any reduction in HbA1c level reduces their risk of long‑term complications. \n\nAgree an individualised lowest achievable HbA1c target with each child or young person with type\xa01\xa0diabetes and their families or carers. Take into account factors such as their daily activities, individual life goals, complications, comorbidities and the risk of hypoglycaemia. \n\nSupport children and young people with type\xa01\xa0diabetes and their families or carers to safely achieve and maintain their individual agreed HbA1c target level. \n\nMeasure HbA1c level 4\xa0times a year in children and young people with type\xa01\xa0diabetes. Think about more frequent testing if they are having difficulty with blood glucose management. [2004, amended 2015]\n\nDiabetes services should document the proportion of children and young people with type\xa01\xa0diabetes who achieve an HbA1c level of 53\xa0mmol/mol (7%) or lower. \n\n## Hyperglycaemia, blood ketone monitoring and intercurrent illness\n\nProvide children and young people with type\xa01\xa0diabetes and their families or carers with individualised oral and written advice ('sick‑day rules') about managing type\xa01\xa0diabetes during intercurrent illness or episodes of hyperglycaemia, including:\n\nmonitoring blood glucose\n\nmonitoring and interpreting blood ketones (beta‑hydroxybutyrate)\n\nadjusting their insulin regimen\n\nfood and fluid intake\n\nwhen and where to get further advice or help.Revisit the advice at least annually. \n\nOffer children and young people with type\xa01\xa0diabetes blood ketone testing strips and a meter. Advise them and their families or carers to test for ketonaemia if they are ill or have hyperglycaemia. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that they should not use blood ketone testing strips after the use‑by date. \n\n## Hypoglycaemia\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers how they can avoid and manage hypoglycaemia. \n\nOffer education for children and young people with type\xa01\xa0diabetes and their families, carers, and teachers about recognising and managing hypoglycaemia. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that they should always have access to an immediate source of fast‑acting glucose and blood glucose monitoring equipment, so that they can check for hypoglycaemia and manage it safely. [2004, amended 2015]\n\nTrain and equip families, carers, and (if appropriate) school nurses and other carers to give intramuscular glucagon for severe hypoglycaemia in an emergency. [2004, amended 2015]\n\nImmediately treat mild-to-moderate hypoglycaemia in children and young people with type\xa01\xa0diabetes as follows:\n\nGive oral fast‑acting glucose (for example, 10\xa0g to 20\xa0g; liquid carbohydrate may be easier to swallow than solid).\n\nBe aware that fast‑acting glucose may need to be given in frequent small amounts because hypoglycaemia can cause vomiting.\n\nRecheck blood glucose levels within 15\xa0minutes (fast‑acting glucose should raise blood glucose levels within 5\xa0to\xa015\xa0minutes), and give more fast‑acting glucose if they still have hypoglycaemia.\n\nAs symptoms improve or blood glucose levels return to normal, give oral complex long-acting carbohydrate to maintain blood glucose levels, unless the child or young person is:\n\n\n\nabout to have a snack or meal\n\nhaving a continuous subcutaneous insulin infusion. [2004, amended 2015]\n\n\n\nFor children and young people with type 1 diabetes who are in hospital, treat severe hypoglycaemia with 10% intravenous glucose if rapid intravenous access is possible. Give a maximum dose of 500 mg/kg body weight (equivalent to a maximum of 5 ml/kg). [2004, amended 2015]\n\nFor children and young people with type\xa01\xa0diabetes who are not in hospital, or if rapid intravenous access is not possible, treat severe hypoglycaemia as follows:\n\nUse intramuscular glucagon or a concentrated oral glucose solution (for example, Glucogel). Do not use oral glucose solution if they have reduced consciousness because this could be dangerous.\n\nIf using intramuscular glucagon:\n\n\n\ngive 1\xa0mg glucagon to children and young people who are over 8\xa0years old, or who weigh 25\xa0kg or more\n\ngive 500 micrograms of glucagon to children who are under 8\xa0years old, or who weigh less than 25\xa0kg.\n\n\n\nSeek medical assistance if blood glucose levels do not respond or symptoms continue for more than 10\xa0minutes.\n\nAs symptoms improve or blood glucose levels return to normal, and once the child or young person is sufficiently awake, give oral complex long‑acting carbohydrate to maintain normal blood glucose levels.\n\nRecheck blood glucose repeatedly in children and young people who have persistently reduced consciousness after a severe hypoglycaemic episode to determine whether further glucose is needed. [2004, amended 2015]\n\nExplain to young people with type\xa01\xa0diabetes how alcohol affects blood glucose levels, and in particular the increased risk of hypoglycaemia (including hypoglycaemia while sleeping). [2004, amended 2015]\n\nExplain to young people with type\xa01\xa0diabetes who drink alcohol that they should:\n\neat food containing carbohydrates before and after drinking\n\nmonitor their blood glucose levels regularly and aim to keep the levels within the recommended range by eating food containing carbohydrates. \n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that when alcohol causes or contributes to hypoglycaemia, glucagon may be ineffective and they may need intravenous glucose. \n\nDiabetes teams should consider referring children and young people with type\xa01\xa0diabetes for assessment of cognitive function if they have frequent hypoglycaemia or recurrent seizures, particularly if these occur at a young age. \n\n## Difficulties with maintaining optimal blood glucose levels\n\nThink about the possibility of non‑adherence to therapy in children and young people with type\xa01\xa0diabetes who have difficulty with blood glucose management, especially in adolescence. [2004, amended 2015]\n\nBe aware that young people with type\xa01 diabetes can have difficulty with blood glucose management during adolescence, and this may in part be due to non‑adherence to therapy. \n\nRaise the issue of non‑adherence to therapy with children and young people with type\xa01\xa0diabetes and their families or carers in a sensitive manner. \n\nBe aware of the possible negative psychological impact of setting targets that may be difficult for a child or young person with type\xa01\xa0diabetes to achieve and maintain. \n\n## Surgery\n\nOnly offer surgery in centres that have dedicated paediatric facilities for children and young people with diabetes. \n\nAll centres caring for children and young people with type\xa01 diabetes should have written protocols on safe surgery for children and young people. The protocols should be agreed between surgical and anaesthetic staff and the diabetes team. \n\nSurgical, anaesthetic and diabetes teams should discuss care for children and young people with type\xa01 diabetes before they are admitted to hospital for elective surgery, and as soon as possible after they are admitted for emergency surgery. [2004, amended 2015]\n\n## Psychological and social issues\n\nBe aware that children and young people with type\xa01 diabetes have a greater risk of emotional and behavioural difficulties. [2004, amended 2015]\n\nOffer children and young people with type\xa01 diabetes and their families or carers emotional support after diagnosis, and tailor this to their emotional, social, cultural and age‑dependent needs. \n\nAssess the emotional and psychological wellbeing of young people with type\xa01\xa0diabetes who have frequent episodes of diabetic ketoacidosis (DKA). [2004, amended 2015]\n\nBe aware that a lack of adequate psychosocial support for children and young people with type\xa01 diabetes has a negative effect on various outcomes (including blood glucose management) and can also reduce their self‑esteem. [2004, amended 2015]\n\nOffer children and young people with type\xa01\xa0diabetes and their families or carers timely and ongoing access to mental health professionals with an understanding of diabetes. This is because they may experience psychological problems (such as anxiety, depression, behavioural and conduct disorders, and family conflict) or psychosocial difficulties that can impact on the management of diabetes and wellbeing. [2004, amended 2015]\n\nSee the NICE guidelines on depression in children and young people and antisocial behaviour and conduct disorders in children and young people for guidance on managing these conditions. \n\nDiabetes teams should have access to mental health professionals to support them in psychological assessment and providing psychosocial support. \n\nOffer children and young people with type\xa01\xa0diabetes who have behavioural or conduct disorders, and their families or carers, access to mental health professionals. \n\nOffer specific family‑based behavioural interventions, such as behavioural family systems therapy, if there are difficulties with diabetes‑related family conflict. \n\nConsider a programme of behavioural intervention therapy or behavioural techniques for children and young people with type\xa01\xa0diabetes if there are concerns about their psychological wellbeing. Choose a type of therapy based on what the child or young person needs help with:\n\nhealth‑related quality of life – for example, counselling or cognitive behavioural therapy (CBT), including CBT focused on quality of life\n\nadherence to diabetes treatment – for example, motivational interviewing or multisystemic therapy\n\nblood glucose management if they have high HbA1c levels (above 69\xa0mmol/mol [8.5%]) – for example, multisystemic therapy. \n\nOffer screening for anxiety and depression to children and young people with type\xa01\xa0diabetes who have persistent difficulty with blood glucose management. \n\nBe aware that children and young people with type\xa01\xa0diabetes may develop anxiety or depression, particularly when they have difficulty with self-management when they have had diabetes for a long time. \n\nRefer children and young people with type\xa01\xa0diabetes and suspected anxiety or depression promptly to child mental health professionals. \n\nBe aware that children and young people with type\xa01\xa0diabetes (in particular, young women) have an increased risk of eating disorders. For more guidance on assessing and managing eating disorders, see the NICE guideline on eating disorders. [2004, amended 2015]\n\nBe aware that children and young people with type\xa01\xa0diabetes and an eating disorder may have associated difficulties with:\n\nblood glucose management (both hyperglycaemia and hypoglycaemia)\n\nsymptoms of gastroparesis. [2004, amended 2015]\n\nFor children and young people with type\xa01\xa0diabetes and an eating disorder, offer joint management involving their diabetes team and child mental health professionals. [2004, amended 2015]\n\n## Monitoring for complications and associated conditions of type\xa01\xa0diabetes\n\nOffer children and young people with type\xa01\xa0diabetes monitoring for:\n\nthyroid disease, at diagnosis and then annually until transfer to adult services\n\nmoderately increased albuminuria (albumin to creatinine ratio [ACR] 3\xa0mg/mmol to 30\xa0mg/mmol) to detect diabetic kidney disease, annually from 12\xa0years\n\nhypertension, annually from 12\xa0years. \n\nRefer children and young people with type\xa01 diabetes for diabetic retinopathy screening from 12 years, in line with Public Health England's diabetic eye screening programme. \n\nFor guidance on monitoring for coeliac disease in children and young people with type\xa01\xa0diabetes, see the NICE guideline on coeliac disease. \n\nFor guidance on managing foot problems in children and young people with type\xa01\xa0diabetes, see the NICE guideline on diabetic foot problems. \n\nBe aware of the following rare complications and associated conditions when children and young people with type\xa01\xa0diabetes attend clinic visits:\n\njuvenile cataracts\n\nnecrobiosis lipoidica\n\nAddison's disease. [2004, amended 2015]\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers the importance of annual monitoring from 12\xa0years for diabetic kidney disease. \n\nFor children and young people with type\xa01\xa0diabetes who are having eye screening, explain to them and their families or carers that:\n\nmonitoring for diabetic retinopathy begins at 12\xa0years (see recommendation 1.2.120) because diabetic retinopathy that needs treatment is extremely rare in children and young people under\xa012\n\nannual monitoring from age 12 is important because if significant diabetic retinopathy is found, early treatment will improve the outcome (for more information, see Public Health England's diabetic eye screening programme)\n\nit will help them keep their eyes healthy and help prevent problems with their vision\n\nthe screening service is effective at identifying problems so that they can be treated early. [2015, amended 2020]\n\nExplain to children and young people with type\xa01\xa0diabetes and their families or carers that:\n\nmonitoring for moderately increased albuminuria (ACR 3\xa0mg/mmol to 30\xa0mg/mmol) to detect diabetic kidney disease begins at 12\xa0years because diabetic kidney disease in children and young people under\xa012 is extremely rare\n\nusing the first urine sample of the day ('early morning urine') to screen for moderately increased albuminuria is important, as this reduces the risk of false positive results\n\nif moderately increased albuminuria is detected, improving blood glucose management will reduce the risk of this progressing to significant diabetic kidney disease\n\nannual monitoring from 12\xa0years is important because if they have diabetic kidney disease, early treatment will improve the outcome. \n\nUse the first urine sample of the day ('early morning urine') to measure the ACR. If the first urine sample of the day is not available, use a random sample, but be aware that this is associated with an increased risk of false positive results. \n\nIf the initial ACR is above 3\xa0mg/mmol but below 30\xa0mg/mmol, confirm the result by repeating the test on 2\xa0further occasions using the first urine samples of the day ('early morning urine') before starting further investigation and therapy. \n\nInvestigate further if the initial ACR is 30\xa0mg/mmol or more (proteinuria). \n\nAdvise children and young people with type\xa01 diabetes and their families and carers at their regular diabetes reviews that:\n\nthey are at higher risk of periodontitis\n\nif they get periodontitis, managing it can improve their blood glucose control and can reduce their risk of hyperglycaemia. \n\nAdvise children and young people with type\xa01 diabetes to have regular oral health reviews (their oral healthcare or dental team will tell them how often, in line with the NICE guideline on dental checks: intervals between oral health reviews). \n\nFor guidance for oral healthcare and dental teams on how to provide oral health advice, see the NICE guideline on oral health promotion. \n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on periodontitis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: periodontitis.\n\nLoading. Please wait.\n\n# Type 2 diabetes\n\n## Education and information\n\nWhen giving children and young people, or their families or carers, information about type 2 diabetes:\n\ntailor the timing, content and delivery of information to their needs and preferences, paying particular attention to people with additional needs such as autistic people or those with learning disabilities, people who have physical or sensory disabilities and people who have difficulties speaking or reading English\n\nensure that the information given supports shared decision making between the child or young person and the multidisciplinary diabetes team.Follow the recommendation in NICE's guideline on shared decision making and babies, children and young people's experience of healthcare. \n\nOffer children and young people with type 2 diabetes and their families or carers a continuing programme of education from diagnosis. Include the following core topics:\n\nthe importance of managing glucose levels, including achieving and maintaining glucose and HbA1c targets\n\nhow and when to take capillary blood glucose measurements (self-monitoring)\n\nhow diet, increasing physical activity and reducing body weight can reduce the symptoms of type 2 diabetes and lead to remission\n\nhow diet, physical activity, body weight and intercurrent illness affects blood glucose levels\n\nhow metformin can help, and its possible adverse effects\n\nthe complications of type 2 diabetes and how to prevent them.See also the recommendations for children and young people in NICE's guideline on identifying, assessing and managing obesity, lifestyle interventions, behavioural interventions, physical activity and dietary approaches for weight management, and recommendations 1.3.68 to 1.3.70 on psychological and social issues in this guideline. [2015, amended 2023]\n\nTailor the education programme to each child or young person with type\xa02\xa0diabetes and their families or carers, taking account of issues such as:\n\npersonal preferences\n\nemotional wellbeing\n\nage and maturity\n\ncultural considerations\n\nexisting knowledge\n\ncurrent and future social circumstances\n\nlife goals. \n\nGive children and young people with type 2 diabetes who are taking insulin, and their families or carers, information and education about:\n\ninsulin therapy (including its aims and how it works)\n\ninsulin delivery (including rotating injection sites within the same body region)\n\ndosage adjustment\n\nthe recognition and management of hypoglycaemia\n\nthe importance of monitoring their glucose levels. \n\nGive children and young people with type 2 diabetes who are offered continuous glucose monitoring (CGM), and their families and carers, information about how to use their chosen device, as part of their continuing programme of education. \n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers that, like people without diabetes, they should have:\n\nregular dental examinations (see the NICE guideline on dental checks: intervals between oral health reviews)\n\nan eye examination by an optician every 2\xa0years. [2004, amended 2015]\n\nEncourage children and young people with type\xa02\xa0diabetes and their families or carers to discuss any concerns and raise any questions they have with their diabetes team. \n\nGive children and young people with type\xa02\xa0diabetes and their families or carers information about diabetes support groups and organisations, and the potential benefits of membership. Give this information after diagnosis and regularly afterwards. [2004, amended 2015]\n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers how to find out about possible government disability benefits. [2004, amended 2015]\n\nFor a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on education and information for children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\nEncourage children and young people with type\xa02\xa0diabetes not to start smoking. Explain the general health problems smoking causes, in particular the risks of vascular complications. [2004, amended 2015]\n\nFor more guidance on preventing smoking, see also the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. [2004, amended 2015]\n\nOffer smoking cessation programmes to children and young people with type\xa02\xa0diabetes who smoke. See also the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. [2004, amended 2015]\n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers about the general dangers of substance misuse and the possible effects on blood glucose levels. [2004, amended 2015]\n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers that the Public Health England Green Book recommends they have:\n\nannual immunisation against influenza\n\nimmunisation against pneumococcal infection if they are taking insulin or oral hypoglycaemic medicines. [2004, amended 2015]\n\n## Dietary management\n\nAt each contact with a child or young person with type\xa02\xa0diabetes who is overweight or obese, advise them and their families or carers about the benefits of exercise and weight loss, and provide support towards achieving this. See also the NICE guidelines on preventing excess weight gain and managing obesity. \n\nOffer children and young people with type\xa02\xa0diabetes dietetic support to help optimise body weight and blood glucose levels. [2004, amended 2015]\n\nAt each contact with a child or young person with type\xa02\xa0diabetes, explain to them and their families or carers how healthy eating can help to:\n\nreduce hyperglycaemia\n\nreduce cardiovascular risk\n\npromote weight loss (see recommendation 1.3.15). \n\nProvide dietary advice to children and young people with type\xa02\xa0diabetes and their families or carers in a sensitive manner. Take into account the difficulties that many people have with losing weight, and how healthy eating can also help with blood glucose levels and avoiding complications. \n\nTake into account social and cultural considerations when providing dietary advice to children and young people with type\xa02\xa0diabetes. \n\nEncourage children and young people with type\xa02\xa0diabetes to eat at least 5\xa0portions of fruit and vegetables each day. \n\nAt each clinic visit for children and young people with type\xa02\xa0diabetes:\n\nmeasure height and weight and plot on an appropriate growth chart\n\ncalculate body mass index.Check for normal growth or significant changes in weight because these may reflect changes in blood glucose levels. [2004, amended 2015]\n\nProvide arrangements for weighing children and young people with type\xa02\xa0diabetes that respect their privacy. [2004, amended 2015]\n\n## At diagnosis\n\nRefer children and young people with suspected type\xa02\xa0diabetes to a multidisciplinary paediatric diabetes team for specialist review to:\n\nconfirm diagnosis and\n\nprovide immediate and continuing care. \n\nOffer children and young people with type 2 diabetes:\n\nadvice and support on dietary management (see recommendations 1.3.15 to 1.3.22)\n\na metformin monotherapy formulation in line with their own preferences\n\nequipment for capillary blood glucose monitoring.See also recommendation 1.3.84 on screening for diabetic retinopathy. In May 2023, the use of formulations other than standard-release metformin was off-label. See NICE's information on prescribing medicines. (2015, updated 2023)\n\nIn addition, offer children and young people with type 2 diabetes:\n\ninsulin if their HbA1c level is 69\xa0mmol/mol (8.5%) or more\n\nbasal-bolus insulin if they have ketosis but not diabetic ketoacidosis (DKA). If the child or young person with type 2 diabetes exhibits signs and symptoms of DKA, see section 1.4 on DKA. \n\nFor a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on what to do at diagnosis for children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\n## Monitoring blood glucose levels and reviewing treatment\n\nFour weeks after diagnosing type\xa02 diabetes and starting metformin in a child or young person, review data from glucose monitoring and, if needed, change treatment (see recommendations on adding liraglutide, dulaglutide, or empagliflozin for people on metformin only or for people on metformin and insulin). \n\nReview treatment for children and young people with type 2 diabetes, as needed, at least every 3 months. Assess glucose trends using available data from glucose monitoring and HbA1c measurements. \n\nIf HbA1c monitoring cannot be used because of disturbed erythrocyte turnover or abnormal haemoglobin type, estimate trends in blood glucose levels using one of the following:\n\nglucose profiles\n\ntotal glycated haemoglobin estimation (if abnormal haemoglobins)\n\nfructosamine estimation. \n\nAdjust the frequency of capillary blood glucose monitoring based on the person's treatment and whether they are using CGM. Ensure they have enough test strips for capillary blood glucose monitoring. \n\nFor a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on monitoring blood glucose levels and reviewing treatment for children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\nMeasure HbA1c using methods that have been calibrated according to the International Federation of Clinical Chemistry standardisation. \n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers that an HbA1c target level of 48\xa0mmol/mol (6.5%) or lower will minimise their risk of long‑term complications. \n\nExplain to children and young people with type\xa02\xa0diabetes who have an HbA1c level above 48\xa0mmol/mol (6.5%) that any reduction in HbA1c level reduces their risk of long‑term complications. \n\nExplain the benefits of safely achieving and maintaining the lowest attainable HbA1c to children and young people with type\xa02\xa0diabetes and their families or carers. \n\nAgree an individualised lowest achievable HbA1c target with each child or young person with type\xa02\xa0diabetes and their families or carers. Take into account factors such as their daily activities, individual life goals, complications and comorbidities. \n\nMeasure HbA1c levels every 3\xa0months in children and young people with type\xa02\xa0diabetes. \n\nSupport children and young people with type\xa02\xa0diabetes and their families or carers to safely achieve and maintain their individual agreed HbA1c target level. \n\nDiabetes services should document the proportion of children and young people with type\xa02 diabetes who achieve an HbA1c level of 53\xa0mmol/mol (7%) or lower. \n\nOffer real-time continuous glucose monitoring (rtCGM) to children and young people with type\xa02 diabetes if any of the following apply. They:\n\nhave a need, condition or disability (including a mental health need, learning disability or cognitive impairment) that means they cannot engage in monitoring their glucose levels by capillary blood glucose monitoring\n\nwould otherwise be advised to self-monitor at least 8 times a day\n\nhave recurrent or severe hypoglycaemia. \n\nConsider rtCGM for children and young people with type\xa02 diabetes who are on insulin therapy. \n\nConsider intermittently scanned continuous glucose monitoring (isCGM, commonly referred to as 'flash') for children and young people with type\xa02 diabetes aged 4 years and over who are on insulin therapy if:\n\nrtCGM is contraindicated for them or\n\nthey express a clear preference for isCGM. In May 2023, use of isCGM for children aged 3 years and under was off-licence. \n\nWhen offering CGM to children and young people with type\xa02 diabetes, choose the appropriate device with them, based on their individual preferences, needs, characteristics, and the functionality of the devices available. See box 1 for factors to consider as part of this discussion. \n\nWhen choosing a\xa0CGM\xa0device, if multiple devices meet the person's needs and preferences, offer the device with the lowest cost. \n\nCGM should be provided by a team with expertise in its use to support children and young people to self-manage their type 2 diabetes. \n\nAdvise children and young people with type 2 diabetes who are using CGM, and their families or carers, that they will still need to take capillary blood glucose measurements, but they can do this less often. Explain that this is because they will need the capillary blood glucose measurements:\n\nto check the accuracy of their CGM device\n\nas a back-up (for example, if the device stops working). \n\nMonitor and review the child or young person's use of CGM when reviewing their diabetes care plan and explain to them the importance of continuously wearing the device. \n\nIf the child or young person is not using their CGM device at least 70% of the time:\n\nask if they are having problems with their device\n\nlook at ways to address any problems or concerns to improve their use of the device, including further education and emotional and psychological support. \n\nCommissioners, providers and healthcare professionals should address inequalities in CGM access and uptake by:\n\nmonitoring who is using CGM\n\nidentifying groups who are eligible but have a lower uptake\n\nmaking plans to engage with these groups to encourage them to consider CGM. \n\nFor a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on continuous glucose monitoring for children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\n## When to reduce insulin for people who have been on it from diagnosis\n\nFor children and young people with type 2 diabetes who have been on insulin therapy from diagnosis, gradually reduce with the aim of stopping insulin therapy if they have achieved:\n\nan HbA1c level of 48\xa0mmol/mol (6.5%) or less or\n\na plasma glucose level of 4\xa0mmol/litre to 7\xa0mmol/litre, on 4 or more days a week, when fasting or before meals or\n\na plasma glucose level of 5\xa0mmol/litre to 9\xa0mmol/litre, on 4 or more days a week, 2\xa0hours after meals.See also recommendations on insulin therapy for children and young people with type 2 diabetes in this guideline. \n\nFor a short explanation of why the committee made the 2023 recommendation, see the rationale and impact section on when to reduce insulin for children and young people with type 2 diabetes who have been on insulin since diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\n## Adding liraglutide, dulaglutide, or empagliflozin\n\nOffer liraglutide or dulaglutide, depending on the person's preference, in addition to metformin, to children and young people aged 10 or over with type 2 diabetes if they have:\n\nan HbA1c level of more than 48\xa0mmol/mol (6.5%) or\n\na plasma glucose level of more than 7\xa0mmol/litre, on 4 or more days a week, when fasting or before meals or\n\na plasma glucose level of more than 9\xa0mmol/litre, on 4 or more days a week, 2 hours after meals.In May 2023, this was an off-label use of dulaglutide. See NICE's information on prescribing medicines. \n\nConsider empagliflozin, in addition to metformin, for children and young people aged 10 or over with type 2 diabetes who:\n\nmeet any of the criteria listed in recommendation 1.3.49\n\nare not able to tolerate liraglutide or dulaglutide or have a clear preference for empagliflozin.In May 2023, this was an off-label use of empagliflozin. See NICE's information on prescribing medicines. \n\nOffer insulin to children and young people with type 2 diabetes in whom an HbA1c level of 48\xa0mmol/mol (6.5%) or less cannot be achieved using metformin with one medicine among liraglutide, dulaglutide or empagliflozin. \n\nOffer liraglutide or dulaglutide in addition to current treatment, rather than increasing insulin, for a child or young person aged 10 or over with type 2 diabetes if:\n\nthey are already on insulin therapy and\n\ntheir HbA1c or glucose levels do not meet the conditions in recommendation 1.3.48 to safely reduce and stop insulin.See also recommendation 1.3.15 on dietary management. In May 2023, this was an off-label use of dulaglutide. See NICE's information on prescribing medicines. \n\nConsider empagliflozin in addition to current treatment, rather than increasing insulin, for a child or young person aged 10 or over with type 2 diabetes if:\n\nthey are already on insulin therapy and\n\ntheir HbA1c or glucose levels do not meet the conditions in recommendation 1.3.48 to safely reduce and stop insulin\xa0and\n\nthey are not able to tolerate liraglutide or dulaglutide or have a clear preference for empagliflozin.See also recommendation 1.3.15 on dietary management. In May 2023, this was an off-label use of empagliflozin. See NICE's information on prescribing medicines. \n\nOnly increase insulin for a child or young person aged 10 or over with type 2 diabetes who is on metformin and insulin if their HbA1c or glucose levels are not in the target ranges listed in recommendation 1.3.48 and:\n\nthey are already also taking liraglutide, dulaglutide or empagliflozin, or a combination of them or\n\nliraglutide, dulaglutide and empagliflozin are not tolerated or contraindicated. \n\nFor children and young people aged 10 or over with type 2 diabetes who are on liraglutide, dulaglutide or empagliflozin, maintain the lowest dose that enables them to achieve the target ranges specified in recommendation 1.3.48. See relevant Medicines and Healthcare products Regulatory Agency (MHRA) advice on the use of SGLT2 inhibitors and specific BNF advice on the use of empagliflozin.\n\nFor a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on adding liraglutide, dulaglutide or empagliflozin to current treatment for children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\n## Insulin therapy\n\nWhen insulin therapy is appropriate (as per the recommendations about prescribing insulin at diagnosis or when to subsequently add insulin in this guideline), discuss the choice of insulin regimen with the child or young person and their family:\n\nexplain the advantages and disadvantages of the different options and whether only basal or a combination of basal and meal-time insulin is required\n\ndiscuss their personal circumstances and preferences\n\nhelp them make an informed decision between the options that are available to them. \n\nProvide children and young people with type\xa02\xa0diabetes insulin injection needles that are the right length for their body fat. \n\nProvide children and young people with type\xa02\xa0diabetes and their families or carers with:\n\nsuitable containers for collecting used needles and other sharps\n\na way to safely get rid of these containers.See also the section on safe use and disposal of sharps in the NICE guideline on healthcare-associated infections. \n\nOffer children and young people with type\xa02\xa0diabetes a review of injection sites at each clinic visit. \n\nIf a child or young person with type\xa02\xa0diabetes does not have optimal blood glucose levels (see recommendations 1.3.31 on HbA1c target and 1.3.48 for HbA1c and plasma glucose targets), offer additional support, such as more contact with their diabetes team. \n\nFor a short explanation of why the committee made the 2023 recommendations, see the rationale and impact section on insulin therapy for children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\n## Changing treatments and updating healthcare plans\n\nEnsure that the paediatric diabetes team updates the child or young person's school healthcare plan as soon as treatment changes in a way that affects the school's involvement, and annually. For recommendations about involving children and young people, and their family and carers, in making decisions about treatment, see:\n\nrecommendation 1.5.4 (2015) on service provision in this guideline\n\nsections 1.2 to 1.4 in NICE's guideline on shared decision making.\n\nFor a short explanation of why the committee made the 2023 recommendation, see the rationale and impact section on changing treatment and updating school healthcare plans for children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\n## Surgery\n\nOnly offer surgery in centres that have dedicated paediatric facilities for children and young people with diabetes. [2004, amended 2015]\n\nAll centres caring for children and young people with type\xa02\xa0diabetes should have written protocols on safe surgery for children and young people. The protocols should be agreed between surgical and anaesthetic staff and the diabetes team. [2004, amended 2015]\n\n## Psychological and social issues\n\nBe aware that children and young people with type\xa02\xa0diabetes have a greater risk of emotional and behavioural difficulties. [2004, amended 2015]\n\nOffer children and young people with type\xa02\xa0diabetes and their families or carers emotional support after diagnosis, and tailor this to their emotional, social, cultural and age‑dependent needs. [2004, amended 2015]\n\nBe aware that children and young people with type\xa02\xa0diabetes have an increased risk of psychological conditions (for example, anxiety, depression, and behavioural and conduct disorders) and complex social factors (for example, family conflict), and these can affect their wellbeing and diabetes management. \n\nBe aware that a lack of adequate psychosocial support for children and young people with type\xa02\xa0diabetes has a negative effect on various outcomes (including blood glucose management) and can also reduce their self‑esteem. [2004, amended 2015]\n\nOffer children and young people with type\xa02\xa0diabetes and their families or carers timely and ongoing access to mental health professionals with an understanding of diabetes. This is because they may experience psychological problems (such as anxiety, depression, behavioural and conduct disorders, and family conflict) or psychosocial difficulties that can impact on the management of diabetes and wellbeing. [2004, amended 2015]\n\nSee the NICE guidelines on depression in children and young people and antisocial behaviour and conduct disorders in children and young people for guidance on managing these conditions. \n\nDiabetes teams should have access to mental health professionals to support them in psychological assessment and providing psychosocial support. [2004, amended 2015]\n\nOffer assessment for anxiety and depression to children and young people with type\xa02\xa0diabetes who have persistent difficulty with blood glucose management. [2004, amended 2015]\n\nRefer children and young people with type\xa02\xa0diabetes and suspected anxiety or depression promptly to child mental health professionals. [2004, amended 2015]\n\nEnsure that children and young people with type\xa02\xa0diabetes and their families or carers have timely and ongoing access to mental health services when needed. \n\n## Monitoring for complications and associated conditions of type\xa02\xa0diabetes\n\nOffer children and young people with type\xa02\xa0diabetes annual monitoring for:\n\nhypertension, starting at diagnosis\n\ndyslipidaemia, starting at diagnosis\n\nmoderately increased albuminuria (albumin to creatinine ratio [ACR] 3\xa0mg/mmol to 30\xa0mg/mmol) to detect diabetic kidney disease, starting at diagnosis. \n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers the importance of annual monitoring for hypertension, dyslipidaemia and diabetic kidney disease. \n\nRefer children and young people with type\xa02 diabetes for diabetic retinopathy screening from 12 years, in line with Public Health England's diabetic eye screening programme. \n\nFor guidance on managing foot problems in children and young people with type\xa02\xa0diabetes, see the NICE guideline on diabetic foot problems. \n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers that monitoring (see recommendation 1.3.74) is important because if they have hypertension, early treatment will reduce their risk of complications. \n\nUse a cuff large enough for the child or young person with type\xa02\xa0diabetes when measuring blood pressure. \n\nIf repeated resting measurements are greater than the 95th percentile for age and sex, confirm hypertension using 24‑hour ambulatory blood pressure monitoring before starting antihypertensive therapy. \n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers that monitoring (see recommendation 1.3.74) is important because if they have dyslipidaemia, early treatment will reduce their risk of complications. \n\nWhen monitoring for dyslipidaemia in children and young people with type\xa02\xa0diabetes, measure total cholesterol, high‑density lipoprotein (HDL) cholesterol, non‑HDL cholesterol and triglyceride concentrations. \n\nConfirm dyslipidaemia using a repeat sample (fasting or non‑fasting) before deciding on further management. \n\nFor children and young people with type\xa02\xa0diabetes who are having eye screening, explain to them and their families or carers that:\n\nbackground retinopathy is often found through screening (see recommendation 1.3.76), and improved blood glucose management will reduce the risk of this progressing to significant diabetic retinopathy\n\nit will help them keep their eyes healthy and prevent problems with their vision\n\nthe screening service is effective at identifying problems so that they can be treated early\n\nat least annual monitoring from 12\xa0years is important because, if significant diabetic retinopathy is found, early treatment will improve the outcome. [2015, amended 2020]\n\nConsider referring children and young people with type\xa02\xa0diabetes who are younger than 12\xa0years to an ophthalmologist for retinal examination if they have difficulty with blood glucose management. \n\nExplain to children and young people with type\xa02\xa0diabetes and their families or carers that:\n\nusing the first urine sample of the day ('early morning urine') to screen for moderately increased albuminuria (ACR 3\xa0mg/mmol to 30\xa0mg/mmol) is important as this reduces the risk of false positive results\n\nif moderately increased albuminuria is detected, improving blood glucose management will reduce the risk of this progressing to significant diabetic kidney disease\n\nannual monitoring (see recommendation 1.3.74) is important because, if they have diabetic kidney disease, early treatment will improve the outcome. \n\nUse the first urine sample of the day ('early morning urine') to measure the ACR. If the first urine sample of the day is not available, use a random sample, but be aware that this is associated with an increased risk of false positive results. \n\nIf the initial ACR is above 3\xa0mg/mmol but below 30\xa0mg/mmol, confirm the result by repeating the test on 2\xa0further occasions using the first urine samples of the day ('early morning urine') before starting further investigation and therapy. \n\nInvestigate further if the initial ACR is 30\xa0mg/mmol or more (proteinuria). \n\nAdvise children and young people with type 2 diabetes and their families and carers at their regular diabetes reviews that:\n\nthey are at higher risk of periodontitis\n\nif they get periodontitis, managing it can improve their blood glucose control and can reduce their risk of hyperglycaemia. \n\nAdvise children and young people with type 2 diabetes to have regular oral health reviews (their oral healthcare or dental team will tell them how often, in line with the NICE guideline on dental checks: intervals between oral health reviews). \n\nFor guidance for oral healthcare and dental teams on how to provide oral health advice, see the NICE guideline on oral health promotion. \n\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on periodontitis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: periodontitis.\n\nLoading. Please wait.\n\n# Diabetic ketoacidosis\n\n## Recognition, referral and diagnosis\n\nMeasure capillary blood glucose at presentation in children and young people without known diabetes who have:\n\nincreased thirst, polyuria, recent unexplained weight loss or excessive tiredness and any of\n\nnausea, vomiting, abdominal pain, hyperventilation, dehydration or reduced level of consciousness. \n\nFor children or young people without known diabetes who have a plasma glucose level above 11\xa0mmol/litre and symptoms that suggest diabetic ketoacidosis (DKA; see recommendation 1.4.1), suspect DKA and immediately send them to a hospital with acute paediatric facilities. \n\nBe aware that children and young people taking insulin for diabetes may develop DKA with normal blood glucose levels. \n\nSuspect DKA even if the blood glucose is normal in a child or young person with known diabetes and any of the following:\n\nnausea or vomiting\n\nabdominal pain\n\nhyperventilation\n\ndehydration\n\nreduced level of consciousness. \n\nWhen DKA is suspected in a child or young person with known diabetes, measure their blood ketones (beta‑hydroxybutyrate), using a near‑patient method if available. Immediately send them to a hospital with acute paediatric facilities if:\n\ntheir blood ketones are elevated\n\na near-patient method for measuring their blood ketones is not available. \n\nIf DKA is suspected or confirmed in a child or young person, explain to them and to their families or carers that DKA is serious and that they need urgent hospital assessment. \n\nWhen a child or young person with suspected or known DKA arrives at hospital, measure their:\n\ncapillary blood glucose\n\ncapillary blood ketones (beta‑hydroxybutyrate) if near‑patient testing is available, or urine ketones if it is not\n\ncapillary or venous pH and bicarbonate. \n\nDiagnose DKA in children and young people with diabetes who have:\n\nhyperglycaemia (plasma glucose more than 11\xa0mmol/litre) and\n\nacidosis (indicated by blood pH below 7.3 or plasma bicarbonate below 15\xa0mmol/litre) and\n\nketonaemia (indicated by blood beta‑hydroxybutyrate above 3\xa0mmol/litre) or ketonuria (++ and above on the standard strip marking scale). \n\nDiagnose DKA severity as follows:\n\nmild DKA if blood pH is below 7.3 or plasma bicarbonate is below 15\xa0mmol/litre\n\nmoderate DKA if blood pH is below 7.2 or plasma bicarbonate is below 10\xa0mmol/litre\n\nsevere DKA if blood pH is below 7.1 or plasma bicarbonate is below 5\xa0mmol/litre. \n\n## Initial management of diabetic ketoacidosis\n\nInform the responsible senior clinician when a child or young person is diagnosed with DKA. \n\nExplain to the child or young person and their families or carers what DKA is, and what care that they may need. \n\nWhen DKA is diagnosed in a child or young person in hospital, record their:\n\nlevel of consciousness\n\nheart rate, blood pressure, temperature, respiratory rate (look for Kussmaul breathing)\n\nhistory of nausea or vomiting\n\nclinical evidence of dehydration\n\nbody weight. \n\nWhen DKA is diagnosed in a child or young person in hospital, measure and record the capillary or venous:\n\npH and pCO2\n\nplasma sodium, potassium, urea and creatinine\n\nplasma bicarbonate. \n\nConsider a near‑patient blood ketone (beta‑hydroxybutyrate) testing method for rapid diagnosis and monitoring of DKA in children and young people in hospital. \n\nChildren and young people with DKA should be cared for in a facility that can provide the level of monitoring and care for DKA specified in section 1.4 of this guideline. \n\nChildren and young people with DKA should be cared for with one‑to‑one nursing either on a high‑dependency unit (preferably a paediatric unit) or on a general paediatric ward, if:\n\nthey are younger than 2\xa0years or\n\nthey have severe DKA (blood pH below 7.1). \n\nThink about inserting a nasogastric tube if a child or young person with DKA has a reduced level of consciousness and is vomiting. \n\nSeek urgent anaesthetic review and discuss with a paediatric critical care specialist if a child or young person with DKA cannot protect their airway because they have a reduced level of consciousness. \n\nDiscuss the use of inotropes with a paediatric critical care specialist if a child or young person with DKA is in hypotensive shock. \n\nThink about sepsis in a child or young person with DKA who has any of the following:\n\nfever or hypothermia\n\nhypotension\n\nrefractory acidosis\n\nlactic acidosis. \n\n## Fluid and insulin therapy\n\nTreat DKA with intravenous fluids and intravenous insulin if the child or young person is not alert, is nauseated or vomiting, or is clinically dehydrated. \n\nDo not give oral fluids to a child or young person who is receiving intravenous fluids for DKA unless ketosis is resolving, they are alert, and they are not nauseated or vomiting. \n\nFor children and young people with DKA who are clinically dehydrated but not in shock:\n\ngive an initial intravenous bolus of 10\xa0ml/kg 0.9% sodium chloride over 30\xa0minutes\n\ndiscuss with the responsible senior paediatrician before giving more than one intravenous bolus of 10\xa0ml/kg 0.9% sodium chloride\n\nonly consider giving a second 10\xa0ml/kg 0.9% sodium chloride intravenous bolus if needed to improve tissue perfusion, and only after reassessing their clinical status\n\nwhen calculating the total fluid requirement, subtract these initial bolus volumes from the total fluid deficit. \n\nFor children and young people who have signs of shock, that is weak, thready (low-volume) pulse and hypotension, give an initial intravenous bolus of 10\xa0ml/kg 0.9% sodium chloride as soon as possible. When calculating the total fluid requirement, do not subtract this fluid bolus from the total fluid deficit. \n\nBe aware that:\n\nshock is rare in children and young people with DKA\n\nprolonged capillary refill, tachycardia and tachypnoea are common in children with moderate-to-severe DKA, but this does not mean the child or young person is in shock (these are signs of vasoconstriction caused by metabolic acidosis and hypocapnia). \n\nCalculate the total fluid requirement for the first 48\xa0hours in children and young people with DKA by adding the estimated fluid deficit to the fluid maintenance requirement:\n\nFor the fluid deficit:\n\n\n\nin mild-to-moderate DKA (blood pH\xa07.1 or above), assume 5%\xa0dehydration (so a 10\xa0kg child needs 500\xa0ml)\n\nin severe DKA (blood pH below 7.1), assume 10%\xa0dehydration\n\naim to replace the deficit evenly over the first 48\xa0hours, but in critically ill children and young people, discuss the fluid regimen early with the senior paediatrician or paediatric intensivist (or both) because the risk of cerebral oedema is higher.\n\n\n\nFor the fluid maintenance requirement, use the Holliday–Segar formula:\n\n\n\ngive 100\xa0ml/kg for the first 10\xa0kg of weight\n\ngive 50\xa0ml/kg for the second 10\xa0kg of weight\n\ngive 20\xa0ml/kg for every kg after this\n\nuse a maximum weight of 75\xa0kg in the calculation. When calculating the total fluid requirement, subtract any initial bolus volumes from the total fluid deficit (unless the child or young person is in shock). \n\n\n\nUse 0.9% sodium chloride without added glucose for both rehydration and maintenance fluid in children and young people with DKA, until the plasma glucose concentration is below 14\xa0mmol/litre. \n\nBe aware that some children and young people with DKA may develop hyperchloremic acidosis, but this resolves on its own over time and specific management is not needed. \n\nInclude 40\xa0mmol/litre (or 20\xa0mmol/500\xa0ml) potassium chloride in all fluids (except the initial intravenous boluses) given to children and young people with DKA, unless they have anuria or their potassium level is above the normal range. Do not delay potassium replacement, because hypokalaemia can occur once the insulin infusion starts. \n\nFor children and young people with potassium levels above the normal range, only add 40\xa0mmol/litre (or 20\xa0mmol/500\xa0ml) potassium chloride to their intravenous fluids if:\n\ntheir potassium is less than 5.5\xa0mmol/litre or\n\nthey have a history of passing urine. \n\nFor children and young people with DKA who have hypokalaemia at presentation, include potassium chloride in intravenous fluids before starting the insulin infusion. \n\nMonitor sodium levels throughout DKA treatment and calculate the corrected sodium initially to identify if the child or young person has hyponatraemia. \n\nWhen monitoring serum sodium levels in children and young people with DKA, be aware that:\n\nserum sodium should rise as DKA is treated as blood glucose falls\n\nfalling serum sodium is a sign of possible cerebral oedema\n\na rapid and ongoing rise in serum sodium concentration may also be a sign of cerebral oedema, caused by the loss of free water in the urine. \n\nDo not give intravenous sodium bicarbonate to children and young people with DKA unless:\n\nthey have compromised cardiac contractility, caused by life-threatening hyperkalaemia or severe acidosis and\n\nyou have discussed with the paediatric intensivist. \n\nDo not give children and young people with DKA additional intravenous fluid to replace urinary losses. \n\nStart an intravenous insulin infusion 1\xa0to\xa02\xa0hours after beginning intravenous fluid therapy in children and young people with DKA. If a child or young person with DKA is using an insulin pump, disconnect the pump when starting intravenous insulin therapy. \n\nWhen treating DKA with intravenous insulin in children and young people, use a soluble insulin infusion at a dosage between 0.05\xa0units/kg/hour and 0.1\xa0units/kg/hour. Do not give bolus doses of intravenous insulin. \n\nIn discussion with a diabetes specialist, think about continuing subcutaneous basal insulin in a child or young person who was using a basal insulin before DKA started. \n\nWhen the plasma glucose concentration falls below 14\xa0mmol/litre in children and young people with DKA, change fluids to 0.9% sodium chloride with 5% glucose and 40\xa0mmol/litre (or 20\xa0mmol/500\xa0ml) potassium chloride. \n\nIf a child or young person's plasma glucose falls below 6\xa0mmol/litre during DKA treatment:\n\nincrease the glucose concentration of the intravenous fluid infusion and\n\nif they have persisting ketosis, continue to give insulin at a dosage of least 0.05\xa0units/kg/hour. \n\nIf the blood beta‑hydroxybutyrate level is not falling within 6\xa0to\xa08\xa0hours in a child or young person with DKA, think about increasing the insulin dosage to 0.1\xa0units/kg/hour or more. \n\nThink about stopping intravenous fluid therapy for DKA in a child or young person if:\n\nketosis is resolving and their blood pH has reached 7.3 and\n\nthey are alert and\n\nthey can take oral fluids without nausea or vomiting.Discuss with the responsible senior paediatrician before stopping intravenous fluid therapy and changing to oral fluids for DKA in a child or young person if they still have mild acidosis or ketosis. \n\nDo not change from intravenous insulin to subcutaneous insulin in a child or young person with DKA until ketosis is resolving, they are alert, and they can take oral fluids without nausea or vomiting. \n\nStart subcutaneous insulin in a child or young person with DKA at least 30\xa0minutes before stopping intravenous insulin. \n\nFor a child or young person with DKA who is using an insulin pump, restart the pump at least 60\xa0minutes before stopping intravenous insulin. Change the insulin cartridge and infusion set and insert the cannula into a new subcutaneous site. \n\nFor a short explanation of why the committee made the 2020 recommendations and how they might affect practice, see the rationale and impact section on fluid therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: fluid therapy for the management of diabetic ketoacidosis.\n\nLoading. Please wait.\n\n## Monitoring during therapy\n\nMonitor and record the following at least hourly in children and young people with DKA:\n\ncapillary blood glucose\n\nheart rate, blood pressure, temperature, respiratory rate (look for Kussmaul breathing)\n\nfluid balance, with fluid input and output charts\n\nlevel of consciousness (using the modified Glasgow Coma Scale). \n\nMonitor and record the level of consciousness (using the modified Glasgow Coma Scale) and heart rate (to detect bradycardia) every 30\xa0minutes in:\n\nchildren under 2\xa0years with DKA\n\nchildren and young people with severe DKA (blood pH below 7.1).This is because these children and young people are at an increased risk of cerebral oedema. \n\nMonitor children and young people having intravenous therapy for DKA using continuous electrocardiogram (ECG) to detect signs of hypokalaemia (including ST‑segment depression and prominent U‑waves). \n\nEnsure that healthcare professionals performing the monitoring described in recommendations 1.4.46, 1.4.47 and 1.4.48 know what to look for and when to seek advice. \n\nAt 2\xa0hours after starting treatment, and then at least every 4\xa0hours, carry out and record the results of the following blood tests in children and young people with DKA:\n\nglucose (laboratory measurement)\n\nblood pH and pCO2\n\nplasma sodium, potassium and urea\n\nbeta‑hydroxybutyrate. \n\nA doctor involved in the care of the child or young person with DKA should review them face‑to‑face at diagnosis and then at least every 4\xa0hours, and more frequently if:\n\nthey are aged under 2\xa0years\n\nthey have severe DKA (blood pH below 7.1)\n\nthere are any other reasons for special concern. \n\nAt each face‑to‑face review of children and young people with DKA, assess the following:\n\nclinical status, including vital signs and neurological status\n\nresults of blood investigations\n\nECG trace\n\ncumulative fluid balance record. \n\nUpdate the child and young person with DKA and their families or carers regularly about their progress. \n\n## Complications of diabetic ketoacidosis\n\nImmediately assess children and young people with DKA for suspected cerebral oedema if they have any of these early manifestations:\n\nheadache\n\nagitation or irritability\n\nunexpected fall in heart rate\n\nincreased blood pressure. \n\nIf cerebral oedema is suspected in a child or young person with DKA, start treatment immediately.\n\nStart treatment for cerebral oedema immediately in children and young people with DKA and any of these signs:\n\ndeterioration in level of consciousness\n\nabnormalities of breathing pattern, such as respiratory pauses\n\noculomotor palsies\n\npupillary inequality or dilatation. \n\nWhen treating cerebral oedema in children and young people with DKA, use the most readily available of:\n\nmannitol (20%, 0.5\xa0g/kg to 1\xa0g/kg over 10 to 15\xa0minutes) or\n\nhypertonic sodium chloride (2.7% or 3%, 2.5\xa0ml/kg to 5\xa0ml/kg over 10 to 15\xa0minutes). \n\nAfter starting treatment for cerebral oedema with mannitol or hypertonic sodium chloride in a child or young person with DKA, immediately seek specialist advice on further management, including which care setting would be best. \n\nIf a child or young person with DKA develops hypokalaemia (potassium below 3\xa0mmol/litre):\n\nthink about temporarily suspending the insulin infusion\n\ndiscuss hypokalaemia management urgently with a paediatric critical care specialist because a central venous catheter is needed to give intravenous potassium solutions above 40\xa0mmol/litre. \n\nBe aware of the increased risk of venous thromboembolism in children and young people with DKA, especially if they have a central venous catheter. \n\n## Avoiding future episodes of diabetic ketoacidosis\n\nAfter a child or young person with known diabetes has recovered from an episode of DKA, discuss what may have led to the episode with them and their families or carers. \n\nThink about the possibility of non‑adherence to therapy in children and young people with established type\xa01\xa0diabetes who present with DKA, especially if they have had multiple episodes of DKA. [2004, amended 2015]\n\nAdvise children and young people who have had DKA and their families or carers how to reduce the risk of future episodes. In particular, explain the importance of managing intercurrent illnesses. \n\n# Service provision\n\nOffer children and young people with diabetes an ongoing integrated package of care, provided by a multidisciplinary paediatric diabetes team. [2004, amended 2015]\n\nThe diabetes team should include members with training in clinical, educational, dietetic, lifestyle, mental health and foot care aspects of diabetes for children and young people. [2004, amended 2015]\n\nOffer children and young people with diabetes and their families or carers 24‑hour access to advice from their diabetes team. [2004, amended 2015]\n\nInvolve children and young people with diabetes and their families or carers in making decisions about the package of care provided by their diabetes team. [2004, amended 2015]\n\nAt diagnosis, offer children and young people with diabetes either home‑based or inpatient management, depending on their clinical need, family circumstances and preferences. Explain that home‑based care with support from the local paediatric diabetes team (including 24‑hour telephone access) is safe, and is as effective as initial inpatient management. [2004, amended 2015]\n\nOffer initial inpatient management to children with diabetes who are under 2\xa0years old. [2004, amended 2015]\n\nThink about initial inpatient management for children and young people with diabetes if there are social or emotional factors that would make home‑based management inappropriate, or if they live a long way from the hospital. [2004, amended 2015]\n\nDiabetes teams should speak regularly with school staff who look after children and young people with type\xa01\xa0diabetes, to provide diabetes education and practical information. [2004, amended 2015]\n\nRecord the details of children and young people with diabetes on a population‑based, practice‑based or clinic‑based diabetes register. [2004, amended 2015]\n\n## Transition from paediatric to adult care\n\nGive young people with diabetes enough time to understand how transition from paediatric to adult services will work, because this improves clinic attendance. [2004, amended 2015]\n\nAgree specific local protocols for transferring young people with diabetes from paediatric to adult services. [2004, amended 2015]\n\nBase the decision on when a young person should transfer to the adult service on their physical development and emotional maturity, and on local circumstances. [2004, amended 2015]\n\nEnsure that transition from the paediatric service occurs at a time of relative stability in the young person's health, and that it is coordinated with other life transitions. [2004, amended 2015]\n\nExplain to young people with type\xa01\xa0diabetes who are preparing for transition to adult services that some aspects of diabetes care will change. [2004, amended 2015]\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Continuous glucose monitoring\n\nThis covers both real-time (rtCGM) and intermittently scanned (isCGM, commonly referred to as 'flash') continuous glucose monitoring.\n\nA continuous glucose monitor is a device that measures blood glucose levels and sends the readings to a display device or smartphone.\n\n## Hyperchloremic acidosis\n\nA persisting base deficit or low bicarbonate concentration, despite evidence of resolving ketosis and clinical improvement.\n\n## Insulin pump\n\nContinuous subcutaneous insulin infusion. A programmable pump and insulin storage device that gives a regular or continuous amount of insulin (usually a rapid‑acting insulin analogue or short‑acting insulin) through a subcutaneous needle or cannula.\n\n## Level 3 carbohydrate counting\n\nCarbohydrate counting with adjustment of insulin dosage according to an insulin to carbohydrate ratio.\n\n## Multiple daily injection basal-bolus regimen\n\nInjections of short‑acting insulin or rapid‑acting insulin analogue before meals, together with 1 or more separate daily injections of intermediate‑acting insulin or long‑acting insulin analogue.\n\n## Periodontitis\n\nA chronic inflammatory gum disease that destroys the supporting tissues of the teeth (the periodontium).\n\nGingivitis is a milder form of periodontal disease than periodontitis. However, gingivitis still causes inflammation in the gum, and if not treated it can lead to periodontitis.\n\n## Once-, twice-, or three‑times daily mixed insulin injections\n\nThese are usually injections of short‑acting insulin or rapid‑acting insulin analogue mixed with intermediate‑acting insulin.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Use of routinely collected real-world data to examine the effectiveness and cost effectiveness of continuous glucose monitoring\n\nBased on routinely collected real-world data, what is the effectiveness and cost effectiveness of continuous glucose monitoring devices to improve glycaemic control in children and young people? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on continuous glucose monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: continuous glucose monitoring in children and young people with type\xa01 diabetes.\n\nLoading. Please wait.\n\n# Effectiveness of glucose-lowering agents used to manage blood glucose levels in children and young people with type 2 diabetes\n\nIn children and young people with type 2 diabetes, what is the effectiveness of glucose-lowering agents used to manage blood glucose levels in adults with type 2 diabetes? \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale section on glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\n# Weekly treatment with glucose-lowering agents for managing blood glucose levels\n\nIn children and young people with type 2 diabetes, what is the effectiveness of weekly treatment with glucose-lowering agents for managing blood glucose levels compared to daily treatment? \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale section on glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes.\n\nLoading. Please wait.\n\n# Continuous glucose monitor sensor adhesive to prevent sensitivities\n\nWhat is the best continuous glucose monitor sensor adhesive to prevent sensitivities to the device, for example local skin reactions? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on continuous glucose monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: continuous glucose monitoring in children and young people with type\xa01 diabetes.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Continuous glucose monitoring in children with type 1 diabetes\n\nRecommendations 1.2.60 to 1.2.70\n\n## Why the committee made the recommendations\n\nThe evidence on real-time continuous glucose monitoring (rtCGM) showed it leads to:\n\na decrease in HbA1c and\n\nan increase in time in range.\n\nThis reflected the committee's experience in clinical practice. They highlighted that the continuous nature of rtCGM, and the fact that it can be connected to the phone or device of a parent or carer so they can track the data, were particularly important components for children and young people.\n\nBecause the evidence showed similar benefits of rtCGM for children and young people as for adults, the committee extrapolated the cost-effectiveness results from adults, concluding that rtCGM was cost effective in this population.\n\nThe committee agreed that children and young people needed support to understand how continuous glucose monitoring (CGM) works, the accuracy of devices and the benefits it can provide, so they emphasised that rtCGM should be provided along with education on how to use it.\n\nIntermittently scanned CGM (isCGM) had no clinically meaningful effect on any of the outcomes that were looked at in the evidence. In the committee's experience, the intermittent nature of isCGM can affect adherence in children and young people.\n\nSince the same clinical benefits were not found for isCGM in children and young people as in adults, the committee agreed those cost-effectiveness findings could not be extrapolated, so they could not conclude that isCGM is a cost-effective technology for the full population of children and young people. They therefore agreed that isCGM should be restricted to children and young people who are unable or do not want to use rtCGM, or who would prefer isCGM. Children and young people who prefer isCGM are likely to have better adherence with this type of device, so it would provide more benefit. The recommendation limits isCGM to children aged 4 and over because no isCGM devices are licensed in children under 4.\n\nThe committee did not make a recommendation on using specific devices because CGM technologies are changing very quickly and this recommendation would soon be out of date. Local healthcare services are better placed to assess which devices are evidence-based and suitable for use at any given time.\n\nThe committee wanted to highlight the importance of providing choice between the different CGM devices because the best device for each person would vary, so they produced a list of what to consider when discussing this with children and young people.\n\nThe committee recommended keeping capillary blood glucose monitoring as a back-up for situations such as when blood glucose levels are changing quickly or when technology fails.\n\nCGM should also be included in the continuing programme of education that children and young people with type\xa01 diabetes are offered. This will increase the likelihood that people will scan and report the results frequently, allowing them to understand and manage their diabetes effectively. In addition, children and young people should be supported by a team with expertise in using CGM. This will help them to use the technology effectively to manage their diabetes.\n\nThe committee made the recommendation about discussing possible problems with children and young people who are not using their device 70% of the time because it is important that the CGM device is used for a significant proportion of time for it to have a positive effect. They wanted to avoid a child or young person feeling 'punished' for using it less than that, but agreed that less than 70% use should trigger a discussion to find out if extra support is needed. While they did not make recommendations on stopping CGM, the committee acknowledged that it may not be offered as a permanent solution and that it can be stopped if it is not being used effectively or not perceived to be providing enough benefit.\n\nDespite the positive recommendations on CGM, the committee were concerned that existing health inequalities may still lead to lower uptake of CGM in some groups of people. To address this, the committee made a recommendation outlining actions for commissioners, providers and healthcare professionals.\n\nOne of the known factors determining the use of CGM devices among children and young people with type\xa01 diabetes is sensitivities to the device, such as local skin reactions to the adhesive used in the sensor. The committee agreed that research is needed to investigate strategies to reduce local skin reactions to promote ease of use and adherence of these devices, so they made a recommendation for research on continuous glucose monitor sensor adhesive to prevent sensitivities.\n\nThe committee also made a recommendation for research using routinely collected real-world data to examine the effectiveness and cost effectiveness of CGM. They agreed that this has the potential to show the direct effects of implemented technology in children and young people instead of interpreting it through the results of clinical trials. Increased monitoring of routine healthcare data including registries and audits would ensure the findings from a broader population is captured.\n\n## How the recommendations might affect practice\n\nThese recommendations are likely to result in broader access to rtCGM and isCGM devices for children and young people. This will increase costs but should reduce inequalities and enable more people to access the technology. Currently, children and young people, and their parents and carers, who have more time and knowledge to advocate or self-advocate are often more likely to gain access to these devices.\n\nSome children and young people have insulin insufficiency because of other conditions. The committee noted that these children and young people would get the same care as children and young people with type 1 diabetes, so they should have access to CGM.\n\nReturn to recommendations\n\n# Periodontitis\n\nRecommendations 1.2.1, 1.2.130 to 1.2.132, and 1.3.90 to 1.3.92\n\n## Why the committee made the recommendations\n\nThere was no evidence for children and young people, so the committee extrapolated from the evidence for adults with type\xa01 and type\xa02 diabetes. There was a lot of consistent evidence showing that adults with diabetes are at increased risk of periodontitis and that non-surgical treatment can improve diabetic control. The clinical and cost effectiveness of periodontal treatment in adults were sufficient to justify the recommendations for children and young people with diabetes.\n\nChildren and young people with diabetes are at increased risk of developing periodontitis. However, in the committee's experience, they are often unaware of this and may not be having regular oral health reviews. To address this, the committee recommended routinely discussing the risk of periodontitis at the child or young person's regular diabetes reviews, alongside eye disease and foot problems.\n\nOral hygiene and the need for regular oral health reviews has been added to the standard education children and young people with diabetes should receive, because this will help them prevent periodontitis.\n\n## How the recommendations might affect practice\n\nFor oral healthcare professionals, the long-term impact of the recommendations is uncertain. The recommendations specify that people should follow existing NICE guidelines on oral health. However, the recommendations may also increase awareness of periodontitis, leading to a possible short-term increase in the number of oral health reviews. Any increase in the number of oral health reviews will potentially impact on services as NHS dental services already have capacity issues.\n\nA short-term increase in the number of oral health reviews will also lead to a short-term increase in costs. However, there is likely to be a larger long-term reduction in costs from the improvement to oral health and diabetes control.\n\nOral healthcare and dental teams will need clear advice on what they need to do for people with diabetes. They will need clear care pathways to improve quality of care and service delivery, in line with the NHS England commissioning standard on dental care for people with diabetes.\n\nNHS dental services are free for children and young people under\xa018, although not everyone makes use of this. The recommendations may encourage more children and young people with diabetes to have regular oral health reviews. Combined with proactive engagement and enhanced support for children and young people with diabetes, this may broaden access to dental and oral healthcare and help to reduce oral health inequalities.\n\nReturn to recommendations\n\n# Glucose-lowering agents for managing blood glucose levels in children and young people with type 2 diabetes\n\n## Education and information\n\nRecommendations 1.3.1, 1.3.2, 1.3.4 and 1.3.5\n\nType 2 diabetes in children and young people can be effectively managed through a combination of:\n\nlifestyle changes (for example, diet and exercise)\n\nblood glucose monitoring and\n\nglucose-lowering agents.\n\nThe committee made recommendations to provide information and education to support all 3.\n\nThey also made 3 further recommendations about education and information. They agreed that:\n\nInsulin therapy to manage blood glucose levels is a complicated and demanding treatment. Children and young people with type 2 diabetes should be given the opportunity to learn about it so that they can more effectively manage their disease.\n\nInformation should be provided in a way that takes the specific needs and preferences of children and young people with type 2 diabetes into account and supports shared decision making.\n\nInformation and education about CGM for those receiving insulin or who are in specific groups should be part of a continuing programme of education because it is likely that they will use it at least once during the course of their lives.\n\nThe recommendations are not expected to substantially affect practice.\n\nReturn to recommendations\n\n## At diagnosis\n\nRecommendations 1.3.23 to 1.3.25\n\nIn the committee's experience, children and young people with type 2 diabetes are sometimes not cared for by a multidisciplinary team, in a specialist paediatric diabetes clinic. When this is the case, the child or young person is not able to access additional essential services such as telephone or mental health support. The committee therefore made a recommendation to ensure equal access to paediatric diabetes services for all children and young people with type 2 diabetes.\n\nVarious formulations of metformin are available, but only the standard-release tablets are licensed for use in a paediatric population. As of April 2023, use of other formulations would be off-label. However, the committee left the choice of metformin monotherapy formulation open on the basis that:\n\nalternative formulations may be more acceptable or better tolerated, and it is common practice for these to be used off-label in such cases\n\nthe unit cost per day of modified-release tablets is the same as that of standard-release tablets.\n\nThe committee also recommended, using their knowledge and experience, that children and young people with type 2 diabetes should be offered capillary blood glucose monitoring equipment to allow them to monitor their own glucose levels.\n\nThe committee agreed, based on their knowledge and experience, that a high HbA1c level at diagnosis justifies adding insulin therapy to metformin to reduce:\n\nblood glucose levels, and therefore reduce the risk of hyperglycaemia\n\nthe risk of developing diabetic ketoacidosis (DKA)\n\nthe risk of hyperglycaemia-related complications in the long term.\n\nThey did not specify which insulin therapy should be used (for example, short-, long-, or intermediate-acting) because they agreed that this choice should be left to the relevant healthcare professional to allow flexibility of treatment.\n\nThey also agreed that the presence of ketosis indicates a current insulin deficiency, so a multiple daily (basal-bolus) insulin injection is needed to ensure, as a matter of safety, that DKA does not develop.\n\nThe recommendations are not expected to substantially affect practice because dietary management is standard practice. It is also common for different metformin formulations to be used because some children and young people prefer formulations other than the standard-release tablet. Given the relatively small number of children and young people with type 2 diabetes in England and Wales (1,560 in all NHS settings as of 2019/20, according to the NHS Digital report on Young People with type 2 diabetes, 2019-20), the provision of equipment for both capillary blood glucose monitoring and insulin is not expected to have a significant resource impact.\n\nReturn to recommendations\n\n## Monitoring blood glucose levels and reviewing treatment\n\nRecommendations 1.3.26 to 1.3.29\n\nThe committee agreed that, for children and young people with type 2 diabetes, it is important to:\n\nachieve an HbA1c level of 48\xa0mmol/mol (6.5%) or lower as early as possible in the treatment pathway to avoid later complications (such as cardiovascular, kidney and liver disease) and\n\navoid staying on the same treatment for too long without reassessing its effectiveness.\n\nAs a result, they also agreed that current guidance to measure HbA1c levels every 3 months should be retained but supplemented with new recommendations, to make provision for an initial visit earlier than 3 months after diagnosis and for the use of data from capillary blood glucose monitoring or CGM. This is because combining HbA1c and glucose monitoring data will allow seeing trends quicker than changes in HbA1c levels alone.\n\nThe target HbA1c level of 48\xa0mmol/mol (6.5%) or lower was chosen because:\n\nit can be used to diagnose type 2 diabetes and\n\nstaying below this level is recommended to minimise the risk of long-term complications (see recommendation 1.3.31).\n\nThe committee agreed, using their knowledge and experience, that a first visit to review glucose data should take place after 4 weeks of metformin monotherapy. A period of 4 weeks was agreed because:\n\nat least 4 weeks of glucose monitoring data is needed to assess whether glucose levels are improving or whether treatment needs to be escalated\n\nalthough current guidance is for the first clinical visit to take place 3\xa0months after diagnosis, in practice, this occurs earlier because newly diagnosed children and young people with type 2 diabetes often need more support than those whose glucose levels have already stabilised\n\nfor children and young people with type 2 diabetes who are also on insulin therapy, safely reducing and stopping insulin typically takes 2 to 6 weeks, so a review of additional CGM data at 4 weeks will help.\n\nGiven the above considerations and the many differences between individual children and young people with type 2 diabetes, the committee agreed that healthcare professionals should carry out subsequent reviews at least every 3 months (the recommended frequency of HbA1c measurements). However, they recognised and allowed for the fact that reviews may be required more often (especially if the child or young person is on insulin therapy).\n\nThe committee acknowledged that there are rare cases in which HbA1c measurements cannot be used (for example, when the child or young person has abnormal haemoglobin). Using their knowledge and experience, they recommended 3 alternative methods of estimating average glycaemia for use in such cases.\n\nThey also agreed that the frequency of monitoring should be based on several factors:\n\nthe type of treatment\n\nthe duration of the child or young person's type 2 diabetes and\n\ntheir general ability to maintain blood glucose within the target range.\n\nFor example, children and young people with type 2 diabetes who are on insulin but not using CGM will need to test their capillary blood glucose 4 to 5 times a day while those using insulin and CGM will not need to test it so often. As blood glucose levels stabilise, frequency of capillary blood glucose monitoring can be reduced. Given these considerations, enough test strips should be prescribed to enable the person to self-monitor as required by their treatment until the next review.\n\nThe recommendations on capillary blood glucose monitoring and an initial review 4 weeks after diagnosis reflect current practice in England and therefore are not expected to have a significant impact.\n\nReturn to recommendations\n\n## Continuous glucose monitoring\n\nRecommendations 1.3.38 to 1.3.47\n\nCGM is already recommended for everyone with type 1 diabetes and in some adults with type 2 diabetes, and the committee agreed that children and young people with type 2 diabetes should be offered the same.\n\nThe committee's decision to include these recommendations was also based on the following:\n\nType 2 diabetes in children and young people is the most aggressive form of the disease, and this population will live with the condition for longer than adults with type 2 diabetes, so timely intervention is important to reduce the risk of developing severe long-term (and possibly life-threatening) complications, such as peripheral neuropathy.\n\nMany children and young people experience health inequalities because of comorbidities (for example, special educational needs or learning disabilities), which can make it difficult for them to conduct capillary blood glucose measurements.\n\nCapillary blood glucose monitoring often requires several finger-prick tests a day, which can be tiring, stressful and have a negative psychological impact on the person. CGM provides another, less invasive way for children and young people with diabetes to manage their blood glucose levels.\n\nSome CGM devices allow glucose data to be shared electronically.\n\nUsing CGM, even in the short term, is likely to improve the child or young person's understanding of their own blood glucose patterns because of the continuous and visual way CGM allows glucose data to be presented.\n\nThe evidence base for the effectiveness of CGM in this population is limited, mostly because of the small number of children and young people with type 2 diabetes. As a result, the committee based recommendations on CGM for this population on the recommendations about CGM for children and young people with type 1 diabetes, in this guideline, and on the recommendations about CGM for adults in NICE's guideline on type 2 diabetes in adults.\n\nThe 2022 evidence review on the effectiveness of CGM to improve blood glucose level management in children and young people with type 1 diabetes concluded that:\n\nrtCGM is more effective than capillary blood glucose monitoring\n\nisCGM is no more effective than capillary blood glucose monitoring.\n\nTherefore, the committee agreed that rtCGM should be considered when children and young people with type 2 diabetes are on insulin therapy because of:\n\nthe increased risk of hypoglycaemia\n\ncomorbidities associated with type 2 diabetes in children and young people and\n\nthe decreasing costs over time of available and appropriate devices.\n\nAs for adults, the committee agreed that CGM should not be considered for all children and young people with type 2 diabetes because some will be able to maintain their blood glucose levels within the target range using glucose-lowering agents that do not increase the risk of hypoglycaemia (such as metformin monotherapy).\n\nThe option to consider isCGM for people over 4 years old was provided because:\n\nsome children and young people with type 2 diabetes have difficulties using rtCGM or may prefer isCGM to rtCGM\n\nin May 2023, isCGM was licensed for children aged 4 years and over.\n\nThe committee agreed that a stronger recommendation to offer rtCGM to 3 specific groups was justified, regardless of whether they are having insulin therapy, because of the child or young person's individual needs and the treatment burden associated with capillary blood glucose monitoring.\n\nRegardless of the reason the child or young person with type 2 diabetes is offered CGM, the committee agreed that it should be provided by a team with expertise in its use, so that support can be provided and any issues with it can be quickly resolved.\n\nThe committee agreed that CGM should not replace capillary blood glucose monitoring because it is still needed both for checking the CGM device and as a back-up. They made some further recommendations about choosing and using a CGM device to encourage adherence and provide support.\n\nFinally, the committee agreed, in line with the recommendations for children and young people with type 1 diabetes, that inequalities in access and uptake of CGM may still occur for those with type 2 diabetes, so they added a recommendation to address this. For example, obesity and type 2 diabetes are also closely associated, as are childhood obesity and socioeconomic status (it is highest among children living in the most deprived areas).\n\nThe availability of devices for rtCGM or isCGM that allow remote sharing of data is increasing, although there can be wide variation in their cost. Some children or young people will also not have access to a mobile phone or compatible electronic device, which the CGM devices may require, so some provision for this may be needed. However, the number of children and young people with type 2 diabetes who will be eligible for CGM will also be relatively low. So, the recommendations to consider or offer CGM is unlikely to have a significant resource impact.\n\nReturn to recommendations\n\n## When to reduce insulin for people who have been on it from diagnosis\n\nRecommendation 1.3.48\n\nThe committee recognised that insulin use substantively increases the risk of hypoglycaemia and weight gain and that it should be gradually reduced and stopped when the person's HbA1c levels is under the 48\xa0mmol/mol (6.5%) threshold. They agreed 3 criteria for when to reduce insulin use, based on those recommended for type 1 diabetes (see recommendation 1.2.55).\n\nThe committee also recognised that the choice of how often glucose levels could exceed the target ranges was somewhat arbitrary, but they were keen to avoid basing decisions on single events and agreed that having low glucose levels more often than not (for example, on 4 or more days a week) would certainly indicate that insulin can be reduced.\n\nThe recommendation is not expected to substantially affect practice.\n\nReturn to recommendation\n\n## Adding liraglutide, dulaglutide, or empagliflozin\n\nRecommendations 1.3.49 to 1.3.55\n\nThe committee made separate recommendations about combining metformin with other glucose-lowering agents for children and young people with type 2 diabetes who are or are not on insulin therapy because insulin therapy is associated with specific risks (such as hypoglycaemia) not associated with metformin monotherapy. However, the overall rationale for these recommendations remains broadly the same and any differences relating to insulin therapy will be noted below.\n\nThree thresholds were chosen for when to initiate metformin therapy with liraglutide, dulaglutide, or empagliflozin (rather than insulin) for children and young people with type 2 diabetes. These thresholds reflect the chosen HbA1c threshold and upper limits of the blood glucose target ranges in recommendation 1.3.48.\n\nOverall, the evidence showed that 2 GLP-1 receptor agonists, liraglutide and dulaglutide, and one SGLT2 inhibitor, empagliflozin, were generally effective in the short term at reducing glucose levels in children and young people with type 2 diabetes. Liraglutide and dulaglutide had significant effects on the majority of critical outcomes, including change in HbA1c level, mean fasting plasma glucose level, and use of insulin rescue medication. Empagliflozin also had significant effects on change in HbA1c percentage level and mean fasting plasma glucose level. No difference on the important outcomes (serious adverse events, gastrointestinal symptoms) was found in the short term.\n\nOnly one trial reported long-term data, comparing liraglutide to placebo, which showed that its effectiveness for managing blood glucose levels was maintained after 52 weeks. However, there was an increased risk of nausea and vomiting.\n\nThough the recommendations mean potentially combining dulaglutide, liraglutide or empagliflozin with metformin earlier than it would be combined for an adult, the committee agreed it is justified by the relatively small number of available treatments for the paediatric population and the risks associated with:\n\nnot achieving an HbA1c level of 48\xa0mmol/mol (6.5%) or lower, and\n\ndeveloping complications related to diabetes.\n\nThe committee agreed that this should be done in preference to offering insulin because of the risks of hypoglycaemia and weight gain associated with insulin use.\n\nThe restriction to children and young people aged 10 years or over reflects the licensing conditions for liraglutide.\n\nThe weaker strength of recommendation for empagliflozin reflects the evidence, suggesting that it is slightly less effective at managing blood glucose levels than liraglutide and dulaglutide, although there was no direct evidence comparing any of these agents to each other.\n\nThe committee also agreed that the lowest dose of liraglutide, dulaglutide, and empagliflozin needed to maintain the target ranges specified in recommendation 1.3.48 should be maintained. This is because higher doses can lead to side effects and poorer treatment adherence. The committee also agreed, using their experience, that a specific warning about the use of empagliflozin was needed because its use as a glucose-lowering agent in the paediatric population is relatively recent.\n\nInsulin use is associated with an increased risk of hypoglycaemia and weight gain. Given this, the committee recommended that, for children and young people with type 2 diabetes on metformin only, insulin should only be offered when other treatments have failed to stabilise glucose levels.\n\nSimilarly, the committee agreed that, for children and young people with type 2 diabetes who are on both metformin and insulin, insulin should only be increased when adding other treatments has failed to stabilise glucose levels. However, the committee recognised that there may be some children and young people with type 2 diabetes in whom other treatments (that is, liraglutide, dulaglutide or empagliflozin) may be contraindicated or not tolerated. The committee agreed that this should not prevent increasing their insulin dose and added a specific provision in the criteria to account for this.\n\nThe committee also discussed whether body mass index should be a criterion for starting treatment with glucose-lowering agents – as it is for adults – but decided that this was not needed because a small proportion of children and young people with type 2 diabetes are not overweight and specifying such a criterion would exclude this group from treatment.\n\nDulaglutide is administered as a weekly injection, whereas liraglutide requires daily injections. Empagliflozin is an oral (tablet) treatment. Because some children and young people may prefer 1 treatment regimen over the other, the committee agreed to recommend both liraglutide and dulaglutide injections and, if contraindicated, oral empagliflozin, even though:\n\nThere is an increased risk of nausea and vomiting associated with long-term use of liraglutide.\n\nThere was no long-term comparative data for dulaglutide or empagliflozin.\n\nDulaglutide, liraglutide or both may be contraindicated in some children and young people with type 2 diabetes.\n\nThe committee recognised that they did not have direct evidence comparing the effectiveness of weekly treatments compared to daily treatments with glucose-lowering agents for managing blood glucose levels. So, they made a research recommendation to:\n\naddress this gap\n\nassess whether weekly injections could help reduce stigma and treatment burden for children and young people with type 2 diabetes.\n\nThere are a lot of medicines that can be used to manage blood glucose levels in adults with type 2 diabetes. In contrast, there are very few licensed, effective and safe medicines to manage blood glucose levels for children and young people with type 2 diabetes. The committee thus made a research recommendation for further clinical trials in children and young people of medicines used for adults.\n\nAs of April 2023, there are 4 other medicines that are licensed for use in the UK in a paediatric population:\n\nexenatide (a GLP-1 receptor agonist)\n\ndapagliflozin (an SGLT2 inhibitor)\n\ninsulin detemir (a long-acting insulin)\n\nneutral protamine Hagedorn (NPH) insulin (an intermediate-acting insulin).\n\nThe committee agreed that the evidence was not sufficient for either of the first 2 licensed medicines to be recommended, nor for one insulin to be recommended over the other.\n\nLiraglutide and dulaglutide are relatively expensive compared to other possible treatments but recommending them is unlikely to surpass NICE's £1 million threshold for significant resource impact. Empagliflozin is approximately half the price of both liraglutide and dulaglutide. However, there was insufficient evidence to construct a full cost-effectiveness model. The committee indicated that the difference in unit cost per dose is relatively small, especially when considering the low prevalence of type 2 diabetes in children and young people. Similar considerations apply to using insulin at diagnosis where the prevalence of type 2 diabetes combined with a high HbA1c level or high blood ketones is even lower.\n\nIncreased support from a paediatric diabetic nurse and consultant will be needed when the child or young person starts on liraglutide, dulaglutide or empagliflozin. However, once the child or young person's HbA1c levels are stabilised, this will no longer be required because repeat prescriptions can be made by the GP.\n\nInsulin is a last resort in the management of type 2 diabetes in children and young people and the recommendations are not expected to substantially affect practice.\n\nReturn to recommendations\n\n## Insulin therapy\n\nRecommendations 1.3.56 to 1.3.60\n\nThe committee based their recommendations on insulin therapy on those for children and young people with type 1 diabetes. Overall, the committee agreed that the choice of insulin therapy should be left to the child or young person with type 2 diabetes (or their families or carers), in consultation with the specialist diabetes paediatric team. The committee made some general recommendations about choosing an insulin regimen, providing appropriate equipment for injections, reviewing injection sites, and providing additional support when their glucose levels are not optimal.\n\nInsulin is a last resort in the management of type 2 diabetes in children and young people and the recommendations are not expected to substantially affect practice.\n\nReturn to recommendations\n\n## Changing treatments and updating school healthcare plans\n\nRecommendation 1.3.61\n\nThe committee agreed that the paediatric diabetes team should update the child or young person's school healthcare plan annually, and when treatment changes in a way that affects the child or young person while they are at school. This will enable coordination of care with the child's or young person's school.\n\nThe recommendation is not expected to substantially affect practice.\n\nReturn to recommendation\n\n# Fluid therapy for diabetic ketoacidosis\n\nRecommendations 1.4.21 to 1.4.34, 1.4.39, 1.4.40 and 1.4.42\n\n## Why the committee made the recommendations\n\nThe 2015 recommendations caused some confusion around when to use oral or intravenous fluids. To address this, the committee looked for research evidence that would help them make clearer recommendations. There was no evidence that compared different routes of administration or different oral fluids for hydration, so the committee updated the recommendations based on their experience and expertise.\n\nIn the 2015 guideline, the rate of fluid administration in DKA was restricted because rapid fluid administration was believed to cause cerebral oedema. However, for the 2020 update there was some randomised controlled trial evidence (particularly the PECARN FLUID trial) comparing the effect of different DKA protocols on outcomes such as mortality or clinically apparent brain injury. This evidence showed no significant difference between the 2 protocols, and it demonstrated that the restrictions on the rate of fluid administration were not needed.\n\nIn response to this evidence, and applying their clinical expertise, the committee updated the recommendations to use more rapid fluid administration (including fluid boluses). They also made a separate recommendation for children and young people who are in shock, as this group need a higher volume of fluids and they need these fluids to be given more rapidly.\n\nWhen the 2015 recommendations were made, rapid fluid administration was believed to cause cerebral oedema. However, more recent randomised controlled trial evidence (particularly the PECARN FLUID trial) has shown that brain injury in this group may be caused by DKA itself because of the resulting cerebral hypoperfusion, reperfusion and neuro-inflammation. If DKA is the cause of brain injury, children and young people would benefit from receiving more fluids in the first 48\xa0hours than was recommended in the 2015 guideline. To address this, the committee updated the recommendation on calculating the fluid maintenance requirement, based on their clinical knowledge and on evidence from the PECARN FLUID trial. The Holliday–Segar formula that they recommended is commonly used in practice and has not been shown to cause any adverse events.\n\nNo evidence was identified on the use of potassium. The committee used their expertise and their understanding of the evidence on the pathophysiology of DKA to update the recommendation. They added more detail about how to care for children and young people with anuria or potassium levels above the normal range. It is essential to not delay adding potassium to fluids because insulin can cause hypokalaemia in this population, which can lead to cardiac arrhythmias and death.\n\nThe committee also used their expertise to make recommendations highlighting complications such as hyperchloremic acidosis.\n\nThe committee used their expertise to make recommendations on monitoring serum sodium levels and identifying children and young people with hyponatraemia.\n\n## How the recommendations might affect practice\n\nThere is variation in practice due to the different beliefs on the causes of cerebral oedema. The new recommendations will be a change in practice in some areas, but they are in line with randomised trial evidence and with other clinical guidance (such as chapter 11 in the 2018 International Society for Paediatric and Adolescent Diabetes DKA guideline).\n\nReturn to recommendations", 'Context': 'Diabetes is a long‑term condition that can have a major impact on the life of a child or young person, as well as their family or carers. In addition to glucose-lowering agents for managing blood glucose levels, diabetes management should include education, support and access to psychological services, as detailed in this guideline. Preparations should also be made for the transition from paediatric to adult services, which have a somewhat different model of care and evidence base.\n\nType\xa01\xa0diabetes is becoming more common in the UK, and since 2004 type\xa02\xa0diabetes is also being diagnosed with increasing frequency. The 2020/21 National Paediatric Diabetes Audit identified 29,000\xa0children and young people with type 1 diabetes and 973 with type 2 being managed within a paediatric diabetes unit.\n\nMuch of the general care for type 2 diabetes is the same as for type 1 diabetes, although the initial management is different. In addition, overweight and obesity associated with type\xa02\xa0diabetes bring an increased risk of renal complications and problems such as hypertension and dyslipidaemia. These differences in management and complications need guidance specific to type 2 diabetes. A variety of genetic conditions (such as maturity‑onset diabetes in the young) and other conditions (such as cystic fibrosis‑related diabetes) may also lead to diabetes in children and young people, but the care of these diverse conditions is beyond the scope of this guideline.\n\nThis guideline recommends attempting to reach a glycated haemoglobin (HbA1c) level near the normal range and near normoglycaemia. This is to further reduce the long-term risks associated with diabetes. Newer technology such as continuous subcutaneous glucose monitoring may also help children and young people to have better blood glucose management, although this is not currently recommended for all children and young people with type 2 diabetes.\n\nBy implementing the strict blood glucose management recommended in this guideline, improvements can be made to diabetes care that reduce the impact of the condition on the future health of children and young people.'}	https://www.nice.org.uk/guidance/ng18	This guideline covers the diagnosis and management of type 1 and type 2 diabetes in children and young people aged under 18. The guideline recommends how to support children and young people and their families and carers to maintain tight control of blood glucose to reduce the long-term risks associated with diabetes.
86a1bda1a635375aece6e32a6aed2a45e134d104	nice	Olaparib for adjuvant treatment of BRCA mutation-positive HER2-negative high-risk early breast cancer after chemotherapy	Olaparib for adjuvant treatment of BRCA mutation-positive HER2-negative high-risk early breast cancer after chemotherapy Evidence-based recommendations on olaparib (Lynparza) for adjuvant treatment of BRCA mutation-positive HER2-negative high-risk early breast cancer after chemotherapy in adults. # Recommendations Olaparib (alone or with endocrine therapy) is recommended, within its marketing authorisation, as an option for the adjuvant treatment of HER2‑negative high-risk early breast cancer that has been treated with neoadjuvant or adjuvant chemotherapy in adults with germline BRCA1 or 2 mutations. It is only recommended if the company provides it according to the commercial arrangement. Why the committee made these recommendations People with BRCA mutation-positive HER2‑negative high-risk early breast cancer usually have chemotherapy followed by surgery (neoadjuvant chemotherapy), or surgery followed by chemotherapy (adjuvant chemotherapy). Clinical trial evidence shows that, compared with placebo, olaparib after neoadjuvant or adjuvant chemotherapy decreases the chance of the cancer returning or getting worse, and increases the length of time people live. The cost-effectiveness estimates for olaparib are within what NICE considers to be an acceptable use of NHS resources. So, olaparib is recommended.# Information about olaparib # Marketing authorisation indication Olaparib (Lynparza, AstraZeneca) has a marketing authorisation as a 'monotherapy or in combination with endocrine therapy for the adjuvant treatment of adult patients with germline BRCA1/2‑mutations who have HER2‑negative, high-risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for olaparib. # Price The list price is £2,317.50 per 56‑pack of 150 mg tablets (excluding VAT; BNF online accessed January 2023). The company has a commercial arrangement. This makes olaparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by AstraZeneca, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need ## BRCA mutation-positive HER2-negative high-risk early breast cancer The patient experts explained that BRCA mutation-positive HER2‑negative high-risk early breast cancer is an aggressive form of cancer with poor outcomes. They also explained that it can be very distressing for people with the condition. It includes hormone receptor-positive and triple-negative breast cancer, the latter having the poorest prognosis. The patient experts explained that there are limited treatment options available for the condition, particularly for triple-negative breast cancer. They thought that many people who have had olaparib appreciated having access to an extra treatment option that has been shown to improve survival. People with HER2‑negative high-risk early breast cancer often worry about the increased risk of their cancer returning after treatment. Also, people with BRCA mutation-positive breast cancer have concerns about whether their relatives have the BRCA1 or 2 mutations and so an increased risk of developing cancer. Having a treatment that has been shown to improve outcomes has a positive effect on mental health. One of the patient experts who had had olaparib highlighted that it is a convenient oral treatment, and only infrequent hospital visits are needed for monitoring. They explained that olaparib's side effects were manageable. They also said that they were able to continue their usual daily activities and maintain a good quality of life while having it, although they did have fatigue. The committee concluded that olaparib would be a welcome adjuvant treatment option to improve outcomes in people with BRCA mutation-positive HER2‑negative high-risk early breast cancer. # Treatment pathway ## Relevant comparator The committee noted that current standard care for BRCA mutation-positive HER2‑negative high-risk early breast cancer is neoadjuvant chemotherapy followed by surgery and surveillance, or surgery followed by adjuvant chemotherapy. The most common chemotherapy regimen is an anthracycline taxane combination plus a platinum therapy. People with hormone receptor-positive HER2‑negative breast cancer may also have adjuvant endocrine therapy after surgery. The committee noted that olaparib would be used after neoadjuvant or adjuvant chemotherapy, either: as monotherapy in triple-negative early breast cancer, or with endocrine treatment in hormone receptor-positive HER2‑negative early breast cancer.Because olaparib would be used in addition to any current therapies, the committee agreed that the relevant comparator was routine monitoring for cancer recurrence. # Clinical evidence ## Generalisability of OlympiA The clinical evidence came from OlympiA, a randomised double-blind placebo-controlled trial (n=1,836). It was done in 23 countries worldwide and included 106 people from the UK. The trial compared olaparib with placebo in people with (germline) BRCA mutation-positive HER2‑negative high-risk early breast cancer. People in the trial had either had neoadjuvant or adjuvant treatment at the point of randomisation. The criteria for defining high risk in OlympiA were: for people with triple-negative breast cancer who had neoadjuvant chemotherapy: residual invasive cancer in the breast, the resected lymph nodes (non-pathological complete response) or both at the time of surgery for people with hormone receptor-positive HER2‑negative breast cancer who had neoadjuvant chemotherapy: residual invasive cancer in the breast, the resected lymph nodes (non-pathologic complete response) or both at the time of surgery, and a score of 3 or more based on pretreatment clinical and post-treatment pathological stage, receptor status and histological grade for people with triple-negative breast cancer who had adjuvant chemotherapy: node-positive or node-negative cancer with a primary tumour of 2 cm or more for people with hormone receptor-positive HER2‑negative breast cancer who had adjuvant chemotherapy: 4 or more pathologically confirmed positive lymph nodes.The clinical experts explained that the criteria for defining high risk were representative of how olaparib would be used in the NHS. They also explained that people with hormone receptor-positive HER2‑negative breast cancer (17.7%) in OlympiA were selected as having cancer with an equivalent high risk of relapse as people with triple-negative breast cancer (82.3%). The clinical experts explained that, in clinical practice, a higher proportion of people would have hormone receptor-positive HER2‑negative breast cancer. They said that the proportions in the trial reflected the lower prevalence of BRCA mutations in people with hormone receptor-positive HER2‑negative breast cancer, and their later enrolment into the trial. The committee agreed that the definition of high-risk early breast cancer in OlympiA was appropriate. It concluded that the trial was broadly generalisable to people who would have olaparib in the NHS. ## Clinical effectiveness The primary outcome in OlympiA was invasive disease-free survival. Secondary outcomes included distant disease-free survival and overall survival. A statistically significant difference in all 3 outcomes was shown with olaparib compared with placebo: Invasive disease-free survival at 4 years was 82.7% in the olaparib arm and 75.4% in the placebo arm (a difference of 7.3%, 95% confidence interval 3.0% to 11.5%). Distant disease-free survival at 4 years was 86.5% in the olaparib arm and 79.1% in the placebo arm (a difference of 7.4%, 95% CI 3.6% to 11.3%). Overall survival at 4 years was 89.8% in the olaparib arm and 86.4% in the placebo arm (a difference of 3.4%, 95% CI -0.1 to 6.8%).The committee noted that event rates were low: 82.7% of people in the olaparib arm and 75.4% in the placebo arm were alive and cancer-free after 4 years. But it concluded that, in the full trial population, adjuvant treatment with olaparib had been shown to improve invasive disease-free survival, distant disease-free survival and overall survival compared with placebo. Also, it agreed that low rates are expected in people who have recently had surgery and chemotherapy with curative intent. ## Efficacy of olaparib in subgroups For the subgroup of people in OlympiA who had triple-negative breast cancer, olaparib statistically significantly improved invasive disease-free survival compared with placebo. For the subgroup of people with hormone receptor-positive HER2‑negative breast cancer, the results were consistent with the overall population but were not statistically significant. The clinical experts advised that this was because: -f the smaller sample size and lower number of events in that subgroup (see section 3.3) OlympiA was not powered to detect differences in subgroups at the latest data cut-off (median 3.5‑year follow up).They also explained that they did not expect to see any difference in treatment effect between the 2 HER2‑negative subgroups in the trial. Also, the committee noted the company's comment that there was no evidence of statistical heterogeneity between subgroups. The committee accepted these comments. # Economic model ## Model design The company presented a 5‑state semi-Markov model to estimate the cost effectiveness of adjuvant treatment with olaparib compared with routine monitoring in people with BRCA mutation-positive HER2‑negative high-risk early breast cancer previously treated with adjuvant or neoadjuvant chemotherapy. The 5 health states were: disease-free; non-metastatic breast cancer (local recurrence); early-onset metastatic breast cancer (recurrence within 2 years); late-onset metastatic breast cancer (recurrence after 2 years); and death. The model estimated the cost effectiveness of olaparib in people with triple-negative breast cancer and people with hormone receptor-positive HER2‑negative breast cancer separately. The EAG described the model as high-quality and largely aligned with NICE's methods for economic evaluation. The committee concluded that the model was suitable for decision making. ## Extrapolating recurrence There was no long-term data from OlympiA to use in the economic model. So, the company and the EAG had to extrapolate the data and make assumptions about recurrence using expert opinion and the published literature. The company used a log-normal distribution to model the risk of recurrence in both the triple-negative and hormone receptor-positive HER2‑negative breast cancer populations. The EAG agreed with the log-normal distribution for the triple-negative population but thought that this was too optimistic for the hormone receptor-positive HER2‑negative population. It preferred the generalised gamma distribution. This gave the smallest difference in long-term invasive disease-free survival for this subgroup. It also resulted in there being an equal risk of recurrence in the olaparib and placebo groups at an earlier time point (5.4 years compared with 14.5 years in the company's model). The company provided scenario analyses varying the time point at which the risk of recurrence was equal, but this only had a small effect on incremental cost-effectiveness ratios (ICERs). The committee agreed that there was insufficient evidence to make an informed decision about whether a log-normal or generalised gamma distribution was more suitable without further follow up from the trial. It noted the clinical experts' opinion that, for long-term invasive disease-free survival, there was little difference between the 2 distributions. ## Risk of recurrence in triple-negative breast cancer population For people with hormone receptor-positive HER2‑negative breast cancer, the company and EAG assumed that the risk of recurrence remained elevated throughout the lifetime horizon of the model. But, for people with triple-negative breast cancer, the company and EAG made different assumptions. The company assumed that, after 5 years, there was a 0% chance of recurrence, while the EAG assumed a 5% risk from year 5 to year 15. The clinical experts explained that most recurrences in people with triple‑negative breast cancer occur in the first 2 to 3 years after diagnosis. They also said that the risk of recurrence after 5 years is very low, although it is not likely to be 0%. They estimated that there may be a 2% to 3% risk of recurrence between year 5 and year 8, and 0% after 8 years. The committee concluded that assuming a 2% to 3% risk of recurrence between year 5 and year 8, while uncertain, was reasonable. ## Extrapolating survival The company and the EAG used different extrapolation curves for estimating survival after early metastatic recurrence. The company used an exponential distribution and the EAG used the Gompertz distribution. The EAG argued that using an exponential distribution is unsuitable when the data violates the proportional hazards assumption. It highlighted that the company had presented evidence that hazards between arms were non-proportional. Both Kaplan–Meier curves and log-cumulative hazards indicated violation of proportional hazards. The EAG thought that the Gompertz distribution gave the most plausible survival difference between arms and, given the long-term uncertainty, was more conservative. The clinical experts noted that the latest publication of the OlympiA data showed that the proportional hazards assumption was met for survival. The committee noted that the choice of extrapolation method had a small effect on the ICER, so did not discuss this further. ## Company's utility values The utility values used in the modelling were a key driver of the cost-effectiveness results, particularly the values for the disease-free health state. The company used health-related quality-of-life data from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ‑C30) in OlympiA, mapped to EQ‑5D‑3L to estimate the utility value for the disease-free health state. It set the non-metastatic breast cancer (local recurrence) utility value to be the same as that for the disease-free health state because the difference between the two was non-significant in the trial. The metastatic breast cancer utility value was sourced from external literature. The EAG had 2 issues with the company's approach. Firstly, it believed that there was a risk of bias because of low completion rates of the EORTC QLQ‑C30 questionnaires. Secondly, it had concerns about the algorithms used to map the data to EQ‑5D‑3L. The EAG highlighted that older algorithms, such as the Crott and Briggs algorithm used in the company's base case, have been shown to produce biased estimates. It also explained that newer algorithms have had insufficient external validation. The committee noted these limitations and questioned whether the company's estimates were plausible. It noted that these were 0.869 for the disease-free and the non-metastatic breast cancer health states and 0.685 for the metastatic breast cancer health state. The committee appreciated that the utility values were estimated from the health-related quality-of-life data in OlympiA. But it was concerned that the values were unrealistically high because the disease-free value was only slightly lower than that of age-matched people in the general population (0.877). The committee considered this to be implausible because people taking olaparib would recently have had both surgery and chemotherapy. Also, this value was not consistent with other technology appraisals of treatments for triple-negative breast cancer. The committee was also not convinced that it was realistic to assume the same utility for the disease-free and non-metastatic breast cancer (local recurrence) health states. This was because of the anxiety associated with having a local recurrence and probable further surgery, possibly including mastectomy. The committee was also aware that the utility values used by the company for metastatic breast cancer were generally higher than those used in some other technology appraisals. For these reasons, the committee concluded that the company's utility values were not appropriate. ## EAG's utility values The EAG used utility values from an external UK study (Verrill et al. 2020) in people with HER2‑positive breast cancer (108 with early and 102 with metastatic breast cancer). This study directly measured health-related quality of life using the EQ‑5D questionnaire. The values were 0.732 for the disease-free, 0.668 for non-metastatic breast cancer and 0.603 for metastatic breast cancer health states. The EAG chose a value for non-metastatic breast cancer that was the midpoint between the disease-free and metastatic breast cancer health states. The committee noted that the estimates were much lower than the company's estimates, possibly because of the older population in Verrill et al. compared with OlympiA. The EAG also presented a sensitivity analysis adjusting for the age difference between Verrill et al. and OlympiA. This increased the utility values to 0.770 for the disease-free, 0.702 for non-metastatic breast cancer and 0.634 for metastatic breast cancer health states. The committee accepted that using the utilities from Verrill et al. had some limitations because of differences in the populations. But it concluded that the utility values from the EAG's age-adjusted estimates using Verrill et al. were the most appropriate of the ones presented by the company and EAG. ## BRCA testing costs The company assumed that olaparib was not associated with additional costs for BRCA testing, which is needed to determine eligibility for olaparib. The rationale for this was that most people with HER2‑negative high-risk early breast cancer will have routine BRCA screening as part of standard care in the NHS. The EAG questioned whether this was the case for people with hormone receptor-positive HER2‑negative early breast cancer and preferred to include BRCA testing costs for this group. The company submitted data suggesting that most people with hormone receptor-positive HER2‑negative high-risk early breast cancer who are potentially eligible for olaparib would already be identified for BRCA testing if the current National Genetic Test Directory criteria were uniformly implemented in clinical practice. This was because OlympiA only recruited people with breast cancer at high risk of recurrence. The clinical experts agreed that most people with hormone receptor-positive HER2‑negative high-risk early breast cancer would be eligible for testing and that training for clinicians would increase implementation. The committee accepted that most people with HER2‑negative early breast cancer at high risk of recurrence meet the current testing criteria, so BRCA testing costs did not need be included in the model. ## Discount rates The company argued that discount rates of 1.5% for costs and outcomes should be applied for the triple-negative breast cancer population instead of rates of 3.5%. The company presented a scenario analysis using the lower rates and this reduced the ICER in the triple-negative breast cancer population substantially. But the committee noted that, for the 1.5% rates to be applicable, the treatment would have to: be used in people who would otherwise die or have a very severely impaired life restore those people to full or near-full health have benefits that are sustained over a very long period.The EAG argued that the immaturity and long-term uncertainty of the data meant that it was unclear whether olaparib will restore people to full health or provide sustained benefits. The committee agreed with this. It also noted that 75.4% of people in the placebo arm of OlympiA had not had an invasive disease-free survival event by 4 years. This indicated that the first criterion was also not met. The committee concluded that olaparib did not meet the eligibility criteria needed for a reduced discount rate to be used. # Cost effectiveness ## Cost-effectiveness estimates for olaparib The base-case ICERs originally submitted by the company for olaparib compared with routine monitoring were above the range normally considered a cost-effective use of NHS resources. That range is £20,000 to £30,000 per quality-adjusted life year (QALY) gained. This was true for both the triple-negative and the hormone receptor-positive HER2‑negative early breast cancer populations. None of the company's scenario analyses substantially changed the results, apart from an analysis that used 1.5% discount rates for costs and outcomes. But the committee had concluded that was not appropriate (see section 3.13). Incorporating the committee's preferred assumptions on utility values (see section 3.10 and section 3.11), and on risk of recurrence in the triple-negative early breast cancer population (see section 3.8), increased the company's ICERs further. After the first committee meeting, the company updated its commercial arrangement and submitted a new analysis using the committee's preferred assumptions. The change to the commercial arrangement resulted in ICERs that were substantially below £30,000 per QALY gained. The ICERs cannot be reported here because of confidential commercial arrangements for subsequent treatments in the pathway. The committee concluded that olaparib is a cost-effective adjuvant treatment for BRCA mutation-positive HER2‑negative high-risk early breast cancer after chemotherapy. # Conclusion ## Olaparib is recommended The committee recognised the unmet need for treatment options for people with BRCA mutation-positive HER2‑negative high-risk early breast cancer (see section 3.1). It also agreed that olaparib is an effective treatment (see section 3.4). After the first committee meeting, the company updated its cost-effectiveness analysis, adopting the committee's preferred assumptions and including a revised commercial arrangement. This reduced the ICERs to substantially below £30,000 per QALY gained. The committee concluded that olaparib is a cost-effective adjuvant treatment for BRCA mutation-positive HER2‑negative high-risk early breast cancer after chemotherapy.	{'Recommendations': 'Olaparib (alone or with endocrine therapy) is recommended, within its marketing authorisation, as an option for the adjuvant treatment of HER2‑negative high-risk early breast cancer that has been treated with neoadjuvant or adjuvant chemotherapy in adults with germline BRCA1 or\xa02 mutations. It is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nPeople with BRCA mutation-positive HER2‑negative high-risk early breast cancer usually have chemotherapy followed by surgery (neoadjuvant chemotherapy), or surgery followed by chemotherapy (adjuvant chemotherapy).\n\nClinical trial evidence shows that, compared with placebo, olaparib after neoadjuvant or adjuvant chemotherapy decreases the chance of the cancer returning or getting worse, and increases the length of time people live.\n\nThe cost-effectiveness estimates for olaparib are within what NICE considers to be an acceptable use of NHS resources. So, olaparib is recommended.', 'Information about olaparib': "# Marketing authorisation indication\n\nOlaparib (Lynparza, AstraZeneca) has a marketing authorisation as a 'monotherapy or in combination with endocrine therapy for the adjuvant treatment of adult patients with germline BRCA1/2‑mutations who have HER2‑negative, high-risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for olaparib.\n\n# Price\n\nThe list price is £2,317.50 per 56‑pack of 150\xa0mg tablets (excluding VAT; BNF online accessed January 2023).\n\nThe company has a commercial arrangement. This makes olaparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by AstraZeneca, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## BRCA mutation-positive HER2-negative high-risk early breast cancer\n\nThe patient experts explained that BRCA mutation-positive HER2‑negative high-risk early breast cancer is an aggressive form of cancer with poor outcomes. They also explained that it can be very distressing for people with the condition. It includes hormone receptor-positive and triple-negative breast cancer, the latter having the poorest prognosis. The patient experts explained that there are limited treatment options available for the condition, particularly for triple-negative breast cancer. They thought that many people who have had olaparib appreciated having access to an extra treatment option that has been shown to improve survival. People with HER2‑negative high-risk early breast cancer often worry about the increased risk of their cancer returning after treatment. Also, people with BRCA mutation-positive breast cancer have concerns about whether their relatives have the BRCA1 or\xa02 mutations and so an increased risk of developing cancer. Having a treatment that has been shown to improve outcomes has a positive effect on mental health. One of the patient experts who had had olaparib highlighted that it is a convenient oral treatment, and only infrequent hospital visits are needed for monitoring. They explained that olaparib's side effects were manageable. They also said that they were able to continue their usual daily activities and maintain a good quality of life while having it, although they did have fatigue. The committee concluded that olaparib would be a welcome adjuvant treatment option to improve outcomes in people with BRCA mutation-positive HER2‑negative high-risk early breast cancer.\n\n# Treatment pathway\n\n## Relevant comparator\n\nThe committee noted that current standard care for BRCA mutation-positive HER2‑negative high-risk early breast cancer is neoadjuvant chemotherapy followed by surgery and surveillance, or surgery followed by adjuvant chemotherapy. The most common chemotherapy regimen is an anthracycline taxane combination plus a platinum therapy. People with hormone receptor-positive HER2‑negative breast cancer may also have adjuvant endocrine therapy after surgery. The committee noted that olaparib would be used after neoadjuvant or adjuvant chemotherapy, either:\n\nas monotherapy in triple-negative early breast cancer, or\n\nwith endocrine treatment in hormone receptor-positive HER2‑negative early breast cancer.Because olaparib would be used in addition to any current therapies, the committee agreed that the relevant comparator was routine monitoring for cancer recurrence.\n\n# Clinical evidence\n\n## Generalisability of OlympiA\n\nThe clinical evidence came from OlympiA, a randomised double-blind placebo-controlled trial (n=1,836). It was done in 23\xa0countries worldwide and included 106\xa0people from the UK. The trial compared olaparib with placebo in people with (germline) BRCA mutation-positive HER2‑negative high-risk early breast cancer. People in the trial had either had neoadjuvant or adjuvant treatment at the point of randomisation. The criteria for defining high risk in OlympiA were:\n\nfor people with triple-negative breast cancer who had neoadjuvant chemotherapy: residual invasive cancer in the breast, the resected lymph nodes (non-pathological complete response) or both at the time of surgery\n\nfor people with hormone receptor-positive HER2‑negative breast cancer who had neoadjuvant chemotherapy: residual invasive cancer in the breast, the resected lymph nodes (non-pathologic complete response) or both at the time of surgery, and a score of 3\xa0or more based on pretreatment clinical and post-treatment pathological stage, receptor status and histological grade\n\nfor people with triple-negative breast cancer who had adjuvant chemotherapy: node-positive or node-negative cancer with a primary tumour of 2\xa0cm or more\n\nfor people with hormone receptor-positive HER2‑negative breast cancer who had adjuvant chemotherapy: 4\xa0or more pathologically confirmed positive lymph nodes.The clinical experts explained that the criteria for defining high risk were representative of how olaparib would be used in the NHS. They also explained that people with hormone receptor-positive HER2‑negative breast cancer (17.7%) in OlympiA were selected as having cancer with an equivalent high risk of relapse as people with triple-negative breast cancer (82.3%). The clinical experts explained that, in clinical practice, a higher proportion of people would have hormone receptor-positive HER2‑negative breast cancer. They said that the proportions in the trial reflected the lower prevalence of BRCA mutations in people with hormone receptor-positive HER2‑negative breast cancer, and their later enrolment into the trial. The committee agreed that the definition of high-risk early breast cancer in OlympiA was appropriate. It concluded that the trial was broadly generalisable to people who would have olaparib in the NHS.\n\n## Clinical effectiveness\n\nThe primary outcome in OlympiA was invasive disease-free survival. Secondary outcomes included distant disease-free survival and overall survival. A statistically significant difference in all 3\xa0outcomes was shown with olaparib compared with placebo:\n\nInvasive disease-free survival at 4\xa0years was 82.7% in the olaparib arm and 75.4% in the placebo arm (a difference of 7.3%, 95% confidence interval [CI] 3.0%\xa0to\xa011.5%).\n\nDistant disease-free survival at 4\xa0years was 86.5% in the olaparib arm and 79.1% in the placebo arm (a difference of 7.4%, 95%\xa0CI 3.6%\xa0to 11.3%).\n\nOverall survival at 4\xa0years was 89.8% in the olaparib arm and 86.4% in the placebo arm (a difference of 3.4%, 95%\xa0CI -0.1\xa0to\xa06.8%).The committee noted that event rates were low: 82.7% of people in the olaparib arm and 75.4% in the placebo arm were alive and cancer-free after 4\xa0years. But it concluded that, in the full trial population, adjuvant treatment with olaparib had been shown to improve invasive disease-free survival, distant disease-free survival and overall survival compared with placebo. Also, it agreed that low rates are expected in people who have recently had surgery and chemotherapy with curative intent.\n\n## Efficacy of olaparib in subgroups\n\nFor the subgroup of people in OlympiA who had triple-negative breast cancer, olaparib statistically significantly improved invasive disease-free survival compared with placebo. For the subgroup of people with hormone receptor-positive HER2‑negative breast cancer, the results were consistent with the overall population but were not statistically significant. The clinical experts advised that this was because:\n\nof the smaller sample size and lower number of events in that subgroup (see section\xa03.3)\n\nOlympiA was not powered to detect differences in subgroups at the latest data cut-off (median 3.5‑year follow up).They also explained that they did not expect to see any difference in treatment effect between the 2\xa0HER2‑negative subgroups in the trial. Also, the committee noted the company's comment that there was no evidence of statistical heterogeneity between subgroups. The committee accepted these comments.\n\n# Economic model\n\n## Model design\n\nThe company presented a 5‑state semi-Markov model to estimate the cost effectiveness of adjuvant treatment with olaparib compared with routine monitoring in people with BRCA mutation-positive HER2‑negative high-risk early breast cancer previously treated with adjuvant or neoadjuvant chemotherapy. The 5\xa0health states were: disease-free; non-metastatic breast cancer (local recurrence); early-onset metastatic breast cancer (recurrence within 2\xa0years); late-onset metastatic breast cancer (recurrence after 2\xa0years); and death. The model estimated the cost effectiveness of olaparib in people with triple-negative breast cancer and people with hormone receptor-positive HER2‑negative breast cancer separately. The EAG described the model as high-quality and largely aligned with NICE's methods for economic evaluation. The committee concluded that the model was suitable for decision making.\n\n## Extrapolating recurrence\n\nThere was no long-term data from OlympiA to use in the economic model. So, the company and the EAG had to extrapolate the data and make assumptions about recurrence using expert opinion and the published literature. The company used a log-normal distribution to model the risk of recurrence in both the triple-negative and hormone receptor-positive HER2‑negative breast cancer populations. The EAG agreed with the log-normal distribution for the triple-negative population but thought that this was too optimistic for the hormone receptor-positive HER2‑negative population. It preferred the generalised gamma distribution. This gave the smallest difference in long-term invasive disease-free survival for this subgroup. It also resulted in there being an equal risk of recurrence in the olaparib and placebo groups at an earlier time point (5.4\xa0years compared with 14.5\xa0years in the company's model). The company provided scenario analyses varying the time point at which the risk of recurrence was equal, but this only had a small effect on incremental cost-effectiveness ratios (ICERs). The committee agreed that there was insufficient evidence to make an informed decision about whether a log-normal or generalised gamma distribution was more suitable without further follow up from the trial. It noted the clinical experts' opinion that, for long-term invasive disease-free survival, there was little difference between the 2\xa0distributions.\n\n## Risk of recurrence in triple-negative breast cancer population\n\nFor people with hormone receptor-positive HER2‑negative breast cancer, the company and EAG assumed that the risk of recurrence remained elevated throughout the lifetime horizon of the model. But, for people with triple-negative breast cancer, the company and EAG made different assumptions. The company assumed that, after 5\xa0years, there was a 0% chance of recurrence, while the EAG assumed a 5% risk from year\xa05 to year\xa015. The clinical experts explained that most recurrences in people with triple‑negative breast cancer occur in the first 2\xa0to 3\xa0years after diagnosis. They also said that the risk of recurrence after 5\xa0years is very low, although it is not likely to be 0%. They estimated that there may be a 2% to 3% risk of recurrence between year\xa05 and year\xa08, and 0% after 8\xa0years. The committee concluded that assuming a 2% to 3% risk of recurrence between year\xa05 and year\xa08, while uncertain, was reasonable.\n\n## Extrapolating survival\n\nThe company and the EAG used different extrapolation curves for estimating survival after early metastatic recurrence. The company used an exponential distribution and the EAG used the Gompertz distribution. The EAG argued that using an exponential distribution is unsuitable when the data violates the proportional hazards assumption. It highlighted that the company had presented evidence that hazards between arms were non-proportional. Both Kaplan–Meier curves and log-cumulative hazards indicated violation of proportional hazards. The EAG thought that the Gompertz distribution gave the most plausible survival difference between arms and, given the long-term uncertainty, was more conservative. The clinical experts noted that the latest publication of the OlympiA data showed that the proportional hazards assumption was met for survival. The committee noted that the choice of extrapolation method had a small effect on the ICER, so did not discuss this further.\n\n## Company's utility values\n\nThe utility values used in the modelling were a key driver of the cost-effectiveness results, particularly the values for the disease-free health state. The company used health-related quality-of-life data from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ‑C30) in OlympiA, mapped to EQ‑5D‑3L to estimate the utility value for the disease-free health state. It set the non-metastatic breast cancer (local recurrence) utility value to be the same as that for the disease-free health state because the difference between the two was non-significant in the trial. The metastatic breast cancer utility value was sourced from external literature. The EAG had 2\xa0issues with the company's approach. Firstly, it believed that there was a risk of bias because of low completion rates of the EORTC QLQ‑C30 questionnaires. Secondly, it had concerns about the algorithms used to map the data to EQ‑5D‑3L. The EAG highlighted that older algorithms, such as the Crott and Briggs algorithm used in the company's base case, have been shown to produce biased estimates. It also explained that newer algorithms have had insufficient external validation. The committee noted these limitations and questioned whether the company's estimates were plausible. It noted that these were 0.869 for the disease-free and the non-metastatic breast cancer health states and 0.685 for the metastatic breast cancer health state. The committee appreciated that the utility values were estimated from the health-related quality-of-life data in OlympiA. But it was concerned that the values were unrealistically high because the disease-free value was only slightly lower than that of age-matched people in the general population (0.877). The committee considered this to be implausible because people taking olaparib would recently have had both surgery and chemotherapy. Also, this value was not consistent with other technology appraisals of treatments for triple-negative breast cancer. The committee was also not convinced that it was realistic to assume the same utility for the disease-free and non-metastatic breast cancer (local recurrence) health states. This was because of the anxiety associated with having a local recurrence and probable further surgery, possibly including mastectomy. The committee was also aware that the utility values used by the company for metastatic breast cancer were generally higher than those used in some other technology appraisals. For these reasons, the committee concluded that the company's utility values were not appropriate.\n\n## EAG's utility values\n\nThe EAG used utility values from an external UK study (Verrill et al. 2020) in people with HER2‑positive breast cancer (108\xa0with early and 102\xa0with metastatic breast cancer). This study directly measured health-related quality of life using the EQ‑5D questionnaire. The values were 0.732 for the disease-free, 0.668 for non-metastatic breast cancer and 0.603 for metastatic breast cancer health states. The EAG chose a value for non-metastatic breast cancer that was the midpoint between the disease-free and metastatic breast cancer health states. The committee noted that the estimates were much lower than the company's estimates, possibly because of the older population in Verrill et al. compared with OlympiA. The EAG also presented a sensitivity analysis adjusting for the age difference between Verrill et al. and OlympiA. This increased the utility values to 0.770 for the disease-free, 0.702 for non-metastatic breast cancer and 0.634 for metastatic breast cancer health states. The committee accepted that using the utilities from Verrill et al. had some limitations because of differences in the populations. But it concluded that the utility values from the EAG's age-adjusted estimates using Verrill et al. were the most appropriate of the ones presented by the company and EAG.\n\n## BRCA testing costs\n\nThe company assumed that olaparib was not associated with additional costs for BRCA testing, which is needed to determine eligibility for olaparib. The rationale for this was that most people with HER2‑negative high-risk early breast cancer will have routine BRCA screening as part of standard care in the NHS. The EAG questioned whether this was the case for people with hormone receptor-positive HER2‑negative early breast cancer and preferred to include BRCA testing costs for this group. The company submitted data suggesting that most people with hormone receptor-positive HER2‑negative high-risk early breast cancer who are potentially eligible for olaparib would already be identified for BRCA testing if the current National Genetic Test Directory criteria were uniformly implemented in clinical practice. This was because OlympiA only recruited people with breast cancer at high risk of recurrence. The clinical experts agreed that most people with hormone receptor-positive HER2‑negative high-risk early breast cancer would be eligible for testing and that training for clinicians would increase implementation. The committee accepted that most people with HER2‑negative early breast cancer at high risk of recurrence meet the current testing criteria, so BRCA testing costs did not need be included in the model.\n\n## Discount rates\n\nThe company argued that discount rates of 1.5% for costs and outcomes should be applied for the triple-negative breast cancer population instead of rates of 3.5%. The company presented a scenario analysis using the lower rates and this reduced the ICER in the triple-negative breast cancer population substantially. But the committee noted that, for the 1.5% rates to be applicable, the treatment would have to:\n\nbe used in people who would otherwise die or have a very severely impaired life\n\nrestore those people to full or near-full health\n\nhave benefits that are sustained over a very long period.The EAG argued that the immaturity and long-term uncertainty of the data meant that it was unclear whether olaparib will restore people to full health or provide sustained benefits. The committee agreed with this. It also noted that 75.4% of people in the placebo arm of OlympiA had not had an invasive disease-free survival event by 4\xa0years. This indicated that the first criterion was also not met. The committee concluded that olaparib did not meet the eligibility criteria needed for a reduced discount rate to be used.\n\n# Cost effectiveness\n\n## Cost-effectiveness estimates for olaparib\n\nThe base-case ICERs originally submitted by the company for olaparib compared with routine monitoring were above the range normally considered a cost-effective use of NHS resources. That range is £20,000 to £30,000 per quality-adjusted life year (QALY) gained. This was true for both the triple-negative and the hormone receptor-positive HER2‑negative early breast cancer populations. None of the company's scenario analyses substantially changed the results, apart from an analysis that used 1.5% discount rates for costs and outcomes. But the committee had concluded that was not appropriate (see section\xa03.13). Incorporating the committee's preferred assumptions on utility values (see section\xa03.10 and section\xa03.11), and on risk of recurrence in the triple-negative early breast cancer population (see section\xa03.8), increased the company's ICERs further. After the first committee meeting, the company updated its commercial arrangement and submitted a new analysis using the committee's preferred assumptions. The change to the commercial arrangement resulted in ICERs that were substantially below £30,000 per QALY gained. The ICERs cannot be reported here because of confidential commercial arrangements for subsequent treatments in the pathway. The committee concluded that olaparib is a cost-effective adjuvant treatment for BRCA mutation-positive HER2‑negative high-risk early breast cancer after chemotherapy.\n\n# Conclusion\n\n## Olaparib is recommended\n\nThe committee recognised the unmet need for treatment options for people with BRCA mutation-positive HER2‑negative high-risk early breast cancer (see section\xa03.1). It also agreed that olaparib is an effective treatment (see section 3.4). After the first committee meeting, the company updated its cost-effectiveness analysis, adopting the committee's preferred assumptions and including a revised commercial arrangement. This reduced the ICERs to substantially below £30,000 per QALY gained. The committee concluded that olaparib is a cost-effective adjuvant treatment for BRCA mutation-positive HER2‑negative high-risk early breast cancer after chemotherapy."}	https://www.nice.org.uk/guidance/ta886	Evidence-based recommendations on olaparib (Lynparza) for adjuvant treatment of BRCA mutation-positive HER2-negative high-risk early breast cancer after chemotherapy in adults.
aa298571f5167b8ff5b5dd6ffeb047e5f14e7d5c	nice	Olaparib for previously treated BRCA mutation-positive hormone-relapsed metastatic prostate cancer	Olaparib for previously treated BRCA mutation-positive hormone-relapsed metastatic prostate cancer Evidence-based recommendations on olaparib (Lynparza) for previously treated BRCA mutation-positive hormone-relapsed metastatic prostate cancer in adults. # Recommendations Olaparib is recommended, within its marketing authorisation, as an option for treating hormone-relapsed metastatic prostate cancer with BRCA1 or BRCA2 mutations that has progressed after a newer hormonal treatment (such as abiraterone or enzalutamide) in adults. Olaparib is only recommended if the company provides it according to the commercial arrangement. Why the committee made these recommendations This evaluation uses new cost-effectiveness estimates to update olaparib for previously treated BRCA mutation-positive hormone-relapsed metastatic prostate cancer (NICE technology appraisal guidance TA831). No new clinical evidence was reviewed. Treatments for BRCA mutation-positive hormone-relapsed metastatic prostate cancer that has progressed after enzalutamide or abiraterone include taxanes (for example, docetaxel or cabazitaxel), radium‑223 dichloride and best supportive care. The company provided evidence based on whether or not people had already had a taxane. This is because people have different treatments depending on whether they have had a taxane before. Clinical trial evidence shows that people taking olaparib have more time before their cancer gets worse, and live longer overall, than people having retreatment with abiraterone or enzalutamide. However, this retreatment is not considered effective and is not standard care in the NHS. For people who have had a taxane before, olaparib has not been directly compared with docetaxel, cabazitaxel or radium‑223 dichloride. An indirect comparison suggests that olaparib increases how long people live compared with cabazitaxel. For people who have not had a taxane before there is also no direct evidence comparing olaparib with docetaxel or best supportive care. But an exploratory indirect comparison suggests that olaparib may increase how long people live compared with both best supportive care and docetaxel. Olaparib likely meets NICE's criteria for a life-extending treatment at the end of life. When taking this into account, the most likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So olaparib is recommended.# Information about olaparib # Marketing authorisation indication Olaparib (Lynparza, AstraZeneca) is indicated 'as monotherapy for the treatment of adult patients with metastatic castration-resistant prostate cancer and BRCA1/2-mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for olaparib. # Price The price for olaparib is £2,317.50 per pack of 56 tablets, each containing 100 mg or 150 mg of the active ingredient (excluding VAT; BNF online, March 2023). The company has a commercial arrangement. This makes olaparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence. # Treatment pathway ## There is an unmet need for new treatments for hormone-relapsed metastatic prostate cancer People with newly diagnosed hormone-sensitive non-metastatic prostate cancer are normally offered androgen deprivation therapy (ADT) or radical therapy such as surgery or radiotherapy. If the disease progresses with ADT, it is known as hormone-relapsed or castration-resistant prostate cancer. Treatment with ADT continues, either alone or with darolutamide or apalutamide. People with newly diagnosed hormone-sensitive metastatic prostate cancer are usually offered ADT alone, ADT with docetaxel with or without prednisolone (from now, referred to as docetaxel), ADT with enzalutamide (see NICE's technology appraisal guidance on enzalutamide for treating hormone-sensitive metastatic prostate cancer), or, if docetaxel is not suitable, ADT with apalutamide (see NICE's technology appraisal guidance on apalutamide for treating hormone-sensitive metastatic prostate cancer). For people with hormone-relapsed metastatic prostate cancer for which chemotherapy is not yet indicated, treatment options include abiraterone or enzalutamide if neither has been used before (see NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated and abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated), or 'watchful waiting'. Darolutamide, enzalutamide, abiraterone and apalutamide are new hormonal agents. Olaparib is a poly-ADP-ribose polymerase (PARP) inhibitor, which works differently to hormonal agents. The clinical experts confirmed that people would have new hormonal agents only once. So, people who have had a new hormonal agent when their cancer was hormone sensitive or non-metastatic would not have it again when their cancer is hormone relapsed and metastatic. After this, treatment options include: docetaxel retreatment with docetaxel for people who had docetaxel when their disease was hormone sensitive cabazitaxel with prednisolone (from now, referred to as cabazitaxel) for people who have already had docetaxel radium‑223 dichloride for people with symptomatic bone metastases and no metastases in the soft internal organs of the body (visceral metastases), and who have already had docetaxel or cannot have it.The patient experts explained that hormone-relapsed metastatic prostate cancer affects all aspects of their lives and is difficult for them, their families and their friends. They highlighted the need for treatments that can extend survival and help them maintain or improve their quality of life because there is no cure. They also explained that they would like more treatment options so they can delay chemotherapy (docetaxel and cabazitaxel) and its adverse effects. This is because the adverse effects, especially those of docetaxel, can be debilitating, even up to 1 year after people have stopped having it. The committee concluded that there is an unmet need for new treatments for hormone-relapsed metastatic prostate cancer. ## The company's approach of considering people who have had or have not had a taxane separately is acceptable The marketing authorisation for olaparib states that it is indicated 'as monotherapy for the treatment of adult patients with metastatic castration-resistant prostate cancer and BRCA1/2-mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent'. The company limited the population in its initial submission to people who have already had a taxane (mainly docetaxel), from now referred to as the 'prior taxane' group. It chose cabazitaxel as the comparator (see section 3.3), which requires previous treatment with docetaxel. The company explained that it did this because its clinical advisers suggested that in the NHS around 75% of people have docetaxel while their disease is hormone sensitive. The ERG agreed that most people who have abiraterone or enzalutamide will have already had treatment with docetaxel, but that this proportion is likely to be less than 75%. The clinical experts explained that having previous treatment with docetaxel is not specified in olaparib's marketing authorisation and should not be a factor when deciding who would have olaparib in NHS practice. The Cancer Drugs Fund clinical lead was disappointed with the company's initial decision to limit the population. The clinical lead explained that many people who do not choose docetaxel early in the pathway might then be unable to have it after developing hormone-relapsed metastatic disease, for example if they become too ill. At the company's initial proposed position, olaparib would never be suitable for them. The clinical and patient experts explained that they are keen to have olaparib available as early in the treatment pathway as possible, but to have it at some point is most important. The committee appreciated that limiting olaparib to people who had had docetaxel would exclude people who cannot or should not have docetaxel but who could benefit from olaparib. It was aware that these people are likely to be older and more likely to have a poorer disease performance status, comorbidities, peripheral sensory neuropathy, poor bone marrow function, poor cognition or chemotherapy contraindications (see NICE's technology appraisal guidance on abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer). The committee also noted that NICE's recent recommendations on darolutamide, enzalutamide and apalutamide mean that more people would choose a new hormonal agent before docetaxel (see NICE's technology appraisal guidance on darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer, enzalutamide for treating hormone-sensitive metastatic prostate cancer, apalutamide with androgen deprivation therapy for treating high-risk hormone-relapsed non-metastatic prostate cancer and apalutamide with androgen deprivation therapy for treating hormone-sensitive metastatic prostate cancer). In response to the first consultation, the company submitted clinical-effectiveness data and exploratory cost-effectiveness analyses for the population who had not had a taxane, from now referred to as the 'no prior taxane' group (see section 3.7, section 3.12 and section 3.23). NICE's process requires a committee to initially appraise a drug across its marketing authorisation rather than by subgroups. However, the committee noted that there are no common comparator treatments for the whole licensed population as comparators are different for people who can and cannot have, or have already had, taxanes (see section 3.3 and section 3.4). Therefore, the committee concluded that the company's approach of considering these groups separately is acceptable. # Comparators ## In the prior taxane group, cabazitaxel, radium‑223 dichloride, and retreatment with docetaxel are all relevant comparators NICE's scope for this appraisal lists docetaxel, cabazitaxel and radium‑223 dichloride as comparators. But the company included only cabazitaxel as a comparator for people who have had treatment with a taxane before. It considered that there was not enough evidence for docetaxel and radium‑223 dichloride. The ERG agreed that there is limited evidence for both docetaxel and radium‑223 dichloride. The company stated that its clinical advice and data from a recent UK national audit suggested that radium‑223 dichloride is often used later in the treatment pathway, once options such as cabazitaxel have been used. The committee recognised that this would mean radium‑223 dichloride was a relevant comparator because it could be used at the same position as olaparib for some people. The company highlighted that NICE's guideline on the diagnosis and management of prostate cancer does not recommend repeat cycles of treatment with docetaxel if the disease recurs after the planned course of chemotherapy is completed. It also pointed out that cabazitaxel is more likely to be used instead of docetaxel retreatment because response rates to docetaxel may decline over time. The committee was aware that retreatment with docetaxel happens in NHS practice, as documented in NICE's technology appraisal guidance on abiraterone, and as noted by stakeholders in this appraisal (see section 3.1). The clinical experts noted that people who had already had both docetaxel and abiraterone or enzalutamide may currently be offered docetaxel again or cabazitaxel. They may also be offered radium‑223 dichloride if they have symptomatic bone metastases and no visceral metastases. The committee appreciated that, in the prior taxane group, docetaxel retreatment, cabazitaxel and radium‑223 dichloride would all be alternatives to olaparib. It noted that patients and their treating clinician would decide which treatment is best. The committee concluded that cabazitaxel is likely to be the main, but not the only, comparator for olaparib in people who have had a taxane. ## In the no prior taxane group, docetaxel and best supportive care are the most relevant comparators For people who have not had treatment with a taxane, the company chose the following comparators depending on the reason for them not having a taxane: docetaxel and best supportive care (ADT and monitoring) for the group of people who had not had docetaxel but for whom docetaxel is appropriate best supportive care only for the group who had not had docetaxel and for whom docetaxel is unsuitable.The committee agreed that these comparators are broadly appropriate but noted that radium‑223 dichloride is also a relevant comparator for some people for whom docetaxel is unsuitable. For radium‑223 dichloride, the company considered that there was not enough evidence on its use, and that it would be limited to a small minority of people. It also stated that radium‑223 is only recommended after docetaxel, so it could not be a comparator in this group. For cabazitaxel, the company stated that it is not an appropriate comparator because docetaxel was more appropriate, and that cabazitaxel can only be used after docetaxel, in line with its licence. The company considered best supportive care would only be suitable when taxanes are not appropriate. The ERG did not comment about the appropriateness of comparators in the no prior taxane group. The committee concluded that the company had used the most appropriate comparators. # Clinical evidence ## In the PROfound trial, the baseline characteristics of people are generalisable to NHS practice, but the comparator treatment is not PROfound was a phase 3, randomised, open-label, multicentre trial of olaparib compared with investigator's choice of enzalutamide or abiraterone in hormone-relapsed metastatic prostate cancer that had progressed on abiraterone, enzalutamide or both. The trial enrolled people with homologous recombination repair gene mutations, including BRCA1, BRCA2, ataxia-telangiectasia mutation and other mutations. It stratified people according to whether they had had taxane treatment before. The primary endpoint was time to disease progression determined radiographically. Overall survival was among the secondary endpoints. The company presented clinical evidence for the population who had BRCA mutations in line with the marketing authorisation (the licensed population). It also presented it for the subgroup of this population who had had taxane treatment before (see section 3.2; from now, referred to as the 'BRCA-mutation, prior taxane subgroup'). The committee was satisfied that baseline characteristics from the BRCA-mutation prior taxane subgroup, including age, Eastern Cooperative Oncology Group performance status and prostate-specific antigen level, are generalisable to people in the NHS. However, it noted that some treatment regimens that people had had before entering the trial, such as having had both abiraterone and enzalutamide, did not reflect NHS practice. The clinical experts did not expect this to modify the treatment effect of olaparib in the trial. Clinical experts explained that retreating with abiraterone or enzalutamide has no clinical benefit and could effectively be considered a placebo. The company acknowledged that the comparator in its trial does not reflect current NHS practice. The committee concluded that baseline characteristics in PROfound were generalisable to NHS practice except for some people having had both enzalutamide and abiraterone before starting the trial. It further concluded that the comparator, that is, retreating with abiraterone or enzalutamide, is not offered in the NHS. ## Olaparib is more effective than retreating with enzalutamide or abiraterone but this comparison does not reflect NHS practice In the licensed population and the BRCA-mutation prior taxane subgroup of PROfound, median progression-free survival was higher with olaparib (9.0 months, 95% confidence interval 7.4 to 10.8) compared with abiraterone or enzalutamide retreatment (1.9 months, 95% CI 1.7 to 3.5). Median overall survival was also higher with olaparib (17.5 months, 95% CI 13.0 to 25.3) than abiraterone or enzalutamide retreatment (11.9 months, 95% CI 8.2 to 15.2). The committee recalled that retreating with abiraterone or enzalutamide is not expected to have a clinical benefit (see section 3.5). The committee concluded that olaparib was effective compared with enzalutamide or abiraterone in PROfound. However, it thought that the results should be interpreted with caution because the comparator arm in the trial does not reflect NHS practice. The committee also concluded that any comparison of olaparib with cabazitaxel or other relevant comparators (see section 3.3) would need to use other sources of data and an indirect treatment comparison. ## Previous treatment with a taxane does not appear to affect the effectiveness of olaparib in PROfound In its response to consultation, the company submitted results from PROfound for a subgroup of people who had not had treatment with docetaxel (see section 3.4 and section 3.12). The results in the no prior taxane group suggested that both progression-free and overall survival were higher with olaparib than with abiraterone or enzalutamide retreatment. The committee noted that, because of the inclusion and exclusion criteria in PROfound, the trial likely excluded many people who cannot or should not have docetaxel in NHS practice. The committee recalled that stratification in the trial was done on the basis of either mutation type or prior taxane, so there was no prespecified subgroup for those with a BRCA mutation who had had a taxane before. The company did provide analyses for those with BRCA mutations in the prior or no prior taxane subgroups. The committee noted this evidence but considered that, as it was not prespecified in the clinical trial protocol, it was a post-hoc analysis, which may introduce uncertainty. It also noted the small size of the subgroup of people who had not had treatment with docetaxel, and the immaturity of overall survival data in this subgroup. It concluded that these results were highly uncertain. The committee noted that it did not see any formal testing of interaction when this subgroup was compared with the subgroup who had had docetaxel. But it acknowledged that the clinical efficacy of olaparib in PROfound did not seem to have been affected by previous treatment with a taxane. ## The company's method for adjusting for treatment switching in PROfound is appropriate, including using recensoring The company explained that, in PROfound, most people switched from abiraterone or enzalutamide to olaparib after radiographic disease progression. The number of people who switched cannot be reported here because the company considers it confidential. The committee recognised that treatment switching biased the treatment effect for overall survival. This was because people in the control arm who switched to olaparib may have benefited from the treatment effect of olaparib and likely lived longer than if they had not switched. The company considered several different methods to adjust for treatment switching. These included the rank preserving structural failure time model (RPSFTM), inverse probability of censoring weights and 2‑stage estimation. The company chose the RPSFTM because it did not depend on time-varying covariates to predict switching, did not reduce the effective sample size, and did not assume that there are no unmeasured confounders. The ERG agreed that the RPSFTM was the most appropriate method. The company did sensitivity analyses to explore and validate the assumption of a common treatment effect in the overall trial population, but not in the BRCA-mutation prior taxane subgroup. The company further explained that it had applied recensoring to remove any censoring bias from the treatment switching-adjusted results. Recensoring involves censoring data before the end of the trial follow-up period. This is to avoid informative censoring related to the association between prognostic factors and treatment switching. Informative censoring can happen when adjusting survival times if some people who switch treatments do not die during the trial. The committee was aware that the main limitation of recensoring is losing longer-term survival information. The ERG preferred to consider results with and without recensoring because both can bias results. The recensoring approach tends to overestimate the effect of treatment, and the approach without recensoring tends to underestimate it. The committee noted that, towards the end of the trial follow-up period, data from very few people contributed towards the estimates of overall survival. Therefore, in this case, recensoring did not lose a large amount of data, but avoided informative censoring. The committee concluded that the company's method for adjusting for treatment switching was appropriate, including using recensoring. ## The indirect comparison of olaparib with cabazitaxel for the prior taxane group is uncertain because of differences between PROfound and CARD The company did not find direct clinical trial evidence comparing olaparib and cabazitaxel so it did indirect treatment comparisons for progression-free survival and overall survival. It used evidence from the CARD trial, a phase 3, randomised, open-label, multicentre trial. The trial compared cabazitaxel with enzalutamide or abiraterone in hormone-relapsed metastatic prostate cancer previously treated with docetaxel and either enzalutamide or abiraterone. The primary endpoint was radiographic progression-free survival. Secondary endpoints included overall survival and skeletal-related events. Clinical experts explained that the comparator in CARD was similar to that in PROfound, that is, people who had already had abiraterone were offered enzalutamide, and vice versa. In the company's indirect treatment comparison, olaparib increased progression-free survival and overall survival compared with cabazitaxel. The results cannot be reported here because the company considers them confidential. The ERG highlighted several differences between the trials. It explained that all people in the PROfound BRCA-mutation prior taxane subgroup had BRCA mutations, but mutation status in CARD was unknown. Some people in PROfound had had cabazitaxel (the company considers the proportion to be confidential so it cannot be reported). The ERG explained that people in CARD had not had cabazitaxel before. Also, the central review of radiographic disease progression imaging was blinded in PROfound, but open-label in CARD. The clinical experts explained that BRCA-mutation status does not affect how well cabazitaxel works. They also noted that previous cabazitaxel is unlikely to affect how well olaparib works because its mode of action is different. The ERG explained that some studies suggested BRCA-mutation status could modify treatment effect, and some suggested it does not. In NICE's technology appraisal guidance on cabazitaxel for hormone-relapsed metastatic prostate cancer treated with docetaxel, the committee considered the TROPIC trial. This compared cabazitaxel plus prednisone with mitoxantrone plus prednisone in hormone-relapsed metastatic prostate cancer that had progressed after docetaxel treatment. In that appraisal, the committee considered that mitoxantrone plus prednisolone was unlikely to have clinical benefits. Therefore, in this appraisal, the committee noted that mitoxantrone was similar to the control arms of PROfound and CARD. In response to consultation, the company explored if it could include TROPIC in its indirect treatment comparison. It argued that the population in TROPIC was not comparable to the population in PROfound. This was because people enrolled in TROPIC had not had treatment with abiraterone or enzalutamide, as in PROfound or CARD. It was also because there were differences in the inclusion and exclusion criteria, and the comparator arms, between TROPIC and PROfound. However, it did present a scenario analysis including TROPIC, which had a small effect on the cost-effectiveness estimates. The ERG agreed that TROPIC should be excluded from the indirect comparison. The committee concluded that there were differences between PROfound and CARD, which led to uncertainty in the company's indirect treatment comparison, and that the population in TROPIC was unlikely to reduce this uncertainty. ## It is inappropriate to adjust for treatment switching in CARD The company did not adjust for treatment switching in CARD as it did in PROfound. It explained that this was because it did not have access to individual patient data from CARD. In its first meeting, the committee considered that overall survival in the cabazitaxel arm in CARD may have been underestimated. This was because 33% of people in the abiraterone or enzalutamide arm switched to cabazitaxel after disease progression. The clinical experts explained that treatment switching was included in the trial protocol in PROfound, but not in CARD. The committee appreciated that this may explain why more people switched treatments in PROfound than in CARD but did not remove the risk of bias. In response to consultation, the company explained that cabazitaxel is available in the NHS and that it was inappropriate to adjust for treatment switching because the trial did not deviate from NHS practice. Adjusting would also cause an imbalance in the abiraterone or enzalutamide arms between CARD and PROfound, which would undermine the anchored indirect treatment comparison. The committee recognised that the need to adjust would also depend on whether the proportion of people switching treatment in the trial reflected NHS practice. It concluded that it was inappropriate to adjust for treatment switching in CARD. However, it acknowledged that there was still some uncertainty in the size of the effect estimate comparing olaparib with cabazitaxel. ## Differences between NHS post-progression treatments and those in PROfound and CARD affect generalisability to NHS practice The committee discussed treatments offered in PROfound and CARD after disease progression. It noted that these treatments did not reflect NHS practice, and that this would affect both costs of treatment and its outcomes (see section 3.19). The company considers that the distribution of post-progression treatments in PROfound is confidential so cannot be reported here. The committee noted that life-extending treatments could have affected the hazard ratios for overall survival seen in PROfound and CARD. If these treatments were offered differently to how they are in the NHS, then the trial results (and costs) would not apply to the NHS. The committee noted that most people in PROfound and CARD had abiraterone or enzalutamide (of those people who had a post-progression treatment after cabazitaxel in CARD, 37% had abiraterone and 37% had enzalutamide). It recalled that these treatments would not offer any clinical benefit and would not be used in NHS practice (see section 3.5). Instead, people in the NHS would have access to life-extending treatments such as radium‑223 dichloride. The committee noted that using radium‑223 dichloride after disease progression on olaparib in PROfound was limited (the proportion is considered confidential and cannot be reported here). However, 15% of people in CARD had radium‑223 dichloride after disease progression on cabazitaxel. In response to consultation, the company excluded abiraterone and enzalutamide from post-progression treatments to align with NHS practice. The company stated that it could not adjust for differences in overall survival because it did not have the data. Instead, it did scenario analyses to explore the effect that differences in post-progression treatments may have had by improving or worsening the hazard ratio for overall survival for olaparib compared with cabazitaxel by 5% and 10%. The committee noted the differences in post-progression treatments between the 2 trials and the NHS. It concluded that this further affected the validity of the company's indirect treatment comparison and its generalisability to NHS practice. ## Analyses comparing olaparib with docetaxel and best supportive care for the no prior taxane group are uncertain The company believed that a robust indirect treatment comparison for olaparib compared with docetaxel in the no prior taxane group was not feasible. This was because of a lack of evidence for docetaxel in the relevant population. So the company did an exploratory indirect treatment comparison comparing olaparib with docetaxel using results from TAX327, a phase 3 randomised trial for docetaxel plus prednisone. The trial compared docetaxel plus prednisone with mitoxantrone plus prednisone, which the company considered not to be an active comparator. This mitoxantrone plus prednisone control arm was used as the anchor for the indirect treatment comparison, with the assumption that it is equivalent to the PROfound control arm of abiraterone or enzalutamide. The primary endpoint in TAX327 was overall survival. The trial did not report progression-free survival, so the company assumed that the size of relative treatment effect of docetaxel on progression-free survival would be the same as that on overall survival. The committee noted that several assumptions related to the TAX327 trial increased the uncertainty in the analyses. This included the generalisability of the trial, which was done before abiraterone or enzalutamide were available. To estimate the effect of olaparib compared with best supportive care, the company assumed the abiraterone or enzalutamide retreatment arms from PROfound could be used as a proxy for best supportive care. The results of the analyses cannot be reported here because the company considers them confidential. However, they showed that olaparib may increase overall survival compared with docetaxel, and may increase overall and progression-free survival compared with best supportive care. The committee noted the wide confidence intervals in the results for both comparisons, likely driven by the small size of the no prior taxane group in PROfound. The committee noted limitations in the olaparib arm, which included the small sample size of the no prior taxane group, treatment switching in the abiraterone or enzalutamide arm, immature overall survival data and lack of direct data to inform progression-free survival estimates. The committee considered that the results suggested that olaparib was more effective than docetaxel or best supportive care for people who had not had a prior taxane. However, given the issues with the analyses, the committee concluded that these results were uncertain. # Economic model ## Hazard ratios from the BRCA-mutation prior taxane subgroup of PROfound should be used to model outcomes for cabazitaxel In its initial submission, the company used patient-level data from the PROfound BRCA-mutation prior taxane subgroup to model the absolute rates of progression-free survival and overall survival for people having olaparib. It then applied hazard ratios for progression-free survival and overall survival from the indirect treatment comparison to that data to model the efficacy for people having cabazitaxel. However, it used hazard ratios from the licensed population rather than from the prior taxane subgroup. The company explained that it did this because olaparib's efficacy in the licensed population and prior taxane populations were similar, and the former group had larger patient numbers. The committee disagreed with the company's approach of comparing a subgroup with the whole group. The committee would have preferred the company to use hazard ratios from the BRCA-mutation prior taxane subgroup to model comparative effectiveness with cabazitaxel. The committee considered the company's approach to be inconsistent. This was because the company had used data from the BRCA-mutation prior taxane subgroup from PROfound for other model inputs, for example, survival, adverse events and baseline characteristics for olaparib. The committee considered it appropriate to match data used in the model to the population under consideration when possible. In its response to consultation, the company agreed with the committee and used the hazard ratios from the BRCA-mutation prior taxane subgroup to model survival on cabazitaxel in the prior taxane group. The committee concluded that the revised company approach was appropriate. ## The company and ERG's approaches to extrapolating overall survival for both treatments in the prior taxane group appear plausible PROfound reported results based on a prespecified analysis in June 2019 for the primary endpoint of radiological progression-free survival. At the latest data cut-off (March 2020) available for overall survival, the trial was still collecting data as planned and, for the prior taxane group there had been 41 events (57%) with olaparib and 27 events (77%) with abiraterone or enzalutamide retreatment. The company used parametric survival curves to fit the trial data and extrapolate it beyond the trial duration because the model used a lifetime horizon. The company initially chose a log-logistic curve to model overall survival but then changed its preference after the first committee meeting. The company had explored more flexible models as requested by the committee but because of poorer statistical fit, the company chose the exponential model, noting it had the best fit. The ERG explained that it had explored other models and had chosen the Rayleigh distribution for treatment with olaparib for its base case, based on the best statistical and visual fit. The committee noted that none of the parametric curves fitted the observed hazard rates for the olaparib arm from the trial well. It noted that the Rayleigh, Weibull and exponential hazard function curves appeared reasonable although possibly pessimistic. The company agreed that these curves were all reasonable and possibly pessimistic but considered the Rayleigh to be the 'worst case' in terms of its predication of overall survival. As a result, the company chose the Weibull distribution. The ERG noted that this was its second preferred option and that there was no statistical or visual difference between this and the Rayleigh model. The ERG noted a considerable decline in the number of patients alive after 24 months and this led to uncertainty in the extrapolation. The committee noted that the cost-effectiveness results were sensitive to the change in distribution in the scenario analyses done by the company and ERG. It agreed that there was little difference in visual and statistical fit between the 2 curves, so deciding which curve was best would involve determining which curve had the most plausible long-term extrapolations. The committee concluded that both extrapolations may be pessimistic, and were equally uncertain and equally plausible. So it took both into account in its decision making. ## Both the company and ERG's approach to extrapolating overall survival for both treatments in the no prior taxane group are plausible The company also extrapolated long-term overall survival in the no prior taxane group. The company selected the log-logistic distribution to extrapolate both arms in the comparisons of olaparib with docetaxel and best supportive care (see section 3.4). The ERG preferred the Rayleigh distribution to extrapolate both arms in both comparisons. The log-logistic and Rayleigh distributions had very similar extrapolations for the docetaxel arm and the best supportive care arms in the 2 different comparisons. However, there were some differences between the distributions in the olaparib arms in both comparisons. The company stated that, to extrapolate overall survival for olaparib, the log-logistic distribution had the best visual fit to the Kaplan–Meier data, the best statistical match and had been validated by clinical input. The ERG considered that the log-logistic model may overestimate long-term survival in the olaparib group in both comparisons and that the Rayleigh distribution provided more realistic extrapolations. The company considered that both the log-logistic and Rayleigh olaparib extrapolations were consistent with the 24‑month Kaplan–Meier data. But it stated that the Rayleigh was overly pessimistic when extrapolating overall survival in the olaparib arm in both comparisons. The committee noted that the difference between the 2 extrapolations started at around 30 months. It predicted that overall survival after this point was substantially higher when the log-logistic distribution was used to extrapolate olaparib, for both comparisons. The committee concluded that both log-logistic and Rayleigh distributions showed a good visual and statistical fit, and had plausible long-term survival predictions, so it would take both into account in its decision making. # Treatment costs ## Data on time to stopping treatment should be used to model olaparib treatment duration and costs In its initial submission, the company assumed that people have olaparib until their disease progresses. It used time until disease progression in PROfound to model olaparib treatment duration and costs, even though there was data from PROfound on time to stopping treatment. It did this to be consistent with the cabazitaxel trial, which provided data on progression-free survival but not time to stopping treatment. The company explained that estimates of median progression-free survival and median time to stopping treatment from PROfound were similar. The committee noted, however, that people may stop olaparib for reasons other than disease progression, for example, adverse effects or personal choice. The ERG preferred to use the time to stopping treatment data from PROfound. It explained that the curve for time to stopping treatment was above the curve for progression-free survival, so the company may have underestimated olaparib's costs. The ERG considered that using the curve for time to stopping treatment aligned with the relative dose-intensity calculation (see section 3.17). The ERG explained that cabazitaxel is administered in hospital every 3 weeks. Therefore, time to stopping treatment and progression-free survival are likely more aligned for cabazitaxel than for olaparib, which is taken as a daily tablet. Also, because cabazitaxel is less expensive than olaparib, the bias of using progression-free survival to estimate its costs would be lower than for olaparib. In its response to the first consultation, the company agreed with the committee's conclusion, notably, that time to stopping treatment better estimates treatment duration and costs of olaparib than progression-free survival. ## Using relative dose intensity from PROfound to estimate the cost of olaparib is acceptable To estimate the cost of olaparib in its original submission, the company used the mean relative dose intensity from PROfound. The relative dose intensity is the proportion of the planned dose of a drug a person takes over a given period of time. The ERG explained that the mean relative dose intensity did not account well for how much of a planned dose of a drug people had over time. So, it did not accurately estimate the mean per-patient cost of olaparib during the trial, and was also not suitable for extrapolation. The ERG preferred to use the median relative dose intensity. The company agreed with this approach during technical engagement. However, the committee was concerned with both the company's initial approach and the ERG's approach. It noted that generally the mean is the preferred metric to estimate costs, but agreed with the ERG's concerns. The committee would have preferred that the company had calculated the costs of olaparib for each person based on their individual dose and treatment duration, and used these estimates to inform the mean per-patient cost of olaparib. The ERG clarified that, unless the company provides it with the individual patient data, it cannot calculate or validate these costs. The ERG suggested an alternative approach of presenting the mean monthly relative dose intensity over time for people remaining on treatment, and the number of observations for each time point. This would illustrate how the mean relative dose intensity changes throughout the model time horizon and how it affects the model results. In its response to consultation, the company argued that the costs of olaparib were appropriately reflected in the model because time to stopping treatment was based on individual patient data. It explained that it did not do an additional analysis based on individual dose because the model was not sensitive to relative dose intensity. It suggested that this was shown in its scenario analysis, in which assuming a full dose for the entire duration of treatment (that is, 100% relative dose intensity) had minimal effect on the cost-effectiveness estimates. The ERG questioned whether the cost of olaparib in the model should be based on the number of tablets consumed or the number of packs prescribed, because the NHS pays for whole packs, not individual tablets. It argued that, if the costs were based on the number of packs prescribed, a relative dose intensity of 100% might be the most reasonable estimate. The ERG highlighted that this concern would not apply to cabazitaxel because it is administered as an intravenous therapy in hospital. The Cancer Drugs Fund clinical lead explained that they expect minimal drug wastage with olaparib. This is because clinicians implement dose adjustments quickly when determining the right dose for an individual person. The committee was satisfied that it was appropriate for the company to exclude drug wastage in its model. It would have preferred the company to use individual patient data from PROfound to calculate the per-patient cost of olaparib, but acknowledged this was likely to have had a small effect on the cost-effectiveness results. It concluded that the company's approach is acceptable for decision making. ## The ERG's estimate of the costs of prophylactic granulocyte colony-stimulating factor in the cabazitaxel arm is appropriate People having cabazitaxel may have prophylactic granulocyte colony-stimulating factor (G‑CSF) to prevent neutropenia. The company and the ERG added the costs of G‑CSF to the costs of having cabazitaxel. In its initial submission, the company assumed that all people having cabazitaxel had prophylactic G‑CSF for 14 days. This was to align with CARD, and cabazitaxel's marketing authorisation, which recommends treatment with G‑CSF 'usually for up to 14 days'. The ERG explained that the company's approach overestimated the use of G‑CSF. In its base case, the ERG assumed that a lower proportion of people have G‑CSF, based on the results of the company's survey with clinical experts (the company considered the exact estimate confidential so it cannot be reported here). The ERG also assumed that treatment would typically last for 7 days, based on clinical opinion. The clinical experts and the Cancer Drugs Fund clinical lead explained that people would be unlikely to have G‑CSF for more than 7 days, and considered the ERG's estimate to be reasonable. In its response to consultation, the company agreed with the ERG's approach. The committee concluded that the ERG's estimate of the costs of prophylactic G‑CSF in the cabazitaxel arm was appropriate. It also acknowledged that the company had followed this approach in its revised cost-effectiveness modelling. ## The company's and ERG's estimates of post-progression treatment costs do not reflect NHS practice but are acceptable Both the company and the ERG incorporated the costs of treatments after disease progression on olaparib and cabazitaxel. The company explained that its model allowed people to have only 1 active treatment after disease progression. The ERG noted that people in PROfound had more than 1 active treatment on average after disease progression. The clinical experts confirmed that people can have multiple treatments after disease progression in NHS practice. After technical engagement, both the company and the ERG assumed that the same proportion of people whose disease progressed on olaparib or cabazitaxel would have an active treatment. The company considers the exact proportions of people having each treatment after disease progression on olaparib to be confidential so they cannot be reported here. People who do not have active treatment would have best supportive care after progression. The company assumed that the treatments offered would differ depending on whether the disease progressed on olaparib or cabazitaxel, and that disease could be retreated with abiraterone or enzalutamide. The ERG acknowledged that, in the NHS, people are likely to have different treatments after progression, depending on their first treatment. However, it noted that there was no reliable data to inform this. It reminded the committee that PROfound and CARD had important differences (see section 3.9) and that using the trials' proportions of post-progression treatments does not reflect NHS practice. The committee again noted that retreatment with abiraterone or enzalutamide would not happen in NHS practice, which was confirmed by the clinical experts. They considered that the company's estimate for the number of people having radium‑223 dichloride in the olaparib arm was too low. They also considered that the ERG's estimate that 55% of people in both arms would have radium‑223 dichloride was too high. In its response to consultation, the company excluded abiraterone and enzalutamide from post-progression treatments. However, it continued to assume people would have different treatment after progression depending on whether they initially had olaparib or cabazitaxel. The company explained that this was because the proportions of post-progression treatments used in the model were based on the clinical trial data from PROfound and CARD. It claimed that the data reflects that people who take olaparib can then have chemotherapy as a subsequent therapy before radium‑223 dichloride. It also claimed that the data reflects that people whose disease progresses on cabazitaxel may have exhausted their treatment options apart from radium‑223 dichloride. So, a higher proportion of people having radium‑223 dichloride than seen in the model is likely. The company highlighted that, after it excluded abiraterone and enzalutamide from its model, the proportion of other subsequent treatments in the model increased. The company provided 2 scenario analyses to explore the effect of the cost of post-progression treatment, in which it excluded: retreatment with cabazitaxel from post-progression treatment options all costs related to post-progression treatments.Both had a minimal effect on the cost-effectiveness estimates. The committee agreed that both the company's and ERG's estimates of post-progression treatment costs did not reflect NHS practice. However, it acknowledged that adequate adjustment for these differences may not be possible, and that it was likely to have a minimal effect on the cost-effectiveness results. Therefore, it concluded that both approaches were not ideal, but were acceptable for decision making. ## The ERG's approach to costing best supportive care is appropriate In its initial submission, the company assumed that the costs of best supportive care differed for people who: had had and stopped an active treatment after their disease had progressed on either olaparib or cabazitaxel did not have an active treatment after progression, that is, had best supportive care directly after olaparib or cabazitaxel.The company explained that this avoided double counting the costs of best supportive care. It also explained that the model structure did not allow estimation of the costs of best supportive care after active treatment. The ERG disagreed with the company's approach and instead assumed the same best supportive care costs were incurred regardless of whether a person had an active treatment after disease progression. The clinical and patient experts explained that everyone would start having palliative care after active treatments had stopped, and that this would be the same for everyone. In its response to consultation, the company agreed with the ERG's approach, and followed it in its revised cost-effectiveness modelling. The committee accepted this approach to costing best supportive care. ## The costs of testing for BRCA mutations should be included in the cost-effectiveness estimates Before starting treatment with olaparib, people must have a BRCA mutation confirmed using a validated test. Section 5 in the NICE guide to the methods of technology appraisal states that 'if a diagnostic test to establish the presence or absence of this biomarker is carried out solely to support the treatment decision for the specific technology, the associated costs of the diagnostic test should be incorporated into the assessments of clinical and cost effectiveness'. The company excluded the costs of testing for BRCA mutations in its initial base case. It explained that this was because the NHS Genomic Test Directory includes this test, so it is likely part of standard NHS practice. The company included the costs of testing in a scenario analysis, using costs from the testing service for ovarian cancer that the company currently funds (the cost per test is confidential and cannot be reported here). The ERG included the testing costs in its base case because its clinical advice suggested the NHS does not currently test for BRCA mutations routinely. One clinical expert noted that they do not routinely test for BRCA mutations unless there is a family history. Another clinical expert explained that they do genomic testing for all people with hormone-relapsed metastatic prostate cancer, and that many oncologists want routine testing in the NHS. The Cancer Drugs Fund clinical lead explained that the NHS Genomic Test Directory includes testing for BRCA mutations. However, he said that testing is not standard NHS care, and the cost of olaparib to the NHS should include testing costs. The ERG explained that it calculated the cost to identify 1 person with BRCA mutations by applying the company's cost per test to the expected prevalence of BRCA mutations in people with hormone-relapsed metastatic prostate cancer. It based this on the prevalence of BRCA mutations in people who entered screening for PROfound (the company considers the value to be confidential and so it cannot be reported here). The clinical experts advised that the prevalence of BRCA mutations in people with hormone-relapsed metastatic prostate cancer in clinical practice is about 10%. In its response to consultation, the company agreed with the ERG's approach and included the cost of testing for BRCA mutations in its revised base case. The committee acknowledged that the revised company approach was appropriate. # Utility values ## The company's utility values based on PROfound are appropriate The company and the ERG used utility values from PROfound for the progression-free and post-progression health states. The utility values are considered confidential by the company so cannot be reported here. The company mapped EQ‑5D‑5L values from PROfound to generate EQ‑5D‑3L values. The company modelled worse quality of life with cabazitaxel and prednisone than with olaparib. Cabazitaxel treatment was associated with an additional decrement of -0.023 (Matza et al. 2013) because it is administered intravenously. Once people stopped having cabazitaxel, their utility reverted to the same as that of olaparib. The company sourced mean utility decrements associated with adverse events and the mean duration of adverse events from NICE's technology appraisal guidance on cabazitaxel for hormone-relapsed metastatic prostate cancer treated with docetaxel and the literature. The committee concluded that the company's utility values were appropriate. # Exploratory analyses ## Exploratory analyses for people who have not had a taxane are highly uncertain The company did exploratory cost-effectiveness analyses for people who had not had a taxane. The committee recalled its remit to look at a technology across the indication in its marketing authorisation. However, it appreciated that no single comparator would be relevant for people who had and who had not had treatment with docetaxel. It also recalled its concerns that people in PROfound who had not had treatment with a taxane were unlikely to represent people who cannot or should not have docetaxel in clinical practice. To compare olaparib with best supportive care, the company used the abiraterone or enzalutamide arm from PROfound as a proxy. At the second committee meeting, the committee noted that the company's exploratory analyses for the no prior taxane group did not mirror the committee's preferred assumptions for the prior taxane group, for example: assuming that the same proportion of people whose disease progressed on olaparib or cabazitaxel would have an active treatment (see section 3.19) adjusting for differences in post-progression treatments between PROfound and NHS practice. In response to the second consultation, the company updated its no prior taxane model to be consistent with the prior taxane model. The committee recalled that, while there may be a benefit for olaparib in overall and progression-free survival, there was substantial uncertainty in the effect estimates from the indirect treatment comparison for the no prior taxane subgroup (see section 3.12). It concluded that the company's exploratory analyses for people who have not had a taxane were uncertain and it would take this into account in its decision making. # End of life ## Olaparib likely meets NICE's criteria for a life-extending treatment at the end of life for people who have and have not had a taxane The committee considered the criteria for 'life-extending treatments at the end of life' outlined in Section 6 of NICE's guide to the methods of technology appraisal, that is: a treatment must be indicated for people with a short life expectancy, normally less than 24 months and there must be sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.Also, the appraisal committees will need to be satisfied that: the estimates of the extension to life are sufficiently robust and can be shown or reasonably inferred from either progression-free survival or overall survival (taking account of trials in which crossover has occurred and been accounted for in the effectiveness review) and the assumptions used in the reference case economic modelling are plausible, objective and robust.The ERG explained that, for the prior taxane group, overall survival with cabazitaxel was less than an average of 24 months when using both the Weibull curve (company updated base case) and Rayleigh curve (ERG's base case) to extrapolate overall survival in the model. The company also presented results from other trials in hormone-relapsed metastatic prostate cancer, COU‑AA‑301 and AFFIRM, in which median overall survival ranged from 16 to 18 months with enzalutamide or abiraterone treatment. The committee noted that, for the no prior taxane group, overall survival with cabazitaxel was also less than an average of 24 months when using both the log-logistic curve (company base case) and Rayleigh curve (ERG's base case) to extrapolate overall survival. The committee was satisfied that olaparib met the end of life criteria for both the prior taxane and no prior taxane groups. The committee acknowledged that both the company and ERG's preferred parametric extrapolations of overall survival predicted at least a 3‑month survival benefit with olaparib compared with cabazitaxel in both the prior taxane and no prior taxane groups. The committee also noted that new hormonal agents are now available much earlier in the treatment pathway (see section 3.1). This would mean that olaparib, which is indicated for treatment if disease has progressed after a new hormonal agent, could also be offered earlier. This could mean a longer life expectancy than modelled by the company. However, according to the data currently presented, it was likely that the end of life criteria were met. The committee concluded that olaparib likely meets NICE's end of life criteria for people who have and have not had a taxane. # Cost-effectiveness estimates ## Olaparib is a cost-effective treatment option for people who have had a taxane at the price chosen by the company Because of confidential commercial arrangements for olaparib, cabazitaxel and other post-progression therapies, the cost-effectiveness estimates cannot be reported here. The committee noted that the company addressed a number of its preferences from its first and second committee meetings, including by: using the hazard ratios from the BRCA-mutation prior taxane subgroup of PROfound to model the efficacy of cabazitaxel in the prior taxane group (see section 3.13) using the time to stopping treatment data to model olaparib treatment duration and costs (see section 3.16) assuming only a proportion of people having cabazitaxel have prophylactic G‑CSF, and have it for an average of 7 days (see section 3.18) assuming treatments available to people after progression on olaparib or cabazitaxel do not include retreatment with abiraterone or enzalutamide (see section 3.19) assuming the cost of best supportive care is the same regardless of whether people had active treatment after progression (see section 3.20) including the cost of testing for BRCA mutations (see section 3.21) addressing other minor differences between the company's and the ERG's models, such as assumptions related to bone and CT scans while on treatment, and costs of ADT.The committee also acknowledged that the company explored some of its preferences from its first meeting in scenario analyses, and that they had a minor impact on cost-effectiveness estimates. Namely, the company explored: whether TROPIC could be included in the indirect treatment comparison (see section 3.9) uncertainty around the effect of post-progression treatments on post-progression survival (see section 3.19) more flexible approaches for extrapolating survival (see section 3.14) uncertainty around dosing of olaparib (see section 3.17) uncertainty around the cost of post-progression treatments in the NHS (see section 3.19).NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted that the end of life criteria were met for olaparib, which means that a maximum acceptable ICER of £50,000 per quality-adjusted life year (QALY) gained applies. However, given that there was significant uncertainty around the network meta-analyses informing the clinical-effectiveness estimates for this appraisal, the committee considered the maximum acceptable ICER would be below this, and it agreed that the probabilistic ICER would better capture the uncertainty associated with the analyses. Applying confidential discounts for cabazitaxel, radium‑223 dichloride, filgrastim and leuprorelin (which are subsequent treatments), and considering its preferences, the committee noted the cost-effectiveness estimates using its preferred assumptions for olaparib compared with cabazitaxel were within the range that NICE normally considers an acceptable use of NHS resources for people who have had treatment with a taxane. This was the case when considering both Weibull and Rayleigh curves for extrapolating overall survival, and the higher threshold for end of life criteria. So, the committee could recommend olaparib for use in the NHS for treating hormone-relapsed metastatic prostate cancer with BRCA1 or BRCA2 mutations that has progressed after abiraterone or enzalutamide in adults who have had treatment with a taxane. ## The cost-effectiveness estimates for people who have not had a taxane are uncertain but suggest olaparib is cost effective The committee recalled high uncertainty in the results from the company's cost-effectiveness modelling for the group of people who have not had treatment with a taxane (see section 3.23). It noted that it had seen no modelling specifically for the group of people who cannot or should not have a taxane in NHS practice. As with the 'prior taxane' group, because of the uncertainties with the evidence, the committee agreed that the maximum acceptable ICER should be below the end of life threshold. The committee agreed that the probabilistic incremental cost-effectiveness ratio (ICER) would better capture the uncertainty associated with the analyses. Because of confidential discounts for cabazitaxel, radium‑223 dichloride, filgrastim and leuprorelin, the cost-effectiveness results cannot be reported here. Most of the probabilistic ICERs were within the range NICE normally considers an acceptable use of NHS resources when considering the higher threshold for meeting end of life criteria. So the committee could recommend olaparib for use in the NHS for people who have not had a taxane, whether they cannot, should not, or choose not to have it. # Other considerations ## There are some equalities considerations The committee recalled its recent appraisal of abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (see NICE's technology appraisal guidance on abiraterone). It noted that, in this appraisal, the company initially limited its submission to people who have already had a taxane, which would be docetaxel in the NHS. It agreed that people who cannot or should not have docetaxel are likely to be older than those who can have docetaxel. The committee also noted that some people with prostate cancer may not identify as men. Age, sex, and gender reassignment are protected characteristics under the Equality Act 2010. ## Olaparib is not innovative because it does not offer benefits not already included in the modelling The company considered olaparib to be inherently innovative because it was the first drug for metastatic hormone-relapsed prostate cancer with a specific biomarker. It also stated that the need to test for the BRCA mutation before using olaparib may encourage earlier diagnosis and lead to cost savings in the NHS. The company also stated that there would be wider benefits of earlier identification of BRCA mutations particularly if the mutation is heritable. However, the committee heard that, in the NHS the BRCA mutation testing that would be used would consist of testing the tumour. So, many of the mutations detected would be somatic mutations (mutations in the tumour cells) and not heritable germline mutations (mutations in the normal cells of the body). The Cancer Drugs Fund clinical lead explained that, if recommended, olaparib would change the treatment pathway and may help to promote BRCA mutation testing in prostate cancer in the NHS. The committee acknowledged these potential advantages. It also noted that corticosteroids given with cabazitaxel have associated adverse effects and that this could possibly be delayed. However, the committee noted that the company had modelled a relative increase in utility for treatment with olaparib compared with cabazitaxel, so it considered that these benefits had been adequately captured in the economic modelling. The committee understood that to consider a technology innovative, a substantial change in management of a condition and benefits not adequately captured in the economic analysis were both needed. It concluded the modelling had captured all the relevant benefits of olaparib.	{'Recommendations': "Olaparib is recommended, within its marketing authorisation, as an option for treating hormone-relapsed metastatic prostate cancer with BRCA1 or BRCA2 mutations that has progressed after a newer hormonal treatment (such as abiraterone or enzalutamide) in adults. Olaparib is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis evaluation uses new cost-effectiveness estimates to update olaparib for previously treated BRCA mutation-positive hormone-relapsed metastatic prostate cancer (NICE technology appraisal guidance TA831). No new clinical evidence was reviewed.\n\nTreatments for BRCA mutation-positive hormone-relapsed metastatic prostate cancer that has progressed after enzalutamide or abiraterone include taxanes (for example, docetaxel or cabazitaxel), radium‑223 dichloride and best supportive care. The company provided evidence based on whether or not people had already had a taxane. This is because people have different treatments depending on whether they have had a taxane before.\n\nClinical trial evidence shows that people taking olaparib have more time before their cancer gets worse, and live longer overall, than people having retreatment with abiraterone or enzalutamide. However, this retreatment is not considered effective and is not standard care in the NHS.\n\nFor people who have had a taxane before, olaparib has not been directly compared with docetaxel, cabazitaxel or radium‑223 dichloride. An indirect comparison suggests that olaparib increases how long people live compared with cabazitaxel.\n\nFor people who have not had a taxane before there is also no direct evidence comparing olaparib with docetaxel or best supportive care. But an exploratory indirect comparison suggests that olaparib may increase how long people live compared with both best supportive care and docetaxel.\n\nOlaparib likely meets NICE's criteria for a life-extending treatment at the end of life. When taking this into account, the most likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So olaparib is recommended.", 'Information about olaparib': "# Marketing authorisation indication\n\nOlaparib (Lynparza, AstraZeneca) is indicated 'as monotherapy for the treatment of adult patients with metastatic castration-resistant prostate cancer and BRCA1/2-mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for olaparib.\n\n# Price\n\nThe price for olaparib is £2,317.50 per pack of 56\xa0tablets, each containing 100\xa0mg or 150\xa0mg of the active ingredient (excluding VAT; BNF online, March 2023). The company has a commercial arrangement. This makes olaparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## There is an unmet need for new treatments for hormone-relapsed metastatic prostate cancer\n\nPeople with newly diagnosed hormone-sensitive non-metastatic prostate cancer are normally offered androgen deprivation therapy (ADT) or radical therapy such as surgery or radiotherapy. If the disease progresses with ADT, it is known as hormone-relapsed or castration-resistant prostate cancer. Treatment with ADT continues, either alone or with darolutamide or apalutamide. People with newly diagnosed hormone-sensitive metastatic prostate cancer are usually offered ADT alone, ADT with docetaxel with or without prednisolone (from now, referred to as docetaxel), ADT with enzalutamide (see NICE's technology appraisal guidance on enzalutamide for treating hormone-sensitive metastatic prostate cancer), or, if docetaxel is not suitable, ADT with apalutamide (see NICE's technology appraisal guidance on apalutamide for treating hormone-sensitive metastatic prostate cancer). For people with hormone-relapsed metastatic prostate cancer for which chemotherapy is not yet indicated, treatment options include abiraterone or enzalutamide if neither has been used before (see NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated and abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated), or 'watchful waiting'. Darolutamide, enzalutamide, abiraterone and apalutamide are new hormonal agents. Olaparib is a poly-ADP-ribose polymerase (PARP) inhibitor, which works differently to hormonal agents. The clinical experts confirmed that people would have new hormonal agents only once. So, people who have had a new hormonal agent when their cancer was hormone sensitive or non-metastatic would not have it again when their cancer is hormone relapsed and metastatic. After this, treatment options include:\n\ndocetaxel\n\nretreatment with docetaxel for people who had docetaxel when their disease was hormone sensitive\n\ncabazitaxel with prednisolone (from now, referred to as cabazitaxel) for people who have already had docetaxel\n\nradium‑223 dichloride for people with symptomatic bone metastases and no metastases in the soft internal organs of the body (visceral metastases), and who have already had docetaxel or cannot have it.The patient experts explained that hormone-relapsed metastatic prostate cancer affects all aspects of their lives and is difficult for them, their families and their friends. They highlighted the need for treatments that can extend survival and help them maintain or improve their quality of life because there is no cure. They also explained that they would like more treatment options so they can delay chemotherapy (docetaxel and cabazitaxel) and its adverse effects. This is because the adverse effects, especially those of docetaxel, can be debilitating, even up to 1\xa0year after people have stopped having it. The committee concluded that there is an unmet need for new treatments for hormone-relapsed metastatic prostate cancer.\n\n## The company's approach of considering people who have had or have not had a taxane separately is acceptable\n\nThe marketing authorisation for olaparib states that it is indicated 'as monotherapy for the treatment of adult patients with metastatic castration-resistant prostate cancer and BRCA1/2-mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent'. The company limited the population in its initial submission to people who have already had a taxane (mainly docetaxel), from now referred to as the 'prior taxane' group. It chose cabazitaxel as the comparator (see section\xa03.3), which requires previous treatment with docetaxel. The company explained that it did this because its clinical advisers suggested that in the NHS around 75% of people have docetaxel while their disease is hormone sensitive. The ERG agreed that most people who have abiraterone or enzalutamide will have already had treatment with docetaxel, but that this proportion is likely to be less than 75%. The clinical experts explained that having previous treatment with docetaxel is not specified in olaparib's marketing authorisation and should not be a factor when deciding who would have olaparib in NHS practice. The Cancer Drugs Fund clinical lead was disappointed with the company's initial decision to limit the population. The clinical lead explained that many people who do not choose docetaxel early in the pathway might then be unable to have it after developing hormone-relapsed metastatic disease, for example if they become too ill. At the company's initial proposed position, olaparib would never be suitable for them. The clinical and patient experts explained that they are keen to have olaparib available as early in the treatment pathway as possible, but to have it at some point is most important. The committee appreciated that limiting olaparib to people who had had docetaxel would exclude people who cannot or should not have docetaxel but who could benefit from olaparib. It was aware that these people are likely to be older and more likely to have a poorer disease performance status, comorbidities, peripheral sensory neuropathy, poor bone marrow function, poor cognition or chemotherapy contraindications (see NICE's technology appraisal guidance on abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer). The committee also noted that NICE's recent recommendations on darolutamide, enzalutamide and apalutamide mean that more people would choose a new hormonal agent before docetaxel (see NICE's technology appraisal guidance on darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer, enzalutamide for treating hormone-sensitive metastatic prostate cancer, apalutamide with androgen deprivation therapy for treating high-risk hormone-relapsed non-metastatic prostate cancer and apalutamide with androgen deprivation therapy for treating hormone-sensitive metastatic prostate cancer). In response to the first consultation, the company submitted clinical-effectiveness data and exploratory cost-effectiveness analyses for the population who had not had a taxane, from now referred to as the 'no prior taxane' group (see section\xa03.7, section\xa03.12 and section\xa03.23). NICE's process requires a committee to initially appraise a drug across its marketing authorisation rather than by subgroups. However, the committee noted that there are no common comparator treatments for the whole licensed population as comparators are different for people who can and cannot have, or have already had, taxanes (see section\xa03.3 and section\xa03.4). Therefore, the committee concluded that the company's approach of considering these groups separately is acceptable.\n\n# Comparators\n\n## In the prior taxane group, cabazitaxel, radium‑223 dichloride, and retreatment with docetaxel are all relevant comparators\n\nNICE's scope for this appraisal lists docetaxel, cabazitaxel and radium‑223 dichloride as comparators. But the company included only cabazitaxel as a comparator for people who have had treatment with a taxane before. It considered that there was not enough evidence for docetaxel and radium‑223 dichloride. The ERG agreed that there is limited evidence for both docetaxel and radium‑223 dichloride. The company stated that its clinical advice and data from a recent UK national audit suggested that radium‑223 dichloride is often used later in the treatment pathway, once options such as cabazitaxel have been used. The committee recognised that this would mean radium‑223 dichloride was a relevant comparator because it could be used at the same position as olaparib for some people. The company highlighted that NICE's guideline on the diagnosis and management of prostate cancer does not recommend repeat cycles of treatment with docetaxel if the disease recurs after the planned course of chemotherapy is completed. It also pointed out that cabazitaxel is more likely to be used instead of docetaxel retreatment because response rates to docetaxel may decline over time. The committee was aware that retreatment with docetaxel happens in NHS practice, as documented in NICE's technology appraisal guidance on abiraterone, and as noted by stakeholders in this appraisal (see section\xa03.1). The clinical experts noted that people who had already had both docetaxel and abiraterone or enzalutamide may currently be offered docetaxel again or cabazitaxel. They may also be offered radium‑223 dichloride if they have symptomatic bone metastases and no visceral metastases. The committee appreciated that, in the prior taxane group, docetaxel retreatment, cabazitaxel and radium‑223 dichloride would all be alternatives to olaparib. It noted that patients and their treating clinician would decide which treatment is best. The committee concluded that cabazitaxel is likely to be the main, but not the only, comparator for olaparib in people who have had a taxane.\n\n## In the no prior taxane group, docetaxel and best supportive care are the most relevant comparators\n\nFor people who have not had treatment with a taxane, the company chose the following comparators depending on the reason for them not having a taxane:\n\ndocetaxel and best supportive care (ADT and monitoring) for the group of people who had not had docetaxel but for whom docetaxel is appropriate\n\nbest supportive care only for the group who had not had docetaxel and for whom docetaxel is unsuitable.The committee agreed that these comparators are broadly appropriate but noted that radium‑223 dichloride is also a relevant comparator for some people for whom docetaxel is unsuitable. For radium‑223 dichloride, the company considered that there was not enough evidence on its use, and that it would be limited to a small minority of people. It also stated that radium‑223 is only recommended after docetaxel, so it could not be a comparator in this group. For cabazitaxel, the company stated that it is not an appropriate comparator because docetaxel was more appropriate, and that cabazitaxel can only be used after docetaxel, in line with its licence. The company considered best supportive care would only be suitable when taxanes are not appropriate. The ERG did not comment about the appropriateness of comparators in the no prior taxane group. The committee concluded that the company had used the most appropriate comparators.\n\n# Clinical evidence\n\n## In the PROfound trial, the baseline characteristics of people are generalisable to NHS practice, but the comparator treatment is not\n\nPROfound was a phase\xa03, randomised, open-label, multicentre trial of olaparib compared with investigator's choice of enzalutamide or abiraterone in hormone-relapsed metastatic prostate cancer that had progressed on abiraterone, enzalutamide or both. The trial enrolled people with homologous recombination repair gene mutations, including BRCA1, BRCA2, ataxia-telangiectasia mutation and other mutations. It stratified people according to whether they had had taxane treatment before. The primary endpoint was time to disease progression determined radiographically. Overall survival was among the secondary endpoints. The company presented clinical evidence for the population who had BRCA mutations in line with the marketing authorisation (the licensed population). It also presented it for the subgroup of this population who had had taxane treatment before (see section\xa03.2; from now, referred to as the 'BRCA-mutation, prior taxane subgroup'). The committee was satisfied that baseline characteristics from the BRCA-mutation prior taxane subgroup, including age, Eastern Cooperative Oncology Group performance status and prostate-specific antigen level, are generalisable to people in the NHS. However, it noted that some treatment regimens that people had had before entering the trial, such as having had both abiraterone and enzalutamide, did not reflect NHS practice. The clinical experts did not expect this to modify the treatment effect of olaparib in the trial. Clinical experts explained that retreating with abiraterone or enzalutamide has no clinical benefit and could effectively be considered a placebo. The company acknowledged that the comparator in its trial does not reflect current NHS practice. The committee concluded that baseline characteristics in PROfound were generalisable to NHS practice except for some people having had both enzalutamide and abiraterone before starting the trial. It further concluded that the comparator, that is, retreating with abiraterone or enzalutamide, is not offered in the NHS.\n\n## Olaparib is more effective than retreating with enzalutamide or abiraterone but this comparison does not reflect NHS practice\n\nIn the licensed population and the BRCA-mutation prior taxane subgroup of PROfound, median progression-free survival was higher with olaparib (9.0\xa0months, 95% confidence interval [CI] 7.4 to 10.8) compared with abiraterone or enzalutamide retreatment (1.9\xa0months, 95% CI 1.7 to 3.5). Median overall survival was also higher with olaparib (17.5\xa0months, 95% CI 13.0 to 25.3) than abiraterone or enzalutamide retreatment (11.9\xa0months, 95% CI 8.2 to 15.2). The committee recalled that retreating with abiraterone or enzalutamide is not expected to have a clinical benefit (see section\xa03.5). The committee concluded that olaparib was effective compared with enzalutamide or abiraterone in PROfound. However, it thought that the results should be interpreted with caution because the comparator arm in the trial does not reflect NHS practice. The committee also concluded that any comparison of olaparib with cabazitaxel or other relevant comparators (see section\xa03.3) would need to use other sources of data and an indirect treatment comparison.\n\n## Previous treatment with a taxane does not appear to affect the effectiveness of olaparib in PROfound\n\nIn its response to consultation, the company submitted results from PROfound for a subgroup of people who had not had treatment with docetaxel (see section\xa03.4 and section\xa03.12). The results in the no prior taxane group suggested that both progression-free and overall survival were higher with olaparib than with abiraterone or enzalutamide retreatment. The committee noted that, because of the inclusion and exclusion criteria in PROfound, the trial likely excluded many people who cannot or should not have docetaxel in NHS practice. The committee recalled that stratification in the trial was done on the basis of either mutation type or prior taxane, so there was no prespecified subgroup for those with a BRCA mutation who had had a taxane before. The company did provide analyses for those with BRCA mutations in the prior or no prior taxane subgroups. The committee noted this evidence but considered that, as it was not prespecified in the clinical trial protocol, it was a post-hoc analysis, which may introduce uncertainty. It also noted the small size of the subgroup of people who had not had treatment with docetaxel, and the immaturity of overall survival data in this subgroup. It concluded that these results were highly uncertain. The committee noted that it did not see any formal testing of interaction when this subgroup was compared with the subgroup who had had docetaxel. But it acknowledged that the clinical efficacy of olaparib in PROfound did not seem to have been affected by previous treatment with a taxane.\n\n## The company's method for adjusting for treatment switching in PROfound is appropriate, including using recensoring\n\nThe company explained that, in PROfound, most people switched from abiraterone or enzalutamide to olaparib after radiographic disease progression. The number of people who switched cannot be reported here because the company considers it confidential. The committee recognised that treatment switching biased the treatment effect for overall survival. This was because people in the control arm who switched to olaparib may have benefited from the treatment effect of olaparib and likely lived longer than if they had not switched. The company considered several different methods to adjust for treatment switching. These included the rank preserving structural failure time model (RPSFTM), inverse probability of censoring weights and 2‑stage estimation. The company chose the RPSFTM because it did not depend on time-varying covariates to predict switching, did not reduce the effective sample size, and did not assume that there are no unmeasured confounders. The ERG agreed that the RPSFTM was the most appropriate method. The company did sensitivity analyses to explore and validate the assumption of a common treatment effect in the overall trial population, but not in the BRCA-mutation prior taxane subgroup. The company further explained that it had applied recensoring to remove any censoring bias from the treatment switching-adjusted results. Recensoring involves censoring data before the end of the trial follow-up period. This is to avoid informative censoring related to the association between prognostic factors and treatment switching. Informative censoring can happen when adjusting survival times if some people who switch treatments do not die during the trial. The committee was aware that the main limitation of recensoring is losing longer-term survival information. The ERG preferred to consider results with and without recensoring because both can bias results. The recensoring approach tends to overestimate the effect of treatment, and the approach without recensoring tends to underestimate it. The committee noted that, towards the end of the trial follow-up period, data from very few people contributed towards the estimates of overall survival. Therefore, in this case, recensoring did not lose a large amount of data, but avoided informative censoring. The committee concluded that the company's method for adjusting for treatment switching was appropriate, including using recensoring.\n\n## The indirect comparison of olaparib with cabazitaxel for the prior taxane group is uncertain because of differences between PROfound and CARD\n\nThe company did not find direct clinical trial evidence comparing olaparib and cabazitaxel so it did indirect treatment comparisons for progression-free survival and overall survival. It used evidence from the CARD trial, a phase\xa03, randomised, open-label, multicentre trial. The trial compared cabazitaxel with enzalutamide or abiraterone in hormone-relapsed metastatic prostate cancer previously treated with docetaxel and either enzalutamide or abiraterone. The primary endpoint was radiographic progression-free survival. Secondary endpoints included overall survival and skeletal-related events. Clinical experts explained that the comparator in CARD was similar to that in PROfound, that is, people who had already had abiraterone were offered enzalutamide, and vice versa. In the company's indirect treatment comparison, olaparib increased progression-free survival and overall survival compared with cabazitaxel. The results cannot be reported here because the company considers them confidential. The ERG highlighted several differences between the trials. It explained that all people in the PROfound BRCA-mutation prior taxane subgroup had BRCA mutations, but mutation status in CARD was unknown. Some people in PROfound had had cabazitaxel (the company considers the proportion to be confidential so it cannot be reported). The ERG explained that people in CARD had not had cabazitaxel before. Also, the central review of radiographic disease progression imaging was blinded in PROfound, but open-label in CARD. The clinical experts explained that BRCA-mutation status does not affect how well cabazitaxel works. They also noted that previous cabazitaxel is unlikely to affect how well olaparib works because its mode of action is different. The ERG explained that some studies suggested BRCA-mutation status could modify treatment effect, and some suggested it does not. In NICE's technology appraisal guidance on cabazitaxel for hormone-relapsed metastatic prostate cancer treated with docetaxel, the committee considered the TROPIC trial. This compared cabazitaxel plus prednisone with mitoxantrone plus prednisone in hormone-relapsed metastatic prostate cancer that had progressed after docetaxel treatment. In that appraisal, the committee considered that mitoxantrone plus prednisolone was unlikely to have clinical benefits. Therefore, in this appraisal, the committee noted that mitoxantrone was similar to the control arms of PROfound and CARD. In response to consultation, the company explored if it could include TROPIC in its indirect treatment comparison. It argued that the population in TROPIC was not comparable to the population in PROfound. This was because people enrolled in TROPIC had not had treatment with abiraterone or enzalutamide, as in PROfound or CARD. It was also because there were differences in the inclusion and exclusion criteria, and the comparator arms, between TROPIC and PROfound. However, it did present a scenario analysis including TROPIC, which had a small effect on the cost-effectiveness estimates. The ERG agreed that TROPIC should be excluded from the indirect comparison. The committee concluded that there were differences between PROfound and CARD, which led to uncertainty in the company's indirect treatment comparison, and that the population in TROPIC was unlikely to reduce this uncertainty.\n\n## It is inappropriate to adjust for treatment switching in CARD\n\nThe company did not adjust for treatment switching in CARD as it did in PROfound. It explained that this was because it did not have access to individual patient data from CARD. In its first meeting, the committee considered that overall survival in the cabazitaxel arm in CARD may have been underestimated. This was because 33% of people in the abiraterone or enzalutamide arm switched to cabazitaxel after disease progression. The clinical experts explained that treatment switching was included in the trial protocol in PROfound, but not in CARD. The committee appreciated that this may explain why more people switched treatments in PROfound than in CARD but did not remove the risk of bias. In response to consultation, the company explained that cabazitaxel is available in the NHS and that it was inappropriate to adjust for treatment switching because the trial did not deviate from NHS practice. Adjusting would also cause an imbalance in the abiraterone or enzalutamide arms between CARD and PROfound, which would undermine the anchored indirect treatment comparison. The committee recognised that the need to adjust would also depend on whether the proportion of people switching treatment in the trial reflected NHS practice. It concluded that it was inappropriate to adjust for treatment switching in CARD. However, it acknowledged that there was still some uncertainty in the size of the effect estimate comparing olaparib with cabazitaxel.\n\n## Differences between NHS post-progression treatments and those in PROfound and CARD affect generalisability to NHS practice\n\nThe committee discussed treatments offered in PROfound and CARD after disease progression. It noted that these treatments did not reflect NHS practice, and that this would affect both costs of treatment and its outcomes (see section\xa03.19). The company considers that the distribution of post-progression treatments in PROfound is confidential so cannot be reported here. The committee noted that life-extending treatments could have affected the hazard ratios for overall survival seen in PROfound and CARD. If these treatments were offered differently to how they are in the NHS, then the trial results (and costs) would not apply to the NHS. The committee noted that most people in PROfound and CARD had abiraterone or enzalutamide (of those people who had a post-progression treatment after cabazitaxel in CARD, 37% had abiraterone and 37% had enzalutamide). It recalled that these treatments would not offer any clinical benefit and would not be used in NHS practice (see section\xa03.5). Instead, people in the NHS would have access to life-extending treatments such as radium‑223 dichloride. The committee noted that using radium‑223 dichloride after disease progression on olaparib in PROfound was limited (the proportion is considered confidential and cannot be reported here). However, 15% of people in CARD had radium‑223 dichloride after disease progression on cabazitaxel. In response to consultation, the company excluded abiraterone and enzalutamide from post-progression treatments to align with NHS practice. The company stated that it could not adjust for differences in overall survival because it did not have the data. Instead, it did scenario analyses to explore the effect that differences in post-progression treatments may have had by improving or worsening the hazard ratio for overall survival for olaparib compared with cabazitaxel by 5% and 10%. The committee noted the differences in post-progression treatments between the 2\xa0trials and the NHS. It concluded that this further affected the validity of the company's indirect treatment comparison and its generalisability to NHS practice.\n\n## Analyses comparing olaparib with docetaxel and best supportive care for the no prior taxane group are uncertain\n\nThe company believed that a robust indirect treatment comparison for olaparib compared with docetaxel in the no prior taxane group was not feasible. This was because of a lack of evidence for docetaxel in the relevant population. So the company did an exploratory indirect treatment comparison comparing olaparib with docetaxel using results from TAX327, a phase 3 randomised trial for docetaxel plus prednisone. The trial compared docetaxel plus prednisone with mitoxantrone plus prednisone, which the company considered not to be an active comparator. This mitoxantrone plus prednisone control arm was used as the anchor for the indirect treatment comparison, with the assumption that it is equivalent to the PROfound control arm of abiraterone or enzalutamide. The primary endpoint in TAX327 was overall survival. The trial did not report progression-free survival, so the company assumed that the size of relative treatment effect of docetaxel on progression-free survival would be the same as that on overall survival. The committee noted that several assumptions related to the TAX327 trial increased the uncertainty in the analyses. This included the generalisability of the trial, which was done before abiraterone or enzalutamide were available. To estimate the effect of olaparib compared with best supportive care, the company assumed the abiraterone or enzalutamide retreatment arms from PROfound could be used as a proxy for best supportive care. The results of the analyses cannot be reported here because the company considers them confidential. However, they showed that olaparib may increase overall survival compared with docetaxel, and may increase overall and progression-free survival compared with best supportive care. The committee noted the wide confidence intervals in the results for both comparisons, likely driven by the small size of the no prior taxane group in PROfound. The committee noted limitations in the olaparib arm, which included the small sample size of the no prior taxane group, treatment switching in the abiraterone or enzalutamide arm, immature overall survival data and lack of direct data to inform progression-free survival estimates. The committee considered that the results suggested that olaparib was more effective than docetaxel or best supportive care for people who had not had a prior taxane. However, given the issues with the analyses, the committee concluded that these results were uncertain.\n\n# Economic model\n\n## Hazard ratios from the BRCA-mutation prior taxane subgroup of PROfound should be used to model outcomes for cabazitaxel\n\nIn its initial submission, the company used patient-level data from the PROfound BRCA-mutation prior taxane subgroup to model the absolute rates of progression-free survival and overall survival for people having olaparib. It then applied hazard ratios for progression-free survival and overall survival from the indirect treatment comparison to that data to model the efficacy for people having cabazitaxel. However, it used hazard ratios from the licensed population rather than from the prior taxane subgroup. The company explained that it did this because olaparib's efficacy in the licensed population and prior taxane populations were similar, and the former group had larger patient numbers. The committee disagreed with the company's approach of comparing a subgroup with the whole group. The committee would have preferred the company to use hazard ratios from the BRCA-mutation prior taxane subgroup to model comparative effectiveness with cabazitaxel. The committee considered the company's approach to be inconsistent. This was because the company had used data from the BRCA-mutation prior taxane subgroup from PROfound for other model inputs, for example, survival, adverse events and baseline characteristics for olaparib. The committee considered it appropriate to match data used in the model to the population under consideration when possible. In its response to consultation, the company agreed with the committee and used the hazard ratios from the BRCA-mutation prior taxane subgroup to model survival on cabazitaxel in the prior taxane group. The committee concluded that the revised company approach was appropriate.\n\n## The company and ERG's approaches to extrapolating overall survival for both treatments in the prior taxane group appear plausible\n\nPROfound reported results based on a prespecified analysis in June\xa02019 for the primary endpoint of radiological progression-free survival. At the latest data cut-off (March\xa02020) available for overall survival, the trial was still collecting data as planned and, for the prior taxane group there had been 41 events (57%) with olaparib and 27 events (77%) with abiraterone or enzalutamide retreatment. The company used parametric survival curves to fit the trial data and extrapolate it beyond the trial duration because the model used a lifetime horizon. The company initially chose a log-logistic curve to model overall survival but then changed its preference after the first committee meeting. The company had explored more flexible models as requested by the committee but because of poorer statistical fit, the company chose the exponential model, noting it had the best fit. The ERG explained that it had explored other models and had chosen the Rayleigh distribution for treatment with olaparib for its base case, based on the best statistical and visual fit. The committee noted that none of the parametric curves fitted the observed hazard rates for the olaparib arm from the trial well. It noted that the Rayleigh, Weibull and exponential hazard function curves appeared reasonable although possibly pessimistic. The company agreed that these curves were all reasonable and possibly pessimistic but considered the Rayleigh to be the 'worst case' in terms of its predication of overall survival. As a result, the company chose the Weibull distribution. The ERG noted that this was its second preferred option and that there was no statistical or visual difference between this and the Rayleigh model. The ERG noted a considerable decline in the number of patients alive after 24\xa0months and this led to uncertainty in the extrapolation. The committee noted that the cost-effectiveness results were sensitive to the change in distribution in the scenario analyses done by the company and ERG. It agreed that there was little difference in visual and statistical fit between the 2 curves, so deciding which curve was best would involve determining which curve had the most plausible long-term extrapolations. The committee concluded that both extrapolations may be pessimistic, and were equally uncertain and equally plausible. So it took both into account in its decision making.\n\n## Both the company and ERG's approach to extrapolating overall survival for both treatments in the no prior taxane group are plausible\n\nThe company also extrapolated long-term overall survival in the no prior taxane group. The company selected the log-logistic distribution to extrapolate both arms in the comparisons of olaparib with docetaxel and best supportive care (see section\xa03.4). The ERG preferred the Rayleigh distribution to extrapolate both arms in both comparisons. The log-logistic and Rayleigh distributions had very similar extrapolations for the docetaxel arm and the best supportive care arms in the 2 different comparisons. However, there were some differences between the distributions in the olaparib arms in both comparisons. The company stated that, to extrapolate overall survival for olaparib, the log-logistic distribution had the best visual fit to the Kaplan–Meier data, the best statistical match and had been validated by clinical input. The ERG considered that the log-logistic model may overestimate long-term survival in the olaparib group in both comparisons and that the Rayleigh distribution provided more realistic extrapolations. The company considered that both the log-logistic and Rayleigh olaparib extrapolations were consistent with the 24‑month Kaplan–Meier data. But it stated that the Rayleigh was overly pessimistic when extrapolating overall survival in the olaparib arm in both comparisons. The committee noted that the difference between the 2 extrapolations started at around 30\xa0months. It predicted that overall survival after this point was substantially higher when the log-logistic distribution was used to extrapolate olaparib, for both comparisons. The committee concluded that both log-logistic and Rayleigh distributions showed a good visual and statistical fit, and had plausible long-term survival predictions, so it would take both into account in its decision making.\n\n# Treatment costs\n\n## Data on time to stopping treatment should be used to model olaparib treatment duration and costs\n\nIn its initial submission, the company assumed that people have olaparib until their disease progresses. It used time until disease progression in PROfound to model olaparib treatment duration and costs, even though there was data from PROfound on time to stopping treatment. It did this to be consistent with the cabazitaxel trial, which provided data on progression-free survival but not time to stopping treatment. The company explained that estimates of median progression-free survival and median time to stopping treatment from PROfound were similar. The committee noted, however, that people may stop olaparib for reasons other than disease progression, for example, adverse effects or personal choice. The ERG preferred to use the time to stopping treatment data from PROfound. It explained that the curve for time to stopping treatment was above the curve for progression-free survival, so the company may have underestimated olaparib's costs. The ERG considered that using the curve for time to stopping treatment aligned with the relative dose-intensity calculation (see section\xa03.17). The ERG explained that cabazitaxel is administered in hospital every 3\xa0weeks. Therefore, time to stopping treatment and progression-free survival are likely more aligned for cabazitaxel than for olaparib, which is taken as a daily tablet. Also, because cabazitaxel is less expensive than olaparib, the bias of using progression-free survival to estimate its costs would be lower than for olaparib. In its response to the first consultation, the company agreed with the committee's conclusion, notably, that time to stopping treatment better estimates treatment duration and costs of olaparib than progression-free survival.\n\n## Using relative dose intensity from PROfound to estimate the cost of olaparib is acceptable\n\nTo estimate the cost of olaparib in its original submission, the company used the mean relative dose intensity from PROfound. The relative dose intensity is the proportion of the planned dose of a drug a person takes over a given period of time. The ERG explained that the mean relative dose intensity did not account well for how much of a planned dose of a drug people had over time. So, it did not accurately estimate the mean per-patient cost of olaparib during the trial, and was also not suitable for extrapolation. The ERG preferred to use the median relative dose intensity. The company agreed with this approach during technical engagement. However, the committee was concerned with both the company's initial approach and the ERG's approach. It noted that generally the mean is the preferred metric to estimate costs, but agreed with the ERG's concerns. The committee would have preferred that the company had calculated the costs of olaparib for each person based on their individual dose and treatment duration, and used these estimates to inform the mean per-patient cost of olaparib. The ERG clarified that, unless the company provides it with the individual patient data, it cannot calculate or validate these costs. The ERG suggested an alternative approach of presenting the mean monthly relative dose intensity over time for people remaining on treatment, and the number of observations for each time point. This would illustrate how the mean relative dose intensity changes throughout the model time horizon and how it affects the model results. In its response to consultation, the company argued that the costs of olaparib were appropriately reflected in the model because time to stopping treatment was based on individual patient data. It explained that it did not do an additional analysis based on individual dose because the model was not sensitive to relative dose intensity. It suggested that this was shown in its scenario analysis, in which assuming a full dose for the entire duration of treatment (that is, 100% relative dose intensity) had minimal effect on the cost-effectiveness estimates. The ERG questioned whether the cost of olaparib in the model should be based on the number of tablets consumed or the number of packs prescribed, because the NHS pays for whole packs, not individual tablets. It argued that, if the costs were based on the number of packs prescribed, a relative dose intensity of 100% might be the most reasonable estimate. The ERG highlighted that this concern would not apply to cabazitaxel because it is administered as an intravenous therapy in hospital. The Cancer Drugs Fund clinical lead explained that they expect minimal drug wastage with olaparib. This is because clinicians implement dose adjustments quickly when determining the right dose for an individual person. The committee was satisfied that it was appropriate for the company to exclude drug wastage in its model. It would have preferred the company to use individual patient data from PROfound to calculate the per-patient cost of olaparib, but acknowledged this was likely to have had a small effect on the cost-effectiveness results. It concluded that the company's approach is acceptable for decision making.\n\n## The ERG's estimate of the costs of prophylactic granulocyte colony-stimulating factor in the cabazitaxel arm is appropriate\n\nPeople having cabazitaxel may have prophylactic granulocyte colony-stimulating factor (G‑CSF) to prevent neutropenia. The company and the ERG added the costs of G‑CSF to the costs of having cabazitaxel. In its initial submission, the company assumed that all people having cabazitaxel had prophylactic G‑CSF for 14\xa0days. This was to align with CARD, and cabazitaxel's marketing authorisation, which recommends treatment with G‑CSF 'usually for up to 14\xa0days'. The ERG explained that the company's approach overestimated the use of G‑CSF. In its base case, the ERG assumed that a lower proportion of people have G‑CSF, based on the results of the company's survey with clinical experts (the company considered the exact estimate confidential so it cannot be reported here). The ERG also assumed that treatment would typically last for 7\xa0days, based on clinical opinion. The clinical experts and the Cancer Drugs Fund clinical lead explained that people would be unlikely to have G‑CSF for more than 7\xa0days, and considered the ERG's estimate to be reasonable. In its response to consultation, the company agreed with the ERG's approach. The committee concluded that the ERG's estimate of the costs of prophylactic G‑CSF in the cabazitaxel arm was appropriate. It also acknowledged that the company had followed this approach in its revised cost-effectiveness modelling.\n\n## The company's and ERG's estimates of post-progression treatment costs do not reflect NHS practice but are acceptable\n\nBoth the company and the ERG incorporated the costs of treatments after disease progression on olaparib and cabazitaxel. The company explained that its model allowed people to have only 1\xa0active treatment after disease progression. The ERG noted that people in PROfound had more than 1\xa0active treatment on average after disease progression. The clinical experts confirmed that people can have multiple treatments after disease progression in NHS practice. After technical engagement, both the company and the ERG assumed that the same proportion of people whose disease progressed on olaparib or cabazitaxel would have an active treatment. The company considers the exact proportions of people having each treatment after disease progression on olaparib to be confidential so they cannot be reported here. People who do not have active treatment would have best supportive care after progression. The company assumed that the treatments offered would differ depending on whether the disease progressed on olaparib or cabazitaxel, and that disease could be retreated with abiraterone or enzalutamide. The ERG acknowledged that, in the NHS, people are likely to have different treatments after progression, depending on their first treatment. However, it noted that there was no reliable data to inform this. It reminded the committee that PROfound and CARD had important differences (see section\xa03.9) and that using the trials' proportions of post-progression treatments does not reflect NHS practice. The committee again noted that retreatment with abiraterone or enzalutamide would not happen in NHS practice, which was confirmed by the clinical experts. They considered that the company's estimate for the number of people having radium‑223 dichloride in the olaparib arm was too low. They also considered that the ERG's estimate that 55% of people in both arms would have radium‑223 dichloride was too high. In its response to consultation, the company excluded abiraterone and enzalutamide from post-progression treatments. However, it continued to assume people would have different treatment after progression depending on whether they initially had olaparib or cabazitaxel. The company explained that this was because the proportions of post-progression treatments used in the model were based on the clinical trial data from PROfound and CARD. It claimed that the data reflects that people who take olaparib can then have chemotherapy as a subsequent therapy before radium‑223 dichloride. It also claimed that the data reflects that people whose disease progresses on cabazitaxel may have exhausted their treatment options apart from radium‑223 dichloride. So, a higher proportion of people having radium‑223 dichloride than seen in the model is likely. The company highlighted that, after it excluded abiraterone and enzalutamide from its model, the proportion of other subsequent treatments in the model increased. The company provided 2\xa0scenario analyses to explore the effect of the cost of post-progression treatment, in which it excluded:\n\nretreatment with cabazitaxel from post-progression treatment options\n\nall costs related to post-progression treatments.Both had a minimal effect on the cost-effectiveness estimates. The committee agreed that both the company's and ERG's estimates of post-progression treatment costs did not reflect NHS practice. However, it acknowledged that adequate adjustment for these differences may not be possible, and that it was likely to have a minimal effect on the cost-effectiveness results. Therefore, it concluded that both approaches were not ideal, but were acceptable for decision making.\n\n## The ERG's approach to costing best supportive care is appropriate\n\nIn its initial submission, the company assumed that the costs of best supportive care differed for people who:\n\nhad had and stopped an active treatment after their disease had progressed on either olaparib or cabazitaxel\n\ndid not have an active treatment after progression, that is, had best supportive care directly after olaparib or cabazitaxel.The company explained that this avoided double counting the costs of best supportive care. It also explained that the model structure did not allow estimation of the costs of best supportive care after active treatment. The ERG disagreed with the company's approach and instead assumed the same best supportive care costs were incurred regardless of whether a person had an active treatment after disease progression. The clinical and patient experts explained that everyone would start having palliative care after active treatments had stopped, and that this would be the same for everyone. In its response to consultation, the company agreed with the ERG's approach, and followed it in its revised cost-effectiveness modelling. The committee accepted this approach to costing best supportive care.\n\n## The costs of testing for BRCA mutations should be included in the cost-effectiveness estimates\n\nBefore starting treatment with olaparib, people must have a BRCA mutation confirmed using a validated test. Section 5 in the NICE guide to the methods of technology appraisal states that 'if a diagnostic test to establish the presence or absence of this biomarker is carried out solely to support the treatment decision for the specific technology, the associated costs of the diagnostic test should be incorporated into the assessments of clinical and cost effectiveness'. The company excluded the costs of testing for BRCA mutations in its initial base case. It explained that this was because the NHS Genomic Test Directory includes this test, so it is likely part of standard NHS practice. The company included the costs of testing in a scenario analysis, using costs from the testing service for ovarian cancer that the company currently funds (the cost per test is confidential and cannot be reported here). The ERG included the testing costs in its base case because its clinical advice suggested the NHS does not currently test for BRCA mutations routinely. One clinical expert noted that they do not routinely test for BRCA mutations unless there is a family history. Another clinical expert explained that they do genomic testing for all people with hormone-relapsed metastatic prostate cancer, and that many oncologists want routine testing in the NHS. The Cancer Drugs Fund clinical lead explained that the NHS Genomic Test Directory includes testing for BRCA mutations. However, he said that testing is not standard NHS care, and the cost of olaparib to the NHS should include testing costs. The ERG explained that it calculated the cost to identify 1\xa0person with BRCA mutations by applying the company's cost per test to the expected prevalence of BRCA mutations in people with hormone-relapsed metastatic prostate cancer. It based this on the prevalence of BRCA mutations in people who entered screening for PROfound (the company considers the value to be confidential and so it cannot be reported here). The clinical experts advised that the prevalence of BRCA mutations in people with hormone-relapsed metastatic prostate cancer in clinical practice is about 10%. In its response to consultation, the company agreed with the ERG's approach and included the cost of testing for BRCA mutations in its revised base case. The committee acknowledged that the revised company approach was appropriate.\n\n# Utility values\n\n## The company's utility values based on PROfound are appropriate\n\nThe company and the ERG used utility values from PROfound for the progression-free and post-progression health states. The utility values are considered confidential by the company so cannot be reported here. The company mapped EQ‑5D‑5L values from PROfound to generate EQ‑5D‑3L values. The company modelled worse quality of life with cabazitaxel and prednisone than with olaparib. Cabazitaxel treatment was associated with an additional decrement of -0.023 (Matza et al. 2013) because it is administered intravenously. Once people stopped having cabazitaxel, their utility reverted to the same as that of olaparib. The company sourced mean utility decrements associated with adverse events and the mean duration of adverse events from NICE's technology appraisal guidance on cabazitaxel for hormone-relapsed metastatic prostate cancer treated with docetaxel and the literature. The committee concluded that the company's utility values were appropriate.\n\n# Exploratory analyses\n\n## Exploratory analyses for people who have not had a taxane are highly uncertain\n\nThe company did exploratory cost-effectiveness analyses for people who had not had a taxane. The committee recalled its remit to look at a technology across the indication in its marketing authorisation. However, it appreciated that no single comparator would be relevant for people who had and who had not had treatment with docetaxel. It also recalled its concerns that people in PROfound who had not had treatment with a taxane were unlikely to represent people who cannot or should not have docetaxel in clinical practice. To compare olaparib with best supportive care, the company used the abiraterone or enzalutamide arm from PROfound as a proxy. At the second committee meeting, the committee noted that the company's exploratory analyses for the no prior taxane group did not mirror the committee's preferred assumptions for the prior taxane group, for example:\n\nassuming that the same proportion of people whose disease progressed on olaparib or cabazitaxel would have an active treatment (see section 3.19)\n\nadjusting for differences in post-progression treatments between PROfound and NHS practice. In response to the second consultation, the company updated its no prior taxane model to be consistent with the prior taxane model. The committee recalled that, while there may be a benefit for olaparib in overall and progression-free survival, there was substantial uncertainty in the effect estimates from the indirect treatment comparison for the no prior taxane subgroup (see section\xa03.12). It concluded that the company's exploratory analyses for people who have not had a taxane were uncertain and it would take this into account in its decision making.\n\n# End of life\n\n## Olaparib likely meets NICE's criteria for a life-extending treatment at the end of life for people who have and have not had a taxane\n\nThe committee considered the criteria for 'life-extending treatments at the end of life' outlined in Section 6 of NICE's guide to the methods of technology appraisal, that is:\n\na treatment must be indicated for people with a short life expectancy, normally less than 24\xa0months and\n\nthere must be sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.Also, the appraisal committees will need to be satisfied that:\n\nthe estimates of the extension to life are sufficiently robust and can be shown or reasonably inferred from either progression-free survival or overall survival (taking account of trials in which crossover has occurred and been accounted for in the effectiveness review) and\n\nthe assumptions used in the reference case economic modelling are plausible, objective and robust.The ERG explained that, for the prior taxane group, overall survival with cabazitaxel was less than an average of 24\xa0months when using both the Weibull curve (company updated base case) and Rayleigh curve (ERG's base case) to extrapolate overall survival in the model. The company also presented results from other trials in hormone-relapsed metastatic prostate cancer, COU‑AA‑301 and AFFIRM, in which median overall survival ranged from 16\xa0to 18\xa0months with enzalutamide or abiraterone treatment. The committee noted that, for the no prior taxane group, overall survival with cabazitaxel was also less than an average of 24\xa0months when using both the log-logistic curve (company base case) and Rayleigh curve (ERG's base case) to extrapolate overall survival. The committee was satisfied that olaparib met the end of life criteria for both the prior taxane and no prior taxane groups. The committee acknowledged that both the company and ERG's preferred parametric extrapolations of overall survival predicted at least a 3‑month survival benefit with olaparib compared with cabazitaxel in both the prior taxane and no prior taxane groups. The committee also noted that new hormonal agents are now available much earlier in the treatment pathway (see section\xa03.1). This would mean that olaparib, which is indicated for treatment if disease has progressed after a new hormonal agent, could also be offered earlier. This could mean a longer life expectancy than modelled by the company. However, according to the data currently presented, it was likely that the end of life criteria were met. The committee concluded that olaparib likely meets NICE's end of life criteria for people who have and have not had a taxane.\n\n# Cost-effectiveness estimates\n\n## Olaparib is a cost-effective treatment option for people who have had a taxane at the price chosen by the company\n\nBecause of confidential commercial arrangements for olaparib, cabazitaxel and other post-progression therapies, the cost-effectiveness estimates cannot be reported here. The committee noted that the company addressed a number of its preferences from its first and second committee meetings, including by:\n\nusing the hazard ratios from the BRCA-mutation prior taxane subgroup of PROfound to model the efficacy of cabazitaxel in the prior taxane group (see section\xa03.13)\n\nusing the time to stopping treatment data to model olaparib treatment duration and costs (see section\xa03.16)\n\nassuming only a proportion of people having cabazitaxel have prophylactic G‑CSF, and have it for an average of 7\xa0days (see section\xa03.18)\n\nassuming treatments available to people after progression on olaparib or cabazitaxel do not include retreatment with abiraterone or enzalutamide (see section\xa03.19)\n\nassuming the cost of best supportive care is the same regardless of whether people had active treatment after progression (see section\xa03.20)\n\nincluding the cost of testing for BRCA mutations (see section\xa03.21)\n\naddressing other minor differences between the company's and the ERG's models, such as assumptions related to bone and CT scans while on treatment, and costs of ADT.The committee also acknowledged that the company explored some of its preferences from its first meeting in scenario analyses, and that they had a minor impact on cost-effectiveness estimates. Namely, the company explored:\n\nwhether TROPIC could be included in the indirect treatment comparison (see section\xa03.9)\n\nuncertainty around the effect of post-progression treatments on post-progression survival (see section\xa03.19)\n\nmore flexible approaches for extrapolating survival (see section\xa03.14)\n\nuncertainty around dosing of olaparib (see section\xa03.17)\n\nuncertainty around the cost of post-progression treatments in the NHS (see section\xa03.19).NICE's guide to the methods of technology appraisal\xa0notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted that the end of life criteria were met for olaparib, which means that a maximum acceptable ICER of £50,000 per quality-adjusted life year (QALY) gained applies. However, given that there was significant uncertainty around the network meta-analyses informing the clinical-effectiveness estimates for this appraisal, the committee considered the maximum acceptable ICER would be below this, and it agreed that the probabilistic ICER would better capture the uncertainty associated with the analyses. Applying confidential discounts for cabazitaxel, radium‑223 dichloride, filgrastim and leuprorelin (which are subsequent treatments), and considering its preferences, the committee noted the cost-effectiveness estimates using its preferred assumptions for olaparib compared with cabazitaxel were within the range that NICE normally considers an acceptable use of NHS resources for people who have had treatment with a taxane. This was the case when considering both Weibull and Rayleigh curves for extrapolating overall survival, and the higher threshold for end of life criteria. So, the committee could recommend olaparib for use in the NHS for treating hormone-relapsed metastatic prostate cancer with BRCA1 or BRCA2 mutations that has progressed after abiraterone or enzalutamide in adults who have had treatment with a taxane.\n\n## The cost-effectiveness estimates for people who have not had a taxane are uncertain but suggest olaparib is cost effective\n\nThe committee recalled high uncertainty in the results from the company's cost-effectiveness modelling for the group of people who have not had treatment with a taxane (see section 3.23). It noted that it had seen no modelling specifically for the group of people who cannot or should not have a taxane in NHS practice. As with the 'prior taxane' group, because of the uncertainties with the evidence, the committee agreed that the maximum acceptable ICER should be below the end of life threshold. The committee agreed that the probabilistic incremental cost-effectiveness ratio (ICER) would better capture the uncertainty associated with the analyses. Because of confidential discounts for cabazitaxel, radium‑223 dichloride, filgrastim and leuprorelin, the cost-effectiveness results cannot be reported here. Most of the probabilistic ICERs were within the range NICE normally considers an acceptable use of NHS resources when considering the higher threshold for meeting end of life criteria. So the committee could recommend olaparib for use in the NHS for people who have not had a taxane, whether they cannot, should not, or choose not to have it.\n\n# Other considerations\n\n## There are some equalities considerations\n\nThe committee recalled its recent appraisal of abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer (see NICE's technology appraisal guidance on abiraterone). It noted that, in this appraisal, the company initially limited its submission to people who have already had a taxane, which would be docetaxel in the NHS. It agreed that people who cannot or should not have docetaxel are likely to be older than those who can have docetaxel. The committee also noted that some people with prostate cancer may not identify as men. Age, sex, and gender reassignment are protected characteristics under the Equality Act 2010.\n\n## Olaparib is not innovative because it does not offer benefits not already included in the modelling\n\nThe company considered olaparib to be inherently innovative because it was the first drug for metastatic hormone-relapsed prostate cancer with a specific biomarker. It also stated that the need to test for the BRCA mutation before using olaparib may encourage earlier diagnosis and lead to cost savings in the NHS. The company also stated that there would be wider benefits of earlier identification of BRCA mutations particularly if the mutation is heritable. However, the committee heard that, in the NHS the BRCA mutation testing that would be used would consist of testing the tumour. So, many of the mutations detected would be somatic mutations (mutations in the tumour cells) and not heritable germline mutations (mutations in the normal cells of the body). The Cancer Drugs Fund clinical lead explained that, if recommended, olaparib would change the treatment pathway and may help to promote BRCA mutation testing in prostate cancer in the NHS. The committee acknowledged these potential advantages. It also noted that corticosteroids given with cabazitaxel have associated adverse effects and that this could possibly be delayed. However, the committee noted that the company had modelled a relative increase in utility for treatment with olaparib compared with cabazitaxel, so it considered that these benefits had been adequately captured in the economic modelling. The committee understood that to consider a technology innovative, a substantial change in management of a condition and benefits not adequately captured in the economic analysis were both needed. It concluded the modelling had captured all the relevant benefits of olaparib."}	https://www.nice.org.uk/guidance/ta887	Evidence-based recommendations on olaparib (Lynparza) for previously treated BRCA mutation-positive hormone-relapsed metastatic prostate cancer in adults.
78b1eed424585f4b6f16e847c71381c504892b3b	nice	Tafasitamab with lenalidomide for treating relapsed or refractory diffuse large B-cell lymphoma	Tafasitamab with lenalidomide for treating relapsed or refractory diffuse large B-cell lymphoma Evidence-based recommendations on tafasitamab (Minjuvi) with lenolidomide for relapsed or refractory diffuse large B-cell lymphoma in adults who cannot have an autologous stem cell transplant. # Recommendations Tafasitamab with lenalidomide is not recommended, within its marketing authorisation, for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have an autologous stem cell transplant. This recommendation is not intended to affect treatment with tafasitamab with lenalidomide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations People with relapsed or refractory diffuse large B‑cell lymphoma who cannot have an autologous stem cell transplant usually have polatuzumab vedotin plus rituximab and bendamustine. The clinical evidence is from a small study that did not directly compare tafasitamab plus lenalidomide with any other treatment. The committee considered that the study results were promising because they show that some people's disease responds to tafasitamab plus lenalidomide. Indirect evidence suggests that people who have tafasitamab plus lenalidomide have more time before their disease gets worse than people who have polatuzumab vedotin plus rituximab and bendamustine. It also suggests that they live longer. But there is uncertainty about these results because the survival times for people having polatuzumab vedotin plus rituximab and bendamustine used in the modelling do not reflect the real-world survival times of the treatment in clinical practice, compared with bendamustine and rituximab alone. The methods used for the indirect comparisons are also not clear. Tafasitamab plus lenalidomide meets NICE's criteria to be considered a life-extending treatment at the end of life. This is because people on standard treatment (polatuzumab vedotin plus rituximab and bendamustine) for relapsed or refractory diffuse large B‑cell lymphoma are likely to live on average less than 2 years. But all the cost-effectiveness estimates for tafasitamab plus lenalidomide are above the range that NICE normally considers to be an acceptable use of NHS resources for end of life treatments. Therefore, it cannot be recommended for routine use in the NHS. Because the cost-effectiveness estimates are high and uncertain, and further evidence is unlikely to resolve this uncertainty, it also cannot be recommended for use in the Cancer Drugs Fund.# Information about tafasitamab with lenalidomide # Marketing authorisation indication Tafasitamab (Minjuvi, Incyte) is indicated, in combination with lenalidomide followed by tafasitamab monotherapy, for 'the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma who are not eligible for autologous stem cell transplant'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for tafasitamab. # Price Tafasitamab costs £705 per 200‑mg vial of powder for concentrate for solution for infusion (excluding VAT; company submission). Tafasitamab costs £120,639 for 12 months of treatment in year 1 and £95,049 for year 2 onwards. The list price of lenalidomide per 21‑capsule pack varies according to capsule size: £3,426.00 (2.5 mg), £3,570.00 (5 mg), £3,675.00 (7.5 mg), £3,780.00 (10 mg), £3,969.00 (15 mg), £4,168.50 (20 mg) and £4,368.00 (25 mg; all prices excluding VAT; BNF online accessed February 2023). The company has a commercial arrangement for tafasitamab, which would have applied if the technology had been recommended. There is a nationally available discount for lenalidomide with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.# Committee discussion The appraisal committee considered evidence submitted by Incyte, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need ## People with diffuse large B‑cell lymphoma would welcome a new treatment option that is more tolerable and improves outcomes Diffuse large B‑cell lymphoma is an aggressive disease. Symptoms usually develop rapidly and progress quickly. The disease is treated with the aim of cure, but 10% to 15% of people have primary refractory disease and a further 20% to 30% relapse. A submission from a patient expert explained that the prognosis for people with relapsed or refractory disease is extremely poor. Treatments are very intensive, needing long stays in hospital and potentially involving serious side effects even after treatment has ended. Any treatment delivered in an outpatient setting (that is, that did not require a stay in hospital) would have a significant, positive effect on the quality of life of people with the condition and their families. The psychological, social and economic impact of the disease for both the person and their carers is considerable. The clinical experts explained that relapsed or refractory disease is treated using salvage chemotherapy followed by an autologous stem cell transplant if the person can have intensive therapy. Clinical experts explained that about 10% to 20% of people with relapsed or refractory disease who can have intensive therapy are cured of the disease after an autologous stem cell transplant. People who cannot have a transplant, or whose disease relapses after a transplant, are usually offered polatuzumab vedotin with bendamustine and rituximab or other rituximab-based chemotherapy regimens. The committee concluded that relapsed or refractory diffuse large B‑cell lymphoma is a devastating condition with a poor prognosis, and that people with the condition have a high unmet need for effective treatments with manageable side effects. # Clinical management ## Polatuzumab vedotin with bendamustine and rituximab is standard care for people who cannot have an autologous stem cell transplant Tafasitamab has a marketing authorisation in combination with lenalidomide for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have an autologous stem cell transplant. The comparators in the NICE scope were: chemotherapy with or without rituximab pixantrone polatuzumab vedotin with bendamustine and rituximab best supportive care.The company submission only included the following as comparator treatments: rituximab with gemcitabine and oxaliplatin polatuzumab vedotin with bendamustine and rituximab bendamustine with rituximab.The reduced number of comparators was based on clinical expert interviews done by the company that suggested that these 3 regimens were the main treatments used in the NHS. The company also justified the choice of comparators by saying that there was limited data for the other comparators. In addition, it pointed out that bendamustine with rituximab was considered a reasonable proxy for standard care in NICE's technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine for treating relapsed or refractory diffuse large B-cell lymphoma. The clinical experts said that some of the low-intensity chemotherapy regimens (with or without rituximab) are rarely used. Polatuzumab vedotin with bendamustine and rituximab has largely replaced other options and is now standard care for people with relapsed or refractory disease who cannot have an autologous stem cell transplant. The committee concluded that the company's choice of comparators was appropriate, and that polatuzumab vedotin with bendamustine and rituximab was the main comparator. # Clinical evidence ## The lack of a direct comparison with any treatment makes the clinical data difficult to interpret The clinical evidence for tafasitamab with lenalidomide came from the phase 2 L‑MIND study. This is an ongoing multicentre, single-arm, open-label study of tafasitamab with lenalidomide in people with relapsed or refractory diffuse large B‑cell lymphoma who could not have an autologous stem cell transplant. Because the study is open label, people in the trial and their healthcare professionals are aware of treatment allocation. The committee highlighted that the study is small, with 81 people recruited, 5 of whom are from the UK. At the October 2020 data cut, median duration of exposure to tafasitamab with lenalidomide was 9.2 months. The primary endpoint of objective response rate (partial and complete response) was 58%. Median overall survival was 33.5 months, and median progression-free survival was 11.6 months. The ERG highlighted several important differences in the baseline characteristics of people in L‑MIND compared with Northend et al. (2022), a retrospective analysis of real-world data from the UK. For example, the proportion of men in Northend et al. was 69% compared with 54% in L‑MIND. Differences were also identified for the presence of bulky disease, International Prognostic Index scores, number of lines of previous therapy, and refractoriness to previous treatment. The committee considered that the study results were promising. However, it concluded that the lack of a direct comparison with any treatment makes the data difficult to interpret. ## The results of the indirect treatment comparisons are very uncertain Because L‑MIND is a single-arm study, indirect treatment comparisons were needed to establish the relative efficacy of tafasitamab plus lenalidomide compared with other treatments. The company used 2 indirect treatment comparison approaches: propensity score matching against RE‑MIND2 and matching-adjusted indirect comparisons against published studies. RE‑MIND2 was an observational, retrospective cohort study of 3,454 adults with relapsed or refractory diffuse large B‑cell lymphoma, including 115 people from the UK. The company used nearest neighbour propensity score matching to balance the cohorts for comparator treatments with L‑MIND based on 9 baseline covariates. In the matching-adjusted indirect comparisons the company adjusted the L‑MIND population using propensity score weighting to be comparable to the populations in 4 published trials of comparator treatments, which were selected using a systematic literature review and expert input. The company used RE‑MIND2 for rituximab with gemcitabine and oxaliplatin and the matching-adjusted indirect comparisons for polatuzumab vedotin with bendamustine and rituximab as well as bendamustine and rituximab. The company chose indirect evidence sources based on alignment to published outcomes. This resulted in RE‑MIND2 not being selected for polatuzumab vedotin with bendamustine and rituximab. All the indirect comparisons suggested that tafasitamab with lenalidomide improved progression-free and overall survival compared with the comparators, but this was not always statistically significant. The ERG highlighted that RE‑MIND2 consists of pooled individual participant data and is preferred in principle to the intervention population adjustment done in the matching-adjusted indirect comparisons. Adjusting the L‑MIND population differently for each comparator treatment population may have led to bias. However, there was uncertainty about the methods used for RE‑MIND2 because the baseline characteristics of the tafasitamab with lenalidomide cohort varied depending on the comparator. The ERG suggested that it was unclear what type of treatment effect is estimated in RE‑MIND2. The committee concluded that, because of the complexity in the methods used for the indirect treatment comparisons, and the potential biases, the results of the indirect comparisons were very uncertain. # The company's economic model ## The company's economic model structure is appropriate for decision making The company presented a 3‑state partitioned survival model to estimate the cost effectiveness of tafasitamab plus lenalidomide compared with rituximab plus gemcitabine and oxaliplatin, polatuzumab vedotin plus bendamustine and rituximab, and bendamustine plus rituximab. The committee agreed that the company's model structure was appropriate for decision making. ## The overall and progression-free survival extrapolations for polatuzumab vedotin with bendamustine and rituximab are highly uncertain The ERG questioned the validity of the company's overall and progression-free survival parametric extrapolations for polatuzumab vedotin with bendamustine and rituximab. The company calculated separate hazard ratios for up to month 4 and after month 4 for both survival outcomes from the matching-adjusted indirect treatment comparison. It applied these hazard ratios to the survival distributions for tafasitamab with lenalidomide to calculate the survival distributions for polatuzumab vedotin with bendamustine and rituximab. The company justified this piecewise approach to estimating hazard ratios by saying that the alternative, a constant hazard ratio, was not possible because the proportional hazards test failed. However, the ERG was concerned that the resulting overall survival extrapolation underestimated survival for polatuzumab vedotin with bendamustine and rituximab compared with NICE's technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. The previous NICE appraisal estimated around 3.1 mean life years and 2.1 quality-adjusted life years (QALYs). In contrast, the company's extrapolation estimated 2.2 mean life years and 1.5 QALYs. On this basis, the ERG preferred to apply a constant hazard ratio from the matching-adjusted indirect comparison, leading to 3.4 mean life years and 2.2 QALYs for polatuzumab vedotin with bendamustine and rituximab. The clinical experts considered that the company's estimates were reasonable because they were closer to the published literature estimates of median overall survival for polatuzumab vedotin with bendamustine and rituximab (between 8.2 and 12.5 months) than the ERG's. The company justified its methodology by saying that it was verified by clinical experts, produced the results most aligned with real-world evidence, and avoided unnecessary complexity. However, the committee noted that tests for proportional hazards did not support a constant hazard. So, it considered that it was not appropriate to apply constant hazard ratios to the L‑MIND data, even using the piecewise approach. It also identified that better approaches were needed to handle the time-varying nature of the observed hazard ratio. The committee agreed that the company should have looked at more ways to include the data from Sehn et al. (2022) in the indirect comparisons. For example, the polatuzumab vedotin with bendamustine and rituximab hazard ratio from Sehn et al. could be applied to the survival outcomes for the propensity score-matched bendamustine and rituximab population. Or, independent survival models could be fitted to the Sehn et al. Kaplan–Meier curves, adding a third arm for tafasitamab with lenalidomide against bendamustine and rituximab from the matching-adjusted indirect comparison; this would have created a partially anchored indirect comparison. The committee was disappointed that the company did not provide such additional analyses in response to the appraisal consultation document. In addition to the ERG's arguments about the company's modelling not reflecting the absolute benefits of polatuzumab vedotin with bendamustine and rituximab, the committee considered that the modelling poorly reflected the relative benefit compared with bendamustine and rituximab alone. For example, Sehn et al. reported a hazard ratio for overall survival of 0.42 for polatuzumab vedotin plus bendamustine and rituximab compared with bendamustine and rituximab alone. The clinical experts also confirmed that polatuzumab vedotin plus bendamustine and rituximab improves survival compared with bendamustine and rituximab alone. However, this is not fully reflected in the company's modelling, with only a small difference in survival estimated. The committee concluded that the company's parametric extrapolations for polatuzumab vedotin with bendamustine and rituximab were implausible. However, the committee also took into account feedback from clinical experts on outcomes observed in clinical practice submitted in response to the appraisal consultation document. These suggested that the estimates from the ERG's base case may be overestimated, despite alignment with NICE's technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. The committee concluded that it would have preferred to see different modelling approaches that both fitted the underlying hazards of the data and produced outcomes more closely reflecting the absolute and relative benefits of polatuzumab vedotin with bendamustine and rituximab compared with bendamustine and rituximab alone, as seen in NICE's guidance on polatuzumab vedotin with rituximab and bendamustine. ## Overall and progression-free survival parametric extrapolations for tafasitamab with lenalidomide are appropriate, despite the uncertainty The company and ERG agreed that the log-normal parametric extrapolation of L‑MIND overall survival data for tafasitamab with lenalidomide was the most appropriate approach. Initially, the company chose a generalised gamma distribution fitted to the data from L‑MIND to model progression-free survival for tafasitamab with lenalidomide, and the ERG preferred a log-normal distribution. However, the ERG noted the resulting hazard profile was inconsistent with the predictions of the clinical experts consulted by the company and overestimated progression-free survival in the long term. The committee noted that there was uncertainty in the modelled progression-free survival extrapolations for tafasitamab with lenalidomide because of heavy patient censoring towards the end of the L‑MIND Kaplan–Meier curve. However, it agreed it was appropriate to consider the log-normal distribution chosen by the ERG. In response to the appraisal consultation document, the company updated its base-case model using the committee's preferred assumption of the log-normal parametric extrapolation of L‑MIND progression-free survival data for tafasitamab with lenalidomide. The committee concluded that the company's approach to modelling tafasitamab with lenalidomide survival was appropriate in its updated base case, while noting the inherent uncertainty. # End of life (before the appeal) ## Tafasitamab with lenalidomide does not meet the end of life criteria The committee considered the criteria for life-extending treatments for people with a short life expectancy in section 6.2.10 of NICE's guide to the methods of technology appraisal 2013. These are: the treatment is indicated for people with a short life expectancy, normally less than 24 months and there is sufficient evidence to indicate that the treatment has the prospect of offering an extension to life, normally of a mean value of at least an additional 3 months, compared with current NHS treatment.In considering these criteria the committee was also aware, from the methods guide, that it should be satisfied that 'the assumptions used in the reference case economic modelling are plausible, objective and robust'.The committee was also aware of the appeal panel conclusions about the short life expectancy criteria as part of NICE's technology appraisal guidance on avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy, particularly section 87 of the appeal decision (see the final appraisal determination 2 committee papers). This states, based on the evidence in that particular appraisal: 'The appeal panel felt that the key stakeholders of NICE would consider it unreasonable to state that life expectancy was not "normally less than 24 months", even if the mean life expectancy was greater than 24 months, if 65% of patients, the significant majority, in the modelled cohort had died prior to 24 months.'The committee carefully reviewed these points and considered the following: There is limited clinical trial data for tafasitamab with lenalidomide. The only source of trial evidence for this appraisal was a single-arm phase 2 study of 80 people (L‑MIND). The relatively small size of this study, short median follow up (13.2 months) and lack of data comparing it with usual NHS treatments makes it difficult to assess the comparative clinical effectiveness of tafasitamab with lenalidomide. This introduces considerable uncertainty in the modelling. The real-world experience in the NHS with polatuzumab vedotin with bendamustine and rituximab. In response to the appraisal consultation document, the clinical experts explained that less favourable survival outcomes have been seen in clinical practice than the estimates in NICE's technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. The recent Northend et al. (2022) study reported on real-world data from the UK including 133 people (78 having standalone treatment rather than bridging to chimeric antigen receptor T‑cell therapy). Clinical experts explained that their experience was more consistent with the estimates from Northend et al. (median survival 10.2 months) and Sehn et al. (2022; median survival 12.4 months) than the estimates from NICE's guidance on polatuzumab vedotin (mean undiscounted survival of over 48 months). Based in part on this evidence, the company and clinical experts considered that end of life criterion 1 was met. The company also suggested that the Sehn et al. survival estimates may be biased by including people who had polatuzumab vedotin with bendamustine and rituximab and then also had chimeric antigen receptor T‑cell therapy. The ERG acknowledged this but explained that it did not expect it to have a big impact on the results because it only affected a few people in the study. There are different survival estimates for polatuzumab vedotin with bendamustine and rituximab. The committee considered survival estimates for polatuzumab vedotin with bendamustine and rituximab from the original Sehn et al. (2019) study and the Sehn et al. (2022) follow-up study. The ERG highlighted that the results of the follow-up study analyses differed substantially from those accepted by the committee for NICE's technology appraisal guidance on polatuzumab vedotin. That appraisal estimated survival with polatuzumab vedotin with bendamustine and rituximab of over 4 years (undiscounted). The committee noted that this figure was also more consistent with the mean undiscounted life years estimates from both the company's (29 months) and the ERG's (48 months) modelling for this appraisal (both estimates longer than 24 months). The summary of modelled and literature-based survival outcomes. The committee considered the following survival outcomes: Median overall survival estimates from Northend et al. (2022; 10.2 months) and Sehn et al. (2022; 12.4 months). Mean overall survival estimates from the company's base-case model for polatuzumab vedotin (29 months undiscounted), the ERG's base case model (48 months undiscounted) and NICE's technology appraisal guidance on polatuzumab vedotin (over 48 months undiscounted). Estimates of the percentage of people alive at 24 months from the company's base-case model (34%), the ERG's base-case model (44%) and Sehn et al. (2022; 38%). The increase in mean undiscounted overall survival with tafasitamab from the company's base-case and ERG's base-case models (29 and 48 months respectively, difference of 19 months).The committee carefully considered the totality of the data and analysis and concluded the following: End of life criterion 2 was met. The indirect comparisons and modelling were uncertain. But it was reasonable to conclude that tafasitamab with lenalidomide is expected to extend life by at least 3 months compared with current NHS treatment. End of life criterion 1 was not met. The committee was concerned by how different the survival estimates for polatuzumab vedotin with rituximab and bendamustine were from the literature and from NICE's technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. It was aware that survival estimates measured using means and medians often give different values. But the appeal panel for NICE's guidance on avelumab agreed that all the evidence should be considered in making the decision. The committee acknowledged that the estimates from the guidance on polatuzumab vedotin may be too optimistic. But it did not consider that they were so overestimated that it was likely that people who have polatuzumab vedotin with rituximab and bendamustine in the NHS have a life expectancy of less than 24 months.The committee therefore concluded that tafasitamab with lenalidomide did not meet the end of life criteria. # Cost-effectiveness estimates (before the appeal) ## Tafasitamab with lenalidomide is not cost effective The committee considered that the most plausible incremental cost-effectiveness ratio (ICER) in the updated company base case was highly uncertain, because of issues with the indirect comparisons and modelling (see sections 3.4, 3.6 and 3.7). It noted that the company's and ERG's base-case probabilistic ICERs (including all the confidential discounts) for tafasitamab plus lenalidomide compared with polatuzumab vedotin plus bendamustine and rituximab were higher than the range normally considered a cost-effective use of NHS resources, even for end of life treatments. The exact results cannot be reported here because they include confidential discounts for other treatments. The committee considered that the company's base-case ICERs were not plausible, because the model survival outputs were not consistent with NICE's technology appraisal guidance on polatuzumab vedotin. It acknowledged that, although the ERG's base case was more closely aligned with these survival outputs, they may overestimate survival for polatuzumab vedotin with bendamustine and rituximab (see section 3.6). The committee concluded that the most plausible ICER was likely to be between the company's and ERG's base-case estimates. It noted that the ERG's base-case ICER was considerably higher than the company's and considerably higher than the level usually considered cost effective. The committee recognised the need for effective treatments in relapsed or refractory diffuse large B‑cell lymphoma. However, tafasitamab with lenalidomide had not been shown to be a cost-effective use of NHS resources in any analyses presented. So it concluded that tafasitamab with lenalidomide could not be recommended for routine use in the NHS. # Cancer Drugs Fund (before the appeal) ## The Cancer Drugs Fund inclusion criteria are not met Having concluded that tafasitamab with lenalidomide could not be recommended for routine use, the committee considered if it could be recommended for use within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee recognised that people with relapsed or refractory diffuse large B‑cell lymphoma have a high unmet clinical need, and that the availability of new treatments is very important. The company said that further data cuts for the L‑MIND clinical study are planned for 2022, which will provide further evidence on survival and response outcomes. However, the committee was concerned because the single-arm phase 2 study will not provide additional comparative evidence. The model would still rely on indirect evidence for comparator treatments, so this would not resolve a key uncertainty. In addition, the committee was not presented with any analysis showing that tafasitamab with lenalidomide has the plausible potential to be cost effective at the proposed price. Therefore, it concluded that tafasitamab with lenalidomide did not meet the criteria for inclusion in the Cancer Drugs Fund. # After the appeal Appeals against the first final appraisal document were submitted and considered by an independent appeal panel. The panel convened for an oral hearing in November 2022 and upheld 1 appeal point, referring the appraisal back to committee for further consideration. ## The committee has considered the appeal point upheld by the appeal panel and the company's revised patient access scheme At the third appraisal committee meeting, the committee considered the appeal panel's decision to uphold 1 appeal point. The upheld appeal point asked the committee to: appraise the technology on the basis that the NICE end of life criteria apply consider the extent, if any, to which this influences the eligibility of tafasitamab for use in the Cancer Drugs Fund.The committee considered this point, including a revised patient access scheme, and the latest confidential discounts for comparator and subsequent treatments. ## Tafasitamab with lenalidomide meets the end of life criteria The committee reconsidered its decision that tafasitamab with lenalidomide does not meet the short life expectancy criterion (see section 3.8). It noted that the appeal panel had a different interpretation of section 6.2.10 of NICE's guide to the methods of technology appraisal 2013. The panel considered that the interpretation of the word 'normally' should be what NICE's stakeholders would reasonably expect the word 'normally' to mean. The appeal panel agreed with the appeal panel for NICE's technology appraisal guidance on avelumab that stakeholders would consider it unreasonable to find that life expectancy was not 'normally less than 24 months' if most people in a trial had died before 24 months, even if mean survival was greater than 24 months. The panel concluded that the dominant evidence used to determine this end of life criterion should reflect survival metrics that are the most meaningful to stakeholders. It also concluded that the 'less than 35% alive after 2 years' cited by the appeal panel for NICE's guidance on avelumab was not setting a precedent for a threshold for applying end of life criteria. The committee accepted the appeal panel's conclusion that the short life expectancy criterion was met. The committee therefore concluded that tafasitamab with lenalidomide meets the criteria to be considered a life-extending treatment at the end of life. ## Tafasitamab with lenalidomide is not a cost-effective use of NHS resources The committee considered that the most plausible ICER in the updated company base case was highly uncertain, because of issues with the indirect comparisons and modelling (see sections 3.4, 3.6 and 3.7). In considering the decision-making ICERs, the committee accounted for all the confidential discounts for comparator and subsequent treatments. This included the impact of the loss of price exclusivity on the price for lenalidomide. During the second committee meeting, it considered the live interim tender price for lenalidomide as provided by the Cancer Drugs Fund lead. It also considered pricing scenarios including the estimated price discount for generic lenalidomide up to and including a 100% discount (that is, no cost for lenalidomide). During the third committee meeting, the committee considered the nationally available tender price for generic lenalidomide as confirmed by the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence. The committee noted that the company's and the ERG's base-case probabilistic ICERs (accounting for all the confidential discounts including lenalidomide) for tafasitamab with lenalidomide compared with polatuzumab vedotin plus bendamustine and rituximab were higher than the range normally considered a cost-effective use of NHS resources for treatments given at the end of life. The exact results cannot be reported here because they include confidential discounts for other treatments. The committee further considered that accepting the appeal panel's conclusion that the short life expectancy criterion is met created an inconsistency. The modelled survival with polatuzumab vedotin plus bendamustine and rituximab was inconsistent between: the company's and ERG's base cases (mean undiscounted survival of 29 and 48 months respectively) and the 10 to 13 months' real-world survival accepted by the appeal panel as reflecting expected survival.The committee was not presented with ICERs based on a model with survival in the comparator arm closer to real-world expectations. The committee considered that such a change would have an impact on incremental costs and benefits. Survival for the polatuzumab arm is estimated by applying a hazard ratio to survival for tafasitamab (see section 3.6). Based on this relationship between tafasitamab and polatuzumab survival in the model, the committee concluded that ICERs reflecting real-world survival for polatuzumab were not likely to be lower than those in the company's base case. It was possible that these could increase markedly. So the committee concluded that the most plausible ICER was likely to be closer to the ERG's base-case estimates. It noted that the ERG's base-case ICER was considerably higher than the company's and considerably higher than the level usually considered cost effective for end of life treatments. The committee recognised the need for effective treatments in relapsed or refractory diffuse large B‑cell lymphoma. But tafasitamab with lenalidomide had not been shown to be a cost-effective use of NHS resources in any analyses presented. So it concluded that tafasitamab with lenalidomide could not be recommended for routine use in the NHS. ## The Cancer Drugs Fund inclusion criteria are not met Having concluded that tafasitamab with lenalidomide could not be recommended for routine use, the committee reconsidered whether it could be recommended for use in the Cancer Drugs Fund. The committee still had the same concerns and conclusion as in section 3.10. It recalled that further evidence collection will not generate additional comparative evidence. The model would still rely on indirect evidence for comparator treatments, so this would not resolve a key uncertainty. Also, the committee was not presented with any analysis showing that tafasitamab with lenalidomide has the plausible potential to be cost effective. This was even taking into account the updated patient access scheme for tafasitamab and the decision that end of life criteria were met. So it concluded that tafasitamab with lenalidomide did not meet the criteria for inclusion in the Cancer Drugs Fund. # Tafasitamab is not innovative, based on the evidence presented In response to the appraisal consultation document, the company highlighted that clinical experts had said in their submissions that they thought that tafasitamab with lenalidomide may have health-related benefits not captured in the QALY calculation. It explained that this could be because tafasitamab has a different mechanism of action to other treatments. It thought this could be a shift in the treatment paradigm for this condition, with the potential for longer treatment durations because of possibly more acceptable toxicity. The committee heard from clinical experts that tafasitamab with lenalidomide was considered to be innovative, but not necessarily a step change. The company said that tafasitamab with lenalidomide could have uncaptured benefits from less patient anxiety and improvements in carers' free time and wellbeing. It said that it also had the advantage of people being able to take it without needing an overnight hospital stay. The committee noted that section 6.3.3 of NICE's guide to the methods of technology appraisal 2013 says that to be considered innovative the technology should add 'demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the reference case QALY measure'. It concluded that, based on the evidence presented, this was not the case for tafasitamab. # Other factors No equality or social value judgement issues were identified. # Conclusion ## Tafasitamab with lenalidomide is not recommended for relapsed or refractory diffuse large B-cell lymphoma There is a high unmet need for effective treatments in relapsed and refractory diffuse large B‑cell lymphoma. Indirect evidence suggests that tafasitamab with lenalidomide may increase progression-free survival and overall survival compared with polatuzumab vedotin with rituximab and bendamustine. However, there is substantial uncertainty in the modelling and the committee was not presented with any analysis showing that tafasitamab with lenalidomide is cost effective. Therefore, tafasitamab with lenalidomide is not recommended for relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have an autologous stem cell transplant.	{'Recommendations': "Tafasitamab with lenalidomide is not recommended, within its marketing authorisation, for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have an autologous stem cell transplant.\n\nThis recommendation is not intended to affect treatment with tafasitamab with lenalidomide that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with relapsed or refractory diffuse large B‑cell lymphoma who cannot have an autologous stem cell transplant usually have polatuzumab vedotin plus rituximab and bendamustine.\n\nThe clinical evidence is from a small study that did not directly compare tafasitamab plus lenalidomide with any other treatment. The committee considered that the study results were promising because they show that some people's disease responds to tafasitamab plus lenalidomide. Indirect evidence suggests that people who have tafasitamab plus lenalidomide have more time before their disease gets worse than people who have polatuzumab vedotin plus rituximab and bendamustine. It also suggests that they live longer. But there is uncertainty about these results because the survival times for people having polatuzumab vedotin plus rituximab and bendamustine used in the modelling do not reflect the real-world survival times of the treatment in clinical practice, compared with bendamustine and rituximab alone. The methods used for the indirect comparisons are also not clear.\n\nTafasitamab plus lenalidomide meets NICE's criteria to be considered a life-extending treatment at the end of life. This is because people on standard treatment (polatuzumab vedotin plus rituximab and bendamustine) for relapsed or refractory diffuse large B‑cell lymphoma are likely to live on average less than 2 years. But all the cost-effectiveness estimates for tafasitamab plus lenalidomide are above the range that NICE normally considers to be an acceptable use of NHS resources for end of life treatments. Therefore, it cannot be recommended for routine use in the NHS.\n\nBecause the cost-effectiveness estimates are high and uncertain, and further evidence is unlikely to resolve this uncertainty, it also cannot be recommended for use in the Cancer Drugs Fund.", 'Information about tafasitamab with lenalidomide': "# Marketing authorisation indication\n\nTafasitamab (Minjuvi, Incyte) is indicated, in combination with lenalidomide followed by tafasitamab monotherapy, for 'the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma who are not eligible for autologous stem cell transplant'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for tafasitamab.\n\n# Price\n\nTafasitamab costs £705 per 200‑mg vial of powder for concentrate for solution for infusion (excluding VAT; company submission). Tafasitamab costs £120,639 for 12\xa0months of treatment in year\xa01 and £95,049 for year\xa02 onwards. The list price of lenalidomide per 21‑capsule pack varies according to capsule size: £3,426.00 (2.5\xa0mg), £3,570.00 (5\xa0mg), £3,675.00 (7.5\xa0mg), £3,780.00 (10\xa0mg), £3,969.00 (15\xa0mg), £4,168.50 (20\xa0mg) and £4,368.00 (25\xa0mg; all prices excluding VAT; BNF online accessed February 2023).\n\nThe company has a commercial arrangement for tafasitamab, which would have applied if the technology had been recommended. There is a nationally available discount for lenalidomide with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.", 'Committee discussion': 'The appraisal committee considered evidence submitted by Incyte, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## People with diffuse large B‑cell lymphoma would welcome a new treatment option that is more tolerable and improves outcomes\n\nDiffuse large B‑cell lymphoma is an aggressive disease. Symptoms usually develop rapidly and progress quickly. The disease is treated with the aim of cure, but 10% to 15% of people have primary refractory disease and a further 20% to 30% relapse. A submission from a patient expert explained that the prognosis for people with relapsed or refractory disease is extremely poor. Treatments are very intensive, needing long stays in hospital and potentially involving serious side effects even after treatment has ended. Any treatment delivered in an outpatient setting (that is, that did not require a stay in hospital) would have a significant, positive effect on the quality of life of people with the condition and their families. The psychological, social and economic impact of the disease for both the person and their carers is considerable. The clinical experts explained that relapsed or refractory disease is treated using salvage chemotherapy followed by an autologous stem cell transplant if the person can have intensive therapy. Clinical experts explained that about 10% to 20% of people with relapsed or refractory disease who can have intensive therapy are cured of the disease after an autologous stem cell transplant. People who cannot have a transplant, or whose disease relapses after a transplant, are usually offered polatuzumab vedotin with bendamustine and rituximab or other rituximab-based chemotherapy regimens. The committee concluded that relapsed or refractory diffuse large B‑cell lymphoma is a devastating condition with a poor prognosis, and that people with the condition have a high unmet need for effective treatments with manageable side effects.\n\n# Clinical management\n\n## Polatuzumab vedotin with bendamustine and rituximab is standard care for people who cannot have an autologous stem cell transplant\n\nTafasitamab has a marketing authorisation in combination with lenalidomide for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have an autologous stem cell transplant. The comparators in the NICE scope were:\n\nchemotherapy with or without rituximab\n\npixantrone\n\npolatuzumab vedotin with bendamustine and rituximab\n\nbest supportive care.The company submission only included the following as comparator treatments:\n\nrituximab with gemcitabine and oxaliplatin\n\npolatuzumab vedotin with bendamustine and rituximab\n\nbendamustine with rituximab.The reduced number of comparators was based on clinical expert interviews done by the company that suggested that these 3 regimens were the main treatments used in the NHS. The company also justified the choice of comparators by saying that there was limited data for the other comparators. In addition, it pointed out that bendamustine with rituximab was considered a reasonable proxy for standard care in NICE\'s technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine for treating relapsed or refractory diffuse large B-cell lymphoma. The clinical experts said that some of the low-intensity chemotherapy regimens (with or without rituximab) are rarely used. Polatuzumab vedotin with bendamustine and rituximab has largely replaced other options and is now standard care for people with relapsed or refractory disease who cannot have an autologous stem cell transplant. The committee concluded that the company\'s choice of comparators was appropriate, and that polatuzumab vedotin with bendamustine and rituximab was the main comparator.\n\n# Clinical evidence\n\n## The lack of a direct comparison with any treatment makes the clinical data difficult to interpret\n\nThe clinical evidence for tafasitamab with lenalidomide came from the phase 2 L‑MIND study. This is an ongoing multicentre, single-arm, open-label study of tafasitamab with lenalidomide in people with relapsed or refractory diffuse large B‑cell lymphoma who could not have an autologous stem cell transplant. Because the study is open label, people in the trial and their healthcare professionals are aware of treatment allocation. The committee highlighted that the study is small, with 81\xa0people recruited, 5\xa0of whom are from the UK. At the October 2020 data cut, median duration of exposure to tafasitamab with lenalidomide was 9.2\xa0months. The primary endpoint of objective response rate (partial and complete response) was 58%. Median overall survival was 33.5\xa0months, and median progression-free survival was 11.6\xa0months. The ERG highlighted several important differences in the baseline characteristics of people in L‑MIND compared with Northend et al. (2022), a retrospective analysis of real-world data from the UK. For example, the proportion of men in Northend et al. was 69% compared with 54% in L‑MIND. Differences were also identified for the presence of bulky disease, International Prognostic Index scores, number of lines of previous therapy, and refractoriness to previous treatment. The committee considered that the study results were promising. However, it concluded that the lack of a direct comparison with any treatment makes the data difficult to interpret.\n\n## The results of the indirect treatment comparisons are very uncertain\n\nBecause L‑MIND is a single-arm study, indirect treatment comparisons were needed to establish the relative efficacy of tafasitamab plus lenalidomide compared with other treatments. The company used 2 indirect treatment comparison approaches: propensity score matching against RE‑MIND2 and matching-adjusted indirect comparisons against published studies. RE‑MIND2 was an observational, retrospective cohort study of 3,454\xa0adults with relapsed or refractory diffuse large B‑cell lymphoma, including 115\xa0people from the UK. The company used nearest neighbour propensity score matching to balance the cohorts for comparator treatments with L‑MIND based on 9 baseline covariates. In the matching-adjusted indirect comparisons the company adjusted the L‑MIND population using propensity score weighting to be comparable to the populations in 4 published trials of comparator treatments, which were selected using a systematic literature review and expert input. The company used RE‑MIND2 for rituximab with gemcitabine and oxaliplatin and the matching-adjusted indirect comparisons for polatuzumab vedotin with bendamustine and rituximab as well as bendamustine and rituximab. The company chose indirect evidence sources based on alignment to published outcomes. This resulted in RE‑MIND2 not being selected for polatuzumab vedotin with bendamustine and rituximab. All the indirect comparisons suggested that tafasitamab with lenalidomide improved progression-free and overall survival compared with the comparators, but this was not always statistically significant. The ERG highlighted that RE‑MIND2 consists of pooled individual participant data and is preferred in principle to the intervention population adjustment done in the matching-adjusted indirect comparisons. Adjusting the L‑MIND population differently for each comparator treatment population may have led to bias. However, there was uncertainty about the methods used for RE‑MIND2 because the baseline characteristics of the tafasitamab with lenalidomide cohort varied depending on the comparator. The ERG suggested that it was unclear what type of treatment effect is estimated in RE‑MIND2. The committee concluded that, because of the complexity in the methods used for the indirect treatment comparisons, and the potential biases, the results of the indirect comparisons were very uncertain.\n\n# The company\'s economic model\n\n## The company\'s economic model structure is appropriate for decision making\n\nThe company presented a 3‑state partitioned survival model to estimate the cost effectiveness of tafasitamab plus lenalidomide compared with rituximab plus gemcitabine and oxaliplatin, polatuzumab vedotin plus bendamustine and rituximab, and bendamustine plus rituximab. The committee agreed that the company\'s model structure was appropriate for decision making.\n\n## The overall and progression-free survival extrapolations for polatuzumab vedotin with bendamustine and rituximab are highly uncertain\n\nThe ERG questioned the validity of the company\'s overall and progression-free survival parametric extrapolations for polatuzumab vedotin with bendamustine and rituximab. The company calculated separate hazard ratios for up to month\xa04 and after month\xa04 for both survival outcomes from the matching-adjusted indirect treatment comparison. It applied these hazard ratios to the survival distributions for tafasitamab with lenalidomide to calculate the survival distributions for polatuzumab vedotin with bendamustine and rituximab. The company justified this piecewise approach to estimating hazard ratios by saying that the alternative, a constant hazard ratio, was not possible because the proportional hazards test failed. However, the ERG was concerned that the resulting overall survival extrapolation underestimated survival for polatuzumab vedotin with bendamustine and rituximab compared with NICE\'s technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. The previous NICE appraisal estimated around 3.1\xa0mean life years and 2.1\xa0quality-adjusted life years (QALYs). In contrast, the company\'s extrapolation estimated 2.2\xa0mean life years and 1.5\xa0QALYs. On this basis, the ERG preferred to apply a constant hazard ratio from the matching-adjusted indirect comparison, leading to 3.4\xa0mean life years and 2.2\xa0QALYs for polatuzumab vedotin with bendamustine and rituximab. The clinical experts considered that the company\'s estimates were reasonable because they were closer to the published literature estimates of median overall survival for polatuzumab vedotin with bendamustine and rituximab (between 8.2 and 12.5\xa0months) than the ERG\'s. The company justified its methodology by saying that it was verified by clinical experts, produced the results most aligned with real-world evidence, and avoided unnecessary complexity. However, the committee noted that tests for proportional hazards did not support a constant hazard. So, it considered that it was not appropriate to apply constant hazard ratios to the L‑MIND data, even using the piecewise approach. It also identified that better approaches were needed to handle the time-varying nature of the observed hazard ratio. The committee agreed that the company should have looked at more ways to include the data from Sehn et al. (2022) in the indirect comparisons. For example, the polatuzumab vedotin with bendamustine and rituximab hazard ratio from Sehn et al. could be applied to the survival outcomes for the propensity score-matched bendamustine and rituximab population. Or, independent survival models could be fitted to the Sehn et al. Kaplan–Meier curves, adding a third arm for tafasitamab with lenalidomide against bendamustine and rituximab from the matching-adjusted indirect comparison; this would have created a partially anchored indirect comparison. The committee was disappointed that the company did not provide such additional analyses in response to the appraisal consultation document. In addition to the ERG\'s arguments about the company\'s modelling not reflecting the absolute benefits of polatuzumab vedotin with bendamustine and rituximab, the committee considered that the modelling poorly reflected the relative benefit compared with bendamustine and rituximab alone. For example, Sehn et al. reported a hazard ratio for overall survival of 0.42 for polatuzumab vedotin plus bendamustine and rituximab compared with bendamustine and rituximab alone. The clinical experts also confirmed that polatuzumab vedotin plus bendamustine and rituximab improves survival compared with bendamustine and rituximab alone. However, this is not fully reflected in the company\'s modelling, with only a small difference in survival estimated. The committee concluded that the company\'s parametric extrapolations for polatuzumab vedotin with bendamustine and rituximab were implausible. However, the committee also took into account feedback from clinical experts on outcomes observed in clinical practice submitted in response to the appraisal consultation document. These suggested that the estimates from the ERG\'s base case may be overestimated, despite alignment with NICE\'s technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. The committee concluded that it would have preferred to see different modelling approaches that both fitted the underlying hazards of the data and produced outcomes more closely reflecting the absolute and relative benefits of polatuzumab vedotin with bendamustine and rituximab compared with bendamustine and rituximab alone, as seen in NICE\'s guidance on polatuzumab vedotin with rituximab and bendamustine.\n\n## Overall and progression-free survival parametric extrapolations for tafasitamab with lenalidomide are appropriate, despite the uncertainty\n\nThe company and ERG agreed that the log-normal parametric extrapolation of L‑MIND overall survival data for tafasitamab with lenalidomide was the most appropriate approach. Initially, the company chose a generalised gamma distribution fitted to the data from L‑MIND to model progression-free survival for tafasitamab with lenalidomide, and the ERG preferred a log-normal distribution. However, the ERG noted the resulting hazard profile was inconsistent with the predictions of the clinical experts consulted by the company and overestimated progression-free survival in the long term. The committee noted that there was uncertainty in the modelled progression-free survival extrapolations for tafasitamab with lenalidomide because of heavy patient censoring towards the end of the L‑MIND Kaplan–Meier curve. However, it agreed it was appropriate to consider the log-normal distribution chosen by the ERG. In response to the appraisal consultation document, the company updated its base-case model using the committee\'s preferred assumption of the log-normal parametric extrapolation of L‑MIND progression-free survival data for tafasitamab with lenalidomide. The committee concluded that the company\'s approach to modelling tafasitamab with lenalidomide survival was appropriate in its updated base case, while noting the inherent uncertainty.\n\n# End of life (before the appeal)\n\n## Tafasitamab with lenalidomide does not meet the end of life criteria\n\nThe committee considered the criteria for life-extending treatments for people with a short life expectancy in section 6.2.10 of NICE\'s guide to the methods of technology appraisal 2013. These are:\n\nthe treatment is indicated for people with a short life expectancy, normally less than 24\xa0months and\n\nthere is sufficient evidence to indicate that the treatment has the prospect of offering an extension to life, normally of a mean value of at least an additional 3\xa0months, compared with current NHS treatment.In considering these criteria the committee was also aware, from the methods guide, that it should be satisfied that \'the assumptions used in the reference case economic modelling are plausible, objective and robust\'.The committee was also aware of the appeal panel conclusions about the short life expectancy criteria as part of NICE\'s technology appraisal guidance on avelumab for maintenance treatment of locally advanced or metastatic urothelial cancer after platinum-based chemotherapy, particularly section\xa087 of the appeal decision (see the final appraisal determination 2 committee papers). This states, based on the evidence in that particular appraisal: \'The appeal panel felt that the key stakeholders of NICE would consider it unreasonable to state that life expectancy was not "normally less than 24 months", even if the mean life expectancy was greater than 24 months, if 65% of patients, the significant majority, in the modelled cohort had died prior to 24 months.\'The committee carefully reviewed these points and considered the following:\n\nThere is limited clinical trial data for tafasitamab with lenalidomide. The only source of trial evidence for this appraisal was a single-arm phase\xa02 study of 80\xa0people (L‑MIND). The relatively small size of this study, short median follow up (13.2\xa0months) and lack of data comparing it with usual NHS treatments makes it difficult to assess the comparative clinical effectiveness of tafasitamab with lenalidomide. This introduces considerable uncertainty in the modelling.\n\nThe real-world experience in the NHS with polatuzumab vedotin with bendamustine and rituximab. In response to the appraisal consultation document, the clinical experts explained that less favourable survival outcomes have been seen in clinical practice than the estimates in NICE\'s technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. The recent Northend et al. (2022) study reported on real-world data from the UK including 133\xa0people (78\xa0having standalone treatment rather than bridging to chimeric antigen receptor T‑cell therapy). Clinical experts explained that their experience was more consistent with the estimates from Northend et al. (median survival 10.2\xa0months) and Sehn et al. (2022; median survival 12.4\xa0months) than the estimates from NICE\'s guidance on polatuzumab vedotin (mean undiscounted survival of over 48 months). Based in part on this evidence, the company and clinical experts considered that end of life criterion 1 was met. The company also suggested that the Sehn et al. survival estimates may be biased by including people who had polatuzumab vedotin with bendamustine and rituximab and then also had chimeric antigen receptor T‑cell therapy. The ERG acknowledged this but explained that it did not expect it to have a big impact on the results because it only affected a few people in the study.\n\nThere are different survival estimates for polatuzumab vedotin with bendamustine and rituximab. The committee considered survival estimates for polatuzumab vedotin with bendamustine and rituximab from the original Sehn et al. (2019) study and the Sehn et al. (2022) follow-up study. The ERG highlighted that the results of the follow-up study analyses differed substantially from those accepted by the committee for NICE\'s technology appraisal guidance on polatuzumab vedotin. That appraisal estimated survival with polatuzumab vedotin with bendamustine and rituximab of over 4\xa0years (undiscounted). The committee noted that this figure was also more consistent with the mean undiscounted life years estimates from both the company\'s (29\xa0months) and the ERG\'s (48\xa0months) modelling for this appraisal (both estimates longer than 24\xa0months).\n\nThe summary of modelled and literature-based survival outcomes. The committee considered the following survival outcomes:\n\n\n\nMedian overall survival estimates from Northend et al. (2022; 10.2\xa0months) and Sehn et al. (2022; 12.4\xa0months).\n\nMean overall survival estimates from the company\'s base-case model for polatuzumab vedotin (29\xa0months undiscounted), the ERG\'s base case model (48\xa0months undiscounted) and NICE\'s technology appraisal guidance on polatuzumab vedotin (over 48\xa0months undiscounted).\n\nEstimates of the percentage of people alive at 24\xa0months from the company\'s base-case model (34%), the ERG\'s base-case model (44%) and Sehn et al. (2022; 38%).\n\nThe increase in mean undiscounted overall survival with tafasitamab from the company\'s base-case and ERG\'s base-case models (29\xa0and 48\xa0months respectively, difference of 19\xa0months).The committee carefully considered the totality of the data and analysis and concluded the following:\n\n\n\nEnd of life criterion 2 was met. The indirect comparisons and modelling were uncertain. But it was reasonable to conclude that tafasitamab with lenalidomide is expected to extend life by at least 3\xa0months compared with current NHS treatment.\n\nEnd of life criterion 1 was not met. The committee was concerned by how different the survival estimates for polatuzumab vedotin with rituximab and bendamustine were from the literature and from NICE\'s technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. It was aware that survival estimates measured using means and medians often give different values. But the appeal panel for NICE\'s guidance on avelumab agreed that all the evidence should be considered in making the decision. The committee acknowledged that the estimates from the guidance on polatuzumab vedotin may be too optimistic. But it did not consider that they were so overestimated that it was likely that people who have polatuzumab vedotin with rituximab and bendamustine in the NHS have a life expectancy of less than 24 months.The committee therefore concluded that tafasitamab with lenalidomide did not meet the end of life criteria.\n\n# Cost-effectiveness estimates (before the appeal)\n\n## Tafasitamab with lenalidomide is not cost effective\n\nThe committee considered that the most plausible incremental cost-effectiveness ratio (ICER) in the updated company base case was highly uncertain, because of issues with the indirect comparisons and modelling (see sections\xa03.4, 3.6 and 3.7). It noted that the company\'s and ERG\'s base-case probabilistic ICERs (including all the confidential discounts) for tafasitamab plus lenalidomide compared with polatuzumab vedotin plus bendamustine and rituximab were higher than the range normally considered a cost-effective use of NHS resources, even for end of life treatments. The exact results cannot be reported here because they include confidential discounts for other treatments. The committee considered that the company\'s base-case ICERs were not plausible, because the model survival outputs were not consistent with NICE\'s technology appraisal guidance on polatuzumab vedotin. It acknowledged that, although the ERG\'s base case was more closely aligned with these survival outputs, they may overestimate survival for polatuzumab vedotin with bendamustine and rituximab (see section\xa03.6). The committee concluded that the most plausible ICER was likely to be between the company\'s and ERG\'s base-case estimates. It noted that the ERG\'s base-case ICER was considerably higher than the company\'s and considerably higher than the level usually considered cost effective. The committee recognised the need for effective treatments in relapsed or refractory diffuse large B‑cell lymphoma. However, tafasitamab with lenalidomide had not been shown to be a cost-effective use of NHS resources in any analyses presented. So it concluded that tafasitamab with lenalidomide could not be recommended for routine use in the NHS.\n\n# Cancer Drugs Fund (before the appeal)\n\n## The Cancer Drugs Fund inclusion criteria are not met\n\nHaving concluded that tafasitamab with lenalidomide could not be recommended for routine use, the committee considered if it could be recommended for use within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE\'s Cancer Drugs Fund methods guide (addendum). The committee recognised that people with relapsed or refractory diffuse large B‑cell lymphoma have a high unmet clinical need, and that the availability of new treatments is very important. The company said that further data cuts for the L‑MIND clinical study are planned for 2022, which will provide further evidence on survival and response outcomes. However, the committee was concerned because the single-arm phase\xa02 study will not provide additional comparative evidence. The model would still rely on indirect evidence for comparator treatments, so this would not resolve a key uncertainty. In addition, the committee was not presented with any analysis showing that tafasitamab with lenalidomide has the plausible potential to be cost effective at the proposed price. Therefore, it concluded that tafasitamab with lenalidomide did not meet the criteria for inclusion in the Cancer Drugs Fund.\n\n# After the appeal\n\nAppeals against the first final appraisal document were submitted and considered by an independent appeal panel. The panel convened for an oral hearing in November 2022 and upheld 1 appeal point, referring the appraisal back to committee for further consideration.\n\n## The committee has considered the appeal point upheld by the appeal panel and the company\'s revised patient access scheme\n\nAt the third appraisal committee meeting, the committee considered the appeal panel\'s decision to uphold 1 appeal point. The upheld appeal point asked the committee to:\n\nappraise the technology on the basis that the NICE end of life criteria apply\n\nconsider the extent, if any, to which this influences the eligibility of tafasitamab for use in the Cancer Drugs Fund.The committee considered this point, including a revised patient access scheme, and the latest confidential discounts for comparator and subsequent treatments.\n\n## Tafasitamab with lenalidomide meets the end of life criteria\n\nThe committee reconsidered its decision that tafasitamab with lenalidomide does not meet the short life expectancy criterion (see section\xa03.8). It noted that the appeal panel had a different interpretation of section 6.2.10 of NICE\'s guide to the methods of technology appraisal 2013. The panel considered that the interpretation of the word \'normally\' should be what NICE\'s stakeholders would reasonably expect the word \'normally\' to mean. The appeal panel agreed with the appeal panel for NICE\'s technology appraisal guidance on avelumab that stakeholders would consider it unreasonable to find that life expectancy was not \'normally less than 24 months\' if most people in a trial had died before 24\xa0months, even if mean survival was greater than 24 months. The panel concluded that the dominant evidence used to determine this end of life criterion should reflect survival metrics that are the most meaningful to stakeholders. It also concluded that the \'less than 35% alive after 2 years\' cited by the appeal panel for NICE\'s guidance on avelumab was not setting a precedent for a threshold for applying end of life criteria. The committee accepted the appeal panel\'s conclusion that the short life expectancy criterion was met. The committee therefore concluded that tafasitamab with lenalidomide meets the criteria to be considered a life-extending treatment at the end of life.\n\n## Tafasitamab with lenalidomide is not a cost-effective use of NHS resources\n\nThe committee considered that the most plausible ICER in the updated company base case was highly uncertain, because of issues with the indirect comparisons and modelling (see sections\xa03.4, 3.6 and 3.7). In considering the decision-making ICERs, the committee accounted for all the confidential discounts for comparator and subsequent treatments. This included the impact of the loss of price exclusivity on the price for lenalidomide. During the second committee meeting, it considered the live interim tender price for lenalidomide as provided by the Cancer Drugs Fund lead. It also considered pricing scenarios including the estimated price discount for generic lenalidomide up to and including a 100% discount (that is, no cost for lenalidomide). During the third committee meeting, the committee considered the nationally available tender price for generic lenalidomide as confirmed by the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence. The committee noted that the company\'s and the ERG\'s base-case probabilistic ICERs (accounting for all the confidential discounts including lenalidomide) for tafasitamab with lenalidomide compared with polatuzumab vedotin plus bendamustine and rituximab were higher than the range normally considered a cost-effective use of NHS resources for treatments given at the end of life. The exact results cannot be reported here because they include confidential discounts for other treatments. The committee further considered that accepting the appeal panel\'s conclusion that the short life expectancy criterion is met created an inconsistency. The modelled survival with polatuzumab vedotin plus bendamustine and rituximab was inconsistent between:\n\nthe company\'s and ERG\'s base cases (mean undiscounted survival of 29 and 48 months respectively) and\n\nthe 10 to 13 months\' real-world survival accepted by the appeal panel as reflecting expected survival.The committee was not presented with ICERs based on a model with survival in the comparator arm closer to real-world expectations. The committee considered that such a change would have an impact on incremental costs and benefits. Survival for the polatuzumab arm is estimated by applying a hazard ratio to survival for tafasitamab (see section\xa03.6). Based on this relationship between tafasitamab and polatuzumab survival in the model, the committee concluded that ICERs reflecting real-world survival for polatuzumab were not likely to be lower than those in the company\'s base case. It was possible that these could increase markedly. So the committee concluded that the most plausible ICER was likely to be closer to the ERG\'s base-case estimates. It noted that the ERG\'s base-case ICER was considerably higher than the company\'s and considerably higher than the level usually considered cost effective for end of life treatments. The committee recognised the need for effective treatments in relapsed or refractory diffuse large B‑cell lymphoma. But tafasitamab with lenalidomide had not been shown to be a cost-effective use of NHS resources in any analyses presented. So it concluded that tafasitamab with lenalidomide could not be recommended for routine use in the NHS.\n\n## The Cancer Drugs Fund inclusion criteria are not met\n\nHaving concluded that tafasitamab with lenalidomide could not be recommended for routine use, the committee reconsidered whether it could be recommended for use in the Cancer Drugs Fund. The committee still had the same concerns and conclusion as in section\xa03.10. It recalled that further evidence collection will not generate additional comparative evidence. The model would still rely on indirect evidence for comparator treatments, so this would not resolve a key uncertainty. Also, the committee was not presented with any analysis showing that tafasitamab with lenalidomide has the plausible potential to be cost effective. This was even taking into account the updated patient access scheme for tafasitamab and the decision that end of life criteria were met. So it concluded that tafasitamab with lenalidomide did not meet the criteria for inclusion in the Cancer Drugs Fund.\n\n# Tafasitamab is not innovative, based on the evidence presented\n\nIn response to the appraisal consultation document, the company highlighted that clinical experts had said in their submissions that they thought that tafasitamab with lenalidomide may have health-related benefits not captured in the QALY calculation. It explained that this could be because tafasitamab has a different mechanism of action to other treatments. It thought this could be a shift in the treatment paradigm for this condition, with the potential for longer treatment durations because of possibly more acceptable toxicity. The committee heard from clinical experts that tafasitamab with lenalidomide was considered to be innovative, but not necessarily a step change. The company said that tafasitamab with lenalidomide could have uncaptured benefits from less patient anxiety and improvements in carers\' free time and wellbeing. It said that it also had the advantage of people being able to take it without needing an overnight hospital stay. The committee noted that section 6.3.3 of NICE\'s guide to the methods of technology appraisal 2013 says that to be considered innovative the technology should add \'demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the reference case QALY measure\'. It concluded that, based on the evidence presented, this was not the case for tafasitamab.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Tafasitamab with lenalidomide is not recommended for relapsed or refractory diffuse large B-cell lymphoma\n\nThere is a high unmet need for effective treatments in relapsed and refractory diffuse large B‑cell lymphoma. Indirect evidence suggests that tafasitamab with lenalidomide may increase progression-free survival and overall survival compared with polatuzumab vedotin with rituximab and bendamustine. However, there is substantial uncertainty in the modelling and the committee was not presented with any analysis showing that tafasitamab with lenalidomide is cost effective. Therefore, tafasitamab with lenalidomide is not recommended for relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have an autologous stem cell transplant.'}	https://www.nice.org.uk/guidance/ta883	Evidence-based recommendations on tafasitamab (Minjuvi) with lenolidomide for relapsed or refractory diffuse large B-cell lymphoma in adults who cannot have an autologous stem cell transplant.
089a49357a8b48abe3bc36b52c412d6d9104f842	nice	Pembrolizumab plus chemotherapy with or without bevacizumab for persistent, recurrent or metastatic cervical cancer	Pembrolizumab plus chemotherapy with or without bevacizumab for persistent, recurrent or metastatic cervical cancer Evidence-based recommendations on pembrolizumab (Keytruda) plus chemotherapy with or without bevacizumab for persistent, recurrent or metastatic cervical cancer in adults. # Recommendations Pembrolizumab plus chemotherapy with or without bevacizumab is recommended for use within the Cancer Drugs Fund as an option for treating persistent, recurrent or metastatic cervical cancer in adults whose tumours express PD‑L1 with a combined positive score (CPS) of at least 1. It is recommended only if: pembrolizumab is stopped at 2 years of uninterrupted treatment, or earlier if disease progresses, and the conditions in the managed access agreement for pembrolizumab are followed. This recommendation is not intended to affect treatment with pembrolizumab plus chemotherapy with or without bevacizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard care for persistent, recurrent or metastatic cervical cancer includes chemotherapy with or without bevacizumab. Evidence from a clinical trial shows that if people have pembrolizumab plus chemotherapy with or without bevacizumab it takes longer for their cancer to get worse than people having standard care. Evidence from this trial also suggests they may live longer. But, it is unclear how much longer it takes for their cancer to get worse, or how long they live, because the trial is ongoing. In this trial, people had pembrolizumab for up to 2 years. Because of the uncertainty in the clinical trial evidence, the cost-effectiveness estimates are also uncertain. Pembrolizumab plus chemotherapy with or without bevacizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. But, even when taking this into account, some of the likely cost‑effectiveness estimates are above what NICE considers an acceptable use of NHS resources. So, pembrolizumab plus chemotherapy with or without bevacizumab cannot be recommended for routine use in the NHS. Collecting and analysing data from the ongoing clinical trial through the Cancer Drugs Fund may reduce the uncertainty in the evidence. So, pembrolizumab plus chemotherapy with or without bevacizumab is recommended for use in the Cancer Drugs Fund.# Information about pembrolizumab # Marketing authorisation indication Pembrolizumab (Keytruda, Merck Sharp and Dohme) 'in combination with chemotherapy with or without bevacizumab, is indicated for 'the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express programmed cell death ligand 1 (PD‑L1) with a combined positive score (CPS) ≥ 1'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for pembrolizumab. # Price The list price is £2,630.00 per 100 mg/4 ml concentrate for solution for infusion vial (excluding VAT; BNF online accessed January 2023). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Merck Sharp and Dohme (MSD), a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need and treatment pathway ## Persistent, recurrent or metastatic cervical cancer has a high disease burden Cervical cancer develops when abnormal cells in the cervix lining grow in an uncontrolled way, forming a tumour. Infection with human papillomavirus is associated with the development of cervical cancer. Cervical cancer is defined as persistent when it does not respond to treatment, recurrent when it has returned after treatment and metastatic when it has spread beyond the cervix to other places in the body. The patient expert explained that people diagnosed with cervical cancer often experience substantial disruption to their quality of life. With a median age of diagnosis of 51 years, many are of working age, with family and dependants. Despite affecting a population that is typically younger than often seen with other cancers, prognosis is poor. Median overall survival with standard treatment (cisplatin and paclitaxel with or without bevacizumab) was just 13 months to 17 months in GOG 240, a randomised phase 3 trial done in people with persistent, recurrent or metastatic cervical cancer. The committee concluded that there is a high disease burden for people with persistent, recurrent or metastatic cervical cancer, and that a treatment that can prolong life but also improve quality of survival by managing symptoms would be welcome. ## There are limited effective treatment options available for persistent, recurrent or metastatic cervical cancer Clinical experts explained that people with persistent, recurrent or metastatic cervical cancer have limited effective treatment options. People usually have paclitaxel plus either carboplatin or cisplatin, with or without bevacizumab. Bevacizumab is considered suitable if the person has a good disease performance status, no significant comorbidities and low risk of bowel fistula formation. The scope and company submission noted that bevacizumab was available as an option through the Cancer Drugs Fund, but the Cancer Drugs Fund clinical lead clarified that bevacizumab is now in routine commissioning for this indication. Although NICE technology appraisal guidance recommends topotecan for treating recurrent and stage 4B cervical cancer, it is not frequently used in clinical practice. The main aim of treatment for persistent, recurrent or metastatic cervical cancer is to relieve symptoms and improve quality of life, and to extend life if possible. The patient expert explained that people with the condition may be worried about the limited time they have left with their family, the lack of available treatment options, and the side effects of treatment. The committee recognised that there are limited effective treatment options available for persistent, recurrent or metastatic cervical cancer. # Clinical evidence ## Pembrolizumab combination is more effective than placebo combination but overall survival is uncertain in the long term The clinical evidence was based on KEYNOTE-826, a phase 3, randomised double-blind placebo-controlled trial in people with recurrent, persistent or metastatic cervical cancer. KEYNOTE-826 compared pembrolizumab plus chemotherapy with or without bevacizumab against placebo plus chemotherapy with or without bevacizumab as a first-line therapy. In line with the marketing authorisation, the company submission presented efficacy data for people whose tumours express PD‑L1 with a combined positive score (CPS) of at least 1. Chemotherapies included in the trial, either with pembrolizumab or placebo, were cisplatin plus paclitaxel or carboplatin plus paclitaxel. In the CPS of at least 1 population, 63.1% of people had bevacizumab. The interim trial results showed a clinically meaningful and statistically significant benefit for the pembrolizumab group compared with the placebo group for both progression-free survival and overall survival. The hazard ratio for progression-free survival by investigator assessment for the CPS of at least 1 population was 0.62 (95% confidence interval 0.50 to 0.77). The hazard ratio for overall survival at 24 months for the CPS of at least 1 population was 0.64 (95% CI 0.50 to 0.81). Median overall survival in the CPS of at least 1 population was not reached in the pembrolizumab group and was 16.3 months in the placebo group. The clinical experts considered that, although people in clinical trials tend to be fitter than those in clinical practice, the overall survival outcomes in the KEYNOTE‑826 placebo group were consistent with those previously seen in GOG 240 (see section 3.1). The ERG noted that although an overall survival benefit for the pembrolizumab group was likely because of the separation of the Kaplan–Meier curves between the treatment arms, the duration and size of the long-term benefit beyond trial follow-up was uncertain. After the first committee meeting, the committee concluded that, based on the available data, pembrolizumab plus chemotherapy with or without bevacizumab is more effective than chemotherapy with or without bevacizumab, but overall survival data is still immature. At the second committee meeting, the clinical expert explained that survival beyond 1 year was considered a good outcome for people with persistent, recurrent or metastatic cervical cancer. In KEYNOTE-826 the survival benefit was already considerable though median overall survival had not yet been reached in the pembrolizumab group. Overall survival data from the interim analysis of KEYNOTE-826 was therefore considered by the clinical expert to be insufficient, not immature. The committee concluded that uncertainty remained about long-term survival for the pembrolizumab group. ## Decision making includes the whole marketing authorisation population In KEYNOTE-826, people with metastatic cervical cancer at initial diagnosis had statistically significantly worse outcomes for progression‑free survival and overall survival than people with non‑metastatic cervical cancer at initial diagnosis. The ERG noted that the hazard ratios for the subgroup of people with metastases at diagnosis were comparable to those in the subgroup of people with a PD‑L1 status of CPS of less than 1, who were excluded from the marketing authorisation. The clinical experts explained that, in clinical practice, there was no differentiation between people with metastatic cervical cancer at initial diagnosis and people with recurrent cervical cancer. The clinical experts also noted that the proportion of people with metastatic cervical cancer at initial diagnosis in KEYNOTE‑826 was higher than they expected in clinical practice. The company cautioned against over‑interpretation of results for people with metastatic cervical cancer at initial diagnosis because KEYNOTE‑826 was not designed or powered to allow for formal testing of the heterogeneity in subgroups. The ERG explained that people in KEYNOTE‑826 were stratified by metastatic status at initial diagnosis so this was not an unplanned subgroup. The committee recalled that it does not seek to create subgroups within the marketing authorisation population for decision making unless there is clear underpinning evidence. Clinical experts explained that they would offer pembrolizumab treatment to people with cervical cancer which was metastatic at initial diagnosis based on the benefits seen in the overall CPS of at least 1 population. The committee concluded that people with metastatic cervical cancer at initial diagnosis was not a relevant subgroup and so decision making would include the whole population included in the marketing authorisation. # The company's economic model ## The most appropriate modelling approach may change when further data from KEYNOTE-826 is available The company presented a 3‑state Markov state transition model to estimate the cost effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy (both with or without bevacizumab). The 3 health states were progression-free survival, progressed disease and death. The company explained that Kaplan–Meier data by response status showed that overall survival in the interim analysis was largely informed by people whose disease had not responded to treatment, and that there was not enough overall survival data for people whose disease responded. Data on overall survival was therefore not mature enough to accurately model long-term survival for people whose disease had and had not responded, particularly those with a complete disease response. It suggested that in this case, a state transition model was more accurate than a partitioned survival model, which relies on direct extrapolation of observed overall survival data. The ERG noted the state transition model approach uses a structural link between progression-free survival and overall survival and implies gains in progression-free survival should translate into gains in overall survival. Although the ERG considered the company's evidence was broadly supportive of this assumption, it noted limited evidence was provided to show a validated relationship between progression-free survival and overall survival in this indication. The ERG also questioned the plausibility of the predicted long-term benefits of pembrolizumab in the model, which were heavily dependent on the approach to extrapolating progression-free survival, and were a direct consequence of the structural link between progression-free survival and overall survival imposed by the state transition model. The committee recalled advice by the NICE Decision Support Unit technical support document 19 that states transition modelling alongside a partitioned survival approach can assist in verifying the plausibility of extrapolations and addressing the uncertainties in the extrapolation period. The committee concluded that although the company's model may be adequate for decision making with the data currently available, when further data becomes available from KEYNOTE‑826, the most appropriate modelling approach may change. ## It is likely that improvements in progression-free survival are associated with an overall survival benefit Overall survival data from KEYNOTE‑826 is immature, with median overall survival not being reached in the pembrolizumab arm in the interim analysis. The cost-effectiveness modelling therefore relied on progression data to inform longer-term mortality extrapolations. The ERG was concerned that the company's economic model predicts an overall survival benefit that is similar in size to the progression-free survival benefit, and this was unproven. However, the company noted that the overall survival and progression-free survival hazard ratios seen within KEYNOTE‑826 were similar (respective point estimates are 0.64 and 0.62 in the CPS of at least 1 population). The committee considered whether gains in progression-free survival would translate into gains in overall survival. The clinical experts explained that there is a lack of treatment options at second line for persistent, recurrent or metastatic cervical cancer which could affect subsequent survival, and non-cancer mortality was unlikely to have a large effect in this population. So, it was likely that the benefit in progression-free survival would be reflected in overall survival. The Cancer Drugs Fund clinical lead agreed that this was biologically plausible and recalled evidence of gains in progression-free survival leading to gains in overall survival in other cancer trials, including cervical cancer. The committee concluded that, based on its earlier conclusion that pembrolizumab improved progression-free survival compared with placebo, it was likely that pembrolizumab also improved overall survival. However, the level of this benefit is uncertain. ## The most appropriate approach for extrapolating time to progression and progression-free survival is uncertain To inform the risk of disease progression or death, the company extrapolated the time to progression and progression-free survival data. The same model type was used for both time to progression and progression-free survival to ensure the model results remained clinically plausible. Model selection was based on statistical fit, visual fit, the desire for common functional form of models to both arms, the plausibility of hazard assumptions and clinical plausibility of the survival predictions. The company stated that 1‑piece models in which a parametric distribution was fitted to the whole Kaplan–Meier curve had poor visual fit to the observed data and were unable to appropriately capture what it considered to be an emerging plateau in the observed survival data. The company's base-case model used a 2‑piece approach to modelling time to progression and progression-free survival. Kaplan–Meier data from KEYNOTE‑826 was used up to 37 weeks, followed by log-logistic parametric survival models fitted to the remaining observed data. The ERG agreed with the company that there was some evidence of an emerging plateau in the time to progression and progression-free survival Kaplan–Meier curves for pembrolizumab. But, it considered there was limited overall survival evidence to support the substantial progression‑free survival and overall survival gains modelled by the company. It also considered that the company's 2‑piece approach led to an optimistic projection of people achieving long-term survival on pembrolizumab. The ERG preferred to use a 1‑piece log-logistic extrapolation for both arms. In response to technical engagement, the company updated their base-case analysis to align with the ERG's preferred 1‑piece log-logistic model for the placebo combination but maintained their preference for the 2‑piece Kaplan–Meier plus log-logistic model for the pembrolizumab group. The company explained that it considered the ERG's preferred 1‑piece log-logistic model for pembrolizumab to be inappropriate because of a very poor visual fit to the observed data. The company also considered that pembrolizumab has a different mechanism of action to the drugs in the placebo group and suggested it may be appropriate to use a separate model type between arms based on criteria described in the NICE Decision Support Unit technical support document 14. The ERG urged caution in the committee accepting different model types between treatment arms given the different shaped distributions, which implied that people can follow different patterns of events depending on which treatment they had. The committee recalled differing model types had been presented in previous appraisals and, although needing adequate justification, may be appropriate if it is accepted that the disease course could be different depending on the treatment received. After the first committee meeting, the committee concluded that the ERG's preferred 1‑piece log-logistic extrapolation for time to progression and progression-free survival may be too pessimistic to reflect the pembrolizumab group, and the company's preferred 2‑piece approach may be too optimistic. It did not consider either approach reliable for decision making without further justification, which could include exploration of other methods for estimating long-term outcomes. In response to consultation, the company submitted additional analyses using spline-based extrapolation methods and a response‑based model to analyse the time to progression and progression-free survival data. The ERG was satisfied that the company had explored the full range of realistic approaches to survival analysis. However, it did not consider that it was possible for the issue to be fully resolved given the current data limitations and noted that future data cuts of KEYNOTE‑826 would contribute to reducing the associated uncertainty. The committee recognised that these additional analyses may address some of the concerns around the company's extrapolation approach but uncertainties remain around the long-term survival projections. It also recognised that the company may not be able to reduce these uncertainties until longer follow-up data is available from KEYNOTE‑826. The committee concluded that the company's updated analyses were helpful for decision making, but the results are still highly uncertain. ## The company's approach for extrapolating post-progression survival in the model is reasonable To inform the risk of death after progression, the company extrapolated the post-progression survival data from KEYNOTE‑826. The company considered it unnecessary to apply a proportional hazards modelling approach when patient-level data was available for both the intervention and comparator. But it decided that the proportional hazards assumption was violated and fitted independent single parametric distributions to model post-progression survival in both treatment arms. The company selected the generalised gamma distribution for the base-case analysis based on statistical and visual fit to the Kaplan–Meier data and the clinical plausibility of long-term extrapolations and hazard functions. It tested the log-normal and log-logistic distributions as well as an assumption of equal post-progression survival based on a generalised gamma distribution fitted to pooled post-progression survival data for both arms from KEYNOTE‑826 in scenario analyses. The ERG was concerned that the long 'tails' predicted by the company's preferred models lacked clinical plausibility. The ERG considered the best match to the observed data was the Weibull curve. The ERG further noted that it is uncertain if any benefits of pembrolizumab will persist beyond progression. The ERG therefore preferred a more conservative assumption in which no treatment effect is assumed to persist beyond progression. It considered 2 scenarios to explore this uncertainty: a pooled post-progression survival curve using a generalised gamma curve preferred by the company and a pooled post‑progression survival curve using a Weibull curve. The ERG applied the pooled survival curve using the generalised gamma distribution in its preferred analysis. The committee considered that people who have pembrolizumab are likely to have at least a modest benefit in post‑progression survival compared with placebo. It concluded the company's use of 1‑piece generalised gamma models to predict post‑progression survival and assuming a differential survival benefit across treatment arms, with people whose disease progresses on pembrolizumab assumed to have longer post-progression survival, was reasonable. ## It is appropriate to assume that people will have pembrolizumab for up to 2 years In KEYNOTE‑826, treatment was stopped at about 2 years (35 cycles). A stopping rule was not included in the marketing authorisation, but the company assumed a stopping rule would apply in line with the trial. The committee therefore concluded that limiting treatment with pembrolizumab to 2 years is in line with KEYNOTE‑826 evidence. ## The duration of benefit for pembrolizumab should include an assumption that the treatment effect wanes after stopping treatment Before technical engagement the company assumed that, despite stopping pembrolizumab treatment after a maximum of 2 years, the treatment benefit would be maintained for a lifetime horizon. It explained that this was because the unique mode of action of pembrolizumab results in an extended period of benefit after treatment has stopped and KEYNOTE‑826 showed no evidence of treatment benefit decreasing over the 22‑month follow-up. The ERG highlighted there was no indication‑specific evidence to support a sustained treatment effect, and that the overall immaturity of the survival evidence means any such claimed benefit was highly uncertain. After technical engagement, the company updated its base case to include a treatment effect waning from 5 years to 7 years after stopping treatment. It also presented an alternative, more conservative, treatment effect waning scenario from 3 years to 5 years after stopping treatment. The ERG base-case analysis assumed a waning of the treatment effect from 2 years to 5 years after stopping treatment. At the first committee meeting, the committee heard that treatment effect waning assumptions had been imposed inconsistently in previous appraisals of immunotherapies. It noted a lack of clear evidence and guidance to inform a precise duration of waning effect but recalled that committees had assumed a waning of the treatment effect from 3 years to 5 years after stopping treatment in previous appraisals for pembrolizumab when a stopping rule had applied. In response to consultation, the company noted the committee's preference, but maintained that its preferred treatment effect waning assumption from 5 years to 7 years after stopping treatment was an appropriate middle ground between a 3- to 5‑year waning period and no waning. At the second committee meeting, the company recalled that there was no evidence of treatment effect waning in multiple 5‑year trials of pembrolizumab and so a treatment effect waning from 3 years to 5 years after stopping treatment was conservative. The ERG noted the 3- to 5‑year waning period was not conservative but was consistent with previous appraisals. The committee concluded that a treatment effect waning from 3 years to 5 years after stopping treatment with a 2‑year stopping rule was reasonable for pembrolizumab. # Utility values ## Using the health-state approach to estimate utilities is appropriate Health-state utilities in the economic model were estimated from health‑related quality of life data collected in KEYNOTE‑826. The company used 2 methods to estimate utility in the economic model: the time-to-death approach and the health-state approach. The time-to-death approach categorises utility based on the length of time before death. The health-state approach categorises utilities based on the health states in the model (progression-free survival, progressed disease and death). The company's base case used the time-to-death approach. It explained that delays between progression and symptoms, and different progression types, may blur the effect of progression on health-related quality of life. Progression-based methods may be less appropriate when assessing immunotherapies because of patients experiencing pseudo-progression, when the action of treatment is mistaken for disease. The ERG had concerns with the time-to-death approach. It considered the time-to-death approach severed the link between progression status and health-related quality of life, violating the accepted conclusion that progression status is a key driver of health-related quality of life. The ERG noted the clinical plausibility of this was unclear. The ERG favoured the health-state approach, explaining that most previous appraisals of immunotherapies had rejected a time-to-death approach. After the first meeting, the committee agreed with the ERG that the health-state approach was preferred because of the lack of evidence to suggest that the underlying mechanism of utility generation was based on time-to-death rather than progression. The committee also recalled the health-state approach was more consistent with other oncology appraisals. In response to consultation, the company acknowledged the committee's preference, and updated its base case to use the health state-based utility values (with a minor correction identified by the company). The ERG was satisfied that the company had updated the model correctly. # End of life ## Pembrolizumab combination meets end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival was not reached in the pembrolizumab arm of KEYNOTE‑826 in the presented interim analysis. A mean 2.19‑year survival benefit for the pembrolizumab arm compared with the placebo arm was estimated from the company base-case model after technical engagement. The ERG base case also supported a mean survival gain of greater than 3 months. The committee acknowledged that these survival estimations were based on the company's and ERG's base cases, so there was an element of uncertainty. The committee agreed that the extension to life for people with recurrent, persistent or metastatic cervical cancer who have pembrolizumab plus chemotherapy with or without bevacizumab is likely to be greater than 3 months compared with standard care. Median overall survival was 16.3 months in the placebo arm of KEYNOTE‑826. Mean overall survival for placebo estimated from the company's and ERG's base-case models after technical engagement was about 25 months. The company noted that in KEYNOTE‑826, 58.3% of people in the placebo arm had died at 24 months. Additionally, GOG 240 indicates that overall survival at 2 years is 28.3% in the chemotherapy-only group and 35.3% in the chemotherapy with bevacizumab group. The committee considered the appeal outcome of NICE's technology appraisal guidance on avelumab that 'normally less than 24 months' allowed a committee discretion to apply end of life criteria even if it felt some measures of life expectancy may be over 24 months. Based on the percentage survival at 24 months in KEYNOTE‑826, overall survival in the chemotherapy arms of GOG 240 and the observed and modelled medians, the committee concluded that survival is normally less than 24 months for people having standard care. Therefore, the committee accepted that the end of life criteria had been met. # Cost-effectiveness estimate ## Because of the uncertainty the maximum acceptable ICER would be substantially below £50,000 per QALY gained NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of confidential commercial arrangements for pembrolizumab, bevacizumab, and post-progression therapies, the ICERs are confidential and cannot be reported here.The committee noted the high level of uncertainty, specifically: the lack of a suitable approach for estimating time to progression and progression-free survival the uncertainty around the level of benefit pembrolizumab will have on overall survival.The committee also agreed that the end of life criteria applied to pembrolizumab, which allows it to consider ICERs of up to £50,000 per QALY gained. In response to consultation, the company considered £50,000 per QALY gained to be the appropriate decision-making threshold. This is because it considered there was enough certainty in the appropriateness of the model structure and in the clinical benefit, as well as consideration of additional benefit it said had not been captured in the model (see section 3.17). It said there was a low risk of decision error because the range of plausible ICER scenarios it had produced were at or below the £50,000 per QALY gained threshold. The ERG disagreed that decision uncertainty was small and recalled that KEYNOTE‑826 follow-up is limited and much of the modelled incremental benefit associated with pembrolizumab is in the extrapolated portion of the survival curve. The committee recognised the high unmet need for people with persistent, recurrent or metastatic cervical cancer and that there would be substantive clinical benefits associated with a positive recommendation for the pembrolizumab group but considered these benefits to already be captured by the model. Given the level of uncertainty, the committee concluded that the maximum acceptable ICER for routine commissioning would be substantially below £50,000 per QALY gained. ## Pembrolizumab plus chemotherapy with or without bevacizumab is not recommended for routine use The committee's preferred assumptions after the first meeting included: modelling a differential post-progression survival benefit across treatment arms using 1‑piece generalised gamma models (see section 3.8) including a treatment effect waning from 3 years to 5 years after discontinuation of pembrolizumab treatment with a 2‑year stopping rule (see section 3.10) using a health-state approach to estimate utilities (see section 3.11).The committee recognised that there were uncertainties and potential flaws in both the company's and ERG's approach to estimating time to progression and progression-free survival, and this had a substantial effect on the ICER. Because of this, the committee did not consider the company's or the ERG's original base cases to be suitable for decision making. In response to consultation, the company submitted additional analyses for estimating time to progression and progression-free survival to validate its original approach. The ERG explained in the second committee meeting that the company's approach considered the best fit to observed trial data for the pembrolizumab group while the ERG's approach considered the most clinically plausible extrapolation for the comparator arm and then focused on applying the same model type for the pembrolizumab arm. It acknowledged that its preferred approach may result in very pessimistic estimates of survival for the pembrolizumab arm but it reiterated that long-term outcomes may also not be as optimistic as predicted by the company's preferred approach. The company's updated base-case ICER for pembrolizumab plus chemotherapy compared with placebo plus chemotherapy (both with or without bevacizumab) was below £50,000 per QALY gained. This was when commercial arrangements for pembrolizumab and all the comparator and subsequent treatments were included. The ERG's estimate was considerably higher. After the second committee meeting, the committee considered analyses including the following assumptions: using a 2‑piece approach to model time to progression and progression-free survival (see section 3.7) several other ERG's preferred assumptions outlined in the first committee meeting, that is: ERG model corrections including costs for GP or nurse visits, blood-counts and thyroid function tests costs including all adverse events of special interest occurring in more than 5% of people including the other company-preferred assumptions, outlined above in this section.The committee concluded that the most plausible ICERs may be within the range usually considered a cost-effective use of NHS resources when the end of life modifier was applied. However, this is associated with high uncertainty, largely because of the insufficiency of trial data to determine the most plausible approach for extrapolating time to progression and progression-free survival. The committee also recalled that, given the level of uncertainty, the maximum acceptable ICER for routine commissioning would be substantially below £50,000 per QALY gained. The committee therefore concluded that it could not recommend pembrolizumab plus chemotherapy with or without bevacizumab for routine use. # Cancer Drugs Fund ## Pembrolizumab plus chemotherapy with or without bevacizumab is recommended for use in the Cancer Drugs Fund The committee considered if pembrolizumab plus chemotherapy with or without bevacizumab could be recommended for treating recurrent, persistent or metastatic cervical cancer within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It noted that: The company had expressed during the second committee meeting that it thought the Cancer Drugs Fund may be appropriate, but that it considered that it had provided sufficient data for the committee to recommend pembrolizumab plus chemotherapy with or without bevacizumab for routine use. Overall survival estimates in the economic model were highly uncertain, based on an assumption that gains in progression-free survival lead to gains in overall survival. Different extrapolation models for progression-free survival and time to progression were preferred by the company and the ERG but the committee did not consider either to be entirely reliable. KEYNOTE‑826 is still ongoing and trial data could help reduce uncertainties about overall survival and extrapolation of progression‑free survival and time to progression. The committee's preferred ICER has plausible potential to be cost effective when the end of life modifier was applied (the cost‑effectiveness estimates are confidential and cannot be reported here).The committee concluded that pembrolizumab plus chemotherapy with or without bevacizumab met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended it for use within the Cancer Drugs Fund as an option for persistent, recurrent or metastatic cervical cancer in adults whose tumours express PD‑L1 with a CPS of at least 1, if the conditions in the managed access agreement are followed. # Other factors ## There are no equality issues relevant to the recommendations The committee heard the potential equality issues raised during consultation. The company noted that metastatic cervical cancer was more common among people with low socioeconomic status as well as ethnic minority groups and migrants who have low engagement with vaccination and screening programmes. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal. Also, during consultation, the patient expert submissions highlighted that there was unequal access to pembrolizumab plus chemotherapy with or without bevacizumab for people with private healthcare insurance in comparison to those without. However, NICE's standard approach to economic modelling (the 'reference case') does not compare NHS healthcare with privately funded healthcare. The committee concluded that there were no relevant equality issues. ## All relevant benefits of the technology were captured in the QALY calculations There have been minimal developments made in managing persistent, recurrent or metastatic cervical cancer over the last decade. Pembrolizumab plus chemotherapy with or without bevacizumab provides benefit for people with persistent, recurrent or metastatic cervical cancer whose tumours express PD‑L1 with a CPS of at least 1. In response to consultation, the company noted health-related quality of life of carers and dependents of people with persistent, recurrent or metastatic cervical cancer had not been included in the economic model. It also explained that, although the utility data was not available, there was likely to be a significant increase in quality of life for people who remained progression‑free beyond 2 years. The ERG recalled the lack of precedent for including additional carer benefits in cancer appraisals. It also considered the magnitude of benefit for people surviving beyond 2 years to likely be minor in terms of determining the ICERs. The committee concluded that all relevant benefits of the technology were captured in the QALY calculations. # Conclusion ## Pembrolizumab plus chemotherapy with or without bevacizumab is recommended in the Cancer Drugs Fund The committee concluded that the most plausible ICERs may be within the range usually considered a cost-effective use of resources when the end of life modifier was applied, but these were associated with high uncertainty. Collecting more evidence may reduce this uncertainty. So, pembrolizumab plus chemotherapy with or without bevacizumab is recommended for use within the Cancer Drugs Fund as an option for treating persistent, recurrent or metastatic cervical cancer in adults whose tumours express PD‑L1 with a CPS of at least 1.	{'Recommendations': "Pembrolizumab plus chemotherapy with or without bevacizumab is recommended for use within the Cancer Drugs Fund as an option for treating persistent, recurrent or metastatic cervical cancer in adults whose tumours express PD‑L1 with a combined positive score (CPS) of at least\xa01. It is recommended only if:\n\npembrolizumab is stopped at 2\xa0years of uninterrupted treatment, or earlier if disease progresses, and\n\nthe conditions in the managed access agreement for pembrolizumab are followed.\n\nThis recommendation is not intended to affect treatment with pembrolizumab plus chemotherapy with or without bevacizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for persistent, recurrent or metastatic cervical cancer includes chemotherapy with or without bevacizumab.\n\nEvidence from a clinical trial shows that if people have pembrolizumab plus chemotherapy with or without bevacizumab it takes longer for their cancer to get worse than people having standard care. Evidence from this trial also suggests they may live longer. But, it is unclear how much longer it takes for their cancer to get worse, or how long they live, because the trial is ongoing. In this trial, people had pembrolizumab for up to 2\xa0years.\n\nBecause of the uncertainty in the clinical trial evidence, the cost-effectiveness estimates are also uncertain. Pembrolizumab plus chemotherapy with or without bevacizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. But, even when taking this into account, some of the likely cost‑effectiveness estimates are above what NICE considers an acceptable use of NHS resources. So, pembrolizumab plus chemotherapy with or without bevacizumab cannot be recommended for routine use in the NHS.\n\nCollecting and analysing data from the ongoing clinical trial through the Cancer Drugs Fund may reduce the uncertainty in the evidence. So, pembrolizumab plus chemotherapy with or without bevacizumab is recommended for use in the Cancer Drugs Fund.", 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp and Dohme) 'in combination with chemotherapy with or without bevacizumab, is indicated for 'the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express programmed cell death ligand\xa01 (PD‑L1) with a combined positive score (CPS) ≥ 1'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nThe list price is £2,630.00 per 100\xa0mg/4\xa0ml concentrate for solution for infusion vial (excluding VAT; BNF online accessed January\xa02023).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck Sharp and Dohme (MSD), a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## Persistent, recurrent or metastatic cervical cancer has a high disease burden\n\nCervical cancer develops when abnormal cells in the cervix lining grow in an uncontrolled way, forming a tumour. Infection with human papillomavirus is associated with the development of cervical cancer. Cervical cancer is defined as persistent when it does not respond to treatment, recurrent when it has returned after treatment and metastatic when it has spread beyond the cervix to other places in the body. The patient expert explained that people diagnosed with cervical cancer often experience substantial disruption to their quality of life. With a median age of diagnosis of 51\xa0years, many are of working age, with family and dependants. Despite affecting a population that is typically younger than often seen with other cancers, prognosis is poor. Median overall survival with standard treatment (cisplatin and paclitaxel with or without bevacizumab) was just 13\xa0months to 17\xa0months in GOG\xa0240, a randomised phase\xa03 trial done in people with persistent, recurrent or metastatic cervical cancer. The committee concluded that there is a high disease burden for people with persistent, recurrent or metastatic cervical cancer, and that a treatment that can prolong life but also improve quality of survival by managing symptoms would be welcome.\n\n## There are limited effective treatment options available for persistent, recurrent or metastatic cervical cancer\n\nClinical experts explained that people with persistent, recurrent or metastatic cervical cancer have limited effective treatment options. People usually have paclitaxel plus either carboplatin or cisplatin, with or without bevacizumab. Bevacizumab is considered suitable if the person has a good disease performance status, no significant comorbidities and low risk of bowel fistula formation. The scope and company submission noted that bevacizumab was available as an option through the Cancer Drugs Fund, but the Cancer Drugs Fund clinical lead clarified that bevacizumab is now in routine commissioning for this indication. Although NICE technology appraisal guidance recommends topotecan for treating recurrent and stage 4B cervical cancer, it is not frequently used in clinical practice. The main aim of treatment for persistent, recurrent or metastatic cervical cancer is to relieve symptoms and improve quality of life, and to extend life if possible. The patient expert explained that people with the condition may be worried about the limited time they have left with their family, the lack of available treatment options, and the side effects of treatment. The committee recognised that there are limited effective treatment options available for persistent, recurrent or metastatic cervical cancer.\n\n# Clinical evidence\n\n## Pembrolizumab combination is more effective than placebo combination but overall survival is uncertain in the long term\n\nThe clinical evidence was based on KEYNOTE-826, a phase\xa03, randomised double-blind placebo-controlled trial in people with recurrent, persistent or metastatic cervical cancer. KEYNOTE-826 compared pembrolizumab plus chemotherapy with or without bevacizumab against placebo plus chemotherapy with or without bevacizumab as a first-line therapy. In line with the marketing authorisation, the company submission presented efficacy data for people whose tumours express PD‑L1 with a combined positive score (CPS) of at least\xa01. Chemotherapies included in the trial, either with pembrolizumab or placebo, were cisplatin plus paclitaxel or carboplatin plus paclitaxel. In the CPS of at least 1\xa0population, 63.1% of people had bevacizumab. The interim trial results showed a clinically meaningful and statistically significant benefit for the pembrolizumab group compared with the placebo group for both progression-free survival and overall survival. The hazard ratio for progression-free survival by investigator assessment for the CPS of at least 1 population was 0.62 (95% confidence interval [CI] 0.50 to 0.77). The hazard ratio for overall survival at 24\xa0months for the CPS of at least 1\xa0population was 0.64 (95% CI 0.50 to 0.81). Median overall survival in the CPS of at least 1 population was not reached in the pembrolizumab group and was 16.3\xa0months in the placebo group. The clinical experts considered that, although people in clinical trials tend to be fitter than those in clinical practice, the overall survival outcomes in the KEYNOTE‑826 placebo group were consistent with those previously seen in GOG\xa0240 (see section\xa03.1). The ERG noted that although an overall survival benefit for the pembrolizumab group was likely because of the separation of the Kaplan–Meier curves between the treatment arms, the duration and size of the long-term benefit beyond trial follow-up was uncertain. After the first committee meeting, the committee concluded that, based on the available data, pembrolizumab plus chemotherapy with or without bevacizumab is more effective than chemotherapy with or without bevacizumab, but overall survival data is still immature. At the second committee meeting, the clinical expert explained that survival beyond 1\xa0year was considered a good outcome for people with persistent, recurrent or metastatic cervical cancer. In KEYNOTE-826 the survival benefit was already considerable though median overall survival had not yet been reached in the pembrolizumab group. Overall survival data from the interim analysis of KEYNOTE-826 was therefore considered by the clinical expert to be insufficient, not immature. The committee concluded that uncertainty remained about long-term survival for the pembrolizumab group.\n\n## Decision making includes the whole marketing authorisation population\n\nIn KEYNOTE-826, people with metastatic cervical cancer at initial diagnosis had statistically significantly worse outcomes for progression‑free survival and overall survival than people with non‑metastatic cervical cancer at initial diagnosis. The ERG noted that the hazard ratios for the subgroup of people with metastases at diagnosis were comparable to those in the subgroup of people with a PD‑L1 status of CPS of less than 1, who were excluded from the marketing authorisation. The clinical experts explained that, in clinical practice, there was no differentiation between people with metastatic cervical cancer at initial diagnosis and people with recurrent cervical cancer. The clinical experts also noted that the proportion of people with metastatic cervical cancer at initial diagnosis in KEYNOTE‑826 was higher than they expected in clinical practice. The company cautioned against over‑interpretation of results for people with metastatic cervical cancer at initial diagnosis because KEYNOTE‑826 was not designed or powered to allow for formal testing of the heterogeneity in subgroups. The ERG explained that people in KEYNOTE‑826 were stratified by metastatic status at initial diagnosis so this was not an unplanned subgroup. The committee recalled that it does not seek to create subgroups within the marketing authorisation population for decision making unless there is clear underpinning evidence. Clinical experts explained that they would offer pembrolizumab treatment to people with cervical cancer which was metastatic at initial diagnosis based on the benefits seen in the overall CPS of at least 1 population. The committee concluded that people with metastatic cervical cancer at initial diagnosis was not a relevant subgroup and so decision making would include the whole population included in the marketing authorisation.\n\n# The company's economic model\n\n## The most appropriate modelling approach may change when further data from KEYNOTE-826 is available\n\nThe company presented a 3‑state Markov state transition model to estimate the cost effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy (both with or without bevacizumab). The 3\xa0health states were progression-free survival, progressed disease and death. The company explained that Kaplan–Meier data by response status showed that overall survival in the interim analysis was largely informed by people whose disease had not responded to treatment, and that there was not enough overall survival data for people whose disease responded. Data on overall survival was therefore not mature enough to accurately model long-term survival for people whose disease had and had not responded, particularly those with a complete disease response. It suggested that in this case, a state transition model was more accurate than a partitioned survival model, which relies on direct extrapolation of observed overall survival data. The ERG noted the state transition model approach uses a structural link between progression-free survival and overall survival and implies gains in progression-free survival should translate into gains in overall survival. Although the ERG considered the company's evidence was broadly supportive of this assumption, it noted limited evidence was provided to show a validated relationship between progression-free survival and overall survival in this indication. The ERG also questioned the plausibility of the predicted long-term benefits of pembrolizumab in the model, which were heavily dependent on the approach to extrapolating progression-free survival, and were a direct consequence of the structural link between progression-free survival and overall survival imposed by the state transition model. The committee recalled advice by the NICE Decision Support Unit technical support document 19 that states transition modelling alongside a partitioned survival approach can assist in verifying the plausibility of extrapolations and addressing the uncertainties in the extrapolation period. The committee concluded that although the company's model may be adequate for decision making with the data currently available, when further data becomes available from KEYNOTE‑826, the most appropriate modelling approach may change.\n\n## It is likely that improvements in progression-free survival are associated with an overall survival benefit\n\nOverall survival data from KEYNOTE‑826 is immature, with median overall survival not being reached in the pembrolizumab arm in the interim analysis. The cost-effectiveness modelling therefore relied on progression data to inform longer-term mortality extrapolations. The ERG was concerned that the company's economic model predicts an overall survival benefit that is similar in size to the progression-free survival benefit, and this was unproven. However, the company noted that the overall survival and progression-free survival hazard ratios seen within KEYNOTE‑826 were similar (respective point estimates are 0.64 and 0.62 in the CPS of at least 1 population). The committee considered whether gains in progression-free survival would translate into gains in overall survival. The clinical experts explained that there is a lack of treatment options at second line for persistent, recurrent or metastatic cervical cancer which could affect subsequent survival, and non-cancer mortality was unlikely to have a large effect in this population. So, it was likely that the benefit in progression-free survival would be reflected in overall survival. The Cancer Drugs Fund clinical lead agreed that this was biologically plausible and recalled evidence of gains in progression-free survival leading to gains in overall survival in other cancer trials, including cervical cancer. The committee concluded that, based on its earlier conclusion that pembrolizumab improved progression-free survival compared with placebo, it was likely that pembrolizumab also improved overall survival. However, the level of this benefit is uncertain.\n\n## The most appropriate approach for extrapolating time to progression and progression-free survival is uncertain\n\nTo inform the risk of disease progression or death, the company extrapolated the time to progression and progression-free survival data. The same model type was used for both time to progression and progression-free survival to ensure the model results remained clinically plausible. Model selection was based on statistical fit, visual fit, the desire for common functional form of models to both arms, the plausibility of hazard assumptions and clinical plausibility of the survival predictions. The company stated that 1‑piece models in which a parametric distribution was fitted to the whole Kaplan–Meier curve had poor visual fit to the observed data and were unable to appropriately capture what it considered to be an emerging plateau in the observed survival data. The company's base-case model used a 2‑piece approach to modelling time to progression and progression-free survival. Kaplan–Meier data from KEYNOTE‑826 was used up to 37\xa0weeks, followed by log-logistic parametric survival models fitted to the remaining observed data. The ERG agreed with the company that there was some evidence of an emerging plateau in the time to progression and progression-free survival Kaplan–Meier curves for pembrolizumab. But, it considered there was limited overall survival evidence to support the substantial progression‑free survival and overall survival gains modelled by the company. It also considered that the company's 2‑piece approach led to an optimistic projection of people achieving long-term survival on pembrolizumab. The ERG preferred to use a 1‑piece log-logistic extrapolation for both arms. In response to technical engagement, the company updated their base-case analysis to align with the ERG's preferred 1‑piece log-logistic model for the placebo combination but maintained their preference for the 2‑piece Kaplan–Meier plus log-logistic model for the pembrolizumab group. The company explained that it considered the ERG's preferred 1‑piece log-logistic model for pembrolizumab to be inappropriate because of a very poor visual fit to the observed data. The company also considered that pembrolizumab has a different mechanism of action to the drugs in the placebo group and suggested it may be appropriate to use a separate model type between arms based on criteria described in the NICE Decision Support Unit technical support document 14. The ERG urged caution in the committee accepting different model types between treatment arms given the different shaped distributions, which implied that people can follow different patterns of events depending on which treatment they had. The committee recalled differing model types had been presented in previous appraisals and, although needing adequate justification, may be appropriate if it is accepted that the disease course could be different depending on the treatment received. After the first committee meeting, the committee concluded that the ERG's preferred 1‑piece log-logistic extrapolation for time to progression and progression-free survival may be too pessimistic to reflect the pembrolizumab group, and the company's preferred 2‑piece approach may be too optimistic. It did not consider either approach reliable for decision making without further justification, which could include exploration of other methods for estimating long-term outcomes. In response to consultation, the company submitted additional analyses using spline-based extrapolation methods and a response‑based model to analyse the time to progression and progression-free survival data. The ERG was satisfied that the company had explored the full range of realistic approaches to survival analysis. However, it did not consider that it was possible for the issue to be fully resolved given the current data limitations and noted that future data cuts of KEYNOTE‑826 would contribute to reducing the associated uncertainty. The committee recognised that these additional analyses may address some of the concerns around the company's extrapolation approach but uncertainties remain around the long-term survival projections. It also recognised that the company may not be able to reduce these uncertainties until longer follow-up data is available from KEYNOTE‑826. The committee concluded that the company's updated analyses were helpful for decision making, but the results are still highly uncertain.\n\n## The company's approach for extrapolating post-progression survival in the model is reasonable\n\nTo inform the risk of death after progression, the company extrapolated the post-progression survival data from KEYNOTE‑826. The company considered it unnecessary to apply a proportional hazards modelling approach when patient-level data was available for both the intervention and comparator. But it decided that the proportional hazards assumption was violated and fitted independent single parametric distributions to model post-progression survival in both treatment arms. The company selected the generalised gamma distribution for the base-case analysis based on statistical and visual fit to the Kaplan–Meier data and the clinical plausibility of long-term extrapolations and hazard functions. It tested the log-normal and log-logistic distributions as well as an assumption of equal post-progression survival based on a generalised gamma distribution fitted to pooled post-progression survival data for both arms from KEYNOTE‑826 in scenario analyses. The ERG was concerned that the long 'tails' predicted by the company's preferred models lacked clinical plausibility. The ERG considered the best match to the observed data was the Weibull curve. The ERG further noted that it is uncertain if any benefits of pembrolizumab will persist beyond progression. The ERG therefore preferred a more conservative assumption in which no treatment effect is assumed to persist beyond progression. It considered 2\xa0scenarios to explore this uncertainty: a pooled post-progression survival curve using a generalised gamma curve preferred by the company and a pooled post‑progression survival curve using a Weibull curve. The ERG applied the pooled survival curve using the generalised gamma distribution in its preferred analysis. The committee considered that people who have pembrolizumab are likely to have at least a modest benefit in post‑progression survival compared with placebo. It concluded the company's use of 1‑piece generalised gamma models to predict post‑progression survival and assuming a differential survival benefit across treatment arms, with people whose disease progresses on pembrolizumab assumed to have longer post-progression survival, was reasonable.\n\n## It is appropriate to assume that people will have pembrolizumab for up to 2 years\n\nIn KEYNOTE‑826, treatment was stopped at about 2\xa0years (35\xa0cycles). A stopping rule was not included in the marketing authorisation, but the company assumed a stopping rule would apply in line with the trial. The committee therefore concluded that limiting treatment with pembrolizumab to 2\xa0years is in line with KEYNOTE‑826 evidence.\n\n## The duration of benefit for pembrolizumab should include an assumption that the treatment effect wanes after stopping treatment\n\nBefore technical engagement the company assumed that, despite stopping pembrolizumab treatment after a maximum of 2\xa0years, the treatment benefit would be maintained for a lifetime horizon. It explained that this was because the unique mode of action of pembrolizumab results in an extended period of benefit after treatment has stopped and KEYNOTE‑826 showed no evidence of treatment benefit decreasing over the 22‑month follow-up. The ERG highlighted there was no indication‑specific evidence to support a sustained treatment effect, and that the overall immaturity of the survival evidence means any such claimed benefit was highly uncertain. After technical engagement, the company updated its base case to include a treatment effect waning from 5\xa0years to 7\xa0years after stopping treatment. It also presented an alternative, more conservative, treatment effect waning scenario from 3\xa0years to 5\xa0years after stopping treatment. The ERG base-case analysis assumed a waning of the treatment effect from 2\xa0years to 5\xa0years after stopping treatment. At the first committee meeting, the committee heard that treatment effect waning assumptions had been imposed inconsistently in previous appraisals of immunotherapies. It noted a lack of clear evidence and guidance to inform a precise duration of waning effect but recalled that committees had assumed a waning of the treatment effect from 3\xa0years to 5\xa0years after stopping treatment in previous appraisals for pembrolizumab when a stopping rule had applied. In response to consultation, the company noted the committee's preference, but maintained that its preferred treatment effect waning assumption from 5\xa0years to 7\xa0years after stopping treatment was an appropriate middle ground between a 3-\xa0to 5‑year waning period and no waning. At the second committee meeting, the company recalled that there was no evidence of treatment effect waning in multiple 5‑year trials of pembrolizumab and so a treatment effect waning from 3\xa0years to 5\xa0years after stopping treatment was conservative. The ERG noted the 3-\xa0to 5‑year waning period was not conservative but was consistent with previous appraisals. The committee concluded that a treatment effect waning from 3\xa0years to 5\xa0years after stopping treatment with a 2‑year stopping rule was reasonable for pembrolizumab.\n\n# Utility values\n\n## Using the health-state approach to estimate utilities is appropriate\n\nHealth-state utilities in the economic model were estimated from health‑related quality of life data collected in KEYNOTE‑826. The company used 2\xa0methods to estimate utility in the economic model: the time-to-death approach and the health-state approach. The time-to-death approach categorises utility based on the length of time before death. The health-state approach categorises utilities based on the health states in the model (progression-free survival, progressed disease and death). The company's base case used the time-to-death approach. It explained that delays between progression and symptoms, and different progression types, may blur the effect of progression on health-related quality of life. Progression-based methods may be less appropriate when assessing immunotherapies because of patients experiencing pseudo-progression, when the action of treatment is mistaken for disease. The ERG had concerns with the time-to-death approach. It considered the time-to-death approach severed the link between progression status and health-related quality of life, violating the accepted conclusion that progression status is a key driver of health-related quality of life. The ERG noted the clinical plausibility of this was unclear. The ERG favoured the health-state approach, explaining that most previous appraisals of immunotherapies had rejected a time-to-death approach. After the first meeting, the committee agreed with the ERG that the health-state approach was preferred because of the lack of evidence to suggest that the underlying mechanism of utility generation was based on time-to-death rather than progression. The committee also recalled the health-state approach was more consistent with other oncology appraisals. In response to consultation, the company acknowledged the committee's preference, and updated its base case to use the health state-based utility values (with a minor correction identified by the company). The ERG was satisfied that the company had updated the model correctly.\n\n# End of life\n\n## Pembrolizumab combination meets end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival was not reached in the pembrolizumab arm of KEYNOTE‑826 in the presented interim analysis. A mean 2.19‑year survival benefit for the pembrolizumab arm compared with the placebo arm was estimated from the company base-case model after technical engagement. The ERG base case also supported a mean survival gain of greater than 3\xa0months. The committee acknowledged that these survival estimations were based on the company's and ERG's base cases, so there was an element of uncertainty. The committee agreed that the extension to life for people with recurrent, persistent or metastatic cervical cancer who have pembrolizumab plus chemotherapy with or without bevacizumab is likely to be greater than 3\xa0months compared with standard care. Median overall survival was 16.3\xa0months in the placebo arm of KEYNOTE‑826. Mean overall survival for placebo estimated from the company's and ERG's base-case models after technical engagement was about 25\xa0months. The company noted that in KEYNOTE‑826, 58.3% of people in the placebo arm had died at 24\xa0months. Additionally, GOG\xa0240 indicates that overall survival at 2\xa0years is 28.3% in the chemotherapy-only group and 35.3% in the chemotherapy with bevacizumab group. The committee considered the appeal outcome of NICE's technology appraisal guidance on avelumab that 'normally less than 24\xa0months' allowed a committee discretion to apply end of life criteria even if it felt some measures of life expectancy may be over 24\xa0months. Based on the percentage survival at 24\xa0months in KEYNOTE‑826, overall survival in the chemotherapy arms of GOG\xa0240 and the observed and modelled medians, the committee concluded that survival is normally less than 24\xa0months for people having standard care. Therefore, the committee accepted that the end of life criteria had been met.\n\n# Cost-effectiveness estimate\n\n## Because of the uncertainty the maximum acceptable ICER would be substantially below £50,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of confidential commercial arrangements for pembrolizumab, bevacizumab, and post-progression therapies, the ICERs are confidential and cannot be reported here.The committee noted the high level of uncertainty, specifically:\n\nthe lack of a suitable approach for estimating time to progression and progression-free survival\n\nthe uncertainty around the level of benefit pembrolizumab will have on overall survival.The committee also agreed that the end of life criteria applied to pembrolizumab, which allows it to consider ICERs of up to £50,000 per QALY gained. In response to consultation, the company considered £50,000 per QALY gained to be the appropriate decision-making threshold. This is because it considered there was enough certainty in the appropriateness of the model structure and in the clinical benefit, as well as consideration of additional benefit it said had not been captured in the model (see section\xa03.17). It said there was a low risk of decision error because the range of plausible ICER scenarios it had produced were at or below the £50,000 per QALY gained threshold. The ERG disagreed that decision uncertainty was small and recalled that KEYNOTE‑826 follow-up is limited and much of the modelled incremental benefit associated with pembrolizumab is in the extrapolated portion of the survival curve. The committee recognised the high unmet need for people with persistent, recurrent or metastatic cervical cancer and that there would be substantive clinical benefits associated with a positive recommendation for the pembrolizumab group but considered these benefits to already be captured by the model. Given the level of uncertainty, the committee concluded that the maximum acceptable ICER for routine commissioning would be substantially below £50,000 per QALY gained.\n\n## Pembrolizumab plus chemotherapy with or without bevacizumab is not recommended for routine use\n\nThe committee's preferred assumptions after the first meeting included:\n\nmodelling a differential post-progression survival benefit across treatment arms using 1‑piece generalised gamma models (see section\xa03.8)\n\nincluding a treatment effect waning from 3\xa0years to 5\xa0years after discontinuation of pembrolizumab treatment with a 2‑year stopping rule (see section\xa03.10)\n\nusing a health-state approach to estimate utilities (see section\xa03.11).The committee recognised that there were uncertainties and potential flaws in both the company's and ERG's approach to estimating time to progression and progression-free survival, and this had a substantial effect on the ICER. Because of this, the committee did not consider the company's or the ERG's original base cases to be suitable for decision making. In response to consultation, the company submitted additional analyses for estimating time to progression and progression-free survival to validate its original approach. The ERG explained in the second committee meeting that the company's approach considered the best fit to observed trial data for the pembrolizumab group while the ERG's approach considered the most clinically plausible extrapolation for the comparator arm and then focused on applying the same model type for the pembrolizumab arm. It acknowledged that its preferred approach may result in very pessimistic estimates of survival for the pembrolizumab arm but it reiterated that long-term outcomes may also not be as optimistic as predicted by the company's preferred approach. The company's updated base-case ICER for pembrolizumab plus chemotherapy compared with placebo plus chemotherapy (both with or without bevacizumab) was below £50,000 per QALY gained. This was when commercial arrangements for pembrolizumab and all the comparator and subsequent treatments were included. The ERG's estimate was considerably higher. After the second committee meeting, the committee considered analyses including the following assumptions:\n\nusing a 2‑piece approach to model time to progression and progression-free survival (see section\xa03.7)\n\nseveral other ERG's preferred assumptions outlined in the first committee meeting, that is:\n\n\n\nERG model corrections\n\nincluding costs for GP or nurse visits, blood-counts and thyroid function tests costs\n\nincluding all adverse events of special interest occurring in more than 5% of people\n\n\n\nincluding the other company-preferred assumptions, outlined above in this section.The committee concluded that the most plausible ICERs may be within the range usually considered a cost-effective use of NHS resources when the end of life modifier was applied. However, this is associated with high uncertainty, largely because of the insufficiency of trial data to determine the most plausible approach for extrapolating time to progression and progression-free survival. The committee also recalled that, given the level of uncertainty, the maximum acceptable ICER for routine commissioning would be substantially below £50,000 per QALY gained. The committee therefore concluded that it could not recommend pembrolizumab plus chemotherapy with or without bevacizumab for routine use.\n\n# Cancer Drugs Fund\n\n## Pembrolizumab plus chemotherapy with or without bevacizumab is recommended for use in the Cancer Drugs Fund\n\nThe committee considered if pembrolizumab plus chemotherapy with or without bevacizumab could be recommended for treating recurrent, persistent or metastatic cervical cancer within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). It noted that:\n\nThe company had expressed during the second committee meeting that it thought the Cancer Drugs Fund may be appropriate, but that it considered that it had provided sufficient data for the committee to recommend pembrolizumab plus chemotherapy with or without bevacizumab for routine use.\n\nOverall survival estimates in the economic model were highly uncertain, based on an assumption that gains in progression-free survival lead to gains in overall survival.\n\nDifferent extrapolation models for progression-free survival and time to progression were preferred by the company and the ERG but the committee did not consider either to be entirely reliable.\n\nKEYNOTE‑826 is still ongoing and trial data could help reduce uncertainties about overall survival and extrapolation of progression‑free survival and time to progression.\n\nThe committee's preferred ICER has plausible potential to be cost effective when the end of life modifier was applied (the cost‑effectiveness estimates are confidential and cannot be reported here).The committee concluded that pembrolizumab plus chemotherapy with or without bevacizumab met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended it for use within the Cancer Drugs Fund as an option for persistent, recurrent or metastatic cervical cancer in adults whose tumours express PD‑L1 with a CPS of at least 1, if the conditions in the managed access agreement are followed.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe committee heard the potential equality issues raised during consultation. The company noted that metastatic cervical cancer was more common among people with low socioeconomic status as well as ethnic minority groups and migrants who have low engagement with vaccination and screening programmes. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal. Also, during consultation, the patient expert submissions highlighted that there was unequal access to pembrolizumab plus chemotherapy with or without bevacizumab for people with private healthcare insurance in comparison to those without. However, NICE's standard approach to economic modelling (the 'reference case') does not compare NHS healthcare with privately funded healthcare. The committee concluded that there were no relevant equality issues.\n\n## All relevant benefits of the technology were captured in the QALY calculations\n\nThere have been minimal developments made in managing persistent, recurrent or metastatic cervical cancer over the last decade. Pembrolizumab plus chemotherapy with or without bevacizumab provides benefit for people with persistent, recurrent or metastatic cervical cancer whose tumours express PD‑L1 with a CPS of at least 1. In response to consultation, the company noted health-related quality of life of carers and dependents of people with persistent, recurrent or metastatic cervical cancer had not been included in the economic model. It also explained that, although the utility data was not available, there was likely to be a significant increase in quality of life for people who remained progression‑free beyond 2\xa0years. The ERG recalled the lack of precedent for including additional carer benefits in cancer appraisals. It also considered the magnitude of benefit for people surviving beyond 2\xa0years to likely be minor in terms of determining the ICERs. The committee concluded that all relevant benefits of the technology were captured in the QALY calculations.\n\n# Conclusion\n\n## Pembrolizumab plus chemotherapy with or without bevacizumab is recommended in the Cancer Drugs Fund\n\nThe committee concluded that the most plausible ICERs may be within the range usually considered a cost-effective use of resources when the end of life modifier was applied, but these were associated with high uncertainty. Collecting more evidence may reduce this uncertainty. So, pembrolizumab plus chemotherapy with or without bevacizumab is recommended for use within the Cancer Drugs Fund as an option for treating persistent, recurrent or metastatic cervical cancer in adults whose tumours express PD‑L1 with a CPS of at least 1."}	https://www.nice.org.uk/guidance/ta885	Evidence-based recommendations on pembrolizumab (Keytruda) plus chemotherapy with or without bevacizumab for persistent, recurrent or metastatic cervical cancer in adults.
fa60d0dd558e189dd74f1ec6971d9df319bc2bf2	nice	Voclosporin with mycophenolate mofetil for treating lupus nephritis	Voclosporin with mycophenolate mofetil for treating lupus nephritis Evidence-based recommendations on voclosporin (Lupkynis) with mycophenolate mofetil for treating lupus nephritis in adults. # Recommendations Voclosporin with mycophenolate mofetil is recommended, within its marketing authorisation, as an option for treating active class 3 to 5 (including mixed class 3 and 5, and 4 and 5) lupus nephritis in adults. It is only recommended if the company provides voclosporin according to the commercial arrangement. Why the committee made this recommendation Treatment options for active lupus nephritis include immunosuppressants such as mycophenolate mofetil. There are several other immunosuppressant options depending on factors such as condition severity, previous treatments and other conditions such as organ damage. Clinical trial evidence suggests voclosporin with mycophenolate mofetil is more effective at stopping lupus nephritis from getting worse than mycophenolate mofetil alone. Indirect comparisons suggest voclosporin with mycophenolate mofetil is more effective than other immunosuppressant options. The most likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So, voclosporin with mycophenolate mofetil is recommended.# Information about voclosporin # Marketing authorisation indication Voclosporin (Lupkynis, Otsuka) is indicated 'in combination with mycophenolate mofetil for the treatment of adult patients with active class 3, 4 or 5 (including mixed class 3/5 and 4/5) lupus nephritis'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for voclosporin. # Price Voclosporin costs £1,000 per 180‑pack of 7.9 mg soft capsules (excluding VAT; company submission). Voclosporin costs £12,167 for 12 months of treatment. The list price of mycophenolate mofetil is £6.23 per 50‑pack of 500 mg tablets (excluding VAT; BNF online accessed March 2023). The company has a commercial arrangement. This makes voclosporin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Otsuka, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need ## Nature of the condition Lupus nephritis is a complication of systemic lupus erythematosus, a chronic condition that causes inflammation in connective tissues. It occurs in around 40% to 60% of people with systemic lupus erythematosus and affects the kidneys, specifically glomeruli cells. Clinical experts highlighted the high unmet need for people with lupus nephritis because the condition is not curable. The disease follows a cycle of relapsing and remitting. Some people develop end-stage renal disease if their condition does not respond to treatment and need dialysis or kidney transplants to survive. Lupus nephritis is a debilitating disease which significantly impacts the lives of people with the condition and those who care for them. Patient experts highlighted the most challenging aspects for people with lupus nephritis are the symptoms, reduced ability to work and impact on mental wellbeing. Patient experts explained that in a 2020 survey of 67 people with lupus nephritis, 81% reported fatigue as the most difficult symptom, followed by joint pain and swelling (60%). People with the condition explained how lack of energy makes every day a challenge. In the same survey 57% of people with lupus nephritis felt isolated once a week and 58% needed help with household care, while 33% needed help with personal care. Carers of people with lupus nephritis are significantly impacted because of helping with daily tasks and having less time to work and socialise. There is also constant anxiety about the health of people with lupus nephritis because of the lack of a cure and because of regular tests to monitor the condition. The committee also heard how carers feel helpless, especially when lupus nephritis symptoms are worse. Patient and clinical experts also explained how current treatments have significant adverse effects. These side effects can cause other conditions that need separate treatment. They also severely impact quality of life and in some cases may affect adherence to dosing regimens. The committee concluded that lupus nephritis is a debilitating condition and there is high unmet need for effective treatments with manageable side effects. # Clinical management ## Treatment options Clinical and patient experts highlighted that lupus nephritis is a highly heterogeneous condition. This may result in considerable differences in treatment options because of varying needs and personal circumstances. Clinical experts explained that lupus nephritis rarely happens in isolation and that treatment choices depend on lots of other factors, including disease severity, previous treatments and comorbidities such as organ damage. They explained that lupus nephritis follows a cycle of relapsing and remitting, meaning treatments are used to either induce or maintain remission. They added that treatments varied only by the immunosuppressives taken with hydroxychloroquine and tapered doses of corticosteroids. The immunosuppressives used to induce remission include methylprednisolone with mycophenolate mofetil, low- and high‑dose cyclophosphamide, rituximab with mycophenolate mofetil, and tacrolimus with or without mycophenolate mofetil. Maintenance treatments include mycophenolate mofetil, azathioprine and tacrolimus monotherapy. The committee concluded that the treatment options for lupus nephritis are highly heterogenous and are expected to frequently change based on disease response. ## Treatment positioning of voclosporin Clinical experts explained that voclosporin, a calcineurin inhibitor, would be an add-on treatment to mycophenolate mofetil and corticosteroids for treating lupus nephritis. The company highlighted that the marketing authorisation for voclosporin does not specify a treatment line. Clinical experts expressed uncertainty about how voclosporin would be used in clinical practice. Some experts agreed it would be used as a first-line induction treatment or a later add-on treatment for people whose condition doesn't respond to mycophenolate mofetil alone, like in the AURORA trials (see section 3.4). Other experts suggested that voclosporin may be used hesitantly in the first line because of the lack of long-term evidence and that use after other treatments is more likely. The EAG explained that calcineurin inhibitors were usually used as later-line treatments. So, clinician hesitation would be expected for using voclosporin as a first-line induction treatment. But it said that mycophenolate mofetil alone was the most suitable comparator if voclosporin was to be used as a first-line treatment. It added that tacrolimus plus mycophenolate mofetil would be the most suitable comparator for later-line treatments. Clinical experts and the Innovative Medicines Fund clinical lead explained that voclosporin would be used to induce remission and not as a maintenance treatment. Clinical experts added that considering induction or maintenance treatment positioning is more appropriate than considering first-line and later lines of treatment. Lupus nephritis follows cycles of relapse and remission so a treatment previously used to induce remission could be considered a treatment option in the future. The company highlighted that voclosporin was used in the AURORA trials as a first- or subsequent-line induction treatment. So, mycophenolate mofetil alone or with tacrolimus are the most appropriate comparators. Stakeholder responses to draft guidance consultation also highlighted the use of voclosporin as an induction treatment. The committee considered that the AURORA trials only showed an ability to induce remission, but voclosporin's mechanism of action suggests maintenance use may also be possible. But it recalled clinical experts' opinion that voclosporin would be used to induce remission and not typically for more than 9 to 12 months, although it may be used again if it was effective at inducing remission. So, the committee concluded that voclosporin would be used to induce remission and not as a long-term maintenance treatment. Based on this, it identified mycophenolate mofetil alone or with tacrolimus as the most appropriate comparators (see section 3.2). # Clinical evidence ## Pivotal clinical trials and outcome measures The clinical evidence for voclosporin was from the phase 3 AURORA 1 and AURORA 2 trials. These were multicentre, double-blind, placebo-controlled randomised trials. AURORA 2 was a 24‑month long-term continuation study for people who had completed the 12‑month AURORA 1 study. People had voclosporin or placebo, plus mycophenolate mofetil and low-dose corticosteroids. The primary endpoint of AURORA 1 was complete renal response at 12 months, which was 40.8% for voclosporin and 22.5% for placebo. AURORA 1 recruited 357 people from 27 countries, 216 of whom also enrolled in AURORA 2. Clinical experts noted that complete renal response in the AURORA trials was a composite endpoint, comprising several measures. This included changes to the urine protein to creatinine ratio and estimated glomerular filtration rate, as well as the use of rescue medication and prednisone. Partial renal response depended only on changes to the urine protein to creatinine ratio. Clinical experts explained that changes in the urine protein to creatinine ratio do not always necessarily lead to meaningful long-term changes in the disease. They suggested using kidney biopsy results as an alternative measure of response but noted the practical challenges of doing kidney biopsies. Although the AURORA trials had some limitations, the committee concluded that they show voclosporin plus mycophenolate mofetil had clear clinical advantages over placebo plus mycophenolate mofetil in inducing renal response when measured by protein in the urine. ## Generalisability of clinical trials The EAG noted that the AURORA trials (see section 3.4) included no people from the UK, so generalisability to the NHS may have been limited. Clinical experts considered that the population included in the AURORA trials is reflective of the population seen in the NHS. However, clinical experts did question the generalisability of the AURORA trials because of the corticosteroid doses used. An expert highlighted that the doses were lower than recommended by guidelines and used in NHS clinical practice. The EAG explained it had clinical advice that agreed the steroid use was lower than in clinical practice, but that the dose would still be effective and in line with clinical guidelines. It also noted that both treatment arms of the AURORA trials had lower-dose steroids. Patient and clinical experts emphasised that a key benefit of voclosporin is the potential ability to have lower-dose steroids. The reduced use of steroids is desirable because of reduced side effects, especially damage to the immune system. However, clinical experts raised concerns that some clinicians would not use lower steroid doses with voclosporin, like in the AURORA trials, and would use standard higher doses based on previous experience. At draft guidance consultation, some stakeholder responses highlighted that steroid use in clinical practice is similar to use in the AURORA trials. Others highlighted that while there is a trend towards using lower doses of steroids within the NHS, this is not yet standard clinical practice. The committee recalled that both treatment arms of the AURORA trials used lower doses of steroids than standard practice and that there was no direct evidence comparing voclosporin's use with higher and lower doses of steroids. The committee concluded that the AURORA trials are generalisable to the UK population but that the steroid doses used may not be reflective of established NHS clinical practice. ## Attrition bias It was noted that 39.5% of people from AURORA 1 did not enrol into AURORA 2. The committee was concerned with the possibility of attrition bias (that is, that discontinuation may not be random and there may be systematic differences between the population who discontinued AURORA 1 and the population who continued enrolment to AURORA 2). The EAG explained that the rate of and reasons for discontinuation were comparable across the trial arms, reducing the risk of bias. But the break in randomisation caused a high risk of bias in AURORA 2. It also noted that response outcomes significantly increased at 12 months and 18 months, caused by the switch from AURORA 1 to AURORA 2 data. In response to committee requests, the company provided scenario analyses that assumed different responses for people who did not enrol in AURORA 2. This included the following 3 scenarios which assumed: last observed response state carried forward people who had voclosporin plus mycophenolate mofetil were 'non-responders' and people who had mycophenolate mofetil had complete response people who had mycophenolate mofetil were 'non-responders' and people who had voclosporin plus mycophenolate mofetil had complete response.The EAG commented that only the last observation carried forward assumption was appropriate because the other scenarios are highly unlikely in clinical practice. The committee acknowledged the efforts of the company to explore accounting for attrition bias in the AURORA 2 data. It noted that only the last observation carried forward scenario was likely to be clinically plausible and that this slightly reduces the cost-effectiveness estimates. The committee concluded that there was some remaining uncertainty about the impact of attrition bias. But, the company had done as much as could be reasonably expected and the provided scenarios had allowed enough exploration of the sensitivity of the results. ## Network meta-analysis Because of the lack of direct evidence comparing voclosporin plus mycophenolate mofetil with other relevant comparators besides mycophenolate mofetil, the company developed a network meta-analysis. The analysis included complete and partial renal response data for the treatment options outlined in section 3.2. Data was identified by a systematic literature review. The company's original base case included a fixed effects network meta‑analysis. The company justified this approach because random effects network meta-analysis estimates were not converging. The EAG suggested implementing a random effects network meta-analysis using informative priors. This is because considerable variation across the included trials could lead to heterogeneity. The company provided a random effects analysis during technical engagement and explained that the fixed and random effect analyses produced similar results. Based on the committee's preference, the random effects network meta-analysis was implemented in the company's updated base case. This suggested that voclosporin plus mycophenolate mofetil was more effective than the comparators. The committee concluded that the network meta-analysis used in the company base case was appropriate but noted that heterogeneity across the populations and included trial outcomes increased uncertainty of the results. # Economic model ## Company's model structure The company developed a cohort-level state-transition Markov model to estimate the cost effectiveness of voclosporin plus mycophenolate mofetil compared with relevant comparators. People were modelled to transition between 3 lupus nephritis-related chronic kidney disease (CKD) states (stages 1 to 3a, stages 3b to 4, stage 5) and death. People with stages 1 to 3a CKD could move between active disease, partial response and complete response substates. People with stages 3b to 4 CKD were only modelled in an active disease substate. People with stage 5 CKD could move between dialysis and kidney transplantation. During technical engagement, the company updated the model to allow disease progression from stages 1 to 3a to stages 3b to 4 CKD, apply consistent death costs, apply correct relative dosing intensity, and reassure the EAG of accurate model inputs and formulas. These changes were to align with some aspects of the EAG's preferred base case, but some issues remained. For instance, in the updated company base case, people with stages 3b to 4 CKD could not have a response in the model. In response to a committee request, the company provided scenario analyses allowing for 2.5% of people with stages 3b to 4 CKD to have a response (based on expert estimates). But the company did not implement the assumption in its base case. It explained that the impact on the cost-effectiveness estimates was small and that experts agreed assuming no response for this subgroup was reasonable. The EAG agreed that the scenario may only have a small impact. But, it also noted that clinical experts had agreed that the number of people who would have a response was not zero, and that this should be reflected in the company base case. The EAG also identified that transition probabilities were uncertain for voclosporin and mycophenolate mofetil. This is because transitions for AURORA 1 and AURORA 2 participants were derived by the 'count method', which is associated with limitations because of small sample sizes. The company explained that it attempted to use alternative statistical methods to estimate transition probabilities, but the approaches provided unrealistic outcomes that did not match the trial data. The EAG acknowledged the company's efforts to reduce uncertainty and agreed with the company's explanation, but it noted that inherent uncertainties with the 'count method' remained. Other modelling issues included: The estimated proportion of people with stage 5 CKD who had kidney transplant was too high in the company's original base case. The EAG included a transplantation rate of 65% in its base case based on clinical advice. The company included this assumption in its updated base case, accepting the preference of the committee. Model transparency was raised as a key issue because the EAG found errors in the model (for example, with adverse event disutility calculations) and multiple instances of insufficient descriptions of calculations and sources of information. At the second committee meeting, the EAG considered that while the model lacked some flexibility to refer to previous treatment settings, overall model transparency had improved and the company had made changes to resolve concerns with model inputs.The committee noted that the company had satisfactorily explored the assumption that people with stages 3b to 4 CKD could not have a response in the model. It concluded that the cost-effectiveness estimates were insensitive to this assumption, and it was not a key uncertainty. The committee noted the company's model still had limitations because it lacked flexibility and prevented the EAG from implementing its preferred base case and cross-checking calculations in the model. However, the committee concluded that the uncertainty had been reduced after draft guidance consultation and model transparency had improved. ## Modelling of costs Modelled monitoring costs were raised as an issue by the EAG because the company excluded additional monitoring costs for voclosporin. This was inconsistent with the modelled costs for tacrolimus, the other calcineurin inhibitor in the model. The company suggested this is because voclosporin has a predictable pharmacokinetic and pharmacodynamic relationship allowing for fixed dosing and no therapeutic drug monitoring, whereas tacrolimus has a complex and unpredictable pharmacokinetic profile that requires monitoring. The committee noted that the summary of product characteristics for voclosporin recommends careful monitoring of renal function. Clinical experts and the Innovative Medicines Fund clinical lead explained that this would be included within routine monitoring for lupus nephritis. They explained that tacrolimus needs therapeutic drug monitoring to confirm optimal dosing and renal toxicity. However, voclosporin does not need this extra monitoring. The committee concluded that extra monitoring costs for voclosporin were not appropriate because of the different monitoring requirements for tacrolimus and voclosporin. The EAG further raised modelled costs as a key issue because the company assumed no treatment discontinuation for non-trial comparators. The company explained this was because of a lack of evidence. Based on clinical expert input, the EAG considered this was a clinically implausible assumption. In response to a committee request, the company updated its base case to include treatment discontinuation for non-trial comparators by assuming discontinuation equal to voclosporin. The EAG preferred to assume discontinuation equal to mycophenolate mofetil in its base case. The committee noted the efforts of the company to include treatment discontinuation for non-trial comparators. The committee considered that there was uncertainty in determining treatment discontinuation of non-trial comparators. However, it concluded that the assumptions of the company and EAG did not have a significant impact on the cost-effectiveness estimates. ## Long-term treatment effects AURORA 1 and AURORA 2 data on voclosporin plus mycophenolate mofetil used in the company's model covered 3 years. So, the company used assumptions to extrapolate data for approximately 69 further years. To do this, the company assumed: long-term transition probabilities for treatments equalled the average transition probabilities for month 30 and month 36, combined with a treatment waning effect for active disease and partial response states, voclosporin plus mycophenolate mofetil transition probabilities equalled those of mycophenolate mofetil alone for complete response states, voclosporin plus mycophenolate mofetil transition probabilities equalled the average of voclosporin plus mycophenolate mofetil and mycophenolate mofetil alone transition probabilities for other comparators were the same as the active disease state.The EAG expressed considerable uncertainty in using on-treatment short-term data to predict off-treatment long-term outcomes. It explained the uncertainty was likely to only be reduced with additional long-term data or clinical expert input. Submissions from stakeholders highlighted that a long-term treatment effect is an unproven assumption, but that short-term benefits can be predictive of improved longer-term outcomes. In response to the uncertainty, the company provided: additional scenario analyses that assumed no relative effect for voclosporin after 36 months evidence of external model output validity by comparing modelled outcomes to those reported in external literature. It claimed that the percentage of people with end-stage renal disease at 5 years and 10 years estimated by the model was comparable to figures reported in Tektonidou et al. (2016) and Gisca et al. (2021). The EAG agreed the comparisons with external literature to validate the model were reasonable, but noted high uncertainty in health states other than end-stage renal disease. This is because only literature reporting on end-stage renal disease, and not on other outcomes estimated in the model, was available. The EAG preferred to assume voclosporin plus mycophenolate mofetil and mycophenolate mofetil alone were equal based on the average transition probabilities for month 30 and month 36. But this functionality was removed in the company model during consultation. Because of this, the EAG was unable to implement its preferred base case, instead adopting a different approach. It assumed voclosporin plus mycophenolate and mycophenolate mofetil alone were equal for all health states. The EAG also recalled the efforts at multiple stages of this evaluation to explore different durations of treatment effect for voclosporin, including no relative effect after 36 months. But it reiterated that the key uncertainty was using short-term data to inform long-term transitions and outcomes, which could not be resolved in the current model and with current efficacy data. The committee determined that the long-term extrapolations could better reflect the relapsing and remitting nature of the disease. It would have preferred to see repeated uses of induction treatment reflected, instead of induction followed by maintenance treatment with other therapies for over 69 years. However, it acknowledged that modelling such extrapolations would be difficult to construct. The committee concluded that longer-term efficacy is difficult to establish and extrapolate from short-term data such as that used in the network meta-analyses, particularly when these are associated with heterogeneity (see section 3.6). It also recalled the lack of model flexibility for the EAG to implement its preferred base case (see section 3.8). The committee noted that if the EAG had been able to implement its preferred base case, the associated incremental cost-effectiveness ratios (ICERs) were expected to reduce. There is uncertainty with both the company's and EAG's approaches to the long-term treatment effect extrapolations. ## Treatment duration The company's model assumed treatment stops at 36 months, in line with the available AURORA data. The company explained that clinical experts supported this modelling assumption. The marketing authorisation for voclosporin does not specify a stopping rule but the summary of product characteristics recommends a risk–benefit analysis at 24 weeks. Clinical advice to the EAG also supported stopping treatment at 36 months in the model. The clinical experts explained that induction treatment with voclosporin is unlikely to be for 36 months. This is because the relapsing and remitting nature of the condition means treatment would be expected for about 9 months to 12 months. But retreatment with voclosporin to induce response would be expected and desirable in the future. In response to a committee request, the company provided scenario analyses for treatment durations of 12 months and 18 months for all treatments (when appropriate). The scenarios also adopted varying response assumptions to reflect the changing treatment duration. The EAG noted that the updated scenarios were helpful in reflecting different treatment durations but results were uncertain because retreatment was not included in the model. The committee noted the efforts of the company in providing scenario analyses that reflected different treatment durations. It considered that not including retreatment in the company's model was a key uncertainty but acknowledged the difficulties in doing so. It concluded that assuming treatment stops at 36 months was arbitrary because treatment discontinuation included in the model captured the treatment durations shown in the clinical trials. It noted that although the modelled treatment duration was 36 months, almost half of people who started voclosporin in AURORA 1 had stopped treatment by this point. This was more people still having treatment at 36 months than expected by clinical experts, who suggested treatment would last roughly 12 months. However, the committee also recalled that retreatment would be expected, meaning it was difficult to determine whether the model accurately reflected treatment durations expected in clinical practice. The committee concluded that modelling an accurate treatment duration was an uncertainty. # Cost-effectiveness estimates ## Company and EAG cost-effectiveness estimates The deterministic cost-effectiveness results include confidential prices for voclosporin and other treatments. Therefore, the exact results cannot be reported here. The company's deterministic base-case ICER for voclosporin plus mycophenolate mofetil against mycophenolate mofetil alone was within what NICE normally considers cost effective. The EAG's corresponding base-case ICER was also within what NICE normally considers cost effective. ICERs varied for other comparator treatments. The committee recalled that the main difference between the EAG's and company's base cases was the approach to extrapolating long-term treatment effects (see section 3.10). It recalled that voclosporin may be associated with additional benefits of lower steroid doses (see section 3.5 and section 3.13). However, it also considered that: without long-term data, both the EAG's and company's base cases were associated with uncertainty model functionality prevented the EAG from implementing its preferred base case (although this would likely decrease the ICERs) the model did not reflect likely retreatment with induction treatments, prompting uncertainty in the ICERs. Given the level of uncertainty associated with the company's model and therefore the cost-effectiveness estimates, the committee determined that the maximum acceptable ICER was towards the lower end of the range normally considered a cost-effective use of NHS resources. The committee concluded voclosporin plus mycophenolate mofetil is likely a cost-effective use of NHS resources. # Other factors ## Innovation Clinical experts suggested that there may be potential uncaptured benefits within the company's model. They highlighted the significant impact of lupus nephritis and treatments on people's immune systems and fertility. In addition, they noted the potential use of voclosporin with lower doses of steroids (see section 3.5) would enable a reduction in the significant harmful effects associated with higher doses of steroids. Experts suggested that such benefits were not captured in the model because the comparator arm also used a lower dose of steroids. The committee recognised the lower dose of steroids used with voclosporin may be an uncaptured benefit but noted that there was some uncertainty around this (see section 3.5). It recalled that that there was no evidence comparing the use of voclosporin with higher and lower doses of steroids. It considered this in its discussion of the cost-effectiveness estimates (see section 3.12). The committee also considered whether voclosporin was innovative. It heard from clinical experts that voclosporin is not considered a step change in treatment for lupus nephritis. This is because other calcineurin inhibitors such as tacrolimus are already used in practice. So, the committee concluded that voclosporin was not innovative for treating lupus nephritis. ## Equality issues Patient and clinical experts identified that people with Indian Asian, African or Caribbean, and Chinese family backgrounds are more likely to have poorer outcomes with lupus nephritis. However, clinical experts also noted that there was no evidence to suggest voclosporin showed different effectiveness for different subgroups of people. The committee heard that women are disproportionately affected by lupus nephritis. It also heard from patient experts how current treatments such as cyclophosphamide can cause infertility or increase the risk of birth defects in a developing fetus. The committee was grateful for these issues being raised but noted that voclosporin is taken with mycophenolate mofetil and steroids. It recalled that mycophenolate mofetil cannot be used during pregnancy and so this would also apply to voclosporin. However, it did note that voclosporin was unlikely to be associated with a risk of permanent infertility. So, it would provide an alternative option to treatments such as cyclophosphamide. The committee also noted that the differences in prevalence cannot usually be resolved in a technology appraisal, although the committee can consider whether a specific equality issue has a significant impact on access to treatment. Overall, the committee agreed that its recommendation would not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no equality issues that would alter its recommendation. # Conclusion ## Recommendation The committee recalled the uncertainty associated with the company's model and long-term treatment effect estimations. It also acknowledged the efforts of the company to address some of the committee's concerns discussed in draft consultation guidance. It recalled that both the EAG's and company's base case were associated with uncertainty. But, plausible cost-effectiveness estimates were sufficiently low enough to be considered a cost-effective use of NHS resources. This means voclosporin plus mycophenolate mofetil is recommended for treating lupus nephritis.	{'Recommendations': 'Voclosporin with mycophenolate mofetil is recommended, within its marketing authorisation, as an option for treating active class\xa03 to\xa05 (including mixed class\xa03 and 5, and 4 and 5) lupus nephritis in adults. It is only recommended if the company provides voclosporin according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nTreatment options for active lupus nephritis include immunosuppressants such as mycophenolate mofetil. There are several other immunosuppressant options depending on factors such as condition severity, previous treatments and other conditions such as organ damage.\n\nClinical trial evidence suggests voclosporin with mycophenolate mofetil is more effective at stopping lupus nephritis from getting worse than mycophenolate mofetil alone. Indirect comparisons suggest voclosporin with mycophenolate mofetil is more effective than other immunosuppressant options.\n\nThe most likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So, voclosporin with mycophenolate mofetil is recommended.', 'Information about voclosporin': "# Marketing authorisation indication\n\nVoclosporin (Lupkynis, Otsuka) is indicated 'in combination with mycophenolate mofetil for the treatment of adult patients with active class\xa03, 4 or 5 (including mixed class 3/5 and 4/5) lupus nephritis'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for voclosporin.\n\n# Price\n\nVoclosporin costs £1,000 per 180‑pack of 7.9\xa0mg soft capsules (excluding VAT; company submission). Voclosporin costs £12,167 for 12\xa0months of treatment. The list price of mycophenolate mofetil is £6.23 per 50‑pack of 500\xa0mg tablets (excluding VAT; BNF online accessed March\xa02023).\n\nThe company has a commercial arrangement. This makes voclosporin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Otsuka, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## Nature of the condition\n\nLupus nephritis is a complication of systemic lupus erythematosus, a chronic condition that causes inflammation in connective tissues. It occurs in around 40% to 60% of people with systemic lupus erythematosus and affects the kidneys, specifically glomeruli cells. Clinical experts highlighted the high unmet need for people with lupus nephritis because the condition is not curable. The disease follows a cycle of relapsing and remitting. Some people develop end-stage renal disease if their condition does not respond to treatment and need dialysis or kidney transplants to survive. Lupus nephritis is a debilitating disease which significantly impacts the lives of people with the condition and those who care for them. Patient experts highlighted the most challenging aspects for people with lupus nephritis are the symptoms, reduced ability to work and impact on mental wellbeing. Patient experts explained that in a 2020 survey of 67\xa0people with lupus nephritis, 81% reported fatigue as the most difficult symptom, followed by joint pain and swelling (60%). People with the condition explained how lack of energy makes every day a challenge. In the same survey 57% of people with lupus nephritis felt isolated once a week and 58% needed help with household care, while 33% needed help with personal care. Carers of people with lupus nephritis are significantly impacted because of helping with daily tasks and having less time to work and socialise. There is also constant anxiety about the health of people with lupus nephritis because of the lack of a cure and because of regular tests to monitor the condition. The committee also heard how carers feel helpless, especially when lupus nephritis symptoms are worse. Patient and clinical experts also explained how current treatments have significant adverse effects. These side effects can cause other conditions that need separate treatment. They also severely impact quality of life and in some cases may affect adherence to dosing regimens. The committee concluded that lupus nephritis is a debilitating condition and there is high unmet need for effective treatments with manageable side effects.\n\n# Clinical management\n\n## Treatment options\n\nClinical and patient experts highlighted that lupus nephritis is a highly heterogeneous condition. This may result in considerable differences in treatment options because of varying needs and personal circumstances. Clinical experts explained that lupus nephritis rarely happens in isolation and that treatment choices depend on lots of other factors, including disease severity, previous treatments and comorbidities such as organ damage. They explained that lupus nephritis follows a cycle of relapsing and remitting, meaning treatments are used to either induce or maintain remission. They added that treatments varied only by the immunosuppressives taken with hydroxychloroquine and tapered doses of corticosteroids. The immunosuppressives used to induce remission include methylprednisolone with mycophenolate mofetil, low- and high‑dose cyclophosphamide, rituximab with mycophenolate mofetil, and tacrolimus with or without mycophenolate mofetil. Maintenance treatments include mycophenolate mofetil, azathioprine and tacrolimus monotherapy. The committee concluded that the treatment options for lupus nephritis are highly heterogenous and are expected to frequently change based on disease response.\n\n## Treatment positioning of voclosporin\n\nClinical experts explained that voclosporin, a calcineurin inhibitor, would be an add-on treatment to mycophenolate mofetil and corticosteroids for treating lupus nephritis. The company highlighted that the marketing authorisation for voclosporin does not specify a treatment line. Clinical experts expressed uncertainty about how voclosporin would be used in clinical practice. Some experts agreed it would be used as a first-line induction treatment or a later add-on treatment for people whose condition doesn't respond to mycophenolate mofetil alone, like in the AURORA trials (see section\xa03.4). Other experts suggested that voclosporin may be used hesitantly in the first line because of the lack of long-term evidence and that use after other treatments is more likely. The EAG explained that calcineurin inhibitors were usually used as later-line treatments. So, clinician hesitation would be expected for using voclosporin as a first-line induction treatment. But it said that mycophenolate mofetil alone was the most suitable comparator if voclosporin was to be used as a first-line treatment. It added that tacrolimus plus mycophenolate mofetil would be the most suitable comparator for later-line treatments. Clinical experts and the Innovative Medicines Fund clinical lead explained that voclosporin would be used to induce remission and not as a maintenance treatment. Clinical experts added that considering induction or maintenance treatment positioning is more appropriate than considering first-line and later lines of treatment. Lupus nephritis follows cycles of relapse and remission so a treatment previously used to induce remission could be considered a treatment option in the future. The company highlighted that voclosporin was used in the AURORA trials as a first- or subsequent-line induction treatment. So, mycophenolate mofetil alone or with tacrolimus are the most appropriate comparators. Stakeholder responses to draft guidance consultation also highlighted the use of voclosporin as an induction treatment. The committee considered that the AURORA trials only showed an ability to induce remission, but voclosporin's mechanism of action suggests maintenance use may also be possible. But it recalled clinical experts' opinion that voclosporin would be used to induce remission and not typically for more than 9\xa0 to 12\xa0months, although it may be used again if it was effective at inducing remission. So, the committee concluded that voclosporin would be used to induce remission and not as a long-term maintenance treatment. Based on this, it identified mycophenolate mofetil alone or with tacrolimus as the most appropriate comparators (see section\xa03.2).\n\n# Clinical evidence\n\n## Pivotal clinical trials and outcome measures\n\nThe clinical evidence for voclosporin was from the phase\xa03 AURORA\xa01 and AURORA\xa02 trials. These were multicentre, double-blind, placebo-controlled randomised trials. AURORA\xa02 was a 24‑month long-term continuation study for people who had completed the 12‑month AURORA\xa01 study. People had voclosporin or placebo, plus mycophenolate mofetil and low-dose corticosteroids. The primary endpoint of AURORA\xa01 was complete renal response at 12\xa0months, which was 40.8% for voclosporin and 22.5% for placebo. AURORA\xa01 recruited 357\xa0people from 27\xa0countries, 216 of whom also enrolled in AURORA\xa02. Clinical experts noted that complete renal response in the AURORA trials was a composite endpoint, comprising several measures. This included changes to the urine protein to creatinine ratio and estimated glomerular filtration rate, as well as the use of rescue medication and prednisone. Partial renal response depended only on changes to the urine protein to creatinine ratio. Clinical experts explained that changes in the urine protein to creatinine ratio do not always necessarily lead to meaningful long-term changes in the disease. They suggested using kidney biopsy results as an alternative measure of response but noted the practical challenges of doing kidney biopsies. Although the AURORA trials had some limitations, the committee concluded that they show voclosporin plus mycophenolate mofetil had clear clinical advantages over placebo plus mycophenolate mofetil in inducing renal response when measured by protein in the urine.\n\n## Generalisability of clinical trials\n\nThe EAG noted that the AURORA trials (see section\xa03.4) included no people from the UK, so generalisability to the NHS may have been limited. Clinical experts considered that the population included in the AURORA trials is reflective of the population seen in the NHS. However, clinical experts did question the generalisability of the AURORA trials because of the corticosteroid doses used. An expert highlighted that the doses were lower than recommended by guidelines and used in NHS clinical practice. The EAG explained it had clinical advice that agreed the steroid use was lower than in clinical practice, but that the dose would still be effective and in line with clinical guidelines. It also noted that both treatment arms of the AURORA trials had lower-dose steroids. Patient and clinical experts emphasised that a key benefit of voclosporin is the potential ability to have lower-dose steroids. The reduced use of steroids is desirable because of reduced side effects, especially damage to the immune system. However, clinical experts raised concerns that some clinicians would not use lower steroid doses with voclosporin, like in the AURORA trials, and would use standard higher doses based on previous experience. At draft guidance consultation, some stakeholder responses highlighted that steroid use in clinical practice is similar to use in the AURORA trials. Others highlighted that while there is a trend towards using lower doses of steroids within the NHS, this is not yet standard clinical practice. The committee recalled that both treatment arms of the AURORA trials used lower doses of steroids than standard practice and that there was no direct evidence comparing voclosporin's use with higher and lower doses of steroids. The committee concluded that the AURORA trials are generalisable to the UK population but that the steroid doses used may not be reflective of established NHS clinical practice.\n\n## Attrition bias\n\nIt was noted that 39.5% of people from AURORA\xa01 did not enrol into AURORA\xa02. The committee was concerned with the possibility of attrition bias (that is, that discontinuation may not be random and there may be systematic differences between the population who discontinued AURORA\xa01 and the population who continued enrolment to AURORA\xa02). The EAG explained that the rate of and reasons for discontinuation were comparable across the trial arms, reducing the risk of bias. But the break in randomisation caused a high risk of bias in AURORA\xa02. It also noted that response outcomes significantly increased at 12\xa0months and 18\xa0months, caused by the switch from AURORA\xa01 to AURORA\xa02 data. In response to committee requests, the company provided scenario analyses that assumed different responses for people who did not enrol in AURORA\xa02. This included the following 3\xa0scenarios which assumed:\n\nlast observed response state carried forward\n\npeople who had voclosporin plus mycophenolate mofetil were 'non-responders' and people who had mycophenolate mofetil had complete response\n\npeople who had mycophenolate mofetil were 'non-responders' and people who had voclosporin plus mycophenolate mofetil had complete response.The EAG commented that only the last observation carried forward assumption was appropriate because the other scenarios are highly unlikely in clinical practice. The committee acknowledged the efforts of the company to explore accounting for attrition bias in the AURORA\xa02 data. It noted that only the last observation carried forward scenario was likely to be clinically plausible and that this slightly reduces the cost-effectiveness estimates. The committee concluded that there was some remaining uncertainty about the impact of attrition bias. But, the company had done as much as could be reasonably expected and the provided scenarios had allowed enough exploration of the sensitivity of the results.\n\n## Network meta-analysis\n\nBecause of the lack of direct evidence comparing voclosporin plus mycophenolate mofetil with other relevant comparators besides mycophenolate mofetil, the company developed a network meta-analysis. The analysis included complete and partial renal response data for the treatment options outlined in section\xa03.2. Data was identified by a systematic literature review. The company's original base case included a fixed effects network meta‑analysis. The company justified this approach because random effects network meta-analysis estimates were not converging. The EAG suggested implementing a random effects network meta-analysis using informative priors. This is because considerable variation across the included trials could lead to heterogeneity. The company provided a random effects analysis during technical engagement and explained that the fixed and random effect analyses produced similar results. Based on the committee's preference, the random effects network meta-analysis was implemented in the company's updated base case. This suggested that voclosporin plus mycophenolate mofetil was more effective than the comparators. The committee concluded that the network meta-analysis used in the company base case was appropriate but noted that heterogeneity across the populations and included trial outcomes increased uncertainty of the results.\n\n# Economic model\n\n## Company's model structure\n\nThe company developed a cohort-level state-transition Markov model to estimate the cost effectiveness of voclosporin plus mycophenolate mofetil compared with relevant comparators. People were modelled to transition between 3\xa0lupus nephritis-related chronic kidney disease (CKD) states (stages\xa01 to 3a, stages\xa03b to 4, stage\xa05) and death. People with stages\xa01 to 3a CKD could move between active disease, partial response and complete response substates. People with stages\xa03b to 4 CKD were only modelled in an active disease substate. People with stage\xa05 CKD could move between dialysis and kidney transplantation. During technical engagement, the company updated the model to allow disease progression from stages\xa01 to 3a to stages\xa03b to\xa04 CKD, apply consistent death costs, apply correct relative dosing intensity, and reassure the EAG of accurate model inputs and formulas. These changes were to align with some aspects of the EAG's preferred base case, but some issues remained. For instance, in the updated company base case, people with stages\xa03b to 4 CKD could not have a response in the model. In response to a committee request, the company provided scenario analyses allowing for 2.5% of people with stages\xa03b to 4 CKD to have a response (based on expert estimates). But the company did not implement the assumption in its base case. It explained that the impact on the cost-effectiveness estimates was small and that experts agreed assuming no response for this subgroup was reasonable. The EAG agreed that the scenario may only have a small impact. But, it also noted that clinical experts had agreed that the number of people who would have a response was not zero, and that this should be reflected in the company base case. The EAG also identified that transition probabilities were uncertain for voclosporin and mycophenolate mofetil. This is because transitions for AURORA\xa01 and AURORA\xa02 participants were derived by the 'count method', which is associated with limitations because of small sample sizes. The company explained that it attempted to use alternative statistical methods to estimate transition probabilities, but the approaches provided unrealistic outcomes that did not match the trial data. The EAG acknowledged the company's efforts to reduce uncertainty and agreed with the company's explanation, but it noted that inherent uncertainties with the 'count method' remained. Other modelling issues included:\n\nThe estimated proportion of people with stage\xa05 CKD who had kidney transplant was too high in the company's original base case. The EAG included a transplantation rate of 65% in its base case based on clinical advice. The company included this assumption in its updated base case, accepting the preference of the committee.\n\nModel transparency was raised as a key issue because the EAG found errors in the model (for example, with adverse event disutility calculations) and multiple instances of insufficient descriptions of calculations and sources of information. At the second committee meeting, the EAG considered that while the model lacked some flexibility to refer to previous treatment settings, overall model transparency had improved and the company had made changes to resolve concerns with model inputs.The committee noted that the company had satisfactorily explored the assumption that people with stages\xa03b to 4 CKD could not have a response in the model. It concluded that the cost-effectiveness estimates were insensitive to this assumption, and it was not a key uncertainty. The committee noted the company's model still had limitations because it lacked flexibility and prevented the EAG from implementing its preferred base case and cross-checking calculations in the model. However, the committee concluded that the uncertainty had been reduced after draft guidance consultation and model transparency had improved.\n\n## Modelling of costs\n\nModelled monitoring costs were raised as an issue by the EAG because the company excluded additional monitoring costs for voclosporin. This was inconsistent with the modelled costs for tacrolimus, the other calcineurin inhibitor in the model. The company suggested this is because voclosporin has a predictable pharmacokinetic and pharmacodynamic relationship allowing for fixed dosing and no therapeutic drug monitoring, whereas tacrolimus has a complex and unpredictable pharmacokinetic profile that requires monitoring. The committee noted that the summary of product characteristics for voclosporin recommends careful monitoring of renal function. Clinical experts and the Innovative Medicines Fund clinical lead explained that this would be included within routine monitoring for lupus nephritis. They explained that tacrolimus needs therapeutic drug monitoring to confirm optimal dosing and renal toxicity. However, voclosporin does not need this extra monitoring. The committee concluded that extra monitoring costs for voclosporin were not appropriate because of the different monitoring requirements for tacrolimus and voclosporin. The EAG further raised modelled costs as a key issue because the company assumed no treatment discontinuation for non-trial comparators. The company explained this was because of a lack of evidence. Based on clinical expert input, the EAG considered this was a clinically implausible assumption. In response to a committee request, the company updated its base case to include treatment discontinuation for non-trial comparators by assuming discontinuation equal to voclosporin. The EAG preferred to assume discontinuation equal to mycophenolate mofetil in its base case. The committee noted the efforts of the company to include treatment discontinuation for non-trial comparators. The committee considered that there was uncertainty in determining treatment discontinuation of non-trial comparators. However, it concluded that the assumptions of the company and EAG did not have a significant impact on the cost-effectiveness estimates.\n\n## Long-term treatment effects\n\nAURORA\xa01 and AURORA\xa02 data on voclosporin plus mycophenolate mofetil used in the company's model covered 3\xa0years. So, the company used assumptions to extrapolate data for approximately 69\xa0further years. To do this, the company assumed:\n\nlong-term transition probabilities for treatments equalled the average transition probabilities for month\xa030 and month\xa036, combined with a treatment waning effect\n\nfor active disease and partial response states, voclosporin plus mycophenolate mofetil transition probabilities equalled those of mycophenolate mofetil alone\n\nfor complete response states, voclosporin plus mycophenolate mofetil transition probabilities equalled the average of voclosporin plus mycophenolate mofetil and mycophenolate mofetil alone\n\ntransition probabilities for other comparators were the same as the active disease state.The EAG expressed considerable uncertainty in using on-treatment short-term data to predict off-treatment long-term outcomes. It explained the uncertainty was likely to only be reduced with additional long-term data or clinical expert input. Submissions from stakeholders highlighted that a long-term treatment effect is an unproven assumption, but that short-term benefits can be predictive of improved longer-term outcomes. In response to the uncertainty, the company provided:\n\nadditional scenario analyses that assumed no relative effect for voclosporin after 36\xa0months\n\nevidence of external model output validity by comparing modelled outcomes to those reported in external literature. It claimed that the percentage of people with end-stage renal disease at 5\xa0years and 10\xa0years estimated by the model was comparable to figures reported in Tektonidou et al. (2016) and Gisca et al. (2021). The EAG agreed the comparisons with external literature to validate the model were reasonable, but noted high uncertainty in health states other than end-stage renal disease. This is because only literature reporting on end-stage renal disease, and not on other outcomes estimated in the model, was available. The EAG preferred to assume voclosporin plus mycophenolate mofetil and mycophenolate mofetil alone were equal based on the average transition probabilities for month\xa030 and month\xa036. But this functionality was removed in the company model during consultation. Because of this, the EAG was unable to implement its preferred base case, instead adopting a different approach. It assumed voclosporin plus mycophenolate and mycophenolate mofetil alone were equal for all health states. The EAG also recalled the efforts at multiple stages of this evaluation to explore different durations of treatment effect for voclosporin, including no relative effect after 36\xa0months. But it reiterated that the key uncertainty was using short-term data to inform long-term transitions and outcomes, which could not be resolved in the current model and with current efficacy data. The committee determined that the long-term extrapolations could better reflect the relapsing and remitting nature of the disease. It would have preferred to see repeated uses of induction treatment reflected, instead of induction followed by maintenance treatment with other therapies for over 69\xa0years. However, it acknowledged that modelling such extrapolations would be difficult to construct. The committee concluded that longer-term efficacy is difficult to establish and extrapolate from short-term data such as that used in the network meta-analyses, particularly when these are associated with heterogeneity (see section\xa03.6). It also recalled the lack of model flexibility for the EAG to implement its preferred base case (see section\xa03.8). The committee noted that if the EAG had been able to implement its preferred base case, the associated incremental cost-effectiveness ratios (ICERs) were expected to reduce. There is uncertainty with both the company's and EAG's approaches to the long-term treatment effect extrapolations.\n\n## Treatment duration\n\nThe company's model assumed treatment stops at 36\xa0months, in line with the available AURORA data. The company explained that clinical experts supported this modelling assumption. The marketing authorisation for voclosporin does not specify a stopping rule but the summary of product characteristics recommends a risk–benefit analysis at 24\xa0weeks. Clinical advice to the EAG also supported stopping treatment at 36\xa0months in the model. The clinical experts explained that induction treatment with voclosporin is unlikely to be for 36\xa0months. This is because the relapsing and remitting nature of the condition means treatment would be expected for about 9\xa0months to 12\xa0months. But retreatment with voclosporin to induce response would be expected and desirable in the future. In response to a committee request, the company provided scenario analyses for treatment durations of 12\xa0months and 18\xa0months for all treatments (when appropriate). The scenarios also adopted varying response assumptions to reflect the changing treatment duration. The EAG noted that the updated scenarios were helpful in reflecting different treatment durations but results were uncertain because retreatment was not included in the model. The committee noted the efforts of the company in providing scenario analyses that reflected different treatment durations. It considered that not including retreatment in the company's model was a key uncertainty but acknowledged the difficulties in doing so. It concluded that assuming treatment stops at 36\xa0months was arbitrary because treatment discontinuation included in the model captured the treatment durations shown in the clinical trials. It noted that although the modelled treatment duration was 36\xa0months, almost half of people who started voclosporin in AURORA\xa01 had stopped treatment by this point. This was more people still having treatment at 36\xa0months than expected by clinical experts, who suggested treatment would last roughly 12\xa0months. However, the committee also recalled that retreatment would be expected, meaning it was difficult to determine whether the model accurately reflected treatment durations expected in clinical practice. The committee concluded that modelling an accurate treatment duration was an uncertainty.\n\n# Cost-effectiveness estimates\n\n## Company and EAG cost-effectiveness estimates\n\nThe deterministic cost-effectiveness results include confidential prices for voclosporin and other treatments. Therefore, the exact results cannot be reported here. The company's deterministic base-case ICER for voclosporin plus mycophenolate mofetil against mycophenolate mofetil alone was within what NICE normally considers cost effective. The EAG's corresponding base-case ICER was also within what NICE normally considers cost effective. ICERs varied for other comparator treatments. The committee recalled that the main difference between the EAG's and company's base cases was the approach to extrapolating long-term treatment effects (see section\xa03.10). It recalled that voclosporin may be associated with additional benefits of lower steroid doses (see section\xa03.5 and section\xa03.13). However, it also considered that:\n\nwithout long-term data, both the EAG's and company's base cases were associated with uncertainty\n\nmodel functionality prevented the EAG from implementing its preferred base case (although this would likely decrease the ICERs)\n\nthe model did not reflect likely retreatment with induction treatments, prompting uncertainty in the ICERs. Given the level of uncertainty associated with the company's model and therefore the cost-effectiveness estimates, the committee determined that the maximum acceptable ICER was towards the lower end of the range normally considered a cost-effective use of NHS resources. The committee concluded voclosporin plus mycophenolate mofetil is likely a cost-effective use of NHS resources.\n\n# Other factors\n\n## Innovation\n\nClinical experts suggested that there may be potential uncaptured benefits within the company's model. They highlighted the significant impact of lupus nephritis and treatments on people's immune systems and fertility. In addition, they noted the potential use of voclosporin with lower doses of steroids (see section\xa03.5) would enable a reduction in the significant harmful effects associated with higher doses of steroids. Experts suggested that such benefits were not captured in the model because the comparator arm also used a lower dose of steroids. The committee recognised the lower dose of steroids used with voclosporin may be an uncaptured benefit but noted that there was some uncertainty around this (see section\xa03.5). It recalled that that there was no evidence comparing the use of voclosporin with higher and lower doses of steroids. It considered this in its discussion of the cost-effectiveness estimates (see section\xa03.12). The committee also considered whether voclosporin was innovative. It heard from clinical experts that voclosporin is not considered a step change in treatment for lupus nephritis. This is because other calcineurin inhibitors such as tacrolimus are already used in practice. So, the committee concluded that voclosporin was not innovative for treating lupus nephritis.\n\n## Equality issues\n\nPatient and clinical experts identified that people with Indian Asian, African or Caribbean, and Chinese family backgrounds are more likely to have poorer outcomes with lupus nephritis. However, clinical experts also noted that there was no evidence to suggest voclosporin showed different effectiveness for different subgroups of people. The committee heard that women are disproportionately affected by lupus nephritis. It also heard from patient experts how current treatments such as cyclophosphamide can cause infertility or increase the risk of birth defects in a developing fetus. The committee was grateful for these issues being raised but noted that voclosporin is taken with mycophenolate mofetil and steroids. It recalled that mycophenolate mofetil cannot be used during pregnancy and so this would also apply to voclosporin. However, it did note that voclosporin was unlikely to be associated with a risk of permanent infertility. So, it would provide an alternative option to treatments such as cyclophosphamide. The committee also noted that the differences in prevalence cannot usually be resolved in a technology appraisal, although the committee can consider whether a specific equality issue has a significant impact on access to treatment. Overall, the committee agreed that its recommendation would not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no equality issues that would alter its recommendation.\n\n# Conclusion\n\n## Recommendation\n\nThe committee recalled the uncertainty associated with the company's model and long-term treatment effect estimations. It also acknowledged the efforts of the company to address some of the committee's concerns discussed in draft consultation guidance. It recalled that both the EAG's and company's base case were associated with uncertainty. But, plausible cost-effectiveness estimates were sufficiently low enough to be considered a cost-effective use of NHS resources. This means voclosporin plus mycophenolate mofetil is recommended for treating lupus nephritis."}	https://www.nice.org.uk/guidance/ta882	Evidence-based recommendations on voclosporin (Lupkynis) with mycophenolate mofetil for treating lupus nephritis in adults.
9edfd5df56a1a951cda23eda0c801749769b40c3	nice	Ripretinib for treating advanced gastrointestinal stromal tumour after 3 or more treatments	Ripretinib for treating advanced gastrointestinal stromal tumour after 3 or more treatments Evidence-based recommendations on ripretinib (Qinlock) for treating gastrointestinal stromal tumour in adults after 3 or more treatments. # Recommendations Ripretinib is not recommended, within its marketing authorisation, for treating advanced gastrointestinal stromal tumour (GIST) in adults after 3 or more kinase inhibitors, including imatinib. This recommendation is not intended to affect treatment with ripretinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Current treatment for advanced GIST, after people have tried the kinase inhibitors imatinib, sunitinib and regorafenib, is best supportive care. Clinical trial evidence shows that ripretinib increases the time before the cancer gets worse and increases how long people live compared with best supportive care. Ripretinib meets NICE's criteria to be considered a life-extending treatment at the end of life. But the economic model does not reflect clinical practice about when to change treatment when advanced GIST gets worse. This means it is not in line with how ripretinib would be used in the NHS. It is not possible to work out if ripretinib is cost effective with the available analyses, so it is not recommended.# Information about ripretinib # Marketing authorisation indication Ripretinib (Qinlock, Deciphera Pharmaceuticals) is indicated for 'the treatment of adult patients with advanced gastrointestinal stromal tumour (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for ripretinib. # Price The list price of ripretinib is £18,400 per 30‑day supply (excluding VAT; company submission). This is based on a 150‑mg dose once daily (three 50 mg tablets). The company has a commercial arrangement, which would have applied if ripretinib had been recommended.# Committee discussion The appraisal committee considered evidence submitted by Deciphera Pharmaceuticals, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition and treatment pathway ## There is an unmet need for treatments for people with advanced GIST who have had 3 or more treatments Gastrointestinal stromal tumour (GIST) is a rare cancer that affects survival and quality of life. The patient experts explained that treatments for advanced GIST cause debilitating symptoms including hand-foot syndrome, severe muscle cramps, diarrhoea and cardiac problems. GIST is treated using tyrosine kinase inhibitors, which are used sequentially and include: imatinib, then sunitinib if there is resistance or intolerance to imatinib, then regorafenib if the cancer progresses on the previous treatments or the previous treatments are intolerable.In their submissions, the patient experts said that as the cancer progresses and the different treatments are tried, secondary mutations are more likely to develop. This can make treatment ineffective. The clinical experts added that there are no fourth-line treatment options for people if their cancer progressed or if they cannot tolerate the available options, other than best supportive care. The clinical experts noted that the only alternative to best supportive care was to take part in a clinical trial but these were rare. The patient and clinical experts also highlighted that there has been unmet need in this disease area for a long time, and that a new treatment option would be welcomed. The patient expert acknowledged the side effects of ripretinib but noted that they were more manageable than the side effects from some of the other tyrosine kinase inhibitors. The committee heard that, because of the limited treatment options for advanced GIST, clinicians aim to maximise the benefit of each treatment option before moving to the next treatment. The clinical experts also noted that it is not UK clinical practice to try treatments again. The committee concluded that there is an unmet need for an effective treatment option for advanced GIST if imatinib, sunitinib and regorafenib have already been tried. # Comparators ## Best supportive care is an appropriate comparator for fourth-line ripretinib The company included best supportive care as the only relevant comparator for ripretinib. But the ERG suggested that continued regorafenib after progression was also a relevant comparator. It pointed out that the National Comprehensive Cancer Network (NCCN) clinical guidelines and the UK GIST guidelines support continuing tyrosine kinase inhibitors after disease progression when no further options are available. The clinical experts explained that determining disease progression is difficult and that both radiological and clinical progression are considered. Size and density of the tumours, treatment tolerability and clinical symptoms are all taken into account. The clinical experts said that because disease progression is difficult to define, people may continue having treatments after radiological progression. The experts also highlighted that there is evidence that continuing treatment with tyrosine kinase inhibitors after progression can slow further progression in some people. They noted that it's unlikely regorafenib would be widely used after disease progression. This is because, in their experience, it only has benefits for a limited time and is associated with toxicities that often outweigh any small increase in clinical benefit after progression. One clinical expert estimated that 1 in 3 people continue having regorafenib after radiological progression. The clinical lead for the Cancer Drugs Fund said that some people would have regorafenib if there is clinical benefit and because it is the last line of treatment. The committee recalled that, because of the limited treatment options, each treatment option is used until the maximum clinical benefit is gained before moving to the next treatment line (see section 3.1). But the clinical experts noted that, because ripretinib has a potential treatment benefit and less toxicity than regorafenib, it's possible people would be switched to it at an earlier point of disease progression, but only after gaining the maximum clinical benefit from regorafenib. The company and ERG agreed that there was limited data to inform an indirect treatment comparison of ripretinib and post-progression regorafenib. The committee acknowledged that, by not having a comparison with post-progression regorafenib, some uncertainty is added around how effective ripretinib is likely to be in the fourth-line treatment setting. But it concluded that best supportive care is likely the most appropriate comparator for this appraisal, given the available evidence. # Clinical evidence ## Ripretinib plus best supportive care is more effective than placebo plus best supportive care The clinical effectiveness evidence for ripretinib compared with best supportive care was from the INVICTUS trial. This was a phase 3, placebo-controlled, double-blind, randomised controlled trial that compared ripretinib plus best supportive care with placebo plus best supportive care. There were 129 adults in the intention-to-treat population, 10 were from the UK. In the trial, ripretinib was continued until disease progression or unacceptable toxicity. At disease progression, people could continue with their current ripretinib dose, double the dose, or stop. People having placebo plus best supportive care could leave the study or switch to ripretinib plus best supportive care at disease progression. Progression was defined by blinded independent central review, which the committee acknowledged was different to the nuanced decision making in clinical practice (see section 3.2). The trial's inclusion criteria involved at least 3 previous treatments and an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2. The trial stratified people according to the number of previous treatments and the ECOG performance score. The hazard ratio for overall survival was 0.41 (95% confidence interval 0.26 to 0.65) and the hazard ratio for progression-free survival was 0.16 (95% CI 0.10 to 0.27). This shows better overall survival and progression-free survival for people having ripretinib plus best supportive care than for people having placebo plus best supportive care. A clinical expert highlighted that the median progression-free survival of 6 months for ripretinib is notable, for a treatment used after 3 or more previous treatments. The committee concluded that ripretinib plus best supportive care is more effective than placebo plus best supportive care for people with advanced GIST after 3 or more treatments. ## Data from the intention-to-treat population of the trial is appropriate for decision making In its submission, the company used data from the intention-to-treat population from INVICTUS to model ripretinib as a fourth-line treatment (that is, after just 3 previous treatments). However, 37% of people in INVICTUS had 4 or more previous treatments. A clinical expert explained that, because INVICTUS was an international trial, off-label tyrosine kinase inhibitors could be used as later-line treatments. The ERG had concerns that the number of previous treatments could be a treatment effect modifier. But the company noted that the hazard ratios for progression-free survival for people who had 3 previous treatments were similar to those for people who had 4 or more previous treatments. The clinical experts said that few people in the NHS have access to more than 3 lines of treatment, so people having treatment in the NHS are more likely to be fitter and have fewer resistant secondary mutations than those who had progressed to more than 4 lines of treatment in the clinical trial. So, the cancer may respond better in people who have fewer than 4 previous treatments than in people who have 4 or more. The ERG also said that the number of previous treatments could be a prognostic factor. It noted that progression-free survival could be longer for people who have had fewer lines of treatment, or alternatively people who had 6 or 7 lines of treatment may have a better disease profile than those who have fewer. The ERG explained that, because there were only small numbers in the subgroups for number of previous treatments, it was difficult to conclude how this affected ripretinib's efficacy. The committee considered that the number of previous treatments was likely to be a treatment effect modifier or prognostic factor and so affect outcomes. How this might affect ripretinib's effectiveness in clinical practice was unclear. The committee recognised the limitations in the evidence but concluded that the data from the intention-to-treat population in the clinical trial was the best available and appropriate for decision making. # Cost effectiveness ## A stopping rule is not appropriate In its submission, the company presented a partitioned survival model with 3 health states to estimate the cost effectiveness of ripretinib plus best supportive care compared with placebo plus best supportive care. The 3 health states were progression-free, progressed disease and death. In the modelling, the company assumed that ripretinib was discontinued at disease progression with no further active treatment. Therefore, the company assumed that time to treatment discontinuation was the same as progression-free survival. This assumption implies that in the model, treatment is stopped when there is radiological progression because progression-free survival from the trial was based on modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. The committee was aware that ripretinib's summary of product characteristics says that treatment 'should continue as long as benefit is observed or until unacceptable toxicity'. It recalled that the clinical experts said that they continue using currently available tyrosine kinase inhibitors for GIST if there is clinical benefit and side effects are manageable, even if there is radiological progression (see section 3.2). The clinical lead for the Cancer Drugs Fund advised that implementing a stopping rule for ripretinib in the NHS would involve a modified RECIST based on progression and not clinical assessment. The company confirmed its position that progression would be based on radiological response rather than including clinical assessment. The clinical experts reiterated the nuanced decision-making process when determining progression in advanced GIST, which considers many factors (see section 3.2). They noted that in INVICTUS there was a 20% discrepancy rate in determining disease progression using blinded independent central review compared with clinical assessment, highlighting the difficulty in assessing disease progression. They added that it would be a difficult decision to stop treatment when there is still clinical benefit, despite radiological progression. The ERG said that at the 2019 data cut in INVICTUS, 49% of people in the ripretinib arm continued open-label ripretinib and 31% of people in the ripretinib arm were still having double-blind ripretinib. So, the number of people continuing ripretinib after progression at the final data cut was between 49% and 80%. During the committee meeting the company noted that around 65% of people had continued ripretinib after progression but the committee was unclear if this was at the final data cut and whether the remaining people had stopped ripretinib or if their cancer had not progressed. The clinical lead for the Cancer Drugs Fund advised the committee that an expanded access programme for ripretinib was currently in place. The company confirmed that eligibility for this was in line with INVICTUS criteria, which allowed ripretinib to be used after radiological disease progression, in addition to double dosing. The clinical lead for the Cancer Drugs Fund highlighted the mismatch of the population in the expanded access programme with the company's intended population for ripretinib treatment using a stopping rule at disease progression. The committee noted that the company's stopping rule did not reflect clinical practice or current guidelines and was not clinically relevant. It also noted the consultation response from a patient organisation that said it did not support using radiological evidence alone to decide when to stop treatment. The company did not remove the stopping rule from its model in response to consultation. The committee concluded that the company's stopping rule does not align with the summary of product characteristics, or clinical practice, and disadvantages people with advanced GIST who may benefit from continued treatment after progression. Therefore, the stopping rule should not be included in the model. ## The extrapolations of overall survival are highly uncertain In its submission, the company adjusted overall survival to account for people in the best supportive care arm of INVICTUS switching to ripretinib after progression. But it did not adjust overall survival for people in the ripretinib arm continuing ripretinib after progression, at the standard dose or doubled dose. So, the company assumed that overall survival was not affected by ripretinib use after progression (see section 3.5). The ERG expected overall survival to be affected by ripretinib use after progression, because of clinical advice and the implausibility of the company's overall survival estimates for the ripretinib arm assuming best supportive care after progression on ripretinib. So, the ERG preferred to use the company's scenario that adjusted overall survival for ripretinib use after disease progression using a simple 2‑stage method with recensoring. The ERG's estimates of overall survival were more than 50% lower than the company's estimates of overall survival in the ripretinib arm, but the exact numbers are confidential so cannot be reported here. The clinical experts highlighted that it was difficult to predict the expected survival after progression with ripretinib. But they noted that if ripretinib follows the activity of other tyrosine kinase inhibitors in earlier lines of treatment for a kinase-driven cancer, then progression is expected to be similarly rapid after stopping treatment. The company acknowledged that the clinical experts' opinions were important to consider, and that it was plausible that there is a positive effect on overall survival from continuing to have ripretinib after disease progression. But it added that it did not find evidence from the INVICTUS data for a negative effect on overall survival if treatment was stopped at progression, so it did not include it in the modelling. The committee recalled that adjusting overall survival for ripretinib use after progression reduces the overall survival, as evidenced in the ERG's base case, but considered that even the adjusted overall survival estimates were optimistic. This is because the survival extrapolations did not have face validity (that is, the results were unexpected) when considering clinical expert opinion on overall survival estimates. The committee expressed concern about the extent to which the overall survival extrapolations reflected clinical practice. The ERG noted that further analyses adjusting overall survival for people in the ripretinib arm continuing ripretinib after disease progression could be explored, in addition to the simple 2‑stage adjustment in the company's model, to give alternative results. The committee agreed that using alternative approaches could help to reduce the uncertainty associated with adjusting the overall survival estimates to account for post-progression use of ripretinib when a stopping rule is used in the model. But the company did not provide any new evidence or analysis in response to consultation. The ERG was able to explore some alternative approaches to modelling treatment switching using the model the company provided at technical engagement. They said that this additional analysis still incorporated the stopping rule and so may not be suitable for decision making. The committee concluded that neither the company's nor the ERG's approaches to modelling overall survival were appropriate because the stopping rule should be removed, meaning the extrapolations for overall survival were not suitable for decision making (see section 3.5). ## The economic modelling does not reflect expected clinical practice The ERG explained that if a stopping rule was not applied in the model, it would expect data from the intention-to-treat population to be presented. This would only be adjusted for people switching to the ripretinib arm from the best supportive care arm, and use costs based on the extrapolated time to treatment discontinuation data. The committee noted that the dose escalation in INVICTUS meant that using data from the intention-to-treat population may mean overall survival is overestimated, and that it would not reflect ripretinib's licensed dose. A clinical expert added that doubling the ripretinib dose could improve progression-free survival but there is uncertainty about how that would affect overall survival because of uncertainty in the size of the population affected. The committee agreed that future extrapolations of overall survival modelling should be validated and reflect clinical practice. The committee considered that the current overall survival estimates for ripretinib after progression were uncertain and did not reflect clinical practice as described by the clinical experts. The committee said that it would have preferred to have seen analyses that aligned time to stopping treatment with the trial evidence because this would reflect ripretinib's anticipated use in clinical practice. The company did not provide any new evidence or analysis in response to consultation, so the committee concluded that the economic modelling did not reflect expected clinical practice. # Health-related quality of life ## The utility values are uncertain and scenario analyses for the company and ERG's preferred utility value should have been explored In its model, the company preferred to use a post-progression utility value from INVICTUS, which excluded the health-related quality of life estimates for people who continued ripretinib after progression for both treatment arms. The ERG considered that this was not appropriate because this utility value was based on people who were randomised to best supportive care who did not switch to ripretinib after progression, which is a small number of people. The ERG also noted that the company's utility value for people in the progressed disease state was high and could lack face validity. Specifically, the ERG noted that if the utility value from INVICTUS was used for the post-progression state, then people progressing at fourth line have a higher utility than people progressing at earlier lines of the treatment pathway. Also, the reduction in the utility value for the post-progression state compared with the progression-free state was small. The ERG preferred to use a utility value of 0.647 from the GRID trial that was used in NICE's technology appraisal guidance on regorafenib for previously treated unresectable or metastatic gastrointestinal stromal tumours. The company explained that it preferred to use estimates from INVICTUS because the GRID trial considered people having regorafenib, and ripretinib has better tolerability than regorafenib (see section 3.1). The clinical experts also noted that regorafenib is associated with considerable side effects, and the dose and schedule are often adjusted to manage side effects. They added that persistent hypertension, hand-foot syndrome, gastrointestinal side effects, diarrhoea, muscle wastage and fatigue are all side effects associated with regorafenib that can persist outside of regorafenib's short therapeutic window. In comparison, the clinical expert's view on the quality of life for people progressing after ripretinib was more optimistic. Overall, the company considered that using the GRID trial utility value could introduce bias because the GRID trial was done in a different population and treatment setting. The committee noted the time period for the final EQ‑5D assessment in INVICTUS, and that the utility value from INVICTUS may not capture the health-related quality of life for the post-progression state. The committee concluded that there were strengths and weaknesses associated with using either source of utility values and that it would like to see scenarios using both the company's and ERG's preferred utility value in the model. The company did not provide any new evidence or analysis after the first committee meeting. This meant no alternative scenarios using the utility values were explored. The committee concluded that the utility values used in the economic modelling were uncertain. # Costs in the model ## It is appropriate to include drug wastage in the model The ERG applied an average 0.25 of a pack wastage per person, translating to 7 days of wastage over a treatment course, in its preferred analysis. In its response to technical engagement, the company argued that wastage applies for less than 5% of people. The clinical lead for the Cancer Drugs Fund supported including drug wastage and considered that 0.25 of a pack wastage was modest. The clinical experts confirmed that drug wastage was likely to be low, and that 7 days of wastage was reasonable. The company did not incorporate drug wastage into its modelling after the first committee meeting. The committee concluded that it was appropriate to include drug wastage, and that the ERG's estimate of 0.25 wastage per person was plausible. # End of life ## Ripretinib meets the end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal 2013. The company and ERG agreed that ripretinib does meet the end of life criteria based on: it being indicated for people with a short life expectancy (that is, less than 24 months) there being sufficient evidence that it can offer an extension to life (that is, a mean value of at least 3 months).The committee concluded that ripretinib meets NICE's criteria to be considered a life-extending treatment at the end of life. # Cost-effectiveness estimate ## No plausible cost-effectiveness estimates can be determined NICE's guide to the methods of technology appraisal 2013 notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee agreed that there were issues with the company's modelling approach and validity of outputs. It noted the high level of uncertainty, specifically: that 37% of people in INVICTUS had 4 or more previous treatments, which is likely a treatment effect modifier or a prognostic factor of outcomes (see section 3.4) the model includes a stopping rule that does not reflect clinical practice (see section 3.5) the overall survival modelling extrapolations are not clinically valid (see section 3.6) the plausibility of the utility value for the ripretinib arm after progression (see section 3.8).Ripretinib meets the end of life criteria (see section 3.10). However, after taking the above factors into account, the committee judged that the company's base-case ICER was not plausible and noted that adjusting overall survival for post-progression ripretinib use caused the ICER to exceed £100,000 per QALY gained. The exact ICERs the committee used for decision making included confidential discounts so cannot be reported here. Because all of the analyses contained a stopping rule that the committee found inappropriate, the committee did not consider any of the results further. To address the committee's preferred assumptions, several updates to the model were needed: removing the stopping rule because it is not clinically appropriate and disadvantages people with advanced GIST (see section 3.5) ensuring the outputs of the model are clinically validated and align with clinical opinion on survival estimates (see section 3.6) adjusting overall survival estimates to account for dose escalation and treatment switching in the INVICTUS trial (see section 3.7) including scenario analyses for both the company's and ERG's preferred utility values (see section 3.8) including the ERG's preferred drug wastage of 0.25 of a pack per person (see section 3.9).The company did not provide any new evidence or analysis in response to consultation. So, the committee was unable to consider any cost-effectiveness estimates that had been generated using its preferred assumptions. At the second committee meeting, the committee reaffirmed that the available cost-effectiveness estimates remained implausible because of the issues described above. # Other factors ## Equalities No equalities issues were raised during the appraisal process. No potential equality issues were identified in the company submission. The committee concluded that there were no equalities issues relevant to the recommendation. ## Ripretinib is not innovative beyond what is captured in the cost-effectiveness estimates The company describe ripretinib as innovative because it: can broadly inhibit wild-type and KIT and PDGFRA mutations addresses an unmet need.The committee acknowledged the company's position that ripretinib is innovative. However, it concluded, and the company agreed, that there were no additional benefits associated with ripretinib that had not been captured in the cost-effectiveness estimates. # Conclusion ## Ripretinib is not recommended The committee recalled that it did not have any cost-effectiveness estimates using its preferred modelling assumptions (see section 3.11). The available evidence did not indicate that ripretinib is an effective use of NHS resources, even when end of life weighting is applied. The economic model did not reflect clinical practice about when to stop treatment with ripretinib, and was not aligned with the NHS expanded access programme. So, the committee concluded that it did not recommend ripretinib for treating advanced GIST after 3 or more treatments.	{'Recommendations': "Ripretinib is not recommended, within its marketing authorisation, for treating advanced gastrointestinal stromal tumour (GIST) in adults after 3 or more kinase inhibitors, including imatinib.\n\nThis recommendation is not intended to affect treatment with ripretinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for advanced GIST, after people have tried the kinase inhibitors imatinib, sunitinib and regorafenib, is best supportive care.\n\nClinical trial evidence shows that ripretinib increases the time before the cancer gets worse and increases how long people live compared with best supportive care.\n\nRipretinib meets NICE's criteria to be considered a life-extending treatment at the end of life. But the economic model does not reflect clinical practice about when to change treatment when advanced GIST gets worse. This means it is not in line with how ripretinib would be used in the NHS. It is not possible to work out if ripretinib is cost effective with the available analyses, so it is not recommended.", 'Information about ripretinib': "# Marketing authorisation indication\n\nRipretinib (Qinlock, Deciphera Pharmaceuticals) is indicated for 'the treatment of adult patients with advanced gastrointestinal stromal tumour (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for ripretinib.\n\n# Price\n\nThe list price of ripretinib is £18,400 per 30‑day supply (excluding VAT; company submission). This is based on a 150‑mg dose once daily (three 50\xa0mg tablets). The company has a commercial arrangement, which would have applied if ripretinib had been recommended.", 'Committee discussion': "The appraisal committee considered evidence submitted by Deciphera Pharmaceuticals, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition and treatment pathway\n\n## There is an unmet need for treatments for people with advanced GIST who have had 3 or more treatments\n\nGastrointestinal stromal tumour (GIST) is a rare cancer that affects survival and quality of life. The patient experts explained that treatments for advanced GIST cause debilitating symptoms including hand-foot syndrome, severe muscle cramps, diarrhoea and cardiac problems. GIST is treated using tyrosine kinase inhibitors, which are used sequentially and include:\n\nimatinib, then\n\nsunitinib if there is resistance or intolerance to imatinib, then\n\nregorafenib if the cancer progresses on the previous treatments or the previous treatments are intolerable.In their submissions, the patient experts said that as the cancer progresses and the different treatments are tried, secondary mutations are more likely to develop. This can make treatment ineffective. The clinical experts added that there are no fourth-line treatment options for people if their cancer progressed or if they cannot tolerate the available options, other than best supportive care. The clinical experts noted that the only alternative to best supportive care was to take part in a clinical trial but these were rare. The patient and clinical experts also highlighted that there has been unmet need in this disease area for a long time, and that a new treatment option would be welcomed. The patient expert acknowledged the side effects of ripretinib but noted that they were more manageable than the side effects from some of the other tyrosine kinase inhibitors. The committee heard that, because of the limited treatment options for advanced GIST, clinicians aim to maximise the benefit of each treatment option before moving to the next treatment. The clinical experts also noted that it is not UK clinical practice to try treatments again. The committee concluded that there is an unmet need for an effective treatment option for advanced GIST if imatinib, sunitinib and regorafenib have already been tried.\n\n# Comparators\n\n## Best supportive care is an appropriate comparator for fourth-line ripretinib\n\nThe company included best supportive care as the only relevant comparator for ripretinib. But the ERG suggested that continued regorafenib after progression was also a relevant comparator. It pointed out that the National Comprehensive Cancer Network (NCCN) clinical guidelines and the UK GIST guidelines support continuing tyrosine kinase inhibitors after disease progression when no further options are available. The clinical experts explained that determining disease progression is difficult and that both radiological and clinical progression are considered. Size and density of the tumours, treatment tolerability and clinical symptoms are all taken into account. The clinical experts said that because disease progression is difficult to define, people may continue having treatments after radiological progression. The experts also highlighted that there is evidence that continuing treatment with tyrosine kinase inhibitors after progression can slow further progression in some people. They noted that it's unlikely regorafenib would be widely used after disease progression. This is because, in their experience, it only has benefits for a limited time and is associated with toxicities that often outweigh any small increase in clinical benefit after progression. One clinical expert estimated that 1 in 3 people continue having regorafenib after radiological progression. The clinical lead for the Cancer Drugs Fund said that some people would have regorafenib if there is clinical benefit and because it is the last line of treatment. The committee recalled that, because of the limited treatment options, each treatment option is used until the maximum clinical benefit is gained before moving to the next treatment line (see section\xa03.1). But the clinical experts noted that, because ripretinib has a potential treatment benefit and less toxicity than regorafenib, it's possible people would be switched to it at an earlier point of disease progression, but only after gaining the maximum clinical benefit from regorafenib. The company and ERG agreed that there was limited data to inform an indirect treatment comparison of ripretinib and post-progression regorafenib. The committee acknowledged that, by not having a comparison with post-progression regorafenib, some uncertainty is added around how effective ripretinib is likely to be in the fourth-line treatment setting. But it concluded that best supportive care is likely the most appropriate comparator for this appraisal, given the available evidence.\n\n# Clinical evidence\n\n## Ripretinib plus best supportive care is more effective than placebo plus best supportive care\n\nThe clinical effectiveness evidence for ripretinib compared with best supportive care was from the INVICTUS trial. This was a phase\xa03, placebo-controlled, double-blind, randomised controlled trial that compared ripretinib plus best supportive care with placebo plus best supportive care. There were 129\xa0adults in the intention-to-treat population, 10 were from the UK. In the trial, ripretinib was continued until disease progression or unacceptable toxicity. At disease progression, people could continue with their current ripretinib dose, double the dose, or stop. People having placebo plus best supportive care could leave the study or switch to ripretinib plus best supportive care at disease progression. Progression was defined by blinded independent central review, which the committee acknowledged was different to the nuanced decision making in clinical practice (see section\xa03.2). The trial's inclusion criteria involved at least 3 previous treatments and an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2. The trial stratified people according to the number of previous treatments and the ECOG performance score. The hazard ratio for overall survival was 0.41 (95% confidence interval [CI] 0.26 to 0.65) and the hazard ratio for progression-free survival was 0.16 (95%\xa0CI 0.10 to 0.27). This shows better overall survival and progression-free survival for people having ripretinib plus best supportive care than for people having placebo plus best supportive care. A clinical expert highlighted that the median progression-free survival of 6\xa0months for ripretinib is notable, for a treatment used after 3 or more previous treatments. The committee concluded that ripretinib plus best supportive care is more effective than placebo plus best supportive care for people with advanced GIST after 3 or more treatments.\n\n## Data from the intention-to-treat population of the trial is appropriate for decision making\n\nIn its submission, the company used data from the intention-to-treat population from INVICTUS to model ripretinib as a fourth-line treatment (that is, after just 3\xa0previous treatments). However, 37% of people in INVICTUS had 4\xa0or more previous treatments. A clinical expert explained that, because INVICTUS was an international trial, off-label tyrosine kinase inhibitors could be used as later-line treatments. The ERG had concerns that the number of previous treatments could be a treatment effect modifier. But the company noted that the hazard ratios for progression-free survival for people who had 3\xa0previous treatments were similar to those for people who had 4\xa0or more previous treatments. The clinical experts said that few people in the NHS have access to more than 3\xa0lines of treatment, so people having treatment in the NHS are more likely to be fitter and have fewer resistant secondary mutations than those who had progressed to more than 4\xa0lines of treatment in the clinical trial. So, the cancer may respond better in people who have fewer than 4\xa0previous treatments than in people who have 4\xa0or more. The ERG also said that the number of previous treatments could be a prognostic factor. It noted that progression-free survival could be longer for people who have had fewer lines of treatment, or alternatively people who had 6\xa0or 7\xa0lines of treatment may have a better disease profile than those who have fewer. The ERG explained that, because there were only small numbers in the subgroups for number of previous treatments, it was difficult to conclude how this affected ripretinib's efficacy. The committee considered that the number of previous treatments was likely to be a treatment effect modifier or prognostic factor and so affect outcomes. How this might affect ripretinib's effectiveness in clinical practice was unclear. The committee recognised the limitations in the evidence but concluded that the data from the intention-to-treat population in the clinical trial was the best available and appropriate for decision making.\n\n# Cost effectiveness\n\n## A stopping rule is not appropriate\n\nIn its submission, the company presented a partitioned survival model with 3\xa0health states to estimate the cost effectiveness of ripretinib plus best supportive care compared with placebo plus best supportive care. The 3\xa0health states were progression-free, progressed disease and death. In the modelling, the company assumed that ripretinib was discontinued at disease progression with no further active treatment. Therefore, the company assumed that time to treatment discontinuation was the same as progression-free survival. This assumption implies that in the model, treatment is stopped when there is radiological progression because progression-free survival from the trial was based on modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. The committee was aware that ripretinib's summary of product characteristics says that treatment 'should continue as long as benefit is observed or until unacceptable toxicity'. It recalled that the clinical experts said that they continue using currently available tyrosine kinase inhibitors for GIST if there is clinical benefit and side effects are manageable, even if there is radiological progression (see section\xa03.2). The clinical lead for the Cancer Drugs Fund advised that implementing a stopping rule for ripretinib in the NHS would involve a modified RECIST based on progression and not clinical assessment. The company confirmed its position that progression would be based on radiological response rather than including clinical assessment. The clinical experts reiterated the nuanced decision-making process when determining progression in advanced GIST, which considers many factors (see section\xa03.2). They noted that in INVICTUS there was a 20% discrepancy rate in determining disease progression using blinded independent central review compared with clinical assessment, highlighting the difficulty in assessing disease progression. They added that it would be a difficult decision to stop treatment when there is still clinical benefit, despite radiological progression. The ERG said that at the 2019 data cut in INVICTUS, 49% of people in the ripretinib arm continued open-label ripretinib and 31% of people in the ripretinib arm were still having double-blind ripretinib. So, the number of people continuing ripretinib after progression at the final data cut was between 49% and 80%. During the committee meeting the company noted that around 65% of people had continued ripretinib after progression but the committee was unclear if this was at the final data cut and whether the remaining people had stopped ripretinib or if their cancer had not progressed. The clinical lead for the Cancer Drugs Fund advised the committee that an expanded access programme for ripretinib was currently in place. The company confirmed that eligibility for this was in line with INVICTUS criteria, which allowed ripretinib to be used after radiological disease progression, in addition to double dosing. The clinical lead for the Cancer Drugs Fund highlighted the mismatch of the population in the expanded access programme with the company's intended population for ripretinib treatment using a stopping rule at disease progression. The committee noted that the company's stopping rule did not reflect clinical practice or current guidelines and was not clinically relevant. It also noted the consultation response from a patient organisation that said it did not support using radiological evidence alone to decide when to stop treatment. The company did not remove the stopping rule from its model in response to consultation. The committee concluded that the company's stopping rule does not align with the summary of product characteristics, or clinical practice, and disadvantages people with advanced GIST who may benefit from continued treatment after progression. Therefore, the stopping rule should not be included in the model.\n\n## The extrapolations of overall survival are highly uncertain\n\nIn its submission, the company adjusted overall survival to account for people in the best supportive care arm of INVICTUS switching to ripretinib after progression. But it did not adjust overall survival for people in the ripretinib arm continuing ripretinib after progression, at the standard dose or doubled dose. So, the company assumed that overall survival was not affected by ripretinib use after progression (see section\xa03.5). The ERG expected overall survival to be affected by ripretinib use after progression, because of clinical advice and the implausibility of the company's overall survival estimates for the ripretinib arm assuming best supportive care after progression on ripretinib. So, the ERG preferred to use the company's scenario that adjusted overall survival for ripretinib use after disease progression using a simple 2‑stage method with recensoring. The ERG's estimates of overall survival were more than 50% lower than the company's estimates of overall survival in the ripretinib arm, but the exact numbers are confidential so cannot be reported here. The clinical experts highlighted that it was difficult to predict the expected survival after progression with ripretinib. But they noted that if ripretinib follows the activity of other tyrosine kinase inhibitors in earlier lines of treatment for a kinase-driven cancer, then progression is expected to be similarly rapid after stopping treatment. The company acknowledged that the clinical experts' opinions were important to consider, and that it was plausible that there is a positive effect on overall survival from continuing to have ripretinib after disease progression. But it added that it did not find evidence from the INVICTUS data for a negative effect on overall survival if treatment was stopped at progression, so it did not include it in the modelling. The committee recalled that adjusting overall survival for ripretinib use after progression reduces the overall survival, as evidenced in the ERG's base case, but considered that even the adjusted overall survival estimates were optimistic. This is because the survival extrapolations did not have face validity (that is, the results were unexpected) when considering clinical expert opinion on overall survival estimates. The committee expressed concern about the extent to which the overall survival extrapolations reflected clinical practice. The ERG noted that further analyses adjusting overall survival for people in the ripretinib arm continuing ripretinib after disease progression could be explored, in addition to the simple 2‑stage adjustment in the company's model, to give alternative results. The committee agreed that using alternative approaches could help to reduce the uncertainty associated with adjusting the overall survival estimates to account for post-progression use of ripretinib when a stopping rule is used in the model. But the company did not provide any new evidence or analysis in response to consultation. The ERG was able to explore some alternative approaches to modelling treatment switching using the model the company provided at technical engagement. They said that this additional analysis still incorporated the stopping rule and so may not be suitable for decision making. The committee concluded that neither the company's nor the ERG's approaches to modelling overall survival were appropriate because the stopping rule should be removed, meaning the extrapolations for overall survival were not suitable for decision making (see section\xa03.5).\n\n## The economic modelling does not reflect expected clinical practice\n\nThe ERG explained that if a stopping rule was not applied in the model, it would expect data from the intention-to-treat population to be presented. This would only be adjusted for people switching to the ripretinib arm from the best supportive care arm, and use costs based on the extrapolated time to treatment discontinuation data. The committee noted that the dose escalation in INVICTUS meant that using data from the intention-to-treat population may mean overall survival is overestimated, and that it would not reflect ripretinib's licensed dose. A clinical expert added that doubling the ripretinib dose could improve progression-free survival but there is uncertainty about how that would affect overall survival because of uncertainty in the size of the population affected. The committee agreed that future extrapolations of overall survival modelling should be validated and reflect clinical practice. The committee considered that the current overall survival estimates for ripretinib after progression were uncertain and did not reflect clinical practice as described by the clinical experts. The committee said that it would have preferred to have seen analyses that aligned time to stopping treatment with the trial evidence because this would reflect ripretinib's anticipated use in clinical practice. The company did not provide any new evidence or analysis in response to consultation, so the committee concluded that the economic modelling did not reflect expected clinical practice.\n\n# Health-related quality of life\n\n## The utility values are uncertain and scenario analyses for the company and ERG's preferred utility value should have been explored\n\nIn its model, the company preferred to use a post-progression utility value from INVICTUS, which excluded the health-related quality of life estimates for people who continued ripretinib after progression for both treatment arms. The ERG considered that this was not appropriate because this utility value was based on people who were randomised to best supportive care who did not switch to ripretinib after progression, which is a small number of people. The ERG also noted that the company's utility value for people in the progressed disease state was high and could lack face validity. Specifically, the ERG noted that if the utility value from INVICTUS was used for the post-progression state, then people progressing at fourth line have a higher utility than people progressing at earlier lines of the treatment pathway. Also, the reduction in the utility value for the post-progression state compared with the progression-free state was small. The ERG preferred to use a utility value of 0.647 from the GRID trial that was used in NICE's technology appraisal guidance on regorafenib for previously treated unresectable or metastatic gastrointestinal stromal tumours. The company explained that it preferred to use estimates from INVICTUS because the GRID trial considered people having regorafenib, and ripretinib has better tolerability than regorafenib (see section\xa03.1). The clinical experts also noted that regorafenib is associated with considerable side effects, and the dose and schedule are often adjusted to manage side effects. They added that persistent hypertension, hand-foot syndrome, gastrointestinal side effects, diarrhoea, muscle wastage and fatigue are all side effects associated with regorafenib that can persist outside of regorafenib's short therapeutic window. In comparison, the clinical expert's view on the quality of life for people progressing after ripretinib was more optimistic. Overall, the company considered that using the GRID trial utility value could introduce bias because the GRID trial was done in a different population and treatment setting. The committee noted the time period for the final EQ‑5D assessment in INVICTUS, and that the utility value from INVICTUS may not capture the health-related quality of life for the post-progression state. The committee concluded that there were strengths and weaknesses associated with using either source of utility values and that it would like to see scenarios using both the company's and ERG's preferred utility value in the model. The company did not provide any new evidence or analysis after the first committee meeting. This meant no alternative scenarios using the utility values were explored. The committee concluded that the utility values used in the economic modelling were uncertain.\n\n# Costs in the model\n\n## It is appropriate to include drug wastage in the model\n\nThe ERG applied an average 0.25 of a pack wastage per person, translating to 7\xa0days of wastage over a treatment course, in its preferred analysis. In its response to technical engagement, the company argued that wastage applies for less than 5% of people. The clinical lead for the Cancer Drugs Fund supported including drug wastage and considered that 0.25 of a pack wastage was modest. The clinical experts confirmed that drug wastage was likely to be low, and that 7\xa0days of wastage was reasonable. The company did not incorporate drug wastage into its modelling after the first committee meeting. The committee concluded that it was appropriate to include drug wastage, and that the ERG's estimate of 0.25 wastage per person was plausible.\n\n# End of life\n\n## Ripretinib meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal 2013. The company and ERG agreed that ripretinib does meet the end of life criteria based on:\n\nit being indicated for people with a short life expectancy (that is, less than 24\xa0months)\n\nthere being sufficient evidence that it can offer an extension to life (that is, a mean value of at least 3\xa0months).The committee concluded that ripretinib meets NICE's criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness estimate\n\n## No plausible cost-effectiveness estimates can be determined\n\nNICE's guide to the methods of technology appraisal 2013 notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee agreed that there were issues with the company's modelling approach and validity of outputs. It noted the high level of uncertainty, specifically:\n\nthat 37% of people in INVICTUS had 4\xa0or more previous treatments, which is likely a treatment effect modifier or a prognostic factor of outcomes (see section\xa03.4)\n\nthe model includes a stopping rule that does not reflect clinical practice (see section\xa03.5)\n\nthe overall survival modelling extrapolations are not clinically valid (see section\xa03.6)\n\nthe plausibility of the utility value for the ripretinib arm after progression (see section\xa03.8).Ripretinib meets the end of life criteria (see section\xa03.10). However, after taking the above factors into account, the committee judged that the company's base-case ICER was not plausible and noted that adjusting overall survival for post-progression ripretinib use caused the ICER to exceed £100,000 per QALY gained. The exact ICERs the committee used for decision making included confidential discounts so cannot be reported here. Because all of the analyses contained a stopping rule that the committee found inappropriate, the committee did not consider any of the results further. To address the committee's preferred assumptions, several updates to the model were needed:\n\nremoving the stopping rule because it is not clinically appropriate and disadvantages people with advanced GIST (see section\xa03.5)\n\nensuring the outputs of the model are clinically validated and align with clinical opinion on survival estimates (see section\xa03.6)\n\nadjusting overall survival estimates to account for dose escalation and treatment switching in the INVICTUS trial (see section\xa03.7)\n\nincluding scenario analyses for both the company's and ERG's preferred utility values (see section\xa03.8)\n\nincluding the ERG's preferred drug wastage of 0.25 of a pack per person (see section\xa03.9).The company did not provide any new evidence or analysis in response to consultation. So, the committee was unable to consider any cost-effectiveness estimates that had been generated using its preferred assumptions. At the second committee meeting, the committee reaffirmed that the available cost-effectiveness estimates remained implausible because of the issues described above.\n\n# Other factors\n\n## Equalities\n\nNo equalities issues were raised during the appraisal process. No potential equality issues were identified in the company submission. The committee concluded that there were no equalities issues relevant to the recommendation.\n\n## Ripretinib is not innovative beyond what is captured in the cost-effectiveness estimates\n\nThe company describe ripretinib as innovative because it:\n\ncan broadly inhibit wild-type and KIT and PDGFRA mutations\n\naddresses an unmet need.The committee acknowledged the company's position that ripretinib is innovative. However, it concluded, and the company agreed, that there were no additional benefits associated with ripretinib that had not been captured in the cost-effectiveness estimates.\n\n# Conclusion\n\n## Ripretinib is not recommended\n\nThe committee recalled that it did not have any cost-effectiveness estimates using its preferred modelling assumptions (see section\xa03.11). The available evidence did not indicate that ripretinib is an effective use of NHS resources, even when end of life weighting is applied. The economic model did not reflect clinical practice about when to stop treatment with ripretinib, and was not aligned with the NHS expanded access programme. So, the committee concluded that it did not recommend ripretinib for treating advanced GIST after 3\xa0or more treatments."}	https://www.nice.org.uk/guidance/ta881	Evidence-based recommendations on ripretinib (Qinlock) for treating gastrointestinal stromal tumour in adults after 3 or more treatments.
8d27c36ff4aaeee2f8cb8331cbdf69cb30a1aaad	nice	Metastatic malignant disease of unknown primary origin in adults: diagnosis and management	Metastatic malignant disease of unknown primary origin in adults: diagnosis and management This guideline covers diagnosing and managing secondary cancer in people aged 18 and over when the site of the primary cancer is unknown. This includes people who have had treatment for cancer before. It aims to improve quality of life by offering advice on tests for identifying the site of the primary cancer and options for managing the person’s condition. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. # Organisation of services and support ## The CUP team and its functions Every hospital with a cancer centre or unit should establish a carcinoma of unknown primary (CUP) team, and ensure that patients have access to the team when a malignancy of undefined primary origin (MUO) is diagnosed. The team should: consist of an oncologist, a palliative care physician and a CUP specialist nurse or key worker as a minimum have administrative support and sufficient designated time in their job plans for this specialist role and have a named lead clinician. The CUP team's named lead clinician should: take managerial responsibility for the CUP service within the cancer centre or unit ensure there is a clinical system for the appropriate care of MUO and CUP patients ensure that each patient has an identified CUP specialist nurse or key worker ensure there is cover for all members of the CUP team during periods of absence ensure that senior clinical input is available to inform decision making and treat patients as necessary ensure that there is a single point of contact for the patient to access the CUP team implement the care pathway and help to educate other healthcare professionals in diagnosing and managing MUO and CUP ensure timely and effective communication between all healthcare professionals involved in the care of patients with MUO or CUP, including primary and palliative care represent the cancer centre or unit at the CUP network site-specific group and CUP network MDT and contribute to regular local and network audits of the management of MUO or CUP. Every hospital with a cancer centre or unit should assign a CUP specialist nurse or key worker to patients diagnosed with MUO or CUP. The CUP specialist nurse or key worker should: take a major role in coordinating the patient's care in line with this guideline liaise with the patient's GP and other community support services ensure that the patient and their carers can get information, advice and support about diagnosis, treatment, palliative care, spiritual and psychosocial concerns meet with the patient in the early stages of the pathway and keep in close contact with the patient regularly by mutual agreement and be an advocate for the patient at CUP team meetings. Refer outpatients with MUO to the CUP team immediately using the rapid referral pathway for cancer, so that all patients are assessed within 2 weeks of referral. A member of the CUP team should assess inpatients with MUO by the end of the next working day after referral. The CUP team should take responsibility for ensuring that a management plan exists which includes: appropriate investigations symptom control access to psychological support and providing information. The CUP team should actively review the outcome of all investigations with a nominated pathologist and radiologist as appropriate. A CUP network MDT should be set up to review the treatment and care of patients with confirmed CUP, or with MUO or provisional CUP and complex diagnostic or treatment issues. This team should carry out established specialist MDT responsibilities. The CUP team should be involved in the patient's care until the patient is: referred to a site-specialist consultant or referred for palliative care alone or diagnosed with a non-malignant condition.If CUP is confirmed, the CUP team should continue managing the patient's care. Every hospital with a cancer centre or unit should ensure that patients are upgraded to the existing cancer waiting times pathway when MUO is suspected or first diagnosed. Every hospital with a cancer centre or unit undertaking diagnostic investigations of patients with MUO should ensure that services are set up for rapid and appropriate investigation of patients according to this guideline, and staff are appropriately trained. ## Organisation of CUP services at network and national level Every cancer network should establish a network site-specific group to define and oversee policies for managing CUP. The group should: ensure that every CUP team in the network is properly set up (see recommendation 1.1.1.1) ensure that the local care pathway for diagnosing and managing CUP is in line with this guideline be aware of the variety of routes by which newly diagnosed patients present advise the cancer network on all matters related to CUP, recognising that many healthcare professionals have limited experience of CUP maintain a network-wide audit of the incidence of CUP, its timely management and patient outcomes arrange and hold regular meetings for the group to report patient outcomes and review the local care pathway. ## Definitions and data collection for MUO and CUP Data and coding definitions for MUO and CUP should be developed and routine statistics should use these definitions. A minimum data set for MUO and CUP should be agreed nationally. The data set should be collected by clinicians seeing MUO and CUP patients and reviewed at network level. A national audit should be established for MUO and CUP patients based on the agreed minimum data set. The National Cancer Intelligence Network should analyse current data on the epidemiology of MUO and CUP and use of the NHS by MUO and CUP patients. # Diagnosis For patients presenting with MUO, diagnosis can be divided into two phases. The aim of the initial diagnostic phase is to perform the most appropriate investigations efficiently, to identify: a primary site, which will guide treatment decisions or non-epithelial malignancy, which can be treated regardless of primary site (for example, lymphoma, other haematological malignancies, melanoma, sarcoma, and germ-cell tumours) or metastatic epithelial or neuro-endocrine malignancy without an identifiable primary site (a diagnosis of provisional CUP).If further investigation is appropriate, a second phase of special investigations may be offered to patients with provisional CUP. When these are complete and if a primary site has still not been identified, a diagnosis of confirmed CUP can be made. In current practice the nature and extent of initial diagnostic tests are not universally agreed, and evidence to support the use of special tests is lacking. The approach used in this guideline has been to: define the core initial tests for patients in whom investigation is clinically relevant examine the contribution of special tests define the best histological assessment of tissue samples examine the best approach for specific presentations or difficult diagnoses. ## Initial diagnostic phase Offer the following investigations to patients with MUO, as clinically appropriate, guided by the patient's symptoms: comprehensive history and physical examination including breast, nodal areas, skin, genital, rectal and pelvic examination full blood count; urea, electrolytes and creatinine; liver function tests; calcium; urinalysis; lactate dehydrogenase chest X-ray myeloma screen (when there are isolated or multiple lytic bone lesions) symptom-directed endoscopy computed tomography (CT) scan of the chest, abdomen and pelvis prostate-specific antigen (PSA) in men (see recommendation 1.2.2.1) cancer antigen 125 (CA125) in women with peritoneal malignancy or ascites (see recommendation 1.2.2.1) alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) (particularly in the presence of midline nodal disease) (see recommendation 1.2.2.1) testicular ultrasound in men with presentations compatible with germ-cell tumours biopsy and standard histological examination, with immunohistochemistry where necessary, to distinguish carcinoma from other malignant diagnoses. ## Second diagnostic phase – special investigations ## Tumour markers Do not measure tumour markers during diagnosis except for: AFP and hCG in patients with presentations compatible with germ-cell tumours (particularly those with mediastinal and/or retroperitoneal masses and in young men). AFP in patients with presentations compatible with hepatocellular cancer. PSA in men with presentations compatible with prostate cancer. CA125 in women with presentations compatible with ovarian cancer (including those with inguinal node, chest, pleural, peritoneal or retroperitoneal presentations). Carefully interpret the results because of limited test specificity. ## Upper and lower gastrointestinal endoscopy Do not carry out upper or lower gastrointestinal (GI) endoscopy in patients with MUO unless the symptoms, histology or radiology suggest a GI primary tumour. ## Mammography Do not offer mammography routinely to women presenting with MUO, unless clinical or pathological features are compatible with breast cancer. ## Breast magnetic resonance imaging Refer patients with adenocarcinoma involving the axillary nodes to a breast cancer MDT for evaluation and treatment. If no breast primary tumour is identified after standard breast investigations, consider dynamic contrast-enhanced breast magnetic resonance imaging (MRI) to identify lesions suitable for targeted biopsy. ## Positron emission tomography–computed tomography Offer positron emission tomography–computed tomography (18F-FDG PET-CT) to patients with provisional CUP presenting with cervical lymphadenopathy with no primary tumour identified on ear, nose and throat panendoscopy if radical treatment is considered to be an option. Consider 18F-FDG PET-CT in patients with provisional CUP with extra-cervical presentations after discussion with the CUP team or CUP network MDT. ## Molecular diagnostic tests Use a panel of antibodies comprising cytokeratin 7 (CK7), CK20, thyroid transcription factor-1 (TTF-1), placental alkaline phosphatase (PLAP), oestrogen receptor (ER; women only) and PSA (men only) in all patients with adenocarcinoma of unknown origin. Use additional immunohistochemistry to refine the differential diagnosis, guided by the results of the panel of antibodies in recommendation 1.2.2.7 and the clinical picture. This recommendation has been withdrawn.For information on genomic diagnostic tests to identify primary tumours in patients with provisional CUP, see the NHS Genomic Medicine Service's national genomic test directory for cancer. ## Investigation of specific clinical presentations ## Intrapulmonary nodules without evidence of endobronchial disease Offer flexible bronchoscopy with biopsy, brushings and washings to patients presenting with intrapulmonary nodules of probable metastatic origin that are unsuitable for percutaneous biopsy, even in the absence of endobronchial or central nodal disease on imaging. Offer video-assisted thoracoscopic surgery (VATS) exploration to patients only after a negative bronchoscopic procedure and where percutaneous biopsy is considered inappropriate. ## Investigation of malignant peritoneal disease Obtain a tissue sample for histological examination in patients with MUO who present with ascites, if technically possible. # Factors influencing management decisions ## When to stop investigations Do not offer further investigations to identify the primary site of origin of the malignancy to patients who are unfit for treatment. Perform investigations only if: the results are likely to affect a treatment decision the patient understands why the investigations are being carried out the patient understands the potential benefits and risks of investigation and treatment and the patient is prepared to accept treatment. Explain to patients and carers if further investigations will not alter treatment options. Provide appropriate emotional and psychological support, information about CUP, treatment options and palliative care. ## Selecting optimal treatment Take account of prognostic factors, in particular performance status, presence of liver metastases, lactate dehydrogenase levels and serum albumin, when making decisions about further diagnostic investigations and treatment. Discuss the patient's prognostic factors with the patient and their relatives or carers, if appropriate, to help them make informed decisions about treatment. Include the patient's prognostic factors in decision aids and other information for patients and their relatives or carers about treatment options. This recommendation has been withdrawn. # Managing specific presentations ## Presentations that may benefit from radical treatment ## Squamous carcinoma involving upper- or mid-neck nodes Refer patients presenting with upper- or mid-neck squamous cell carcinoma and an unidentified primary tumour to a head and neck MDT for evaluation and treatment. ## Adenocarcinoma involving the axillary nodes Refer patients with adenocarcinoma involving the axillary nodes to a breast cancer MDT for evaluation and treatment. ## Squamous carcinoma involving the inguinal nodes Refer patients with squamous carcinoma confined to the inguinal nodes to a specialist surgeon in an appropriate MDT to consider treatment with curative intent. Offer patients with operable disease either: superficial lymphadenectomy and consider post-lymphadenectomy radiotherapy (for patients with risk factors for residual disease, for example multiple involved nodes or extracapsular spread) or simple excision of clinically involved nodes, followed by radiotherapy. ## Solitary metastases Do not investigate a tumour inappropriately because this may make radical treatment ineffective. For example, biopsy of a primary bone tumour may mean that the patient needs more extensive surgery than usual. Percutaneous biopsy of a potentially resectable liver metastasis may compromise outcome. Consider that an apparent metastasis could be an unusual primary tumour. Refer patients with a solitary tumour in the liver, brain, bone, skin or lung to the appropriate MDT to consider radical local treatment. ## Presentations with a poor prognosis ## Multiple metastases including brain involvement Refer patients presenting with apparent brain metastases as the only sign of malignant disease after initial and special investigations to a neuro-oncology MDT for evaluation and treatment. Do not offer chemotherapy to patients with brain metastases of unknown primary origin except as part of a controlled clinical trial. Inform patients with brain metastases of unknown primary origin and their carers that there is no evidence that any treatment offers improved survival and there is limited evidence of improvement in neurological symptoms with surgery and/or whole brain radiotherapy. # Systemic treatment ## Chemotherapy in patients with confirmed CUP If chemotherapy is being considered for patients with confirmed CUP, with no clinical features suggesting a specific treatable syndrome, inform patients about the potential benefits and risks of treatment. Offer patients with confirmed CUP the opportunity to enter clinical trials. If chemotherapy is offered outside clinical trials, take into account the clinical and pathological characteristics of the tumour, the toxicity profile of the drugs, their ease of administration and response rate when choosing which treatment to use. ## Chemotherapy for recognised treatable syndromes Offer patients chemotherapy directed at a specific treatable syndrome if they have: confirmed CUP with clinical and/or laboratory features of a specific treatable syndrome and adequate performance status. Offer patients the opportunity to enter clinical trials. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. ## Malignancy of undefined primary origin (MUO) Metastatic malignancy identified on the basis of a limited number of tests, without an obvious primary site, before comprehensive investigation. ## Provisional carcinoma of unknown primary origin (provisional CUP) Metastatic epithelial or neuro-endocrine malignancy identified on the basis of histology or cytology, with no primary site detected despite a selected initial screen of investigations, before specialist review and possible further specialised investigations. ## Confirmed carcinoma of unknown primary origin (confirmed CUP) Metastatic epithelial or neuro-endocrine malignancy identified on the basis of final histology, with no primary site detected despite a selected initial screen of investigations, specialist review, and further specialised investigations as appropriate.# Recommendations for research The guideline development group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The guideline development group's full set of recommendations for research is detailed in the full guideline. # Clinical studies group for CUP A clinical studies group should be established at National Cancer Research Network (NCRN) level for CUP, to coordinate and direct a broad portfolio of research examining basic science, clinical studies, organisational processes and patient-centred topics ## Why this is important The existence of a national organisation to guide and facilitate research has revolutionised cancer care in the UK. High-quality, rapidly accruing trials have resulted in improved outcomes for patients with all common cancers. Patients with CUP cannot benefit from similar advances because there is no national research strategy addressing their needs. Establishing an NCRN clinical studies group for CUP with a comprehensive portfolio of relevant trials would redress this inequality. # Use of PET-CT in the MUO diagnostic pathway Further research is needed to determine whether the use of 18F-FDG PET-CT early in the CUP management pathway reduces the number of investigations that the patient is subjected to. ## Why this is important Tests early in the diagnostic pathway of patients with MUO are selected on the basis of clinical factors (suspicion about a possible primary site) and test-related factors (expected yield, ease of access, ease of use, cost). Investigation is an iterative process in which the results of one round of tests inform the selection of subsequent tests. 18F-FDG PET-CT may reveal a primary tumour that would either not be detected using standard tests, or that would have been detected only after a protracted and costly series of other tests. Using 18F-FDG PET-CT early in the diagnostic pathway may reveal useful clinical information more quickly and more cost effectively than current diagnostic strategies. Comparison of established methods of investigation with early use of 18F-FDG PET-CT is therefore warranted. # Decision aids Decision aids should be developed and research carried out to evaluate their benefit. ## Why this is important Decision aids have been shown to help breast cancer patients when they face difficult choices. Such aids could be of even greater value to patients with CUP. Research to evaluate the benefits, ease of use and acceptability of such tools to both clinicians and patients should be conducted. Such studies could be an adjunct to larger trials of chemotherapy. # Gene-expression-based profiling Prospective randomised trials should be undertaken in patients with confirmed CUP to evaluate whether chemotherapy guided by gene-expression-based profiling is superior to treatment guided by conventional clinical and pathological factors. ## Why this is important Selection of optimal chemotherapy for patients with cancer is largely based on knowing the organ of origin of the tumour. For patients with CUP this is not known and decisions are therefore based on the likely organ of origin, as determined by tests such as histology. The limited benefit of treatment selected on this basis highlights the ineffectiveness of current tests in guiding treatment. If the likely organ of origin were more accurately defined there may be a greater chance that treatment would be more effective. Gene-expression-based profiling reliably defines the organ of origin of tumour samples, and the information this test provides in cases of CUP may translate into superior outcomes. Comparing the outcome of chemotherapy selected using conventional factors with the outcome of chemotherapy based on a putative organ of origin defined by gene-expression-based profiling would determine whether this technique could be a beneficial addition to standard management in CUP. # Defining optimal systemic therapy Randomised controlled clinical trials should be undertaken in patients with confirmed CUP to define optimal systemic therapy. ## Why this is important The evidence currently used to guide selection of systemic treatment for patients with CUP is very limited, and mainly based on phase II non-comparative studies. In the majority of patients it is uncertain whether systemic treatment offers any advantages over supportive care alone. Randomised controlled trials comparing different interventions should be conducted in well-defined groups of patients with CUP to define optimal treatment. Such trials should include in their design methods to assess cost-effectiveness and patient-centred factors such as quality of life.# Context Patients with 'cancer of unknown primary origin' have metastatic malignant disease without an identifiable primary site. For patients with this condition the type of tumour, the extent of its spread, and the outcome of treatment all vary widely. Most patients have malignancy that appears to derive from epithelial cells, that is, 'carcinoma of unknown primary origin' (CUP). Patients with tumours of non-epithelial lineage (melanoma, sarcoma, lymphoma, germ cell) are not considered in this guideline because their care is covered in existing guidelines for their specific tumour type. They form a distinct minority because their tumours can often be managed satisfactorily even without an identifiable primary site. CUP is currently an inexact term because it is often applied to patients who have had only limited investigations. In this guideline a patient who presents with metastatic malignancy (in the form of tumour masses or effusions) identified on clinical examination or by imaging, without an obvious primary site, is regarded as having 'malignancy of undefined primary origin' (MUO). 'Provisional carcinoma of unknown primary origin' (provisional CUP) is used to refer to patients with metastatic malignancy of proven epithelial, neuro-endocrine or undifferentiated lineage, after initial, but not exhaustive investigations. Although a primary site will be found in most of these patients, or a non-epithelial malignancy diagnosed, in some patients a primary site will not be found and a diagnosis of 'provisional CUP' will change to a diagnosis of 'confirmed CUP' after the results of all tests are complete. Definitions of MUO and CUP are given in the section on terms used in this guideline. In England and Wales, over 10,000 cases of CUP occur annually and it is the fourth most common cause of cancer death. Patients presenting with MUO and those who are ultimately diagnosed with confirmed CUP are disadvantaged in many ways. The following problems in current practice have been identified: Lack of agreed definitions of the clinical entity. No referral guidelines for suspected cancer relevant to patients without an obvious or strongly suspected primary. No system to rapidly identify patients and to ensure early specialist involvement. Lack of efficient arrangements to manage the initial diagnostic phase. Uncertainty about appropriate diagnostic tests, including the use of new technologies. Lack of a team structure to efficiently care for newly presenting patients. Insufficient specialist oncology expertise. Lack of dedicated key workers or specialist nurses. Referral to inappropriate site-specific cancer teams. Lack of support and information for patients. Delays in involvement of specialist palliative care. Lack of an overall organisational structure to ensure high-quality care. Uncertainty about optimal treatment. Lack of adequate epidemiology data. No research organisation. The aim of this guideline is to address the needs of patients with CUP, which are not covered by current NICE cancer service guidance. There is important overlap between the developments necessary for optimal management of MUO and CUP and the acute oncology initiatives in the National Chemotherapy Advisory Group (NCAG) report on Chemotherapy Services in England: Ensuring quality and safety. This guideline complements and supports the relevant recommendations in the NCAG report. The guideline requires the development of a CUP specialist role for oncologists, multidisciplinary team (MDT) functioning, and site-specific group organisation in line with practice for cancers with identified primary sites. It is expected that many consultant oncologists who develop a specialist interest in CUP will also be involved in organising and delivering aspects of the acute oncology service for newly presenting patients with previously undiagnosed cancer. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# Organisation of services and support\n\n## The CUP team and its functions\n\nEvery hospital with a cancer centre or unit should establish a carcinoma of unknown primary (CUP) team, and ensure that patients have access to the team when a malignancy of undefined primary origin (MUO) is diagnosed. The team should:\n\nconsist of an oncologist, a palliative care physician and a CUP specialist nurse or key worker as a minimum\n\nhave administrative support and sufficient designated time in their job plans for this specialist role and\n\nhave a named lead clinician.\n\nThe CUP team's named lead clinician should:\n\ntake managerial responsibility for the CUP service within the cancer centre or unit\n\nensure there is a clinical system for the appropriate care of MUO and CUP patients\n\nensure that each patient has an identified CUP specialist nurse or key worker\n\nensure there is cover for all members of the CUP team during periods of absence\n\nensure that senior clinical input is available to inform decision making and treat patients as necessary\n\nensure that there is a single point of contact for the patient to access the CUP team\n\nimplement the care pathway and help to educate other healthcare professionals in diagnosing and managing MUO and CUP\n\nensure timely and effective communication between all healthcare professionals involved in the care of patients with MUO or CUP, including primary and palliative care\n\nrepresent the cancer centre or unit at the CUP network site-specific group and CUP network MDT and\n\ncontribute to regular local and network audits of the management of MUO or CUP.\n\nEvery hospital with a cancer centre or unit should assign a CUP specialist nurse or key worker to patients diagnosed with MUO or CUP. The CUP specialist nurse or key worker should:\n\ntake a major role in coordinating the patient's care in line with this guideline\n\nliaise with the patient's GP and other community support services\n\nensure that the patient and their carers can get information, advice and support about diagnosis, treatment, palliative care, spiritual and psychosocial concerns\n\nmeet with the patient in the early stages of the pathway and keep in close contact with the patient regularly by mutual agreement and\n\nbe an advocate for the patient at CUP team meetings.\n\nRefer outpatients with MUO to the CUP team immediately using the rapid referral pathway for cancer, so that all patients are assessed within 2\xa0weeks of referral. A member of the CUP team should assess inpatients with MUO by the end of the next working day after referral. The CUP team should take responsibility for ensuring that a management plan exists which includes:\n\nappropriate investigations\n\nsymptom control\n\naccess to psychological support and\n\nproviding information.\n\nThe CUP team should actively review the outcome of all investigations with a nominated pathologist and radiologist as appropriate.\n\nA CUP network MDT should be set up to review the treatment and care of patients with confirmed CUP, or with MUO or provisional CUP and complex diagnostic or treatment issues. This team should carry out established specialist MDT responsibilities.\n\nThe CUP team should be involved in the patient's care until the patient is:\n\nreferred to a site-specialist consultant or\n\nreferred for palliative care alone or\n\ndiagnosed with a non-malignant condition.If CUP is confirmed, the CUP team should continue managing the patient's care.\n\nEvery hospital with a cancer centre or unit should ensure that patients are upgraded to the existing cancer waiting times pathway when MUO is suspected or first diagnosed.\n\nEvery hospital with a cancer centre or unit undertaking diagnostic investigations of patients with MUO should ensure that services are set up for rapid and appropriate investigation of patients according to this guideline, and staff are appropriately trained.\n\n## Organisation of CUP services at network and national level\n\nEvery cancer network should establish a network site-specific group to define and oversee policies for managing CUP. The group should:\n\nensure that every CUP team in the network is properly set up (see recommendation\xa01.1.1.1)\n\nensure that the local care pathway for diagnosing and managing CUP is in line with this guideline\n\nbe aware of the variety of routes by which newly diagnosed patients present\n\nadvise the cancer network on all matters related to CUP, recognising that many healthcare professionals have limited experience of CUP\n\nmaintain a network-wide audit of the incidence of CUP, its timely management and patient outcomes\n\narrange and hold regular meetings for the group to report patient outcomes and review the local care pathway.\n\n## Definitions and data collection for MUO and CUP\n\nData and coding definitions for MUO and CUP should be developed and routine statistics should use these definitions.\n\nA minimum data set for MUO and CUP should be agreed nationally. The data set should be collected by clinicians seeing MUO and CUP patients and reviewed at network level.\n\nA national audit should be established for MUO and CUP patients based on the agreed minimum data set.\n\nThe National Cancer Intelligence Network should analyse current data on the epidemiology of MUO and CUP and use of the NHS by MUO and CUP patients.\n\n# Diagnosis\n\nFor patients presenting with MUO, diagnosis can be divided into two phases. The aim of the initial diagnostic phase is to perform the most appropriate investigations efficiently, to identify:\n\na primary site, which will guide treatment decisions or\n\nnon-epithelial malignancy, which can be treated regardless of primary site (for example, lymphoma, other haematological malignancies, melanoma, sarcoma, and germ-cell tumours) or\n\nmetastatic epithelial or neuro-endocrine malignancy without an identifiable primary site (a diagnosis of provisional CUP).If further investigation is appropriate, a second phase of special investigations may be offered to patients with provisional CUP. When these are complete and if a primary site has still not been identified, a diagnosis of confirmed CUP can be made. In current practice the nature and extent of initial diagnostic tests are not universally agreed, and evidence to support the use of special tests is lacking. The approach used in this guideline has been to:\n\ndefine the core initial tests for patients in whom investigation is clinically relevant\n\nexamine the contribution of special tests\n\ndefine the best histological assessment of tissue samples\n\nexamine the best approach for specific presentations or difficult diagnoses.\n\n## Initial diagnostic phase\n\nOffer the following investigations to patients with MUO, as clinically appropriate, guided by the patient's symptoms:\n\ncomprehensive history and physical examination including breast, nodal areas, skin, genital, rectal and pelvic examination\n\nfull blood count; urea, electrolytes and creatinine; liver function tests; calcium; urinalysis; lactate dehydrogenase\n\nchest X-ray\n\nmyeloma screen (when there are isolated or multiple lytic bone lesions)\n\nsymptom-directed endoscopy\n\ncomputed tomography (CT) scan of the chest, abdomen and pelvis\n\nprostate-specific antigen (PSA) in men (see recommendation\xa01.2.2.1)\n\ncancer antigen 125 (CA125) in women with peritoneal malignancy or ascites (see recommendation\xa01.2.2.1)\n\nalpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) (particularly in the presence of midline nodal disease) (see recommendation\xa01.2.2.1)\n\ntesticular ultrasound in men with presentations compatible with germ-cell tumours\n\nbiopsy and standard histological examination, with immunohistochemistry where necessary, to distinguish carcinoma from other malignant diagnoses.\n\n## Second diagnostic phase – special investigations\n\n## Tumour markers\n\nDo not measure tumour markers during diagnosis except for:\n\nAFP and hCG in patients with presentations compatible with germ-cell tumours (particularly those with mediastinal and/or retroperitoneal masses and in young men).\n\nAFP in patients with presentations compatible with hepatocellular cancer.\n\nPSA in men with presentations compatible with prostate cancer.\n\nCA125 in women with presentations compatible with ovarian cancer (including those with inguinal node, chest, pleural, peritoneal or retroperitoneal presentations). Carefully interpret the results because of limited test specificity.\n\n## Upper and lower gastrointestinal endoscopy\n\nDo not carry out upper or lower gastrointestinal (GI) endoscopy in patients with MUO unless the symptoms, histology or radiology suggest a GI primary tumour.\n\n## Mammography\n\nDo not offer mammography routinely to women presenting with MUO, unless clinical or pathological features are compatible with breast cancer.\n\n## Breast magnetic resonance imaging\n\nRefer patients with adenocarcinoma involving the axillary nodes to a breast cancer MDT for evaluation and treatment. If no breast primary tumour is identified after standard breast investigations, consider dynamic contrast-enhanced breast magnetic resonance imaging (MRI) to identify lesions suitable for targeted biopsy.\n\n## Positron emission tomography–computed tomography\n\nOffer positron emission tomography–computed tomography (18F-FDG PET-CT) to patients with provisional CUP presenting with cervical lymphadenopathy with no primary tumour identified on ear, nose and throat panendoscopy if radical treatment is considered to be an option.\n\nConsider 18F-FDG PET-CT in patients with provisional CUP with extra-cervical presentations after discussion with the CUP team or CUP network MDT.\n\n## Molecular diagnostic tests\n\nUse a panel of antibodies comprising cytokeratin 7 (CK7), CK20, thyroid transcription factor-1 (TTF-1), placental alkaline phosphatase (PLAP), oestrogen receptor (ER; women only) and PSA (men only) in all patients with adenocarcinoma of unknown origin.\n\nUse additional immunohistochemistry to refine the differential diagnosis, guided by the results of the panel of antibodies in recommendation 1.2.2.7 and the clinical picture.\n\nThis recommendation has been withdrawn.For information on genomic diagnostic tests to identify primary tumours in patients with provisional CUP, see the NHS Genomic Medicine Service's national genomic test directory for cancer.\n\n## Investigation of specific clinical presentations\n\n## Intrapulmonary nodules without evidence of endobronchial disease\n\nOffer flexible bronchoscopy with biopsy, brushings and washings to patients presenting with intrapulmonary nodules of probable metastatic origin that are unsuitable for percutaneous biopsy, even in the absence of endobronchial or central nodal disease on imaging.\n\nOffer video-assisted thoracoscopic surgery (VATS) exploration to patients only after a negative bronchoscopic procedure and where percutaneous biopsy is considered inappropriate.\n\n## Investigation of malignant peritoneal disease\n\nObtain a tissue sample for histological examination in patients with MUO who present with ascites, if technically possible.\n\n# Factors influencing management decisions\n\n## When to stop investigations\n\nDo not offer further investigations to identify the primary site of origin of the malignancy to patients who are unfit for treatment.\n\nPerform investigations only if:\n\nthe results are likely to affect a treatment decision\n\nthe patient understands why the investigations are being carried out\n\nthe patient understands the potential benefits and risks of investigation and treatment and\n\nthe patient is prepared to accept treatment.\n\nExplain to patients and carers if further investigations will not alter treatment options. Provide appropriate emotional and psychological support, information about CUP, treatment options and palliative care.\n\n## Selecting optimal treatment\n\nTake account of prognostic factors, in particular performance status, presence of liver metastases, lactate dehydrogenase levels and serum albumin, when making decisions about further diagnostic investigations and treatment.\n\nDiscuss the patient's prognostic factors with the patient and their relatives or carers, if appropriate, to help them make informed decisions about treatment.\n\nInclude the patient's prognostic factors in decision aids and other information for patients and their relatives or carers about treatment options.\n\nThis recommendation has been withdrawn.\n\n# Managing specific presentations\n\n## Presentations that may benefit from radical treatment\n\n## Squamous carcinoma involving upper- or mid-neck nodes\n\nRefer patients presenting with upper- or mid-neck squamous cell carcinoma and an unidentified primary tumour to a head and neck MDT for evaluation and treatment.\n\n## Adenocarcinoma involving the axillary nodes\n\nRefer patients with adenocarcinoma involving the axillary nodes to a breast cancer MDT for evaluation and treatment.\n\n## Squamous carcinoma involving the inguinal nodes\n\nRefer patients with squamous carcinoma confined to the inguinal nodes to a specialist surgeon in an appropriate MDT to consider treatment with curative intent.\n\nOffer patients with operable disease either:\n\nsuperficial lymphadenectomy and consider post-lymphadenectomy radiotherapy (for patients with risk factors for residual disease, for example multiple involved nodes or extracapsular spread) or\n\nsimple excision of clinically involved nodes, followed by radiotherapy.\n\n## Solitary metastases\n\nDo not investigate a tumour inappropriately because this may make radical treatment ineffective. For example, biopsy of a primary bone tumour may mean that the patient needs more extensive surgery than usual. Percutaneous biopsy of a potentially resectable liver metastasis may compromise outcome. Consider that an apparent metastasis could be an unusual primary tumour.\n\nRefer patients with a solitary tumour in the liver, brain, bone, skin or lung to the appropriate MDT to consider radical local treatment.\n\n## Presentations with a poor prognosis\n\n## Multiple metastases including brain involvement\n\nRefer patients presenting with apparent brain metastases as the only sign of malignant disease after initial and special investigations to a neuro-oncology MDT for evaluation and treatment.\n\nDo not offer chemotherapy to patients with brain metastases of unknown primary origin except as part of a controlled clinical trial.\n\nInform patients with brain metastases of unknown primary origin and their carers that there is no evidence that any treatment offers improved survival and there is limited evidence of improvement in neurological symptoms with surgery and/or whole brain radiotherapy.\n\n# Systemic treatment\n\n## Chemotherapy in patients with confirmed CUP\n\nIf chemotherapy is being considered for patients with confirmed CUP, with no clinical features suggesting a specific treatable syndrome, inform patients about the potential benefits and risks of treatment.\n\nOffer patients with confirmed CUP the opportunity to enter clinical trials.\n\nIf chemotherapy is offered outside clinical trials, take into account the clinical and pathological characteristics of the tumour, the toxicity profile of the drugs, their ease of administration and response rate when choosing which treatment to use.\n\n## Chemotherapy for recognised treatable syndromes\n\nOffer patients chemotherapy directed at a specific treatable syndrome if they have:\n\nconfirmed CUP with clinical and/or laboratory features of a specific treatable syndrome and\n\nadequate performance status.\n\nOffer patients the opportunity to enter clinical trials.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Malignancy of undefined primary origin (MUO)\n\nMetastatic malignancy identified on the basis of a limited number of tests, without an obvious primary site, before comprehensive investigation.\n\n## Provisional carcinoma of unknown primary origin (provisional CUP)\n\nMetastatic epithelial or neuro-endocrine malignancy identified on the basis of histology or cytology, with no primary site detected despite a selected initial screen of investigations, before specialist review and possible further specialised investigations.\n\n## Confirmed carcinoma of unknown primary origin (confirmed CUP)\n\nMetastatic epithelial or neuro-endocrine malignancy identified on the basis of final histology, with no primary site detected despite a selected initial screen of investigations, specialist review, and further specialised investigations as appropriate.", 'Recommendations for research': "The guideline development group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The guideline development group's full set of recommendations for research is detailed in the full guideline.\n\n# Clinical studies group for CUP\n\nA clinical studies group should be established at National Cancer Research Network (NCRN) level for CUP, to coordinate and direct a broad portfolio of research examining basic science, clinical studies, organisational processes and patient-centred topics\n\n## Why this is important\n\nThe existence of a national organisation to guide and facilitate research has revolutionised cancer care in the UK. High-quality, rapidly accruing trials have resulted in improved outcomes for patients with all common cancers. Patients with CUP cannot benefit from similar advances because there is no national research strategy addressing their needs. Establishing an NCRN clinical studies group for CUP with a comprehensive portfolio of relevant trials would redress this inequality.\n\n# Use of PET-CT in the MUO diagnostic pathway\n\nFurther research is needed to determine whether the use of 18F-FDG PET-CT early in the CUP management pathway reduces the number of investigations that the patient is subjected to.\n\n## Why this is important\n\nTests early in the diagnostic pathway of patients with MUO are selected on the basis of clinical factors (suspicion about a possible primary site) and test-related factors (expected yield, ease of access, ease of use, cost). Investigation is an iterative process in which the results of one round of tests inform the selection of subsequent tests. 18F-FDG PET-CT may reveal a primary tumour that would either not be detected using standard tests, or that would have been detected only after a protracted and costly series of other tests. Using 18F-FDG PET-CT early in the diagnostic pathway may reveal useful clinical information more quickly and more cost effectively than current diagnostic strategies. Comparison of established methods of investigation with early use of 18F-FDG PET-CT is therefore warranted.\n\n# Decision aids\n\nDecision aids should be developed and research carried out to evaluate their benefit.\n\n## Why this is important\n\nDecision aids have been shown to help breast cancer patients when they face difficult choices. Such aids could be of even greater value to patients with CUP. Research to evaluate the benefits, ease of use and acceptability of such tools to both clinicians and patients should be conducted. Such studies could be an adjunct to larger trials of chemotherapy.\n\n# Gene-expression-based profiling\n\nProspective randomised trials should be undertaken in patients with confirmed CUP to evaluate whether chemotherapy guided by gene-expression-based profiling is superior to treatment guided by conventional clinical and pathological factors.\n\n## Why this is important\n\nSelection of optimal chemotherapy for patients with cancer is largely based on knowing the organ of origin of the tumour. For patients with CUP this is not known and decisions are therefore based on the likely organ of origin, as determined by tests such as histology. The limited benefit of treatment selected on this basis highlights the ineffectiveness of current tests in guiding treatment. If the likely organ of origin were more accurately defined there may be a greater chance that treatment would be more effective. Gene-expression-based profiling reliably defines the organ of origin of tumour samples, and the information this test provides in cases of CUP may translate into superior outcomes. Comparing the outcome of chemotherapy selected using conventional factors with the outcome of chemotherapy based on a putative organ of origin defined by gene-expression-based profiling would determine whether this technique could be a beneficial addition to standard management in CUP.\n\n# Defining optimal systemic therapy\n\nRandomised controlled clinical trials should be undertaken in patients with confirmed CUP to define optimal systemic therapy.\n\n## Why this is important\n\nThe evidence currently used to guide selection of systemic treatment for patients with CUP is very limited, and mainly based on phase II non-comparative studies. In the majority of patients it is uncertain whether systemic treatment offers any advantages over supportive care alone. Randomised controlled trials comparing different interventions should be conducted in well-defined groups of patients with CUP to define optimal treatment. Such trials should include in their design methods to assess cost-effectiveness and patient-centred factors such as quality of life.", 'Context': "Patients with 'cancer of unknown primary origin' have metastatic malignant disease without an identifiable primary site. For patients with this condition the type of tumour, the extent of its spread, and the outcome of treatment all vary widely. Most patients have malignancy that appears to derive from epithelial cells, that is, 'carcinoma of unknown primary origin' (CUP). Patients with tumours of non-epithelial lineage (melanoma, sarcoma, lymphoma, germ cell) are not considered in this guideline because their care is covered in existing guidelines for their specific tumour type. They form a distinct minority because their tumours can often be managed satisfactorily even without an identifiable primary site.\n\nCUP is currently an inexact term because it is often applied to patients who have had only limited investigations. In this guideline a patient who presents with metastatic malignancy (in the form of tumour masses or effusions) identified on clinical examination or by imaging, without an obvious primary site, is regarded as having 'malignancy of undefined primary origin' (MUO). 'Provisional carcinoma of unknown primary origin' (provisional CUP) is used to refer to patients with metastatic malignancy of proven epithelial, neuro-endocrine or undifferentiated lineage, after initial, but not exhaustive investigations. Although a primary site will be found in most of these patients, or a non-epithelial malignancy diagnosed, in some patients a primary site will not be found and a diagnosis of 'provisional CUP' will change to a diagnosis of 'confirmed CUP' after the results of all tests are complete. Definitions of MUO and CUP are given in the section on terms used in this guideline.\n\nIn England and Wales, over 10,000\xa0cases of CUP occur annually and it is the fourth most common cause of cancer death. Patients presenting with MUO and those who are ultimately diagnosed with confirmed CUP are disadvantaged in many ways. The following problems in current practice have been identified:\n\nLack of agreed definitions of the clinical entity.\n\nNo referral guidelines for suspected cancer relevant to patients without an obvious or strongly suspected primary.\n\nNo system to rapidly identify patients and to ensure early specialist involvement.\n\nLack of efficient arrangements to manage the initial diagnostic phase.\n\nUncertainty about appropriate diagnostic tests, including the use of new technologies.\n\nLack of a team structure to efficiently care for newly presenting patients.\n\nInsufficient specialist oncology expertise.\n\nLack of dedicated key workers or specialist nurses.\n\nReferral to inappropriate site-specific cancer teams.\n\nLack of support and information for patients.\n\nDelays in involvement of specialist palliative care.\n\nLack of an overall organisational structure to ensure high-quality care.\n\nUncertainty about optimal treatment.\n\nLack of adequate epidemiology data.\n\nNo research organisation.\n\nThe aim of this guideline is to address the needs of patients with CUP, which are not covered by current NICE cancer service guidance.\n\nThere is important overlap between the developments necessary for optimal management of MUO and CUP and the acute oncology initiatives in the National Chemotherapy Advisory Group (NCAG) report on Chemotherapy Services in England: Ensuring quality and safety. This guideline complements and supports the relevant recommendations in the NCAG report.\n\nThe guideline requires the development of a CUP specialist role for oncologists, multidisciplinary team (MDT) functioning, and site-specific group organisation in line with practice for cancers with identified primary sites. It is expected that many consultant oncologists who develop a specialist interest in CUP will also be involved in organising and delivering aspects of the acute oncology service for newly presenting patients with previously undiagnosed cancer.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients."}	https://www.nice.org.uk/guidance/cg104	This guideline covers diagnosing and managing secondary cancer in people aged 18 and over when the site of the primary cancer is unknown. This includes people who have had treatment for cancer before. It aims to improve quality of life by offering advice on tests for identifying the site of the primary cancer and options for managing the person’s condition.
f98de2496956592f2a4274f3d017ff6d7b6216b7	nice	Tezepelumab for treating severe asthma	Tezepelumab for treating severe asthma Evidence-based recommendations on tezepelumab (Tezspire) for treating severe asthma in people 12 years and over. # Recommendations Tezepelumab as an add-on maintenance treatment is recommended as an option for severe asthma in people 12 years and over, when treatment with high-dose inhaled corticosteroids plus another maintenance treatment has not worked well enough. It is recommended only if people: have had 3 or more exacerbations in the previous year, or are having maintenance oral corticosteroids.Tezepelumab is recommended only if the company provides it according to the commercial arrangement. Stop tezepelumab if the rate of severe asthma exacerbations, or the maintenance oral corticosteroid dose, have not been reduced by at least 50% at 12 months. These recommendations are not intended to affect treatment with tezepelumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by them, their clinician, and their parents or carers. Why the committee made these recommendations Severe asthma is usually treated with inhaled corticosteroids plus another maintenance treatment. Oral corticosteroids are sometimes used to prevent exacerbations (asthma attacks), but they may have negative effects in the long-term. Some people with severe asthma can have biological treatments. Tezepelumab is another biological treatment. Clinical trial results show that tezepelumab, when added to usual treatment, reduces exacerbations and the dose of oral corticosteroids needed, compared with placebo. An indirect comparison of tezepelumab with other biological treatments suggests similar clinical effectiveness, but this is uncertain. The cost-effectiveness estimates show that tezepelumab as an add-on maintenance therapy is cost effective compared with standard care and other biological treatments. So, tezepelumab is recommended when treatment with high-dose inhaled corticosteroids plus another maintenance treatment has not worked well enough, for people who have had 3 or more exacerbations in the previous year or who are having maintenance oral corticosteroids.# Information about tezepelumab # Marketing authorisation indication Tezepelumab (Tezspire, AstraZeneca) is indicated as 'an add-on maintenance treatment in adults and adolescents 12 years and older with severe asthma who are inadequately controlled despite high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for tezepelumab. # Price The list price for tezepelumab is £1,265 per 210 mg prefilled syringe per vial (company submission, May 2022). The company has a commercial arrangement. This makes tezepelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Condition background ## Living with severe asthma is physically and emotionally challenging Severe asthma is a distressing and socially isolating condition. Patient experts commented that exacerbations can happen without warning, causing fear. Exacerbations may result in hospitalisation and can be life threatening. The symptoms of severe asthma mean that people often feel tired and unable to work or play, and they may need help with day-to-day activities. The patient experts explained that severe asthma can also affect mental health. The committee understood that people with severe asthma often have difficulties doing day-to-day tasks. People may also have negative effects, including bone damage, from long-term use of standard treatments. People may go on to require surgery because of weak bones. The committee concluded that living with severe asthma is physically and emotionally challenging. # Treatment pathway ## Standard care includes oral corticosteroids and biological treatments as add-ons to first-line treatments Asthma treatment in clinical practice follows the NICE guideline on asthma and the Global Initiative for Asthma (GINA) guideline (which includes the use of biological treatments). If asthma becomes uncontrolled despite inhaled corticosteroids (usually offered with another treatment), then low-dose oral corticosteroids or biological treatments are added. The clinical and patient experts explained that biological treatments are preferred to oral corticosteroids because they have fewer negative effects. Biological treatments may be offered as add-on options if asthma is not controlled well enough with maintenance treatment with high-dose inhaled corticosteroids plus a long-acting beta-agonist or another treatment. The committee noted that, when it met, the choice of available biological treatments, such as anti-interleukin‑5 inhibitors, was based on the phenotype and biomarker profile of asthma. See NICE's technology appraisal guidance on benralizumab, mepolizumab, reslizumab, dupilumab and omalizumab. Patient experts highlighted that biological treatments have been life changing for some people. But not all people with severe asthma can have them because of the specific eligibility criteria. The clinical experts explained that immunoglobulin E, blood eosinophil count and fractional exhaled nitric oxide (FeNO) levels are used to assess and manage severe asthma. They noted that blood eosinophil count and FeNO levels are routinely measured in clinical practice. They also explained that most people with severe asthma usually have 1 or 2 of these biomarkers, but relatively few people have all 3 biomarkers. The committee understood that standard treatment for severe asthma includes oral corticosteroids and several biological treatments as add-ons to first-line treatments. ## A treatment option without the need for biomarker assessment would be welcomed The clinical and patient experts explained that about 5% of people with severe asthma who have regular treatment cannot have existing biological treatments. The patient experts added that long-term use of oral corticosteroids could suppress people's biomarkers, meaning they cannot have existing biological treatments. Both the clinical and patient experts explained that there is an unmet need for treatments that reduce exacerbations and improve asthma control. The patient experts explained that for many people with severe asthma that does not respond to standard treatments (including biological treatments), long-term oral corticosteroids are the only option. They noted these may have negative effects, including osteoporosis, cataracts, glaucoma, skin conditions, reflux oesophagitis, non-alcoholic fatty liver, and weight gain. The clinical expert noted that, in practice, people can switch to a different biological treatment if there was no response to the previous one. But in this situation people would need to have biomarker assessment again. So, a new treatment without the need for biomarker assessment would benefit people. The committee understood that there is an unmet need for people with severe asthma who cannot have existing biological treatments because of their biomarker profiles. So, it concluded that a new treatment option without the need for biomarker assessment would be welcomed. ## The company's proposed positioning of tezepelumab as an add-on to first-line treatment is appropriate Tezepelumab has a marketing authorisation as an add-on maintenance treatment in people 12 years and over with severe asthma that is inadequately controlled despite high-dose inhaled corticosteroids plus another maintenance treatment. The company proposed tezepelumab for a narrower population than in the marketing authorisation. This was people: who had 3 or more exacerbations in the year before, or who are having maintenance oral corticosteroids.The company explained that the existing biological treatments target specific biomarkers (see section 3.3). People with severe asthma often have a biomarker that overlaps with other phenotypes or fluctuates, and some people have no defined inflammation. The company explained that tezepelumab has a unique mechanism of action, which could make it effective for different asthma phenotypes regardless of biomarker profiles. It proposed tezepelumab as an add-on treatment to first-line standard care regardless of biomarker profiles or eligibility. If recommended, tezepelumab would be an alternative option for people with low biomarkers (not eligible for existing biological treatment), as well as those with high biomarkers (eligible for existing add-on biological treatments). The committee noted that there were several subpopulations to be considered based on biomarker eligibility at different positions in the treatment pathway. It concluded that the company's positioning of tezepelumab is appropriate, and it considered the evidence presented for these subpopulations in its decision making. # Comparators ## Relevant comparators are standard care plus add-on biological treatments, and standard care alone The company provided evidence on tezepelumab compared with standard care with or without add-on biological treatments (see section 3.2). The committee agreed that standard care plus add-on biological treatments, and standard care alone, were relevant comparators for tezepelumab. # Treatment response ## The company's updated definition of treatment response is appropriate Reducing exacerbations and the dose of maintenance oral corticosteroids taken are primary outcomes in the company's pivotal clinical trials (see section 3.8). The EAG noted that the tezepelumab trials did not define treatment response. The company assumed that any reduction in exacerbations or maintenance oral corticosteroid dose from baseline was a treatment response. The EAG considered the company's original definition of response inappropriate and not clinically meaningful. It considered that a reduction of between 20% and 50% in exacerbations was an appropriate treatment response, which was in line with the clinical advice it had received. The EAG also noted that using an alternative definition of response, for example, a 20% reduction in exacerbations, was likely to affect the post-assessment transition probabilities in the model. The company explained that using an alternative definition for treatment response of 20% reduction in exacerbations would have little effect on a person's eligibility to continue treatment after 52 weeks (see section 3.14). This is because it would only affect people with 6 or more exacerbations in the previous year. The patient expert explained that for severe asthma, any reduction in exacerbations or maintenance oral corticosteroid dose may not be seen as clinically meaningful in clinical practice. But it could mean qualitative improvement in quality of life. The committee noted the wide spectrum of asthma phenotypes and symptoms (see section 3.2) and queried how the reduction would be meaningfully measured in practice. The clinical expert explained that a holistic view would be needed in practice when response is assessed. People may have natural variation in symptoms or biomarkers from year to year, but these would be relatively small. A reduction in exacerbations may be associated with symptom improvement, but there needs to be a threshold in practice, and this is usually set at 50%. This allows quicker switching to another biological treatment if a person's asthma does not respond. At the first meeting, the committee concluded that a 50% reduction in exacerbations would be more appropriate. In response to consultation, the company explained that it had obtained a clinical opinion from severe asthma specialists who confirmed that they would consider an appropriate definition of response to be: for people not having maintenance oral corticosteroids: 50% reduction in exacerbations for people having maintenance oral corticosteroids: 50% reduction in their dose.The company explained that the committee's requested scenario of 50% reduction in exacerbations and maintenance oral corticosteroid dose use in people already having oral maintenance corticosteroids was not in line with clinical practice. It was also not consistent with previous NICE technology appraisal guidance on mepolizumab, benralizumab and reslizumab for treating severe asthma. Stakeholder comments in response to the consultation, and the clinical expert at the second appraisal committee meeting, agreed with the company's updated definition of response. The committee concluded that the company's updated definition of treatment response was appropriate for decision making. # Clinical-effectiveness evidence ## Populations in the company's trials reflect the NHS The clinical evidence came from 3 multicentre, randomised, double-blind, placebo-controlled trials: PATHWAY (n=550), NAVIGATOR (n=1,059) and SOURCE (n=150). These trials compared 210 mg tezepelumab every 4 weeks with placebo for people 18 years and over (except NAVIGATOR, which included people 12 years and over). People in the trials had severe asthma with 2 or more exacerbations in the previous year (except SOURCE, which included people with 1 or more exacerbations in the previous year). This included people having medium-to-high doses of inhaled corticosteroids. The 3 trials were done globally; NAVIGATOR was the only trial that included people from the UK. The EAG noted that the baseline characteristics of the trial populations were well balanced in the 2 arms. The clinical experts and the EAG considered that the populations of PATHWAY, NAVIGATOR and SOURCE reflected those with severe asthma seen in the NHS. The committee concluded that the trial populations were generally representative of people in the NHS. ## Tezepelumab is clinically effective compared with placebo for severe asthma The primary outcome was annualised asthma exacerbation rate (AAER) at 52 weeks in PATHWAY and NAVIGATOR. In SOURCE this was a secondary outcome at 48 weeks. The primary outcome in SOURCE was percentage reduction from baseline in maintenance oral corticosteroid dose without loss of asthma control at 48 weeks. The trials showed tezepelumab was associated with a greater reduction in AAER at 52 weeks compared with placebo. In PATHWAY, the rate ratio (RR) was 0.29, (95% confidence interval 0.16 to 0.51); in NAVIGATOR the RR was 0.44, (95% CI 0.37 to 0.53). The committee noted that largely similar results were reported in SOURCE (the company considers this data confidential, so it cannot be reported here). The 3 trials assessed multiple secondary outcomes. The committee focused on AAER-related hospitalisations or emergency department visits, which also informed the model. The results from PATHWAY and NAVIGATOR suggested that tezepelumab was more effective than placebo at reducing AAER-related hospitalisations at 52 weeks. The difference in AAER-related hospitalisations was not statistically significant in SOURCE (the company considers this data to be confidential, so it cannot be reported here). Largely similar results were found for other secondary outcomes. Evidence from NAVIGATOR and SOURCE also shows that tezepelumab was associated with a greater improvement in quality of life as measured by EQ‑5D‑5L when compared with placebo. No subgroup analysis (see section 3.9) was done for this outcome. The committee concluded that tezepelumab is clinically effective in severe asthma compared with placebo. ## Tezepelumab is generally more effective than placebo for severe asthma in pre-planned and post-hoc subgroups The company also presented clinical trial evidence assessing tezepelumab's clinical effectiveness compared with placebo in pre-planned subgroups. The company also presented post-hoc subgroup analysis based on eligibility for biological treatments (see section 3.2). For the pre-planned subgroups, results from PATHWAY and NAVIGATOR suggested that tezepelumab was more effective than placebo in reducing AAER. This was in subgroups stratified by: baseline blood eosinophil count (at least 300 cells per microlitre or less than 300 cells per microlitre ) baseline FeNO level (24 or 25 and above parts per billion, or less than 24 or 25 parts per billion) baseline inhaled corticosteroid dose (medium or high-dose ) number of exacerbations in the previous 12 months (1 to 2, or 3 or more exacerbations in the previous 12 months ) baseline FeNO status (positive or negative ) at 52 weeks. In SOURCE, tezepelumab was more effective than placebo in reducing maintenance oral corticosteroid dose in subgroups with a higher baseline blood eosinophil count (defined as 150 or 300 cells per microlitre and above) at 48 weeks. Largely similar results for AAER reductions were also reported from NAVIGATOR for most post-hoc subgroups at 52 weeks. In SOURCE, tezepelumab reduced AAER in the anti-interleukin-5-eligible and omalizumab-eligible subgroups but not in the non-biologic eligible subgroup (see section 3.2) at 48 weeks. But the number of events captured in the subgroup analyses was small. The results are academic in confidence so cannot be reported here. The committee concluded that the clinical trial evidence suggested that tezepelumab is generally more effective than placebo in reducing AAER or maintenance oral corticosteroid dose in pre-planned or post-hoc subgroups. # Network meta-analysis ## The company's indirect treatment comparisons are highly uncertain There was no direct comparison between tezepelumab and existing biological treatments including omalizumab, reslizumab, benralizumab, mepolizumab and dupilumab. So, the company did a series of network meta-analyses (NMAs) comparing the clinical effectiveness of tezepelumab with these biological treatments in the NICE-recommended subpopulations. It also compared tezepelumab with standard care alone in the subpopulation who cannot have existing biological treatments. The NMAs were done for several outcomes. The EAG noted that for the outcome of AAER, NMAs for both the intention-to-treat (ITT) population and for subpopulations defined by biological therapy eligibility were available. But it was only the results from the subgroup NMAs that informed the model. For the outcome of reduction in AAER-related hospitalisations, the only NMA available was done in the ITT population. For reduction in oral corticosteroid dose, NMAs were done in both the ITT population and subpopulations, and the company used the NMA results for the subpopulation with a baseline blood eosinophil count of at least 300 cells per microlitre. It highlighted that the results of the NMAs based on different populations were blended in the model. The EAG also explained that not all of the biomarkers that defined relevant biological treatment-eligible subpopulations (see section 3.2) were consistently available across trials included in the NMAs. The uncertainty about this meant that its impact on the NMA results was unknown. The committee noted that the company's NMA results suggested that tezepelumab appeared to be more effective than other biological treatments in reducing AAER and oral corticosteroid dose in the assessed subpopulations. It further noted that it appeared to be more effective than other biological treatments in reducing AAER-related hospitalisation in the ITT population. But most 95% credible intervals for the reported RRs crossed 1, which meant that it was possible that there was no difference in treatment effect between the interventions compared. In most subpopulations and in the ITT population the only substantial difference was between tezepelumab and placebo. For the subgroups defined by baseline blood eosinophil count, the committee noted that the results suggested that tezepelumab was associated with a greater reduction in AAER than placebo when the subpopulation was defined as having a blood eosinophil count of either 300 or 150 cells and above per microlitre. But this was not the case for this same outcome when the subpopulation was defined as having a blood eosinophil count of less than 300 cells per microlitre. The committee understood that the biomarker evidence in the trials (which informed the NMAs) did not all match the biomarkers used for the NICE-recommended treatments. The committee understood that there were challenges in evidence generation. At the first meeting, the committee concluded that the results of the company's NMAs were highly uncertain, and it would like to see uncertainties addressed. In response to consultation, the company updated its base-case NMA inputs in the population who were eligible for reslizumab. This was so that the NMA data for the subgroup with a baseline blood eosinophil count of at least 300 cells per microlitre informed all NMA-based comparisons in the economic model (this included comparisons with reslizumab, mepolizumab and benralizumab). The EAG agreed with these changes and incorporated them in its updated base case because they reflect the relevant guidance for these treatments. For the comparison with dupilumab the company used NMA data relating to the 200 mg dose. This corrected an error in their previous NMA that had used a higher dose (300 mg) not used in clinical practice. The EAG was concerned that the company provided no additional information to clarify the impact of the error. The EAG preferred to use the subgroup with baseline blood eosinophil count of at least 150 cells per microlitre to inform its updated base-case analyses for the duplimumab comparison. The results of the updated subgroup analyses suggested that tezepelumab was associated with a greater reduction in AAER compared with other biological treatments. The company also provided scenarios based on a simulated treatment comparison and a comparison to published NMAs. The EAG considered that the uncertainty that related to matching exact subgroups to data from comparator trials was still not fully resolved by the company's scenarios presented. The committee considered that the company's original and updated NMAs both had considerable uncertainty. This was because of the unresolvable limitations in the evidence, and because the biomarker evidence in the trials did not all match the biomarkers used for the NICE-recommended treatments. The committee was satisfied that the company had explored the uncertainty in its updated NMAs and that there were unresolvable challenges in matching exact subgroup data because of the lack of evidence. The committee concluded that tezepelumab is likely to have a similar clinical effectiveness compared with existing biological treatments, but that this is highly uncertain. # Economic model ## The company's model structure is appropriate for decision making The company used a 5‑state Markov model comparing tezepelumab with standard care in people with severe asthma. The model included 5 health states: controlled asthma, uncontrolled asthma, uncontrolled asthma with exacerbation, controlled asthma with exacerbation, and dead. Controlled asthma was defined as an asthma control questionnaire (ACQ)‑6 score of less than 1.5. Uncontrolled was defined as an ACQ‑6 score of more than 1.5. An exacerbation was defined as a worsening of asthma needing oral corticosteroids for at least 3 consecutive days, an emergency department attendance or hospitalisation. The model had a lifetime horizon (60 years) and a cycle length of 4 weeks. The EAG considered the model structure appropriate but it noted the uncertainty about the company's approach of modelling exacerbations as controlled and uncontrolled (see section 3.13). The committee concluded that the company's model structure was appropriate for decision making. ## It is appropriate to use an ACQ-6 score of 1.5 as a cut-off to define asthma status in the model The committee noted that the company used an ACQ‑6 cut-off score of 1.5 to define asthma control status as either uncontrolled (more than 1.5) or controlled (less than 1.5) in the model. The EAG preferred using a cut-off of 1 to define the health states. It noted that the NAVIGATOR trial defined an ACQ‑6 score of between 0.75 and less than 1.5 as 'partially controlled' asthma. It considered that using the cut-off of 1.5 rather than 1 would misclassify some asthma that was not well controlled as well controlled, and overestimate the treatment effectiveness in the model. The EAG explained that a study by Juniper et al. (2006) suggested that the crossover point between well controlled and not well controlled asthma was close to an ACQ‑6 score of 1. The EAG noted that a cut-off of 1.5 was used in the recommendations in NICE's technology appraisal guidance on dupilumab, benralizumab and reslizumab. But it considered that aligning with previously accepted assumptions was not sufficient justification. The company explained that it had considered using partially controlled asthma as a third health state, but did not implement it because of the multiple subgroups being considered. So, the subgroup would have been informed by a small population. The company and clinical experts noted that Juniper et al. (2006) was part of a larger study (GOAL), which included very mild asthma. This is different from the population indicated in tezepelumab's marketing authorisation. It explained that GOAL included 3 cohorts; people: who have not had inhaled corticosteroids having low-dose inhaled corticosteroids having medium-dose inhaled corticosteroids. The clinical expert agreed with the company's approach of using an ACQ‑6 score of 1.5 as a cut-off to define asthma control status. The committee concluded that using the ACQ‑6 score of 1.5 as cut-off to define asthma control states was appropriate for decision making. ## The company's approach of modelling asthma exacerbations as controlled and uncontrolled is acceptable for decision making The company's model prohibited the transitions from controlled asthma to uncontrolled asthma with exacerbation and from uncontrolled asthma to controlled asthma with exacerbation. The EAG considered it inappropriate and noted that the transition probabilities from both the asthma exacerbation health states to the controlled asthma state may have been overestimated in the company's model. According to the EAG, this was because people who transition from the controlled asthma exacerbation health state are more likely to return to the controlled rather than the uncontrolled asthma state in the model. But clinical opinion received by the EAG suggested that people can have exacerbations in any health state. But the risk of having an exacerbation will be different, so the transition probability will be different depending on which health state they started in. Clinical opinion received by the EAG also noted that if people were in an uncontrolled asthma state and having an exacerbation, they may be more likely to go back to having uncontrolled asthma than having controlled asthma. The company explained that its approach was in line with the recommendations in NICE's technology appraisal guidance on benralizumab. It also disagreed that the transition probabilities from exacerbation states to the controlled asthma health state were overestimated, because they were derived from the trials. It explained that distinguishing between exacerbations in previously controlled asthma from asthma not previously controlled could capture the differences in health-related quality of life, costs and mortality between the 2 states. But a single health state for exacerbation would not. The clinical expert explained that there is no fundamental difference in exacerbations regardless of the previous asthma state. He also noted that it is not common to have an exacerbation if the asthma is well controlled. In practice, an exacerbation would last for about a week and people having an exacerbation would be considered to have uncontrolled asthma. The clinical expert considered that the company's approach to modelling exacerbations was reasonable. The committee agreed that the company's approach of modelling exacerbations was acceptable for decision making. ## The company's approach of using different transition probabilities after 52 weeks is appropriate The company included a one-off stopping at 52 weeks in the model. After 52 weeks, it implemented a different set of transition probabilities for people whose asthma was considered to have responded. The EAG considered that this overestimated the treatment effect in the model because the stopping had been accounted for. Because of the lack of data, the EAG was unable to implement different transition probabilities in the model. So, it set the transition probabilities before and after 52 weeks to be equal in the model, and considered this approach to be conservative. The company explained that the one-off stopping at 52 weeks reflected the stopping rules in previous NICE technology appraisals for other add-on biological treatments. It considered it was appropriate to have a different set of transition probabilities for people with response after 52 weeks. This was because people whose asthma does not respond would stop treatment at this point. Only those whose asthma had responded would remain in the model. The committee concluded that the company's approach was acceptable. ## The company's mortality estimates are appropriate Mortality was a driver of cost effectiveness in the company's model. The company originally assumed that deaths from asthma could only occur through exacerbations. The EAG considered that the probabilities used by the company overestimated asthma-related mortality for people under 75 years. The EAG re-estimated mortality risk for people under 75 years based on 2020 Office of National Statistics mortality data for England, which resulted in an average probability of 0.001 for death per cycle (4‑weekly) for its base case. The EAG also did a scenario analysis using an asthma mortality estimate based on NICE's technology appraisal guidance on benralizumab. The clinical expert noted that asthma mortality might be higher than both the company's and the EAG's estimates in clinical practice. He also explained that death can occur not only because of exacerbations but also because of long-term use of oral corticosteroids. At the first committee meeting, the committee accepted the company's asthma-related mortality estimates for decision making. In response to consultation, the company did a UK-based real-world study of all-cause mortality in people not eligible for biological treatment to inform its updated base case. This study explored electronic health records (2012 to 2017) from the Clinical Practice Research Datalink (CPRD) for people who had 3 or more exacerbations in the previous year or who were having maintenance oral corticosteroids and were ineligible for biological treatments based on NICE's recommendations. It highlighted that it had selected a population not eligible for biological treatment, to calibrate mortality in the standard care arm of its model. The results suggested that all-cause mortality for people with severe asthma was substantially higher than that predicted by its model. The results were also in line with Roche et al. (2022), a study based on French real-world evidence. The EAG explained that the real-world study was well done and reduced some uncertainty in the mortality estimates. It noted, however, that the results were only applicable to a subset of people who were ineligible for biological treatment, but had been applied across all subgroups in the company's model. The EAG considered that it would have been more appropriate to apply the overall population estimates across all subgroups to get more precise estimates. Alternatively, mortality rates by subgroup could have been estimated and then applied to their respective populations individually in the model. The EAG also considered that the multiplier used by the company to adjust the mortality rate to match the CPRD rates was uncertain because of the limited sample size of the CPRD data. The EAG also noted that calibrating exacerbation-related mortality to all-cause mortality may have overestimated mortality in the model. It also noted that a recent multinational cohort study by Engelkes et al. (2020) on severe asthma reported lower all-cause mortality rates in the UK than in the company's CPRD analysis. But it acknowledged that the study population was not the population of interest for this appraisal and had a lower disease burden. The committee noted that the company's original base-case asthma-related mortality estimates were more appropriate but that its CPRD analysis was informative for the non-biological eligible group. It concluded that it would consider cost-effectiveness scenarios using both the company's original base-case asthma-related mortality estimates and the all-cause mortality CPRD data (only in the non-biological eligible subgroup) in its decision making. ## The company's updated approach to utility gain with biological treatments is appropriate The company assumed a utility increment for people who had a biological treatment, which was not associated with any health state in the model. The committee questioned the face validity (that is, the clinical plausibility) of using this utility increment. The company explained that it applied this utility gain in the model because the benefits of the treatment were not fully captured. This was because its model structure considered asthma as either controlled or uncontrolled and that a third health state, partially controlled, was considered but not implemented (see section 3.13). The company explained that it did a regression analysis based on the EQ‑5D‑5L data collected in the tezepelumab clinical trials. The results suggested the regression coefficient was statistically significant. The company considered its approach in line with NICE's technology appraisal guidance on benralizumab and omalizumab, in which an effect of biological treatment on utility over and above treatment effect was accepted by the committee. The EAG explained that the effectiveness of biological treatments should be reflected in the modelled health states. It considered that adding an additional utility increment with borderline statistical significance over and above the asthma control and exacerbations was not appropriate. The EAG also noted that in NICE's technology appraisal guidance on benralizumab and omalizumab, the biological treatment effect-related utilities were attached to the health states in the model. At its first meeting the committee concluded that the company's approach of assuming an additional utility gain for biological treatments was not appropriate. In response to consultation, the company explained that it had identified an error in its original regression analysis and had corrected its base case. The updated results suggested that the regression coefficient was no longer statistically significant for biological-specific utility, so it removed the additional utility gain for biological treatments in its updated base case. The committee agreed that the company's updated base case was appropriate. # Cost-effectiveness estimates ## The committee's preferred base case included the company's updated treatment response definition The committee considered the results for all the relevant comparators. For those eligible for biological treatments the relevant comparators are: anti-interleukin‑5 inhibitors (mepolizumab and benralizumab), omalizumab, reslizumab, and dupilumab. For people for whom biological treatments are unsuitable a comparison with standard care was made. The committee noted its preferred assumptions, which it updated after the first committee meeting. The committee preferred base-case assumptions that were aligned to the EAG's, and these included: For people not having maintenance oral corticosteroids: 50% reduction in exacerbations (see section 3.6). For people having maintenance oral corticosteroids: 50% reduction in their dose (see section 3.6). The company's updated NMA using the subgroup with baseline blood eosinophil count of at least 300 cells per microlitre (for reslizumab, mepolizumab, benralizumab) and the EAG's preferred subgroup with baseline blood eosinophil count of at least 150 cells per microlitre for the comparison with dupilumab (see section 3.10). The company's original base-case mortality estimates, with a scenario using the updated estimates for the non-biological eligible group only (see section 3.15). The company's updated approach to utility gain (see section 3.16). ## Tezepelumab is cost effective for treating severe asthma when biological treatments are suitable For the subgroups eligible for biological treatments, the committee's preferred base-case incremental cost-effectiveness ratios (ICERs) were all below £20,000 per quality-adjusted life year (QALY) gained. The results included the confidential prices for other biological treatments, which means they cannot be reported here. The committee reiterated the uncertainty associated with the NMAs. But it agreed that the most plausible ICER was unlikely to be above what NICE normally considers an acceptable use of NHS resources in all subgroups eligible for biological treatments. The committee concluded that tezepelumab is cost effective compared with the biological treatments mepolizumab, benralizumab, resilizumab, dupilumab and omalizumab. ## Tezepelumab is cost effective for treating severe asthma when biological treatments are not suitable For the subgroup not eligible for biological treatments, the committee's preferred base-case ICER was at the higher range of what NICE usually considers a cost-effective use of NHS resources. But the committee noted that when the CPRD mortality rates were applied (see section 3.15) the ICER was below £20,000 per QALY gained. The results included the confidential prices for standard care treatments, which means they cannot be reported here. Section 6 of NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee recalled that there is a high unmet need for people with severe asthma who cannot have existing biological treatments. It also considered that tezepelumab may have uncaptured benefits. Further, the committee understood that the updated mortality estimates using the CPRD data reduced the ICER substantially, and only a small movement between the original and revised company mortality estimates brought the ICER below the threshold. The committee concluded that tezepelumab is cost effective compared with standard care in people not eligible for biological treatments. # Other factors ## There may be additional benefits of tezepelumab not captured, but this is uncertain The company considered tezepelumab to be innovative because of its mechanism of action, making it suitable for the broader severe asthma subtype population. The clinical experts noted that tezepelumab has the potential to be used for various severe asthma subtypes. They noted that if tezepelumab was approved, people would have another treatment option if their asthma does not respond to standard care. The patient experts also noted that tezepelumab may improve treatment adherence for people who find it more difficult to adhere to standard care. An example is people with mental health issues. The committee recalled the patient expert comments on biological treatments also improving people's quality of life (see section 3.6), because they can provide stability. This allows people to plan more and have more control of their lives. But the committee also noted the uncertainties in the clinical evidence and the model. It concluded that tezepelumab may have additional benefits that have not been captured in the cost-effectiveness analysis, but these are difficult to untangle because of the uncertainties in the evidence and around some of the company's model assumptions. ## Equality issues The committee noted that severe asthma and its subtypes disproportionately affect women, with about 60% of people with severe asthma being women. The committee considered whether this was partly because of the potential effect of hormone levels on immunity and consequently on asthma. The clinical experts explained that this is not fully understood, because of a lack of evidence. But it is known that hormonal stress can affect immunity and as such people's health. They also noted that there is no evidence that suggests that biological treatments affect people differently based on sex. The committee considered that the recommendation would not restrict access for some people over others. No other equality or social value judgement issues were identified. # Conclusion ## Tezepelumab is recommended for treating severe asthma The committee concluded that tezepelumab as an add-on maintenance treatment is recommended for routine commissioning for treating severe asthma in people 12 years and over, when treatment with high-dose inhaled corticosteroids plus another maintenance treatment has not worked well enough. It is recommended only if: people have had 3 or more exacerbations in the previous year or are having maintenance oral corticosteroids the company provides tezepelumab according to the commercial arrangement.	{'Recommendations': 'Tezepelumab as an add-on maintenance treatment is recommended as an option for severe asthma in people 12\xa0years and over, when treatment with high-dose inhaled corticosteroids plus another maintenance treatment has not worked well enough. It is recommended only if people:\n\nhave had 3 or more exacerbations in the previous year, or\n\nare having maintenance oral corticosteroids.Tezepelumab is recommended only if the company provides it according to the commercial arrangement.\n\nStop tezepelumab if the rate of severe asthma exacerbations, or the maintenance oral corticosteroid dose, have not been reduced by at least 50% at 12 months.\n\nThese recommendations are not intended to affect treatment with tezepelumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by them, their clinician, and their parents or carers.\n\nWhy the committee made these recommendations\n\nSevere asthma is usually treated with inhaled corticosteroids plus another maintenance treatment. Oral corticosteroids are sometimes used to prevent exacerbations (asthma attacks), but they may have negative effects in the long-term. Some people with severe asthma can have biological treatments. Tezepelumab is another biological treatment.\n\nClinical trial results show that tezepelumab, when added to usual treatment, reduces exacerbations and the dose of oral corticosteroids needed, compared with placebo. An indirect comparison of tezepelumab with other biological treatments suggests similar clinical effectiveness, but this is uncertain.\n\nThe cost-effectiveness estimates show that tezepelumab as an add-on maintenance therapy is cost effective compared with standard care and other biological treatments. So, tezepelumab is recommended when treatment with high-dose inhaled corticosteroids plus another maintenance treatment has not worked well enough, for people who have had 3 or more exacerbations in the previous year or who are having maintenance oral corticosteroids.', 'Information about tezepelumab': "# Marketing authorisation indication\n\nTezepelumab (Tezspire, AstraZeneca) is indicated as 'an add-on maintenance treatment in adults and adolescents 12\xa0years and older with severe asthma who are inadequately controlled despite high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for tezepelumab.\n\n# Price\n\nThe list price for tezepelumab is £1,265 per 210\xa0mg prefilled syringe per vial (company submission, May\xa02022). The company has a commercial arrangement. This makes tezepelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Condition background\n\n## Living with severe asthma is physically and emotionally challenging\n\nSevere asthma is a distressing and socially isolating condition. Patient experts commented that exacerbations can happen without warning, causing fear. Exacerbations may result in hospitalisation and can be life threatening. The symptoms of severe asthma mean that people often feel tired and unable to work or play, and they may need help with day-to-day activities. The patient experts explained that severe asthma can also affect mental health. The committee understood that people with severe asthma often have difficulties doing day-to-day tasks. People may also have negative effects, including bone damage, from long-term use of standard treatments. People may go on to require surgery because of weak bones. The committee concluded that living with severe asthma is physically and emotionally challenging.\n\n# Treatment pathway\n\n## Standard care includes oral corticosteroids and biological treatments as add-ons to first-line treatments\n\nAsthma treatment in clinical practice follows the NICE guideline on asthma and the Global Initiative for Asthma (GINA) guideline (which includes the use of biological treatments). If asthma becomes uncontrolled despite inhaled corticosteroids (usually offered with another treatment), then low-dose oral corticosteroids or biological treatments are added. The clinical and patient experts explained that biological treatments are preferred to oral corticosteroids because they have fewer negative effects. Biological treatments may be offered as add-on options if asthma is not controlled well enough with maintenance treatment with high-dose inhaled corticosteroids plus a long-acting beta-agonist or another treatment. The committee noted that, when it met, the choice of available biological treatments, such as anti-interleukin‑5 inhibitors, was based on the phenotype and biomarker profile of asthma. See NICE's technology appraisal guidance on benralizumab, mepolizumab, reslizumab, dupilumab and omalizumab. Patient experts highlighted that biological treatments have been life changing for some people. But not all people with severe asthma can have them because of the specific eligibility criteria. The clinical experts explained that immunoglobulin\xa0E, blood eosinophil count and fractional exhaled nitric oxide (FeNO) levels are used to assess and manage severe asthma. They noted that blood eosinophil count and FeNO levels are routinely measured in clinical practice. They also explained that most people with severe asthma usually have 1 or 2 of these biomarkers, but relatively few people have all 3 biomarkers. The committee understood that standard treatment for severe asthma includes oral corticosteroids and several biological treatments as add-ons to first-line treatments.\n\n## A treatment option without the need for biomarker assessment would be welcomed\n\nThe clinical and patient experts explained that about 5% of people with severe asthma who have regular treatment cannot have existing biological treatments. The patient experts added that long-term use of oral corticosteroids could suppress people's biomarkers, meaning they cannot have existing biological treatments. Both the clinical and patient experts explained that there is an unmet need for treatments that reduce exacerbations and improve asthma control. The patient experts explained that for many people with severe asthma that does not respond to standard treatments (including biological treatments), long-term oral corticosteroids are the only option. They noted these may have negative effects, including osteoporosis, cataracts, glaucoma, skin conditions, reflux oesophagitis, non-alcoholic fatty liver, and weight gain. The clinical expert noted that, in practice, people can switch to a different biological treatment if there was no response to the previous one. But in this situation people would need to have biomarker assessment again. So, a new treatment without the need for biomarker assessment would benefit people. The committee understood that there is an unmet need for people with severe asthma who cannot have existing biological treatments because of their biomarker profiles. So, it concluded that a new treatment option without the need for biomarker assessment would be welcomed.\n\n## The company's proposed positioning of tezepelumab as an add-on to first-line treatment is appropriate\n\nTezepelumab has a marketing authorisation as an add-on maintenance treatment in people 12\xa0years and over with severe asthma that is inadequately controlled despite high-dose inhaled corticosteroids plus another maintenance treatment. The company proposed tezepelumab for a narrower population than in the marketing authorisation. This was people:\n\nwho had 3 or more exacerbations in the year before, or\n\nwho are having maintenance oral corticosteroids.The company explained that the existing biological treatments target specific biomarkers (see section\xa03.3). People with severe asthma often have a biomarker that overlaps with other phenotypes or fluctuates, and some people have no defined inflammation. The company explained that tezepelumab has a unique mechanism of action, which could make it effective for different asthma phenotypes regardless of biomarker profiles. It proposed tezepelumab as an add-on treatment to first-line standard care regardless of biomarker profiles or eligibility. If recommended, tezepelumab would be an alternative option for people with low biomarkers (not eligible for existing biological treatment), as well as those with high biomarkers (eligible for existing add-on biological treatments). The committee noted that there were several subpopulations to be considered based on biomarker eligibility at different positions in the treatment pathway. It concluded that the company's positioning of tezepelumab is appropriate, and it considered the evidence presented for these subpopulations in its decision making.\n\n# Comparators\n\n## Relevant comparators are standard care plus add-on biological treatments, and standard care alone\n\nThe company provided evidence on tezepelumab compared with standard care with or without add-on biological treatments (see section\xa03.2). The committee agreed that standard care plus add-on biological treatments, and standard care alone, were relevant comparators for tezepelumab.\n\n# Treatment response\n\n## The company's updated definition of treatment response is appropriate\n\nReducing exacerbations and the dose of maintenance oral corticosteroids taken are primary outcomes in the company's pivotal clinical trials (see section\xa03.8). The EAG noted that the tezepelumab trials did not define treatment response. The company assumed that any reduction in exacerbations or maintenance oral corticosteroid dose from baseline was a treatment response. The EAG considered the company's original definition of response inappropriate and not clinically meaningful. It considered that a reduction of between 20% and 50% in exacerbations was an appropriate treatment response, which was in line with the clinical advice it had received. The EAG also noted that using an alternative definition of response, for example, a 20% reduction in exacerbations, was likely to affect the post-assessment transition probabilities in the model. The company explained that using an alternative definition for treatment response of 20% reduction in exacerbations would have little effect on a person's eligibility to continue treatment after 52\xa0weeks (see section\xa03.14). This is because it would only affect people with 6\xa0or more exacerbations in the previous year. The patient expert explained that for severe asthma, any reduction in exacerbations or maintenance oral corticosteroid dose may not be seen as clinically meaningful in clinical practice. But it could mean qualitative improvement in quality of life. The committee noted the wide spectrum of asthma phenotypes and symptoms (see section\xa03.2) and queried how the reduction would be meaningfully measured in practice. The clinical expert explained that a holistic view would be needed in practice when response is assessed. People may have natural variation in symptoms or biomarkers from year to year, but these would be relatively small. A reduction in exacerbations may be associated with symptom improvement, but there needs to be a threshold in practice, and this is usually set at 50%. This allows quicker switching to another biological treatment if a person's asthma does not respond. At the first meeting, the committee concluded that a 50% reduction in exacerbations would be more appropriate. In response to consultation, the company explained that it had obtained a clinical opinion from severe asthma specialists who confirmed that they would consider an appropriate definition of response to be:\n\nfor people not having maintenance oral corticosteroids: 50% reduction in exacerbations\n\nfor people having maintenance oral corticosteroids: 50% reduction in their dose.The company explained that the committee's requested scenario of 50% reduction in exacerbations and maintenance oral corticosteroid dose use in people already having oral maintenance corticosteroids was not in line with clinical practice. It was also not consistent with previous NICE technology appraisal guidance on mepolizumab, benralizumab and reslizumab for treating severe asthma. Stakeholder comments in response to the consultation, and the clinical expert at the second appraisal committee meeting, agreed with the company's updated definition of response. The committee concluded that the company's updated definition of treatment response was appropriate for decision making.\n\n# Clinical-effectiveness evidence\n\n## Populations in the company's trials reflect the NHS\n\nThe clinical evidence came from 3 multicentre, randomised, double-blind, placebo-controlled trials: PATHWAY (n=550), NAVIGATOR (n=1,059) and SOURCE (n=150). These trials compared 210\xa0mg tezepelumab every 4\xa0weeks with placebo for people 18\xa0years and over (except NAVIGATOR, which included people 12\xa0years and over). People in the trials had severe asthma with 2\xa0or more exacerbations in the previous year (except SOURCE, which included people with 1\xa0or more exacerbations in the previous year). This included people having medium-to-high doses of inhaled corticosteroids. The 3\xa0trials were done globally; NAVIGATOR was the only trial that included people from the UK. The EAG noted that the baseline characteristics of the trial populations were well balanced in the 2\xa0arms. The clinical experts and the EAG considered that the populations of PATHWAY, NAVIGATOR and SOURCE reflected those with severe asthma seen in the NHS. The committee concluded that the trial populations were generally representative of people in the NHS.\n\n## Tezepelumab is clinically effective compared with placebo for severe asthma\n\nThe primary outcome was annualised asthma exacerbation rate (AAER) at 52\xa0weeks in PATHWAY and NAVIGATOR. In SOURCE this was a secondary outcome at 48\xa0weeks. The primary outcome in SOURCE was percentage reduction from baseline in maintenance oral corticosteroid dose without loss of asthma control at 48\xa0weeks. The trials showed tezepelumab was associated with a greater reduction in AAER at 52\xa0weeks compared with placebo. In PATHWAY, the rate ratio (RR) was 0.29, (95% confidence interval [CI] 0.16 to 0.51); in NAVIGATOR the RR was 0.44, (95% CI 0.37 to 0.53). The committee noted that largely similar results were reported in SOURCE (the company considers this data confidential, so it cannot be reported here). The 3\xa0trials assessed multiple secondary outcomes. The committee focused on AAER-related hospitalisations or emergency department visits, which also informed the model. The results from PATHWAY and NAVIGATOR suggested that tezepelumab was more effective than placebo at reducing AAER-related hospitalisations at 52\xa0weeks. The difference in AAER-related hospitalisations was not statistically significant in SOURCE (the company considers this data to be confidential, so it cannot be reported here). Largely similar results were found for other secondary outcomes. Evidence from NAVIGATOR and SOURCE also shows that tezepelumab was associated with a greater improvement in quality of life as measured by EQ‑5D‑5L when compared with placebo. No subgroup analysis (see section\xa03.9) was done for this outcome. The committee concluded that tezepelumab is clinically effective in severe asthma compared with placebo.\n\n## Tezepelumab is generally more effective than placebo for severe asthma in pre-planned and post-hoc subgroups\n\nThe company also presented clinical trial evidence assessing tezepelumab's clinical effectiveness compared with placebo in pre-planned subgroups. The company also presented post-hoc subgroup analysis based on eligibility for biological treatments (see section\xa03.2). For the pre-planned subgroups, results from PATHWAY and NAVIGATOR suggested that tezepelumab was more effective than placebo in reducing AAER. This was in subgroups stratified by:\n\nbaseline blood eosinophil count (at least 300\xa0cells per microlitre or less than 300\xa0cells per microlitre [PATHWAY and NAVIGATOR])\n\nbaseline FeNO level (24 [PATHWAY] or 25 [NAVIGATOR] and above parts per billion, or less than 24 [PATHWAY] or 25 [NAVIGATOR] parts per billion)\n\nbaseline inhaled corticosteroid dose (medium or high-dose [PATHWAY])\n\nnumber of exacerbations in the previous 12 months (1 to 2, or 3 or more exacerbations in the previous 12\xa0months [PATHWAY])\n\nbaseline FeNO status (positive or negative [NAVIGATOR]) at 52\xa0weeks. In SOURCE, tezepelumab was more effective than placebo in reducing maintenance oral corticosteroid dose in subgroups with a higher baseline blood eosinophil count (defined as 150 or 300\xa0cells per microlitre and above) at 48\xa0weeks. Largely similar results for AAER reductions were also reported from NAVIGATOR for most post-hoc subgroups at 52\xa0weeks. In SOURCE, tezepelumab reduced AAER in the anti-interleukin-5-eligible and omalizumab-eligible subgroups but not in the non-biologic eligible subgroup (see section\xa03.2) at 48 weeks. But the number of events captured in the subgroup analyses was small. The results are academic in confidence so cannot be reported here. The committee concluded that the clinical trial evidence suggested that tezepelumab is generally more effective than placebo in reducing AAER or maintenance oral corticosteroid dose in pre-planned or post-hoc subgroups.\n\n# Network meta-analysis\n\n## The company's indirect treatment comparisons are highly uncertain\n\nThere was no direct comparison between tezepelumab and existing biological treatments including omalizumab, reslizumab, benralizumab, mepolizumab and dupilumab. So, the company did a series of network meta-analyses (NMAs) comparing the clinical effectiveness of tezepelumab with these biological treatments in the NICE-recommended subpopulations. It also compared tezepelumab with standard care alone in the subpopulation who cannot have existing biological treatments. The NMAs were done for several outcomes. The EAG noted that for the outcome of AAER, NMAs for both the intention-to-treat (ITT) population and for subpopulations defined by biological therapy eligibility were available. But it was only the results from the subgroup NMAs that informed the model. For the outcome of reduction in AAER-related hospitalisations, the only NMA available was done in the ITT population. For reduction in oral corticosteroid dose, NMAs were done in both the ITT population and subpopulations, and the company used the NMA results for the subpopulation with a baseline blood eosinophil count of at least 300\xa0cells per microlitre. It highlighted that the results of the NMAs based on different populations were blended in the model. The EAG also explained that not all of the biomarkers that defined relevant biological treatment-eligible subpopulations (see section\xa03.2) were consistently available across trials included in the NMAs. The uncertainty about this meant that its impact on the NMA results was unknown. The committee noted that the company's NMA results suggested that tezepelumab appeared to be more effective than other biological treatments in reducing AAER and oral corticosteroid dose in the assessed subpopulations. It further noted that it appeared to be more effective than other biological treatments in reducing AAER-related hospitalisation in the ITT population. But most 95% credible intervals for the reported RRs crossed 1, which meant that it was possible that there was no difference in treatment effect between the interventions compared. In most subpopulations and in the ITT population the only substantial difference was between tezepelumab and placebo. For the subgroups defined by baseline blood eosinophil count, the committee noted that the results suggested that tezepelumab was associated with a greater reduction in AAER than placebo when the subpopulation was defined as having a blood eosinophil count of either 300 or 150\xa0cells and above per microlitre. But this was not the case for this same outcome when the subpopulation was defined as having a blood eosinophil count of less than 300\xa0cells per microlitre. The committee understood that the biomarker evidence in the trials (which informed the NMAs) did not all match the biomarkers used for the NICE-recommended treatments. The committee understood that there were challenges in evidence generation. At the first meeting, the committee concluded that the results of the company's NMAs were highly uncertain, and it would like to see uncertainties addressed. In response to consultation, the company updated its base-case NMA inputs in the population who were eligible for reslizumab. This was so that the NMA data for the subgroup with a baseline blood eosinophil count of at least 300\xa0cells per microlitre informed all NMA-based comparisons in the economic model (this included comparisons with reslizumab, mepolizumab and benralizumab). The EAG agreed with these changes and incorporated them in its updated base case because they reflect the relevant guidance for these treatments. For the comparison with dupilumab the company used NMA data relating to the 200\xa0mg dose. This corrected an error in their previous NMA that had used a higher dose (300\xa0mg) not used in clinical practice. The EAG was concerned that the company provided no additional information to clarify the impact of the error. The EAG preferred to use the subgroup with baseline blood eosinophil count of at least 150\xa0cells per microlitre to inform its updated base-case analyses for the duplimumab comparison. The results of the updated subgroup analyses suggested that tezepelumab was associated with a greater reduction in AAER compared with other biological treatments. The company also provided scenarios based on a simulated treatment comparison and a comparison to published NMAs. The EAG considered that the uncertainty that related to matching exact subgroups to data from comparator trials was still not fully resolved by the company's scenarios presented. The committee considered that the company's original and updated NMAs both had considerable uncertainty. This was because of the unresolvable limitations in the evidence, and because the biomarker evidence in the trials did not all match the biomarkers used for the NICE-recommended treatments. The committee was satisfied that the company had explored the uncertainty in its updated NMAs and that there were unresolvable challenges in matching exact subgroup data because of the lack of evidence. The committee concluded that tezepelumab is likely to have a similar clinical effectiveness compared with existing biological treatments, but that this is highly uncertain.\n\n# Economic model\n\n## The company's model structure is appropriate for decision making\n\nThe company used a 5‑state Markov model comparing tezepelumab with standard care in people with severe asthma. The model included 5 health states: controlled asthma, uncontrolled asthma, uncontrolled asthma with exacerbation, controlled asthma with exacerbation, and dead. Controlled asthma was defined as an asthma control questionnaire (ACQ)‑6 score of less than 1.5. Uncontrolled was defined as an ACQ‑6 score of more than 1.5. An exacerbation was defined as a worsening of asthma needing oral corticosteroids for at least 3\xa0consecutive days, an emergency department attendance or hospitalisation. The model had a lifetime horizon (60\xa0years) and a cycle length of 4\xa0weeks. The EAG considered the model structure appropriate but it noted the uncertainty about the company's approach of modelling exacerbations as controlled and uncontrolled (see section\xa03.13). The committee concluded that the company's model structure was appropriate for decision making.\n\n## It is appropriate to use an ACQ-6 score of 1.5 as a cut-off to define asthma status in the model\n\nThe committee noted that the company used an ACQ‑6 cut-off score of 1.5 to define asthma control status as either uncontrolled (more than 1.5) or controlled (less than 1.5) in the model. The EAG preferred using a cut-off of 1 to define the health states. It noted that the NAVIGATOR trial defined an ACQ‑6 score of between 0.75 and less than 1.5 as 'partially controlled' asthma. It considered that using the cut-off of 1.5 rather than 1 would misclassify some asthma that was not well controlled as well controlled, and overestimate the treatment effectiveness in the model. The EAG explained that a study by Juniper et al. (2006) suggested that the crossover point between well controlled and not well controlled asthma was close to an ACQ‑6 score of 1. The EAG noted that a cut-off of 1.5 was used in the recommendations in NICE's technology appraisal guidance on dupilumab, benralizumab and reslizumab. But it considered that aligning with previously accepted assumptions was not sufficient justification. The company explained that it had considered using partially controlled asthma as a third health state, but did not implement it because of the multiple subgroups being considered. So, the subgroup would have been informed by a small population. The company and clinical experts noted that Juniper et al. (2006) was part of a larger study (GOAL), which included very mild asthma. This is different from the population indicated in tezepelumab's marketing authorisation. It explained that GOAL included 3 cohorts; people:\n\nwho have not had inhaled corticosteroids\n\nhaving low-dose inhaled corticosteroids\n\nhaving medium-dose inhaled corticosteroids. The clinical expert agreed with the company's approach of using an ACQ‑6 score of 1.5 as a cut-off to define asthma control status. The committee concluded that using the ACQ‑6 score of 1.5 as cut-off to define asthma control states was appropriate for decision making.\n\n## The company's approach of modelling asthma exacerbations as controlled and uncontrolled is acceptable for decision making\n\nThe company's model prohibited the transitions from controlled asthma to uncontrolled asthma with exacerbation and from uncontrolled asthma to controlled asthma with exacerbation. The EAG considered it inappropriate and noted that the transition probabilities from both the asthma exacerbation health states to the controlled asthma state may have been overestimated in the company's model. According to the EAG, this was because people who transition from the controlled asthma exacerbation health state are more likely to return to the controlled rather than the uncontrolled asthma state in the model. But clinical opinion received by the EAG suggested that people can have exacerbations in any health state. But the risk of having an exacerbation will be different, so the transition probability will be different depending on which health state they started in. Clinical opinion received by the EAG also noted that if people were in an uncontrolled asthma state and having an exacerbation, they may be more likely to go back to having uncontrolled asthma than having controlled asthma. The company explained that its approach was in line with the recommendations in NICE's technology appraisal guidance on benralizumab. It also disagreed that the transition probabilities from exacerbation states to the controlled asthma health state were overestimated, because they were derived from the trials. It explained that distinguishing between exacerbations in previously controlled asthma from asthma not previously controlled could capture the differences in health-related quality of life, costs and mortality between the 2 states. But a single health state for exacerbation would not. The clinical expert explained that there is no fundamental difference in exacerbations regardless of the previous asthma state. He also noted that it is not common to have an exacerbation if the asthma is well controlled. In practice, an exacerbation would last for about a week and people having an exacerbation would be considered to have uncontrolled asthma. The clinical expert considered that the company's approach to modelling exacerbations was reasonable. The committee agreed that the company's approach of modelling exacerbations was acceptable for decision making.\n\n## The company's approach of using different transition probabilities after 52\xa0weeks is appropriate\n\nThe company included a one-off stopping at 52\xa0weeks in the model. After 52\xa0weeks, it implemented a different set of transition probabilities for people whose asthma was considered to have responded. The EAG considered that this overestimated the treatment effect in the model because the stopping had been accounted for. Because of the lack of data, the EAG was unable to implement different transition probabilities in the model. So, it set the transition probabilities before and after 52\xa0weeks to be equal in the model, and considered this approach to be conservative. The company explained that the one-off stopping at 52\xa0weeks reflected the stopping rules in previous NICE technology appraisals for other add-on biological treatments. It considered it was appropriate to have a different set of transition probabilities for people with response after 52\xa0weeks. This was because people whose asthma does not respond would stop treatment at this point. Only those whose asthma had responded would remain in the model. The committee concluded that the company's approach was acceptable.\n\n## The company's mortality estimates are appropriate\n\nMortality was a driver of cost effectiveness in the company's model. The company originally assumed that deaths from asthma could only occur through exacerbations. The EAG considered that the probabilities used by the company overestimated asthma-related mortality for people under 75\xa0years. The EAG re-estimated mortality risk for people under 75\xa0years based on 2020 Office of National Statistics mortality data for England, which resulted in an average probability of 0.001 for death per cycle (4‑weekly) for its base case. The EAG also did a scenario analysis using an asthma mortality estimate based on NICE's technology appraisal guidance on benralizumab. The clinical expert noted that asthma mortality might be higher than both the company's and the EAG's estimates in clinical practice. He also explained that death can occur not only because of exacerbations but also because of long-term use of oral corticosteroids. At the first committee meeting, the committee accepted the company's asthma-related mortality estimates for decision making. In response to consultation, the company did a UK-based real-world study of all-cause mortality in people not eligible for biological treatment to inform its updated base case. This study explored electronic health records (2012 to 2017) from the Clinical Practice Research Datalink (CPRD) for people who had 3 or more exacerbations in the previous year or who were having maintenance oral corticosteroids and were ineligible for biological treatments based on NICE's recommendations. It highlighted that it had selected a population not eligible for biological treatment, to calibrate mortality in the standard care arm of its model. The results suggested that all-cause mortality for people with severe asthma was substantially higher than that predicted by its model. The results were also in line with Roche et al. (2022), a study based on French real-world evidence. The EAG explained that the real-world study was well done and reduced some uncertainty in the mortality estimates. It noted, however, that the results were only applicable to a subset of people who were ineligible for biological treatment, but had been applied across all subgroups in the company's model. The EAG considered that it would have been more appropriate to apply the overall population estimates across all subgroups to get more precise estimates. Alternatively, mortality rates by subgroup could have been estimated and then applied to their respective populations individually in the model. The EAG also considered that the multiplier used by the company to adjust the mortality rate to match the CPRD rates was uncertain because of the limited sample size of the CPRD data. The EAG also noted that calibrating exacerbation-related mortality to all-cause mortality may have overestimated mortality in the model. It also noted that a recent multinational cohort study by Engelkes et al. (2020) on severe asthma reported lower all-cause mortality rates in the UK than in the company's CPRD analysis. But it acknowledged that the study population was not the population of interest for this appraisal and had a lower disease burden. The committee noted that the company's original base-case asthma-related mortality estimates were more appropriate but that its CPRD analysis was informative for the non-biological eligible group. It concluded that it would consider cost-effectiveness scenarios using both the company's original base-case asthma-related mortality estimates and the all-cause mortality CPRD data (only in the non-biological eligible subgroup) in its decision making.\n\n## The company's updated approach to utility gain with biological treatments is appropriate\n\nThe company assumed a utility increment for people who had a biological treatment, which was not associated with any health state in the model. The committee questioned the face validity (that is, the clinical plausibility) of using this utility increment. The company explained that it applied this utility gain in the model because the benefits of the treatment were not fully captured. This was because its model structure considered asthma as either controlled or uncontrolled and that a third health state, partially controlled, was considered but not implemented (see section\xa03.13). The company explained that it did a regression analysis based on the EQ‑5D‑5L data collected in the tezepelumab clinical trials. The results suggested the regression coefficient was statistically significant. The company considered its approach in line with NICE's technology appraisal guidance on benralizumab and omalizumab, in which an effect of biological treatment on utility over and above treatment effect was accepted by the committee. The EAG explained that the effectiveness of biological treatments should be reflected in the modelled health states. It considered that adding an additional utility increment with borderline statistical significance over and above the asthma control and exacerbations was not appropriate. The EAG also noted that in NICE's technology appraisal guidance on benralizumab and omalizumab, the biological treatment effect-related utilities were attached to the health states in the model. At its first meeting the committee concluded that the company's approach of assuming an additional utility gain for biological treatments was not appropriate. In response to consultation, the company explained that it had identified an error in its original regression analysis and had corrected its base case. The updated results suggested that the regression coefficient was no longer statistically significant for biological-specific utility, so it removed the additional utility gain for biological treatments in its updated base case. The committee agreed that the company's updated base case was appropriate.\n\n# Cost-effectiveness estimates\n\n## The committee's preferred base case included the company's updated treatment response definition\n\nThe committee considered the results for all the relevant comparators. For those eligible for biological treatments the relevant comparators are: anti-interleukin‑5 inhibitors (mepolizumab and benralizumab), omalizumab, reslizumab, and dupilumab. For people for whom biological treatments are unsuitable a comparison with standard care was made. The committee noted its preferred assumptions, which it updated after the first committee meeting. The committee preferred base-case assumptions that were aligned to the EAG's, and these included:\n\nFor people not having maintenance oral corticosteroids: 50% reduction in exacerbations (see section\xa03.6).\n\nFor people having maintenance oral corticosteroids: 50% reduction in their dose (see section\xa03.6).\n\nThe company's updated NMA using the subgroup with baseline blood eosinophil count of at least 300\xa0cells per microlitre (for reslizumab, mepolizumab, benralizumab) and the EAG's preferred subgroup with baseline blood eosinophil count of at least 150\xa0cells per microlitre for the comparison with dupilumab (see section\xa03.10).\n\nThe company's original base-case mortality estimates, with a scenario using the updated estimates for the non-biological eligible group only (see section\xa03.15).\n\nThe company's updated approach to utility gain (see section\xa03.16).\n\n## Tezepelumab is cost effective for treating severe asthma when biological treatments are suitable\n\nFor the subgroups eligible for biological treatments, the committee's preferred base-case incremental cost-effectiveness ratios (ICERs) were all below £20,000 per quality-adjusted life year (QALY) gained. The results included the confidential prices for other biological treatments, which means they cannot be reported here. The committee reiterated the uncertainty associated with the NMAs. But it agreed that the most plausible ICER was unlikely to be above what NICE normally considers an acceptable use of NHS resources in all subgroups eligible for biological treatments. The committee concluded that tezepelumab is cost effective compared with the biological treatments mepolizumab, benralizumab, resilizumab, dupilumab and omalizumab.\n\n## Tezepelumab is cost effective for treating severe asthma when biological treatments are not suitable\n\nFor the subgroup not eligible for biological treatments, the committee's preferred base-case ICER was at the higher range of what NICE usually considers a cost-effective use of NHS resources. But the committee noted that when the CPRD mortality rates were applied (see section 3.15) the ICER was below £20,000 per QALY gained. The results included the confidential prices for standard care treatments, which means they cannot be reported here. Section\xa06 of NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee recalled that there is a high unmet need for people with severe asthma who cannot have existing biological treatments. It also considered that tezepelumab may have uncaptured benefits. Further, the committee understood that the updated mortality estimates using the CPRD data reduced the ICER substantially, and only a small movement between the original and revised company mortality estimates brought the ICER below the threshold. The committee concluded that tezepelumab is cost effective compared with standard care in people not eligible for biological treatments.\n\n# Other factors\n\n## There may be additional benefits of tezepelumab not captured, but this is uncertain\n\nThe company considered tezepelumab to be innovative because of its mechanism of action, making it suitable for the broader severe asthma subtype population. The clinical experts noted that tezepelumab has the potential to be used for various severe asthma subtypes. They noted that if tezepelumab was approved, people would have another treatment option if their asthma does not respond to standard care. The patient experts also noted that tezepelumab may improve treatment adherence for people who find it more difficult to adhere to standard care. An example is people with mental health issues. The committee recalled the patient expert comments on biological treatments also improving people's quality of life (see section\xa03.6), because they can provide stability. This allows people to plan more and have more control of their lives. But the committee also noted the uncertainties in the clinical evidence and the model. It concluded that tezepelumab may have additional benefits that have not been captured in the cost-effectiveness analysis, but these are difficult to untangle because of the uncertainties in the evidence and around some of the company's model assumptions.\n\n## Equality issues\n\nThe committee noted that severe asthma and its subtypes disproportionately affect women, with about 60% of people with severe asthma being women. The committee considered whether this was partly because of the potential effect of hormone levels on immunity and consequently on asthma. The clinical experts explained that this is not fully understood, because of a lack of evidence. But it is known that hormonal stress can affect immunity and as such people's health. They also noted that there is no evidence that suggests that biological treatments affect people differently based on sex. The committee considered that the recommendation would not restrict access for some people over others. No other equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Tezepelumab is recommended for treating severe asthma\n\nThe committee concluded that tezepelumab as an add-on maintenance treatment is recommended for routine commissioning for treating severe asthma in people 12\xa0years and over, when treatment with high-dose inhaled corticosteroids plus another maintenance treatment has not worked well enough. It is recommended only if:\n\npeople have had 3 or more exacerbations in the previous year or are having maintenance oral corticosteroids\n\nthe company provides tezepelumab according to the commercial arrangement."}	https://www.nice.org.uk/guidance/ta880	Evidence-based recommendations on tezepelumab (Tezspire) for treating severe asthma in people 12 years and over.
34aa5f133e62c877dd1acab143373261081e01e5	nice	Daytime intraoral neuromuscular electrical tongue stimulation using a removable device for obstructive sleep apnoea	Daytime intraoral neuromuscular electrical tongue stimulation using a removable device for obstructive sleep apnoea Evidence-based recommendations on daytime intraoral neuromuscular electrical tongue stimulation using a removable device for obstructive sleep apnoea. This involves placing a mouthpiece around the tongue inside the mouth (intraoral). It delivers electrical stimulation to the muscles of the tongue (neuromuscular). The aim is to reduce airway obstruction during sleep. # Recommendations Evidence on the safety and efficacy of daytime intraoral neuromuscular electrical tongue stimulation using a removable device for obstructive sleep apnoea is inadequate in quality and quantity. So, this procedure should be used only in research. Find out what only in research means on the NICE interventional procedures guidance page. Further research should include suitably powered randomised controlled trials and analysis of observational data, to assess efficacy, safety and adherence. Research should report details of patient selection, duration of treatment and effect, effect on snoring and sleep apnoea, quality of life and complications.# The condition, current treatments and procedure # The condition Obstructive sleep apnoea (OSA) is a condition in which the upper airway narrows or closes during sleep when the throat muscles intermittently relax. This causes reduced breathing (hypopnoea) or breathing to temporarily stop (apnoea). OSA can lead to major neurocognitive and cardiovascular sequelae. # Current treatments Management of OSA includes lifestyle changes (such as weight loss), continuous positive airway pressure, oral devices (mandibular advancement devices), neuromuscular electrical stimulation and upper airway surgery. # The procedure In this procedure, an intraoral removable device is used to deliver neuromuscular electrical stimulation to the intrinsic and extrinsic (genioglossus) muscles of the tongue. The aim is to improve tongue endurance and reduce airway obstruction during sleep. A mouthpiece with an electrode array that fits onto the tongue is placed in the mouth by the person during the daytime while they are awake. Bipolar biphasic current is then delivered for about 20 minutes with predetermined low frequency stimulation and rest periods. The mouthpiece is removed once the session is complete. The intensity of the stimulation is controlled by the person, for example by using a smartphone app. An entire therapy usually lasts about 6 weeks, with a 20-minute daytime session each day while awake.	{'Recommendations': 'Evidence on the safety and efficacy of daytime intraoral neuromuscular electrical tongue stimulation using a removable device for obstructive sleep apnoea is inadequate in quality and quantity. So, this procedure should be used only in research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include suitably powered randomised controlled trials and analysis of observational data, to assess efficacy, safety and adherence. Research should report details of patient selection, duration of treatment and effect, effect on snoring and sleep apnoea, quality of life and complications.', 'The condition, current treatments and procedure': '# The condition\n\nObstructive sleep apnoea (OSA) is a condition in which the upper airway narrows or closes during sleep when the throat muscles intermittently relax. This causes reduced breathing (hypopnoea) or breathing to temporarily stop (apnoea). OSA can lead to major neurocognitive and cardiovascular sequelae.\n\n# Current treatments\n\nManagement of OSA includes lifestyle changes (such as weight loss), continuous positive airway pressure, oral devices (mandibular advancement devices), neuromuscular electrical stimulation and upper airway surgery.\n\n# The procedure\n\nIn this procedure, an intraoral removable device is used to deliver neuromuscular electrical stimulation to the intrinsic and extrinsic (genioglossus) muscles of the tongue. The aim is to improve tongue endurance and reduce airway obstruction during sleep.\n\nA mouthpiece with an electrode array that fits onto the tongue is placed in the mouth by the person during the daytime while they are awake. Bipolar biphasic current is then delivered for about 20\xa0minutes with predetermined low frequency stimulation and rest periods. The mouthpiece is removed once the session is complete. The intensity of the stimulation is controlled by the person, for example by using a smartphone app. An entire therapy usually lasts about 6\xa0weeks, with a 20-minute daytime session each day while awake.'}	https://www.nice.org.uk/guidance/ipg760	Evidence-based recommendations on daytime intraoral neuromuscular electrical tongue stimulation using a removable device for obstructive sleep apnoea. This involves placing a mouthpiece around the tongue inside the mouth (intraoral). It delivers electrical stimulation to the muscles of the tongue (neuromuscular). The aim is to reduce airway obstruction during sleep.
2db1021fd97c630db3ff346f73343236c99f11c5	nice	Endoscopic ultrasound-guided biliary drainage for biliary obstruction	Endoscopic ultrasound-guided biliary drainage for biliary obstruction Evidence-based recommendations on endoscopic ultrasound-guided biliary drainage for biliary obstruction. This involves passing a thin tube (called an endoscope) with an ultrasound probe at the tip through the mouth and into the stomach or small intestine. The blockage is located using sound waves and punctured. A short, wire mesh tube that acts like a scaffold (called a stent) is then inserted into the blocked duct. This allows bile to drain into the gut. # Recommendations Evidence on the safety and efficacy of endoscopic ultrasound-guided biliary drainage (EUS‑BD) for biliary obstruction caused by distal malignant disease is adequate to support using this procedure. This is provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Evidence on the safety and efficacy of EUS‑BD for biliary obstruction caused by malignant hilar or benign disease is inadequate in quality and quantity. So, this procedure should be used only in research. Find out what only in research means on the NICE interventional procedures guidance page. Further research should report details of patient selection, where the obstruction is, and whether this procedure has been done after failed endoscopic retrograde cholangiopancreatography. Patient selection should be done by a multidisciplinary team or, in an emergency, only after agreement with an experienced hepatobiliary team. This procedure should only be done in specialised centres by a clinician with specific training and experience in the procedure.# The condition, current treatments and procedure # The condition Biliary obstruction involves blockage of any duct that carries bile from the liver to the gallbladder or from the gallbladder to the small intestine. It may have benign or malignant causes, and can lead to symptoms including jaundice, nausea and abdominal pain, itching, pale stools and dark urine. # Current treatments Current standard management of biliary obstruction usually includes stenting using endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic biliary drainage (PTBD). For malignant obstruction, treatment may also include chemotherapy, biological therapy, photodynamic therapy and radiofrequency ablation. # The procedure Endoscopic ultrasound-guided biliary drainage (EUS‑BD) is an alternative procedure when ERCP is not possible; ERCP fails in a small proportion of people because of the nature of the obstruction or their anatomy (which may be altered because of disease progression or previous surgery). EUS‑BD is also a minimally invasive alternative to PTBD, which is conventionally offered when ERCP has failed. The aim of the procedure is to reduce biliary obstruction and allow the biliary tract to drain. EUS‑BD may be done under conscious sedation or general anaesthesia. It involves inserting an echoendoscope through the mouth and oesophagus into the stomach or duodenum. Using ultrasound guidance, the biliary tract is punctured with a needle. A contrast agent may be injected to enhance imaging. A guidewire is then passed into the biliary tract at the site of the puncture, which is dilated to create a fistula. Finally, a metal or plastic stent is deployed into the biliary tract to allow biliary drainage into the stomach or small intestine. Stent delivery systems may also be used to do EUS‑BD without needle puncture, dilation or insertion of a guidewire. EUS‑BD can be done using several different techniques and stents can be deployed through multiple access routes. The 2 most common techniques, endoscopic ultrasound-guided choledochoduodenostomy (EUS‑CDS) and endoscopic ultrasound-guided hepaticogastrostomy (EUS‑HGS), both use a transluminal approach. In EUS‑CDS, the extrahepatic bile duct is punctured, and the stent is deployed via the duodenal bulb. In EUS‑HGS, the left hepatic duct is punctured, and the stent is deployed via the stomach. Stents may also be deployed using a transpapillary approach in which the guidewire is passed into the duodenum. In endoscopic ultrasound-guided antegrade stenting (EUS‑AGS), the stent is placed across the biliary obstruction. In the endoscopic ultrasound-guided rendezvous technique (EUS‑RV), the echoendoscope is swapped with an ERCP duodenoscope after placement of the guidewire, and a conventional ERCP is done before stent placement. The choice of technique depends on the cause of the biliary obstruction and the anatomy of the person having the procedure.	{'Recommendations': 'Evidence on the safety and efficacy of endoscopic ultrasound-guided biliary drainage (EUS‑BD) for biliary obstruction caused by distal malignant disease is adequate to support using this procedure. This is provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nEvidence on the safety and efficacy of EUS‑BD for biliary obstruction caused by malignant hilar or benign disease is inadequate in quality and quantity. So, this procedure should be used only in research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should report details of patient selection, where the obstruction is, and whether this procedure has been done after failed endoscopic retrograde cholangiopancreatography.\n\nPatient selection should be done by a multidisciplinary team or, in an emergency, only after agreement with an experienced hepatobiliary team.\n\nThis procedure should only be done in specialised centres by a clinician with specific training and experience in the procedure.', 'The condition, current treatments and procedure': '# The condition\n\nBiliary obstruction involves blockage of any duct that carries bile from the liver to the gallbladder or from the gallbladder to the small intestine. It may have benign or malignant causes, and can lead to symptoms including jaundice, nausea and abdominal pain, itching, pale stools and dark urine.\n\n# Current treatments\n\nCurrent standard management of biliary obstruction usually includes stenting using endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic biliary drainage (PTBD). For malignant obstruction, treatment may also include chemotherapy, biological therapy, photodynamic therapy and radiofrequency ablation.\n\n# The procedure\n\nEndoscopic ultrasound-guided biliary drainage (EUS‑BD) is an alternative procedure when ERCP is not possible; ERCP fails in a small proportion of people because of the nature of the obstruction or their anatomy (which may be altered because of disease progression or previous surgery). EUS‑BD is also a minimally invasive alternative to PTBD, which is conventionally offered when ERCP has failed. The aim of the procedure is to reduce biliary obstruction and allow the biliary tract to drain.\n\nEUS‑BD may be done under conscious sedation or general anaesthesia. It involves inserting an echoendoscope through the mouth and oesophagus into the stomach or duodenum. Using ultrasound guidance, the biliary tract is punctured with a needle. A contrast agent may be injected to enhance imaging.\n\nA guidewire is then passed into the biliary tract at the site of the puncture, which is dilated to create a fistula. Finally, a metal or plastic stent is deployed into the biliary tract to allow biliary drainage into the stomach or small intestine. Stent delivery systems may also be used to do EUS‑BD without needle puncture, dilation or insertion of a guidewire.\n\nEUS‑BD can be done using several different techniques and stents can be deployed through multiple access routes. The 2 most common techniques, endoscopic ultrasound-guided choledochoduodenostomy (EUS‑CDS) and endoscopic ultrasound-guided hepaticogastrostomy (EUS‑HGS), both use a transluminal approach. In EUS‑CDS, the extrahepatic bile duct is punctured, and the stent is deployed via the duodenal bulb. In EUS‑HGS, the left hepatic duct is punctured, and the stent is deployed via the stomach.\n\nStents may also be deployed using a transpapillary approach in which the guidewire is passed into the duodenum. In endoscopic ultrasound-guided antegrade stenting (EUS‑AGS), the stent is placed across the biliary obstruction. In the endoscopic ultrasound-guided rendezvous technique (EUS‑RV), the echoendoscope is swapped with an ERCP duodenoscope after placement of the guidewire, and a conventional ERCP is done before stent placement. The choice of technique depends on the cause of the biliary obstruction and the anatomy of the person having the procedure.'}	https://www.nice.org.uk/guidance/ipg761	Evidence-based recommendations on endoscopic ultrasound-guided biliary drainage for biliary obstruction. This involves passing a thin tube (called an endoscope) with an ultrasound probe at the tip through the mouth and into the stomach or small intestine. The blockage is located using sound waves and punctured. A short, wire mesh tube that acts like a scaffold (called a stent) is then inserted into the blocked duct. This allows bile to drain into the gut.
5ac394123c9a0d760a6a842935bc2236ff20611a	nice	Hypertension in pregnancy: diagnosis and management	Hypertension in pregnancy: diagnosis and management This guideline covers diagnosing and managing hypertension (high blood pressure), including pre-eclampsia, during pregnancy, labour and birth. It also includes advice for women with hypertension who wish to conceive and women who have had a pregnancy complicated by hypertension. It aims to improve care during pregnancy, labour and birth for women and their babies. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Reducing the risk of hypertensive disorders in pregnancy ## Symptoms of pre-eclampsia Advise pregnant women to see a healthcare professional immediately if they experience symptoms of pre-eclampsia. Symptoms include: severe headache problems with vision, such as blurring or flashing before the eyes severe pain just below the ribs vomiting sudden swelling of the face, hands or feet. See the NICE guideline on antenatal care for advice on risk factors and symptoms of pre-eclampsia. ## Antiplatelet agents For the indication in recommendations 1.1.2 and 1.1.3, although its use is common in UK clinical practice, at the time of publication (June 2019), aspirin did not have a UK marketing authorisation. Community pharmacies cannot legally sell aspirin as a pharmacy medicine for prevention of pre-eclampsia in pregnancy in England. Aspirin for this indication must be prescribed. The prescriber should see the summary of product characteristics for the manufacturer's advice on use in pregnancy. See NICE's information on prescribing medicines. Advise pregnant women at high risk of pre-eclampsia to take 75 mg to 150 mg of aspirin daily from 12 weeks until the birth of the baby. Women at high risk are those with any of the following: hypertensive disease during a previous pregnancy chronic kidney disease autoimmune disease such as systemic lupus erythematosus or antiphospholipid syndrome type 1 or type 2 diabetes chronic hypertension. Advise pregnant women with more than 1 moderate risk factor for pre-eclampsia to take 75 mg to 150 mg of aspirin daily from 12 weeks until the birth of the baby. Factors indicating moderate risk are: nulliparity age 40 years or older pregnancy interval of more than 10 years body mass index (BMI) of 35 kg/m2 or more at first visit family history of pre-eclampsia multi-fetal pregnancy. ## Other pharmaceutical agents Do not use the following to prevent hypertensive disorders during pregnancy: nitric oxide donors progesterone diuretics low molecular weight heparin. ## Nutritional supplements Do not recommend the following supplements solely with the aim of preventing hypertensive disorders during pregnancy: magnesium folic acid antioxidants (vitamins C and E) fish oils or algal oils garlic. ## Diet Do not recommend salt restriction during pregnancy solely to prevent gestational hypertension or pre-eclampsia. ## Lifestyle Give the same advice on rest, exercise and work to women with chronic hypertension or at risk of hypertensive disorders during pregnancy as healthy pregnant women. See the NICE guideline on antenatal care. ## Diabetes For women with pre-existing diabetes or gestational diabetes, see the NICE guideline on diabetes in pregnancy. # Assessment of proteinuria in hypertensive disorders of pregnancy Interpret proteinuria measurements for pregnant women in the context of a full clinical review of symptoms, signs and other investigations for pre-eclampsia. Use an automated reagent-strip reading device for dipstick screening for proteinuria in pregnant women in secondary care settings. If dipstick screening is positive (1+ or more), use albumin:creatinine ratio or protein:creatinine ratio to quantify proteinuria in pregnant women. Do not use first morning urine void to quantify proteinuria in pregnant women. Do not routinely use 24‑hour urine collection to quantify proteinuria in pregnant women. If using protein:creatinine ratio to quantify proteinuria in pregnant women: use 30 mg/mmol as a threshold for significant proteinuria if the result is 30 mg/mmol or above and there is still uncertainty about the diagnosis of pre-eclampsia, consider re‑testing on a new sample, alongside clinical review. If using albumin:creatinine ratio as an alternative to protein:creatinine ratio to diagnose pre-eclampsia in pregnant women with hypertension: use 8 mg/mmol as a diagnostic threshold if the result is 8 mg/mmol or above and there is still uncertainty about the diagnosis of pre-eclampsia, consider re‑testing on a new sample, alongside clinical review. For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessment of proteinuria . Full details of the evidence and the committee's discussion are in evidence review G: assessment of proteinuria. Loading. Please wait. # Management of chronic hypertension in pregnancy ## Pre-pregnancy advice Offer women with chronic hypertension referral to a specialist in hypertensive disorders of pregnancy to discuss the risks and benefits of treatment. Advise women who take angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs): that there is an increased risk of congenital abnormalities if these drugs are taken during pregnancy to discuss alternative antihypertensive treatment with the healthcare professional responsible for managing their hypertension, if they are planning pregnancy to discuss alternative treatment with the healthcare professional responsible for managing their condition, if ACE inhibitors or ARBs are being taken for other conditions such as renal disease. In 2014, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, which states 'Use in women who are planning pregnancy should be avoided unless absolutely necessary, in which case the potential risks and benefits should be discussed'. Stop antihypertensive treatment in women taking ACE inhibitors or ARBs if they become pregnant (preferably within 2 working days of notification of pregnancy) and offer alternatives. Advise women who take thiazide or thiazide-like diuretics: that there may be an increased risk of congenital abnormalities and neonatal complications if these drugs are taken during pregnancy to discuss alternative antihypertensive treatment with the healthcare professional responsible for managing their hypertension, if they are planning pregnancy. Advise women who take antihypertensive treatments other than ACE inhibitors, ARBs, thiazide or thiazide-like diuretics that the limited evidence available has not shown an increased risk of congenital malformation with such treatments. ## Treatment of chronic hypertension Offer pregnant women with chronic hypertension advice on: weight management exercise healthy eating lowering the amount of salt in their diet. Provide this advice in line with the NICE guideline on hypertension in adults. Continue with existing antihypertensive treatment if safe in pregnancy, or switch to an alternative treatment, unless: sustained systolic blood pressure is less than 110 mmHg or sustained diastolic blood pressure is less than 70 mmHg or the woman has symptomatic hypotension. Offer antihypertensive treatment to pregnant women who have chronic hypertension and who are not already on treatment if they have: sustained systolic blood pressure of 140 mmHg or higher or sustained diastolic blood pressure of 90 mmHg or higher. When using medicines to treat hypertension in pregnancy, aim for a target blood pressure of 135/85 mmHg. Consider labetalol to treat chronic hypertension in pregnant women. Consider nifedipine for women in whom labetalol is not suitable, or methyldopa if both labetalol and nifedipine are not suitable. Base the choice on any pre-existing treatment, side-effect profiles, risks (including fetal effects) and the woman's preference. At the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines. Offer pregnant women with chronic hypertension aspirin 75 mg to 150 mg once daily from 12 weeks. Although its use is common in UK clinical practice, at the time of publication (June 2019), aspirin did not have a UK marketing authorisation for this indication. Community pharmacies cannot legally sell aspirin as a pharmacy medicine for prevention of pre-eclampsia in pregnancy in England. Aspirin for this indication must be prescribed. The prescriber should see the summary of product characteristics for the manufacturer's advice on use in pregnancy. See NICE's information on prescribing medicines. Offer placental growth factor (PLGF)-based testing to help rule out pre-eclampsia between 20 weeks and 36 weeks and 6 days of pregnancy, if women with chronic hypertension are suspected of developing pre-eclampsia. (See the NICE diagnostics guidance on PLGF-based testing to help diagnose suspected preterm pre-eclampsia). For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on treatment of chronic hypertension . Full details of the evidence and the committee's discussion are in evidence review A: interventions for chronic hypertension. Loading. Please wait. ## Antenatal appointments In women with chronic hypertension, schedule additional antenatal appointments based on the individual needs of the woman and her baby. This may include: weekly appointments if hypertension is poorly controlled appointments every 2 to 4 weeks if hypertension is well-controlled. ## Timing of birth Do not offer planned early birth before 37 weeks to women with chronic hypertension whose blood pressure is lower than 160/110 mmHg, with or without antihypertensive treatment, unless there are other medical indications. For women with chronic hypertension whose blood pressure is lower than 160/110 mmHg after 37 weeks, with or without antihypertensive treatment, timing of birth and maternal and fetal indications for birth should be agreed between the woman and the senior obstetrician. If planned early birth is necessary (see recommendation 1.5.7 in the section on timing of birth), offer a course of antenatal corticosteroids and magnesium sulfate if indicated, in line with the NICE guideline on preterm labour and birth. ## Postnatal investigation, monitoring and treatment In women with chronic hypertension who have given birth, measure blood pressure: daily for the first 2 days after birth at least once between day 3 and day 5 after birth as clinically indicated if antihypertensive treatment is changed after birth. In women with chronic hypertension who have given birth: aim to keep blood pressure lower than 140/90 mmHg continue antihypertensive treatment, if required (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding) -ffer a review of antihypertensive treatment 2 weeks after the birth, with their GP or specialist. If a woman has taken methyldopa to treat chronic hypertension during pregnancy, stop within 2 days after the birth and change to an alternative antihypertensive treatment (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding). Offer women with chronic hypertension a medical review 6 to 8 weeks after the birth with their GP or specialist as appropriate. # Management of gestational hypertension ## Assessment and treatment of gestational hypertension In women with gestational hypertension, a full assessment should be carried out in a secondary care setting by a healthcare professional who is trained in the management of hypertensive disorders of pregnancy. In women with gestational hypertension, take account of the following risk factors that require additional assessment and follow‑up: nulliparity age 40 years or older pregnancy interval of more than 10 years family history of pre-eclampsia multi-fetal pregnancy BMI of 35 kg/m2 or more gestational age at presentation previous history of pre-eclampsia or gestational hypertension pre-existing vascular disease pre-existing kidney disease. Offer women with gestational hypertension the tests and treatment listed in table 1. Management Hypertension: blood pressure (BP) of 140/90 to 159/109 mmHg Severe hypertension: blood pressure of 160/110 mmHg or more Admission to hospital Do not routinely admit to hospital Admit, but if BP falls below 160/110 mmHg, then manage as for hypertension Antihypertensive pharmacological treatment Offer pharmacological treatment if BP remains above 140/90 mmHg Offer pharmacological treatment to all women Target blood pressure once on antihypertensive treatment Aim for BP of 135/85 mmHg or less Aim for BP of 135/85 mmHg or less Blood pressure measurement Once or twice a week (depending on BP) until BP is 135/85 mmHg or less Every 15 to 30 minutes until BP is less than 160/110 mmHg Dipstick proteinuria testing (Use an automated reagent-strip reading device for dipstick screening for proteinuria in a secondary care setting) Once or twice a week (with BP measurement) Daily while admitted Blood tests Measure full blood count, liver function and renal function at presentation and then weekly Measure full blood count, liver function and renal function at presentation and then weekly Placental growth factor (PLGF)-based testing Carry out PLGF-based testing on 1 occasion (in accordance with NICE guidance, see recommendation 1.4.4) if there is suspicion of pre-eclampsia Carry out PLGF-based testing on 1 occasion (in accordance with NICE guidance, see recommendation 1.4.4) if there is suspicion of pre-eclampsia Fetal assessment Offer fetal heart auscultation at every antenatal appointment Carry out ultrasound assessment of the fetus at diagnosis and, if normal, repeat every 2 to 4 weeks, if clinically indicated Carry out a cardiotocography (CTG) only if clinically indicated (For advice, see the section on fetal monitoring) Offer fetal heart auscultation at every antenatal appointment Carry out ultrasound assessment of the fetus at diagnosis and, if normal, repeat every 2 weeks, if severe hypertension persists Carry out a CTG at diagnosis and then only if clinically indicated (For advice, see the section on fetal monitoring Offer placental growth factor (PLGF)-based testing to help rule out pre-eclampsia in women presenting with suspected pre-eclampsia (for example, with gestational hypertension) between 20 weeks and 36 weeks and 6 days of pregnancy. (See the NICE diagnostics guidance on PLGF-based testing to help diagnose suspected preterm pre-eclampsia.) Consider labetalol to treat gestational hypertension. Consider nifedipine for women in whom labetalol is not suitable, and methyldopa if labetalol or nifedipine are not suitable. Base the choice on side-effect profiles, risk (including fetal effects) and the woman's preferences. At the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines. Do not offer bed rest in hospital as a treatment for gestational hypertension. For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on monitoring and treatment of gestational hypertension . Full details of the evidence and the committee's discussion are in evidence review B: monitoring gestational hypertension. Loading. Please wait. ## Timing of birth Do not offer planned early birth before 37 weeks to women with gestational hypertension whose blood pressure is lower than 160/110 mmHg, unless there are other medical indications. For women with gestational hypertension whose blood pressure is lower than 160/110 mmHg after 37 weeks, timing of birth, and maternal and fetal indications for birth should be agreed between the woman and the senior obstetrician. If planned early birth is necessary (see recommendation 1.5.7 in the section on timing of birth), offer a course of antenatal corticosteroids and magnesium sulfate if indicated, in line with the NICE guideline on preterm labour and birth. ## Postnatal investigation, monitoring and treatment In women with gestational hypertension who have given birth, measure blood pressure: daily for the first 2 days after birth at least once between day 3 and day 5 after birth as clinically indicated if antihypertensive treatment is changed after birth. In women with gestational hypertension who have given birth: continue antihypertensive treatment if required (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding) advise women that the duration of their postnatal antihypertensive treatment will usually be similar to the duration of their antenatal treatment (but may be longer) reduce antihypertensive treatment if their blood pressure falls below 130/80 mmHg. If a woman has taken methyldopa to treat gestational hypertension, stop within 2 days after the birth and change to an alternative treatment if necessary (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding). For women with gestational hypertension who did not take antihypertensive treatment and have given birth, start antihypertensive treatment if their blood pressure is 150/100 mmHg or higher. Write a care plan for women with gestational hypertension who have given birth and are being transferred to community care that includes all of the following: who will provide follow‑up care, including medical review if needed frequency of blood pressure monitoring needed thresholds for reducing or stopping treatment indications for referral to primary care for blood pressure review. Offer women who have had gestational hypertension and who remain on antihypertensive treatment, a medical review with their GP or specialist 2 weeks after transfer to community care. Offer all women who have had gestational hypertension a medical review with their GP or specialist 6 to 8 weeks after the birth. # Management of pre-eclampsia ## Assessing pre-eclampsia Assessment of women with pre-eclampsia should be performed by a healthcare professional trained in the management of hypertensive disorders of pregnancy. Carry out a full clinical assessment at each antenatal appointment for women with pre-eclampsia, and offer admission to hospital for surveillance and any interventions needed if there are concerns for the wellbeing of the woman or baby. Concerns could include any of the following: sustained systolic blood pressure of 160 mmHg or higher any maternal biochemical or haematological investigations that cause concern, for example, a new and persistent: rise in creatinine (90 micromol/litre or more, 1 mg/100 ml or more) or rise in alanine transaminase (over 70 IU/litre, or twice upper limit of normal range) or fall in platelet count (under 150,000/microlitre) signs of impending eclampsia signs of impending pulmonary oedema -ther signs of severe pre-eclampsia suspected fetal compromise any other clinical signs that cause concern. Consider using either the fullPIERS or PREP-S validated risk prediction models to help guide decisions about the most appropriate place of care (such as the need for in utero transfer) and thresholds for intervention. When using a risk prediction model, take into account that: fullPIERS is intended for use at any time during pregnancy PREP-S is intended for use only up to 34 weeks of pregnancy fullPIERS and PREP‑S models do not predict outcomes for babies. For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessment of women with pre-eclampsia . Full details of the evidence and the committee's discussion are in evidence review C: prediction of complications in pre-eclampsia. Loading. Please wait. ## Treatment of pre-eclampsia Offer women with pre-eclampsia the tests and treatments listed in table 2. Management Hypertension: blood pressure (BP) of 140/90 to 159/109 mmHg Severe hypertension: blood pressure of 160/110 mmHg or more Admission to hospital Admit if any clinical concerns for the wellbeing of the woman or baby (see recommendation 1.5.2) or if high risk of adverse events suggested by the fullPIERS or PREP‑S risk prediction models Admit, but if BP falls below 160/110 mmHg, then manage as for hypertension Antihypertensive pharmacological treatment Offer pharmacological treatment if BP remains above 140/90 mmHg Offer pharmacological treatment to all women Target blood pressure once on antihypertensive treatment Aim for BP of 135/85 mmHg or less Aim for BP of 135/85 mmHg or less Blood pressure measurement At least every 48 hours, and more frequently if the woman is admitted to hospital Every 15 to 30 minutes until BP is less than 160/110 mmHg, then at least 4 times daily while the woman is an inpatient, depending on clinical circumstances Dipstick proteinuria testing (Use an automated reagent-strip reading device for dipstick screening for proteinuria in a secondary care setting) Only repeat if clinically indicated, for example, if new symptoms and signs develop or if there is uncertainty over diagnosis Only repeat if clinically indicated, for example, if new symptoms and signs develop or if there is uncertainty over diagnosis Blood tests Measure full blood count, liver function and renal function twice a week Measure full blood count, liver function and renal function 3 times a week Fetal assessment Offer fetal heart auscultation at every antenatal appointment Carry out ultrasound assessment of the fetus at diagnosis and, if normal, repeat every 2 weeks Carry out a cardiotocography (CTG) at diagnosis and then only if clinically indicated (For advice, see the section on fetal monitoring) Offer fetal heart auscultation at every antenatal appointment Carry out ultrasound assessment of the fetus at diagnosis and, if normal, repeat every 2 weeks Carry out a CTG at diagnosis and then only if clinically indicated (For advice, see the section on fetal monitoring) Offer labetalol to treat hypertension in pregnant women with pre-eclampsia. Offer nifedipine for women in whom labetalol is not suitable, and methyldopa if labetalol or nifedipine are not suitable. Base the choice on any pre-existing treatment, side-effect profiles, risks (including fetal effects) and the woman's preference. At the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines. ## Timing of birth Record maternal and fetal thresholds for planned early birth before 37 weeks in women with pre-eclampsia. Thresholds for considering planned early birth could include (but are not limited to) any of the following known features of severe pre-eclampsia: inability to control maternal blood pressure despite using 3 or more classes of antihypertensives in appropriate doses maternal pulse oximetry less than 90% progressive deterioration in liver function, renal function, haemolysis, or platelet count -ngoing neurological features, such as severe intractable headache, repeated visual scotomata, or eclampsia placental abruption reversed end-diastolic flow in the umbilical artery doppler velocimetry, a non-reassuring cardiotocograph, or stillbirth. Other features not listed above may also be considered in the decision to plan early birth. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. Involve a senior obstetrician in any decisions on timing of birth for women with pre-eclampsia. Discuss with the anaesthetic team if birth is planned in a woman with pre-eclampsia. Discuss with the neonatal team if birth is planned in a woman with pre-eclampsia, and neonatal complications are anticipated. Offer intravenous magnesium sulfate and a course of antenatal corticosteroids if indicated, if early birth is planned for women with preterm pre-eclampsia, in line with the NICE guideline on preterm labour and birth. Decide on timing of birth in women with pre-eclampsia as recommended in table 3. Weeks of pregnancy Timing of birth Before 34 weeks Continue surveillance unless there are indications (see recommendation 1.5.7 in the section on timing of birth) for planned early birth. Offer intravenous magnesium sulfate and a course of antenatal corticosteroids in line with the NICE guideline on preterm labour and birth. From 34 weeks to 36 weeks plus 6 days Continue surveillance unless there are indications (see recommendation 1.5.7 in the section on timing of birth) for planned early birth. When considering the option of planned early birth, take into account the woman's and baby's condition, risk factors (such as maternal comorbidities, multi-fetal pregnancy) and availability of neonatal unit beds. Consider a course of antenatal corticosteroids in line with the NICE guideline on preterm labour and birth. weeks onwards Initiate birth within 24 to 48 hours. For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on monitoring and treatment of pre-eclampsia and timing of birth . Full details of the evidence and the committee's discussion are in evidence review D: interventions for pre-eclampsia. Loading. Please wait. ## Postnatal investigation, monitoring and treatment (including after discharge from critical care) In women with pre-eclampsia who did not take antihypertensive treatment and have given birth, measure blood pressure: at least 4 times a day while the woman is an inpatient at least once between day 3 and day 5 after birth -n alternate days until normal, if blood pressure was abnormal on days 3 to 5. In women with pre-eclampsia who did not take antihypertensive treatment and have given birth, start antihypertensive treatment if blood pressure is 150/100 mmHg or higher. Ask women with pre-eclampsia who have given birth about severe headache and epigastric pain each time blood pressure is measured. In women with pre-eclampsia who took antihypertensive treatment and have given birth, measure blood pressure: at least 4 times a day while the woman is an inpatient every 1 to 2 days for up to 2 weeks after transfer to community care until the woman is off treatment and has no hypertension. For women with pre-eclampsia who have taken antihypertensive treatment and have given birth: continue antihypertensive treatment (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding) consider reducing antihypertensive treatment if their blood pressure falls below 140/90 mmHg reduce antihypertensive treatment if their blood pressure falls below 130/80 mmHg. If a woman has taken methyldopa to treat pre-eclampsia, stop within 2 days after the birth and change to an alternative treatment if necessary (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding). Offer women with pre-eclampsia who have given birth transfer to community care if all of the following criteria have been met: there are no symptoms of pre-eclampsia blood pressure, with or without treatment, is 150/100 mmHg or less blood test results are stable or improving. Write a care plan for women with pre-eclampsia who have given birth and are being transferred to community care that includes all of the following: who will provide follow‑up care, including medical review if needed frequency of blood pressure monitoring thresholds for reducing or stopping treatment indications for referral to primary care for blood pressure review self-monitoring for symptoms. Offer women who have had pre-eclampsia and who remain on antihypertensive treatment, a medical review with their GP or specialist 2 weeks after transfer to community care. Offer all women who have had pre-eclampsia a medical review with their GP or specialist 6 to 8 weeks after the birth. In women who have pre-eclampsia with mild or moderate hypertension, or after step-down from critical care: measure platelet count, transaminases and serum creatinine 48 to 72 hours after birth or step-down do not repeat platelet count, transaminases or serum creatinine measurements if results are normal at 48 to 72 hours. If biochemical and haematological indices are outside the reference range in women with pre-eclampsia who have given birth, repeat platelet count, transaminases and serum creatinine measurements as clinically indicated until results return to normal. In women with pre-eclampsia who have given birth, carry out a urinary reagent-strip test 6 to 8 weeks after the birth. Offer women who had pre-eclampsia and still have proteinuria (1+ or more) at 6 to 8 weeks after the birth, a further review with their GP or specialist at 3 months after the birth to assess kidney function. Consider referring women with an abnormal kidney function assessment at 3 months for a specialist kidney assessment in line with the NICE guideline on chronic kidney disease. # Fetal monitoring ## Fetal monitoring in chronic hypertension In women with chronic hypertension, carry out an ultrasound for fetal growth and amniotic fluid volume assessment, and umbilical artery doppler velocimetry at 28 weeks, 32 weeks and 36 weeks. In women with chronic hypertension, only carry out cardiotocography if clinically indicated. ## Fetal monitoring in gestational hypertension In women with gestational hypertension, carry out an ultrasound for fetal growth and amniotic fluid volume assessment and umbilical artery doppler velocimetry at diagnosis and if normal repeat every 2 to 4 weeks, if clinically indicated. In women with gestational hypertension, only carry out cardiotocography if clinically indicated. ## Fetal monitoring in pre-eclampsia or severe gestational hypertension Carry out cardiotocography at diagnosis of pre-eclampsia or severe gestational hypertension. If conservative management of pre-eclampsia or severe gestational hypertension is planned, carry out all the following tests at diagnosis: ultrasound for fetal growth and amniotic fluid volume assessment umbilical artery doppler velocimetry. If the results of all fetal monitoring are normal in women with pre-eclampsia or severe gestational hypertension, do not routinely repeat cardiotocography unless clinically indicated. In women with pre-eclampsia or severe gestational hypertension, repeat cardiotocography if any of the following occur: the woman reports a change in fetal movement vaginal bleeding abdominal pain deterioration in maternal condition. In women with pre-eclampsia or severe gestational hypertension, repeat ultrasound for fetal growth and amniotic fluid volume assessment or umbilical artery doppler velocimetry every 2 weeks, with subsequent surveillance and monitoring determined by the findings of these scans. For women with pre-eclampsia or severe gestational hypertension, write a care plan that includes all of the following: the timing and nature of future fetal monitoring fetal indications for birth and if and when antenatal corticosteroids should be given plans for discussion with neonatal paediatricians and obstetric anaesthetists. ## Women who need additional fetal monitoring Carry out an ultrasound for fetal growth and amniotic fluid volume assessment and umbilical artery doppler velocimetry starting at between 28 and 30 weeks (or at least 2 weeks before previous gestational age of onset if earlier than 28 weeks) and repeating 4 weeks later in women with previous: severe pre-eclampsia pre-eclampsia that resulted in birth before 34 weeks pre-eclampsia with a baby whose birth weight was less than the 10th centile intrauterine death placental abruption. In women who need additional fetal monitoring (see recommendation 1.6.11), carry out cardiotocography only if clinically indicated. # Intrapartum care Give advice and treatment to women with hypertensive disorders of pregnancy in line with the NICE guideline on intrapartum care, unless there are recommendations in this guideline on the same topic. Offer care in accordance with the NICE guideline on intrapartum care for women with hypertension whether treated or untreated, and not just on the basis of blood pressure in labour. Give women with chronic hypertension advice and care in line with the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies. ## Blood pressure During labour, measure blood pressure: hourly, in women with hypertension every 15 to 30 minutes until blood pressure is less than 160/110 mmHg in women with severe hypertension. Continue use of antenatal antihypertensive treatment during labour. ## Haematological and biochemical monitoring Determine the need for haematological and biochemical tests during labour in women with hypertension using the same criteria as in the antenatal period even if regional analgesia is being considered. ## Care during epidural analgesia Do not preload women who have severe pre-eclampsia with intravenous fluids before establishing low-dose epidural analgesia or combined spinal epidural analgesia. ## Management of second stage of labour Do not routinely limit the duration of the second stage of labour in women with controlled hypertension. Consider operative or assisted birth in the second stage of labour for women with severe hypertension whose hypertension has not responded to initial treatment. # Medical management of severe hypertension, severe pre-eclampsia or eclampsia in a critical care setting ## Anticonvulsants If a woman in a critical care setting who has severe hypertension or severe pre-eclampsia has or previously had an eclamptic fit, give intravenous magnesium sulfate. Consider giving intravenous magnesium sulfate to women with severe pre-eclampsia who are in a critical care setting if birth is planned within 24 hours. Consider the need for magnesium sulfate treatment, if 1 or more of the following features of severe pre-eclampsia is present: -ngoing or recurring severe headaches visual scotomata nausea or vomiting epigastric pain -liguria and severe hypertension progressive deterioration in laboratory blood tests (such as rising creatinine or liver transaminases, or falling platelet count). Use the Collaborative Eclampsia Trial regimen for administration of magnesium sulfate: A loading dose of 4 g should be given intravenously over 5 to 15 minutes, followed by an infusion of 1 g/hour maintained for 24 hours. If the woman has had an eclamptic fit, the infusion should be continued for 24 hours after the last fit. Recurrent fits should be treated with a further dose of 2 g to 4 g given intravenously over 5 to 15 minutes. The MHRA has issued a warning about the risk of skeletal adverse effects in the neonate following prolonged or repeated use of magnesium sulfate in pregnancy. Maternal administration of magnesium sulfate for longer than 5 to 7 days in pregnancy has been associated with skeletal adverse effects and hypocalcaemia and hypermagnesemia in neonates. If use of magnesium sulfate in pregnancy is prolonged or repeated, consider monitoring of neonates for abnormal calcium and magnesium levels and skeletal adverse effects. Do not use diazepam, phenytoin or other anticonvulsants as an alternative to magnesium sulfate in women with eclampsia. ## Antihypertensives Treat women with severe hypertension who are in critical care during pregnancy or after birth immediately with 1 of the following: labetalol (oral or intravenous) -ral nifedipine intravenous hydralazine. At the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines. In women with severe hypertension who are in critical care, monitor their response to treatment: to ensure that their blood pressure falls to identify adverse effects for both the woman and the baby to modify treatment according to response. Consider using up to 500 ml crystalloid fluid before or at the same time as the first dose of intravenous hydralazine in the antenatal period. ## Corticosteroids for fetal lung maturation If early birth is considered likely within 7 days in women with pre-eclampsia, offer a course of antenatal corticosteroids in line with the NICE guideline on preterm labour and birth. ## Corticosteroids to manage HELLP syndrome Do not use dexamethasone or betamethasone for the treatment of HELLP syndrome. ## Fluid balance and volume expansion Do not use volume expansion in women with severe pre-eclampsia unless hydralazine is the antenatal antihypertensive. In women with severe pre-eclampsia, limit maintenance fluids to 80 ml/hour unless there are other ongoing fluid losses (for example, haemorrhage). ## Caesarean section versus induction of labour Choose mode of birth for women with severe hypertension, severe pre-eclampsia or eclampsia according to the clinical circumstances and the woman's preference. ## Referral to critical care Refer women with severe hypertension or severe pre-eclampsia to the appropriate critical care setting using the criteria in table 4. Critical care level Clinical criteria Level 3 care Severe pre-eclampsia and needing ventilation Level 2 care Step-down from level 3 or severe pre-eclampsia with any of the following complications: eclampsia HELLP syndrome haemorrhage hyperkalaemia severe oliguria coagulation support intravenous antihypertensive treatment initial stabilisation of severe hypertension evidence of cardiac failure abnormal neurology Level 1 care Pre-eclampsia with hypertension Ongoing conservative antenatal management of severe preterm hypertension Step-down treatment after the birth # Antihypertensive treatment during the postnatal period, including during breastfeeding For the indications in recommendations 1.9.4, 1.9.6 and 1.9.8, in 2009, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update on ACE inhibitors and angiotensin II receptor antagonists: recommendations on how to use during breastfeeding, and a subsequent clarification was issued in 2014 stating that 'although ACE inhibitors and angiotensin II receptor antagonists are generally not recommended for use by breastfeeding mothers, they are not absolutely contraindicated. Healthcare professionals may prescribe these medicines during breastfeeding if they consider that this treatment is essential for the lactating mother. In mothers who are breastfeeding older infants, the use of captopril, enalapril, or quinapril may be considered if an ACE inhibitor is necessary for the mother. Careful follow-up of the infant for possible signs of hypotension is recommended'. For the indications in recommendations 1.9.5 and 1.9.6, at the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines. Advise women with hypertension who wish to breastfeed that their treatment can be adapted to accommodate breastfeeding, and that the need to take antihypertensive medication does not prevent them from breastfeeding. Explain to women with hypertension who wish to breastfeed that: antihypertensive medicines can pass into breast milk most antihypertensive medicines taken while breastfeeding only lead to very low levels in breast milk, so the amounts taken in by babies are very small and would be unlikely to have any clinical effect most medicines are not tested in pregnant or breastfeeding women, so disclaimers in the manufacturer's information are not because of any specific safety concerns or evidence of harm.Make decisions on treatment together with the woman, based on her preferences. As antihypertensive agents have the potential to transfer into breast milk: consider monitoring the blood pressure of babies, especially those born preterm, who have symptoms of low blood pressure for the first few weeks when discharged home, advise women to monitor their babies for drowsiness, lethargy, pallor, cold peripheries or poor feeding. Offer enalapril to treat hypertension in women during the postnatal period, with appropriate monitoring of maternal renal function and maternal serum potassium. For women of black African or Caribbean family origin with hypertension during the postnatal period, consider antihypertensive treatment with: nifedipine or amlodipine if the woman has previously used this to successfully control her blood pressure. For women with hypertension in the postnatal period, if blood pressure is not controlled with a single medicine, consider a combination of nifedipine (or amlodipine) and enalapril. If this combination is not tolerated or is ineffective, consider either: adding atenolol or labetalol to the combination treatment or swapping 1 of the medicines already being used for atenolol or labetalol. When treating women with antihypertensive medication during the postnatal period, use medicines that are taken once daily when possible. Where possible, avoid using diuretics or angiotensin receptor blockers to treat hypertension in women in the postnatal period who are breastfeeding or expressing milk. Treat women with hypertension in the postnatal period who are not breastfeeding and who are not planning to breastfeed in line with the NICE guideline on hypertension in adults. For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on antihypertensive treatment during breastfeeding . Full details of the evidence and the committee's discussion are in evidence review E: postnatal management of hypertension. Loading. Please wait. # Advice and follow-up at transfer to community care ## Risk of recurrence of hypertensive disorders of pregnancy Advise women with hypertensive disorders of pregnancy that the overall risk of recurrence in future pregnancies is approximately 1 in 5 (see table 5). Prevalence of hypertensive disorder in a future pregnancy Any hypertension in previous or current pregnancy Pre-eclampsia in previous or current pregnancy Gestational hypertension in previous or current pregnancy Any hypertension Approximately 21% (1 in 5 women) Approximately 20% (1 in 5 women) Approximately 22% (1 in 5 women) Pre-eclampsia Approximately 14% (1 in 7 women) Up to approximately 16% (1 in 6 women) If birth was at 28 to 34 weeks: approximately 33% (1 in 3 women) (No evidence was identified for women who gave birth at less than 28 weeks, but the committee agreed that the risk was likely to be at least as high, if not higher, than that for women who gave birth between 28 and 34 weeks) If birth was at 34 to 37 weeks: approximately 23% (1 in 4 women) Approximately 7% (1 in 14 women) Gestational hypertension Approximately 9% (1 in 11 women) Between approximately 6 and 12% (up to 1 in 8 women) Between approximately 11% and 15% (up to 1 in 7 women) Chronic hypertension Not applicable Approximately 2% (up to 1 in 50 women) Approximately 3% (up to 1 in 34 women) ## Long-term risk of cardiovascular disease Advise women who have had a hypertensive disorder of pregnancy that this is associated with an increased risk of hypertension and cardiovascular disease in later life (see table 6). Risk of future cardiovascular disease Any hypertension in current or previous pregnancy Pre-eclampsia in current or previous pregnancy Gestational hypertension in current or previous pregnancy Chronic hypertension in current or previous pregnancy Major adverse cardiovascular event Risk increased (up to approximately 2 times) Risk increased (approximately 1.5 to 3 times) Risk increased (approximately 1.5 to 3 times) Risk increased (approximately 1.7 times) Cardiovascular mortality Risk increased (up to approximately 2 times) Risk increased (approximately 2 times) (no data) (no data) Stroke Risk increased (up to approximately 1.5 times) Risk increased (approximately 2 to 3 times) Risk may be increased Risk increased (approximately 1.8 times) Hypertension Risk increased (approximately 2 to 4 times) Risk increased (approximately 2 to 5 times) Risk increased (approximately 2 to 4 times) (not applicable) Notes: Risks described are overall estimates, summarised from risk ratios, odds ratios and hazard ratios. Increased risk is compared to the background risk in women who did not have hypertensive disorders during pregnancy. Absolute risks are not reported, because these will vary considerably, depending on the follow-up time (range from 1 to 40 years postpartum). Advise women who have had a hypertensive disorder of pregnancy to discuss how to reduce their risk of cardiovascular disease, including hypertensive disorders, with their GP or specialist. This may include: avoiding smoking, as recommended in the NICE guideline on tobacco maintaining a healthy lifestyle, as recommended in the NICE guideline on cardiovascular disease maintaining a healthy weight, as recommended in the NICE guideline on obesity. In women who have had pre-eclampsia or hypertension with early birth before 34 weeks, consider pre-pregnancy counselling to discuss possible risks of recurrent hypertensive disorders of pregnancy, and how to lower them for any future pregnancies. For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see rationale and impact section on risk of recurrence of hypertensive disorders of pregnancy and long-term cardiovascular disease . Full details of the evidence and the committee's discussion are in evidence review F: advice at discharge. Loading. Please wait. ## Body mass index and recurrence of hypertensive disorders of pregnancy Advise women who have had pre-eclampsia to achieve and keep a BMI within the healthy range before their next pregnancy (18.5 to 24.9 kg/m2). See also the NICE guideline on obesity. ## Inter-pregnancy interval and recurrence of hypertensive disorders of pregnancy Advise women who have had pre-eclampsia that the likelihood of recurrence increases with an inter-pregnancy interval greater than 10 years. ## Long-term risk of end-stage kidney disease Tell women with a history of pre-eclampsia who have no proteinuria and no hypertension at the postnatal review (6 to 8 weeks after the birth) that although the relative risk of end-stage kidney disease is increased, the absolute risk is low and no further follow‑up is necessary. ## Thrombophilia and the risk of pre-eclampsia Do not routinely perform screening for thrombophilia in women who have had pre-eclampsia. # Terms used in this guideline ## Chronic hypertension Hypertension that is present at the booking visit, or before 20 weeks, or if the woman is already taking antihypertensive medication when referred to maternity services. It can be primary or secondary in aetiology. ## Eclampsia A convulsive condition associated with pre-eclampsia. ## Gestational hypertension New hypertension presenting after 20 weeks of pregnancy without significant proteinuria. ## HELLP syndrome Haemolysis, elevated liver enzymes and low platelet count. ## Hypertension Blood pressure of 140 mmHg systolic or higher, or 90 mmHg diastolic or higher. ## Multi-fetal pregnancy A pregnancy with more than 1 baby (such as twins, triplets). ## Pre-eclampsia New onset of hypertension (over 140 mmHg systolic or over 90 mmHg diastolic) after 20 weeks of pregnancy and the coexistence of 1 or more of the following new-onset conditions: proteinuria (urine protein:creatinine ratio of 30 mg/mmol or more or albumin:creatinine ratio of 8 mg/mmol or more, or at least 1 g/litre on dipstick testing) or -ther maternal organ dysfunction: renal insufficiency (creatinine 90 micromol/litre or more, 1.02 mg/100 ml or more) liver involvement (elevated transaminases with or without right upper quadrant or epigastric abdominal pain) neurological complications such as eclampsia, altered mental status, blindness, stroke, clonus, severe headaches or persistent visual scotomata haematological complications such as thrombocytopenia (platelet count below 150,000/microlitre), disseminated intravascular coagulation or haemolysis uteroplacental dysfunction such as fetal growth restriction, abnormal umbilical artery doppler waveform analysis, or stillbirth. ## Severe hypertension Blood pressure over 160 mmHg systolic or over 110 mmHg diastolic. ## Severe pre-eclampsia Pre-eclampsia with severe hypertension that does not respond to treatment or is associated with ongoing or recurring severe headaches, visual scotomata, nausea or vomiting, epigastric pain, oliguria and severe hypertension, as well as progressive deterioration in laboratory blood tests such as rising creatinine or liver transaminases or falling platelet count, or failure of fetal growth or abnormal doppler findings.# Recommendations for research As part of the 2019 update, the guideline committee made 6 research recommendations on the management of pregnancy with chronic hypertension, pre-eclampsia, fetal monitoring, the use of antihypertensives in breastfeeding and advice and follow‑up. A research recommendation from the 2010 guideline which was superseded by these new research recommendations was deleted, and 3 research recommendations where research was now underway or had been completed were also deleted. # Key recommendations for research ## Management of chronic hypertension in pregnancy In women who need treatment for chronic hypertension in pregnancy, what is the effectiveness and safety of antihypertensive agents (compared in head-to-head trials) in improving maternal and perinatal outcomes? For a short explanation of why the committee made this recommendation for research, see the rationale and impact section on pre-eclampsia . Full details of the evidence and the committee's discussion are in evidence review A: interventions for chronic hypertension. Loading. Please wait. ## Management of hypertension in pregnancy In women who need treatment for hypertension in pregnancy, what are the adverse neonatal outcomes associated with maternal use of beta blockers (or mixed alpha-beta blockers)? For a short explanation of why the committee made this recommendation for research, see the rationale and impact section on chronic hypertension . Full details of the evidence and the committee's discussion are in evidence review A: interventions for chronic hypertension. Loading. Please wait. ## Management of pre-eclampsia In which women with pre-eclampsia is inpatient management associated with better outcomes for women and babies? For a short explanation of why the committee made this recommendation for research, see the rationale and impact section on pre-eclampsia . Full details of the evidence and the committee's discussion are in evidence review B: monitoring gestational hypertension. Loading. Please wait. ## Antihypertensive treatment during the postnatal period In women who need treatment for high blood pressure after birth, what is the effectiveness and safety (including in breastfeeding women) of antihypertensive agents in achieving adequate blood pressure control? For a short explanation of why the committee made this recommendation for research, see the rationale and impact section on antihypertensive treatment during breastfeeding . Full details of the evidence and the committee's discussion are in evidence review E: postnatal management of hypertension. Loading. Please wait. ## Fetal monitoring In women with hypertensive disorders of pregnancy, what is the optimal fetal monitoring strategy to detect small for gestational age infants? For a short explanation of why the committee made this recommendation for research, see the rationale and impact section on fetal monitoring . Full details of the evidence and the committee's discussion are in evidence review B: monitoring gestational hypertension. Loading. Please wait. ## Advice and follow-up at transfer to community care In women who have had hypertension during pregnancy, what interventions reduce the risk of a) recurrent hypertensive disorders of pregnancy, and b) subsequent cardiovascular disease? For a short explanation of why the committee made this recommendation for research, see the rationale and impact section on follow up after hypertensive disorders of pregnancy . Full details of the evidence and the committee's discussion are in evidence review F: advice at discharge. Loading. Please wait. # Other recommendations for research (from 2010 guideline) ## Haematological and biochemical monitoring in women with gestational hypertension What is the role of assessing haematological or biochemical parameters at diagnosis of gestational hypertension and during surveillance of gestational hypertension? # Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion. # Assessment of proteinuria Recommendations 1.2.1 to 1.2.7 ## Why the committee made the recommendations The committee were aware that there is often over-reliance on a proteinuria result in the diagnosis of pre-eclampsia, and agreed that healthcare professionals should use the results of a full clinical review, including severity of hypertension and other signs and symptoms, before making a diagnosis of pre-eclampsia. The committee amended the recommendation on automated dipstick tests from the 2010 guideline to emphasise that this should be used as a screening tool for proteinuria. The committee highlighted the importance of using automated dipstick analysis in secondary care rather than visual analysis, which they were aware from their experience has a higher error rate. Protein:creatinine ratio (PCR) and albumin:creatinine ratio (ACR) were both shown to have high specificity and high sensitivity at the chosen thresholds (30 mg/mmol and 8 mg/mmol respectively), and therefore either could be used depending on local availability. The committee agreed that using both tests together did not have any additional diagnostic benefit. There was some evidence that using the first morning urine void in assessment of proteinuria can lead to lower diagnostic accuracy, and so the committee recommended against using this. As PCR and ACR show very high diagnostic accuracy, they should be used in place of 24‑hour urine collection, which is awkward for women and could delay identification of proteinuria. However, there are rare occasions when it might be more appropriate to use 24‑hour collection (for example, women with renal complications), and so the committee agreed it should not be ruled out entirely. There was good evidence that a PCR of 30 mg/mmol had good diagnostic accuracy, showing high sensitivity and specificity and should be used as the threshold for significant proteinuria. However, the committee recommended retesting for results above 30 mg/mmol if there is still diagnostic uncertainty (for example, the woman has no other clinical signs or symptoms of pre-eclampsia) because there is large variation in protein excretion during the day and from day to day. The committee agreed that this would prevent women being diagnosed with pre-eclampsia on the basis of a single raised PCR result. Evidence from a single study showed high sensitivity and specificity for an ACR result of 8 mg/mmol to diagnose proteinuria. However, the committee were also aware of further results from a large, UK‑based study, which provided further evidence for the efficacy of a threshold of 8 mg/mmol in the diagnosis of severe pre-eclampsia. The committee were aware that this threshold is different to that used for detection of microalbuminuria in the non-pregnant population. However, they agreed that, on the basis of the evidence reviewed, it was appropriate to use a threshold of 8 mg/mmol for pregnant women. As with PCR, the committee were aware that women are sometimes diagnosed with pre-eclampsia on the basis of a single raised ACR, and that this may lead to over-diagnosis. Therefore, they made a recommendation to consider repeating the ACR measurement if there was ongoing clinical uncertainty about the diagnosis. No evidence was reviewed that examined the timing of repeat testing for either ACR or PCR, and so no recommendations could be made regarding this. ## How the recommendations might affect practice The recommendation to take account of other clinical features when assessing women for suspected pre-eclampsia might lead to an increased need for follow‑up and surveillance. However, this will also reduce the chance that a diagnosis of pre-eclampsia is missed by raising awareness of the multi-system nature of the disease, and so could reduce the number of women who go on to develop complications from undiagnosed pre-eclampsia. Not all secondary care units currently use automated dipstick analysis to screen for proteinuria, so the recommendations might increase the need for automated reagent-strip reading devices. However, the accuracy and reliability of screening will be improved, reducing the need for further investigations for some women and correctly identifying more women who need further testing or investigations. Moving from 24‑hour urine collection to spot urine ACR or PCR will save time, with potential for faster diagnosis, and a reduction in inaccuracies because of incomplete samples. It is also likely to improve quality of life, as the process of completing a 24‑hour urine collection is time-consuming and awkward. A PCR of 30 mg/mmol is already used routinely as a diagnostic threshold and therefore should not change practice. Currently units may use different ACR levels for diagnosis and so the recommendation to use 8 mg/mmol will standardise practice. Recommendations have been made for the use of either ACR or PCR allowing local decisions to use whichever test is available, so this should not affect practice. Repeating the PCR or ACR test may incur a small additional cost. However, this should reduce the false positive rate, and mean some women will avoid unnecessary follow‑up or intensive monitoring (such as hospital admission) if their proteinuria resolves and is shown to be transient. Return to recommendations # Treatment of chronic hypertension Recommendations 1.3.6 to 1.3.12 ## Why the committee made the recommendations The committee agreed that pregnant woman with chronic hypertension should be offered lifestyle advice similar to other adults with hypertension, and in line with the NICE guideline on hypertension in adults. There was very little evidence available on treatment initiation thresholds for chronic hypertension in pregnancy, so the committee based their recommendations on the values specified in the recent Control of Hypertension in Pregnancy Study (CHIPS) and the NICE guideline on hypertension in adults. There was evidence for target blood pressure levels from the large CHIPS trial, so the committee made recommendations based on this. There was some very limited evidence of both benefits and harms for different antihypertensive medicines. However, there was not enough evidence to recommend one treatment over another. As labetalol, nifedipine and methyldopa had been recommended in the previous guideline (for gestational hypertension and pre-eclampsia), and these medicines had been used for many years in pregnancy, the committee agreed they should be preferred treatment options for chronic hypertension in pregnancy. Labetalol is specifically licensed for use in pregnancy and so is suggested as the first-line option, with nifedipine as the next alternative, and methyldopa as the third option (as it may lead to more side effects and be the least effective option of the 3). There was some very limited evidence for the benefits of aspirin in reducing preterm births and neonatal unit admissions, so the committee retained the recommendation on aspirin from the previous guideline, but incorporated it into the section on the treatment of chronic hypertension in pregnancy. The committee noted that the studies used different doses of aspirin (ranging from 50 mg to 150 mg daily), and that common practice in the UK was to offer 75 mg to 150 mg, therefore this dose range was recommended. The committee were aware of the link between chronic hypertension and both pre-existing and gestational diabetes, therefore they made an overarching recommendation at the beginning of the guideline to cross-refer to the existing NICE guideline on diabetes in pregnancy. The committee made a new recommendation referring to the NICE diagnostics guidance on placental growth factor (PLGF) testing as this may be applicable to women with chronic hypertension. As there is currently a lack of evidence on the difference in outcomes between different antihypertensive medications, and concerns about possible adverse neonatal events from beta blockers, the committee made research recommendations on these topics. ## How the recommendations might affect practice Based on these recommendations, a clear blood pressure target should now be set for women with chronic hypertension in pregnancy who need antihypertensive treatment to improve consistency of treatment targets. Starting treatment for hypertension and offering aspirin to women with chronic hypertension who are pregnant are standard care, so these recommendations are not expected to change practice significantly. Return to recommendations # Monitoring and treatment of gestational hypertension Recommendations 1.4.3 and 1.4.4 ## Why the committee made the recommendations The committee updated the table from the previous guideline on the management of pregnancy with gestational hypertension. There was very little evidence available on treatment initiation thresholds for gestational hypertension in pregnancy, so the committee made recommendations using the values specified in the recent Control of Hypertension in Pregnancy Study (CHIPS). There was evidence for target blood pressure levels from the large CHIPS trial, so the committee made recommendations based on this. The committee made a new recommendation referring to the NICE diagnostics guidance on placental growth factor (PLGF) testing as this is applicable to women with gestational hypertension. The committee were aware of the link between gestational hypertension and both pre-existing and gestational diabetes, therefore they made an overarching recommendation at the beginning of the guideline to cross-refer to the existing NICE guideline on diabetes in pregnancy. There was no evidence on fetal monitoring in gestational hypertension, so the committee made a research recommendation on the optimal fetal monitoring strategy to detect small for gestational age infants. ## How the recommendations might affect practice The recommendations reflect current clinical practice in many units, but may help standardise practice across the NHS for units that currently use other blood pressure targets. Return to recommendations # Assessment of women with pre-eclampsia Recommendations 1.5.2 to 1.5.4 ## Why the committee made the recommendations The committee agreed, based on their clinical expertise, that women with pre-eclampsia should have a full clinical assessment at every antenatal appointment and should be admitted to hospital if there are any concerns about the wellbeing of the woman or her baby. The committee agreed that this would include (but was not limited to) reasons such as severe hypertension or other features of pre-eclampsia indicating increased risk of adverse outcomes. There was some evidence that the fullPIERS and PREP‑S models can help identify women at different risks of adverse outcomes because of pre-eclampsia. There was more extensive validation of the fullPIERS model, and the validation studies were conducted in populations from a range of healthcare settings. The PREP‑S model had been developed using a UK population, and validated using data from similar multinational settings. It was noted that further validation of PREP‑S was unlikely to be conducted, because of the cost of conducting these studies. The committee therefore agreed that both models could be considered as options, in addition to a full clinical assessment, to help guide decisions relating to interventions and place of care. The tools predict adverse outcomes in women, but are not designed to predict outcomes for babies. The committee agreed it was important to highlight this. ## How the recommendations might affect practice The use of a full clinical assessment and validated models to predict risk may improve consistency in current practice with regard to admission to hospital for women with pre-eclampsia. Some centres offer admission to all women with pre-eclampsia, whereas others only offer it to a small proportion of women. The guidance might increase the number of women who are admitted to hospital in some centres if admission is not currently routine, but might decrease admission in other centres, thus standardising practice. Return to recommendations # Monitoring and treatment of pre-eclampsia and timing of birth Recommendations 1.5.5, 1.5.7 and 1.5.12 ## Why the committee made the recommendations The committee updated the table from the previous guideline on the management of pregnancy with pre-eclampsia. There was limited evidence on the best place of treatment for women with pre-eclampsia. Because of this, the committee made recommendations based on other evidence they reviewed (see evidence review C), which showed that women should be admitted if there were concerns for the wellbeing of the woman or her baby, or a high risk of complications of pre-eclampsia predicted using the fullPIERS or PREP‑S model. (See the section of the guideline on assessing pre-eclampsia and evidence review C for more details on the use of the fullPIERS and PREP‑S models.) There was no evidence on treatment initiation thresholds or target blood pressure levels for pre-eclampsia, so the committee based their recommendations on the NICE guideline on hypertension in adults and the values specified in the Control of Hypertension In Pregnancy Study (CHIPS; see evidence review A), which included women with chronic or gestational hypertension. There was some very limited evidence of both benefits and harms for different pharmacological interventions. However, as there was not enough evidence to recommend one treatment over another, the committee adopted the choices from the previous guideline and recommended choosing a treatment based on previous treatments, side-effect profiles and the woman's preferences. Labetalol is specifically licensed for use in pregnancy and so is suggested as the first-line option, with nifedipine as the next alternative, and methyldopa as the third option (as it may lead to more side effects and be the least effective option of the 3). There was limited evidence on the benefits and harms of planned early birth compared with expectant management of pregnancy in women with pre-eclampsia, so the committee recommended that decisions about timing of birth should be based on whether the woman and baby are at risk of adverse outcomes if pregnancy is prolonged. These recommendations were based on those from the previous guideline, and expanded based on international guidelines, which were used by the committee in their clinical practice. Based on the data from HYPITAT‑II study, the committee also agreed that pregnancies in women with pre-eclampsia could be managed with continued surveillance to 37 weeks, unless there were specific concerns or indications to offer a planned early birth before then. There was limited evidence to guide the best place of care for women with pre-eclampsia and their babies, so the committee made a research recommendation. ## How the recommendations might affect practice The recommendations are in line with current best clinical practice, so are unlikely to cause a significant change in practice. Currently, some units admit all women with pre-eclampsia routinely, some only admit women who they believe to be at a high risk of complications, and some admit very few. Standardising practice could therefore increase or reduce the number of women who will be admitted, depending on a unit's current practice, but is likely to reduce unwanted variance between units. Return to recommendations # Antihypertensive treatment during the postnatal period, including during breastfeeding Recommendations 1.9.1 to 1.9.7 and 1.9.9 ## Why the committee made the recommendations There was very little evidence on the efficacy and safety of antihypertensive agents in postnatal women, so the committee made recommendations based on the NICE guideline on hypertension in adults, with adaptations based on the potential effects of medicines on the baby. The committee therefore recommended the use of an angiotensin converting enzyme (ACE) inhibitor as first-line treatment, except in women of African or Caribbean family origin, in whom a calcium-channel blocker would be used first line. The choice of second-line medicine was modified from the NICE guideline on hypertension in adults as angiotensin receptor blockers, thiazide and thiazide-like diuretics are not recommended during breastfeeding. Therefore, the committee agreed that beta-blockers should be used as the second-line antihypertensive agent. The committee also agreed that the medicines with once-daily administration should be used wherever possible and for this reason the committee recommended enalapril in preference to captopril (which is taken 3 times daily) and atenolol as an alternative to labetalol (which is taken 2 to 4 times daily). Based on their experience, the committee made recommendations on advice for women who wish to breastfeed while taking antihypertensives, and on the monitoring of babies whose mothers are taking antihypertensives. As there was very little evidence on the effectiveness and safety of antihypertensives for postnatal use, the committee revised the research recommendation made in the 2010 guideline. ## How the recommendations might affect practice There is currently wide variation in practice over use of antihypertensive treatment in the postnatal period, and these recommendations may reduce variation in practice. The recommendations could lead to an increase in the use of atenolol instead of labetalol in the postnatal period. Return to recommendations # Risk of recurrence of hypertensive disorders of pregnancy and long-term cardiovascular disease Recommendations 1.10.1 to 1.10.4 ## Why the committee made the recommendations Long-term follow‑up studies of women who have experienced hypertensive disorders during pregnancy showed an increased risk of long-term cardiovascular disease and a higher prevalence of hypertensive disorders in subsequent pregnancies compared with women unaffected by hypertensive disorders. There was no evidence on which interventions could reduce the risk of recurrence of hypertensive disorders of pregnancy or future cardiovascular disease, so the committee made a research recommendation. ## How the recommendations might affect practice Providing guidance and advice to women on future risks and signposting appropriate care and lifestyle advice may be an additional activity for some healthcare professionals, compared with current practice. Return to recommendations# Context Hypertensive disorders during pregnancy affect around 8% to 10% of all pregnant women and can be associated with substantial complications for the woman and the baby. Women can have hypertension before pregnancy or it can be diagnosed in the first 20 weeks (known as chronic hypertension), new onset of hypertension occurring in the second half of pregnancy (gestational hypertension) or new hypertension with features of multi-organ involvement (pre-eclampsia). Although the proportion of women with pregnancy hypertensive disorders overall appears to have stayed reasonably stable, maternal mortality from hypertensive causes has fallen dramatically: less than 1 woman in every million who gives birth now dies from pre-eclampsia. There is consensus that introduction of the 2010 NICE evidence-based guidelines, together with the findings from the confidential enquiry into maternal deaths, has made a pivotal contribution to this fall in maternal mortality. However, hypertension in pregnancy continues to cause substantial maternal morbidity, stillbirths and neonatal deaths, and perinatal morbidity. Women with hypertension in pregnancy are also at increased risk of cardiovascular disease later in life. Variations in care contribute to inequity in adverse outcomes. Adoption and implementation of evidence-based national guidelines have a central role in reducing this variance and improving care and outcomes across the maternity service. Research that has been done since publication of the previous guideline has addressed areas of uncertainty and highlighted where the recommendations can be updated. A surveillance report from 2017 identified new studies in the following areas: management of pregnancy with chronic hypertension management of pregnancy with gestational hypertension management of pregnancy with pre-eclampsia breastfeeding advice and follow‑up care at transfer to community care. The scope of this update was limited to these sections; it did not include other areas being looked at by other groups (for example, screening strategies for pre-eclampsia, which is being evaluated by the UK National Screening Committee), and did not look into alternative approaches to categorisation of hypertension in pregnancy (for example, looking at treatment for all types of pregnancy hypertension together, rather than within the subdivisions of chronic hypertension, gestational hypertension and pre-eclampsia). This update has also clarified the basis for the current definition of pre-eclampsia, in order to better align with the stated aims of the 2010 guideline to be consistent with those agreed by the International Society for the Study of Hypertension in Pregnancy (ISSHP). The aim of the 2019 guideline is to present updated evidence-based recommendations, relevant to practising clinicians, while identifying outstanding areas of uncertainty that need further research. There is a strong argument for uptake of these new guidelines into clinical practice, in order to minimise unnecessary variance and provide optimal care for women and their babies. In doing this, low rates of maternal mortality should be maintained, and progress on reduction of maternal morbidity and perinatal morbidity and mortality can be pursued.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Reducing the risk of hypertensive disorders in pregnancy\n\n## Symptoms of pre-eclampsia\n\nAdvise pregnant women to see a healthcare professional immediately if they experience symptoms of pre-eclampsia. Symptoms include:\n\nsevere headache\n\nproblems with vision, such as blurring or flashing before the eyes\n\nsevere pain just below the ribs\n\nvomiting\n\nsudden swelling of the face, hands or feet. See the NICE guideline on antenatal care for advice on risk factors and symptoms of pre-eclampsia. [2010, amended 2019]\n\n## Antiplatelet agents\n\nFor the indication in recommendations 1.1.2 and 1.1.3, although its use is common in UK clinical practice, at the time of publication (June 2019), aspirin did not have a UK marketing authorisation. Community pharmacies cannot legally sell aspirin as a pharmacy medicine for prevention of pre-eclampsia in pregnancy in England. Aspirin for this indication must be prescribed. The prescriber should see the summary of product characteristics for the manufacturer's advice on use in pregnancy. See NICE's information on prescribing medicines.\n\nAdvise pregnant women at high risk of pre-eclampsia to take 75\xa0mg to 150\xa0mg of aspirin daily from 12\xa0weeks until the birth of the baby. Women at high risk are those with any of the following:\n\nhypertensive disease during a previous pregnancy\n\nchronic kidney disease\n\nautoimmune disease such as systemic lupus erythematosus or antiphospholipid syndrome\n\ntype\xa01 or type\xa02 diabetes\n\nchronic hypertension. [2010, amended 2019]\n\nAdvise pregnant women with more than 1\xa0moderate risk factor for pre-eclampsia to take 75\xa0mg to 150\xa0mg of aspirin daily from 12\xa0weeks until the birth of the baby. Factors indicating moderate risk are:\n\nnulliparity\n\nage 40\xa0years or older\n\npregnancy interval of more than 10\xa0years\n\nbody mass index (BMI) of 35\xa0kg/m2 or more at first visit\n\nfamily history of pre-eclampsia\n\nmulti-fetal pregnancy. [2010, amended 2019]\n\n## Other pharmaceutical agents\n\nDo not use the following to prevent hypertensive disorders during pregnancy:\n\nnitric oxide donors\n\nprogesterone\n\ndiuretics\n\nlow molecular weight heparin. \n\n## Nutritional supplements\n\nDo not recommend the following supplements solely with the aim of preventing hypertensive disorders during pregnancy:\n\nmagnesium\n\nfolic acid\n\nantioxidants (vitamins\xa0C and\xa0E)\n\nfish oils or algal oils\n\ngarlic. \n\n## Diet\n\nDo not recommend salt restriction during pregnancy solely to prevent gestational hypertension or pre-eclampsia. \n\n## Lifestyle\n\nGive the same advice on rest, exercise and work to women with chronic hypertension or at risk of hypertensive disorders during pregnancy as healthy pregnant women. See the NICE guideline on antenatal care. [2010, amended 2019]\n\n## Diabetes\n\nFor women with pre-existing diabetes or gestational diabetes, see the NICE guideline on diabetes in pregnancy. \n\n# Assessment of proteinuria in hypertensive disorders of pregnancy\n\nInterpret proteinuria measurements for pregnant women in the context of a full clinical review of symptoms, signs and other investigations for pre-eclampsia. \n\nUse an automated reagent-strip reading device for dipstick screening for proteinuria in pregnant women in secondary care settings. \n\nIf dipstick screening is positive (1+ or more), use albumin:creatinine ratio or protein:creatinine ratio to quantify proteinuria in pregnant women. \n\nDo not use first morning urine void to quantify proteinuria in pregnant women. \n\nDo not routinely use 24‑hour urine collection to quantify proteinuria in pregnant women. \n\nIf using protein:creatinine ratio to quantify proteinuria in pregnant women:\n\nuse 30\xa0mg/mmol as a threshold for significant proteinuria\n\nif the result is 30\xa0mg/mmol or above and there is still uncertainty about the diagnosis of pre-eclampsia, consider re‑testing on a new sample, alongside clinical review. \n\nIf using albumin:creatinine ratio as an alternative to protein:creatinine ratio to diagnose pre-eclampsia in pregnant women with hypertension:\n\nuse 8\xa0mg/mmol as a diagnostic threshold\n\nif the result is 8\xa0mg/mmol or above and there is still uncertainty about the diagnosis of pre-eclampsia, consider re‑testing on a new sample, alongside clinical review. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessment of proteinuria\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: assessment of proteinuria.\n\nLoading. Please wait.\n\n# Management of chronic hypertension in pregnancy\n\n## Pre-pregnancy advice\n\nOffer women with chronic hypertension referral to a specialist in hypertensive disorders of pregnancy to discuss the risks and benefits of treatment. [2010, amended 2019]\n\nAdvise women who take angiotensin-converting enzyme (ACE) inhibitors or angiotensin\xa0II receptor blockers (ARBs):\n\nthat there is an increased risk of congenital abnormalities if these drugs are taken during pregnancy\n\nto discuss alternative antihypertensive treatment with the healthcare professional responsible for managing their hypertension, if they are planning pregnancy\n\nto discuss alternative treatment with the healthcare professional responsible for managing their condition, if ACE inhibitors or ARBs are being taken for other conditions such as renal disease. [2010, amended 2019]In 2014, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update on\xa0ACE inhibitors and angiotensin\xa0II receptor antagonists: not for use in pregnancy, which states 'Use in women who are planning pregnancy should be avoided unless absolutely necessary, in which case the potential risks and benefits should be discussed'.\n\nStop antihypertensive treatment in women taking ACE inhibitors or ARBs if they become pregnant (preferably within 2\xa0working days of notification of pregnancy) and offer alternatives. \n\nAdvise women who take thiazide or thiazide-like diuretics:\n\nthat there may be an increased risk of congenital abnormalities and neonatal complications if these drugs are taken during pregnancy\n\nto discuss alternative antihypertensive treatment with the healthcare professional responsible for managing their hypertension, if they are planning pregnancy. [2010, amended 2019]\n\nAdvise women who take antihypertensive treatments other than ACE inhibitors, ARBs, thiazide or thiazide-like diuretics that the limited evidence available has not shown an increased risk of congenital malformation with such treatments. [2010, amended 2019]\n\n## Treatment of chronic hypertension\n\nOffer pregnant women with chronic hypertension advice on:\n\nweight management\n\nexercise\n\nhealthy eating\n\nlowering the amount of salt in their diet. Provide this advice in line with the NICE guideline on hypertension in adults. \n\nContinue with existing antihypertensive treatment if safe in pregnancy, or switch to an alternative treatment, unless:\n\nsustained systolic blood pressure is less than 110\xa0mmHg or\n\nsustained diastolic blood pressure is less than 70\xa0mmHg or\n\nthe woman has symptomatic hypotension. \n\nOffer antihypertensive treatment to pregnant women who have chronic hypertension and who are not already on treatment if they have:\n\nsustained systolic blood pressure of 140\xa0mmHg or higher or\n\nsustained diastolic blood pressure of 90\xa0mmHg or higher. \n\nWhen using medicines to treat hypertension in pregnancy, aim for a target blood pressure of 135/85\xa0mmHg. \n\nConsider labetalol to treat chronic hypertension in pregnant women. Consider nifedipine for women in whom labetalol is not suitable, or methyldopa if both labetalol and nifedipine are not suitable. Base the choice on any pre-existing treatment, side-effect profiles, risks (including fetal effects) and the woman's preference. At the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines.\n\nOffer pregnant women with chronic hypertension aspirin 75\xa0mg to 150\xa0mg once daily from 12\xa0weeks. Although its use is common in UK clinical practice, at the time of publication (June 2019), aspirin did not have a UK marketing authorisation for this indication. Community pharmacies cannot legally sell aspirin as a pharmacy medicine for prevention of pre-eclampsia in pregnancy in England. Aspirin for this indication must be prescribed. The prescriber should see the summary of product characteristics for the manufacturer's advice on use in pregnancy. See NICE's information on prescribing medicines.\n\nOffer placental growth factor (PLGF)-based testing to help rule out pre-eclampsia between 20\xa0weeks and 36\xa0weeks and 6\xa0days of pregnancy, if women with chronic hypertension are suspected of developing pre-eclampsia. (See the NICE diagnostics guidance on PLGF-based testing to help diagnose suspected preterm pre-eclampsia). [2019, amended 2023]\n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on treatment of chronic hypertension\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: interventions for chronic hypertension.\n\nLoading. Please wait.\n\n## Antenatal appointments\n\nIn women with chronic hypertension, schedule additional antenatal appointments based on the individual needs of the woman and her baby. This may include:\n\nweekly appointments if hypertension is poorly controlled\n\nappointments every 2\xa0to\xa04\xa0weeks if hypertension is well-controlled. [2010, amended 2019]\n\n## Timing of birth\n\nDo not offer planned early birth before 37\xa0weeks to women with chronic hypertension whose blood pressure is lower than 160/110\xa0mmHg, with or without antihypertensive treatment, unless there are other medical indications. [2010, amended 2019]\n\nFor women with chronic hypertension whose blood pressure is lower than 160/110\xa0mmHg after 37\xa0weeks, with or without antihypertensive treatment, timing of birth and maternal and fetal indications for birth should be agreed between the woman and the senior obstetrician. \n\nIf planned early birth is necessary (see recommendation\xa01.5.7 in the section on timing of birth), offer a course of antenatal corticosteroids and magnesium sulfate if indicated, in line with the NICE guideline on preterm labour and birth. [2010, amended 2019]\n\n## Postnatal investigation, monitoring and treatment\n\nIn women with chronic hypertension who have given birth, measure blood pressure:\n\ndaily for the first 2\xa0days after birth\n\nat least once between day\xa03 and day\xa05 after birth\n\nas clinically indicated if antihypertensive treatment is changed after birth. \n\nIn women with chronic hypertension who have given birth:\n\naim to keep blood pressure lower than 140/90\xa0mmHg\n\ncontinue antihypertensive treatment, if required (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding)\n\noffer a review of antihypertensive treatment 2\xa0weeks after the birth, with their GP or specialist. [2010, amended 2019]\n\nIf a woman has taken methyldopa to treat chronic hypertension during pregnancy, stop within 2\xa0days after the birth and change to an alternative antihypertensive treatment (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding). [2010, amended 2019]\n\nOffer women with chronic hypertension a medical review 6\xa0to 8\xa0weeks after the birth with their GP or specialist as appropriate. [2010, amended 2019]\n\n# Management of gestational hypertension\n\n## Assessment and treatment of gestational hypertension\n\nIn women with gestational hypertension, a full assessment should be carried out in a secondary care setting by a healthcare professional who is trained in the management of hypertensive disorders of pregnancy. [2010, amended 2019]\n\nIn women with gestational hypertension, take account of the following risk factors that require additional assessment and follow‑up:\n\nnulliparity\n\nage 40\xa0years or older\n\npregnancy interval of more than 10\xa0years\n\nfamily history of pre-eclampsia\n\nmulti-fetal pregnancy\n\nBMI of 35\xa0kg/m2 or more\n\ngestational age at presentation\n\nprevious history of pre-eclampsia or gestational hypertension\n\npre-existing vascular disease\n\npre-existing kidney disease. \n\nOffer women with gestational hypertension the tests and treatment listed in table\xa01. \n\nManagement\n\nHypertension:\n\nblood pressure (BP) of 140/90 to 159/109\xa0mmHg\n\nSevere hypertension:\n\nblood pressure of 160/110\xa0mmHg or more\n\nAdmission to hospital\n\nDo not routinely admit to hospital\n\nAdmit, but if BP falls below 160/110\xa0mmHg, then manage as for hypertension\n\nAntihypertensive pharmacological treatment\n\nOffer pharmacological treatment if BP remains above 140/90\xa0mmHg\n\nOffer pharmacological treatment to all women\n\nTarget blood pressure once on antihypertensive treatment\n\nAim for BP of 135/85\xa0mmHg or less\n\nAim for BP of 135/85\xa0mmHg or less\n\nBlood pressure measurement\n\nOnce or twice a week (depending on BP) until BP is 135/85\xa0mmHg or less\n\nEvery 15 to 30\xa0minutes until BP is less than 160/110\xa0mmHg\n\nDipstick proteinuria testing\n\n(Use an automated reagent-strip reading device for dipstick screening for proteinuria in a secondary care setting)\n\nOnce or twice a week (with BP measurement)\n\nDaily while admitted\n\nBlood tests\n\nMeasure full blood count, liver function and renal function at presentation and then weekly\n\nMeasure full blood count, liver function and renal function at presentation and then weekly\n\nPlacental growth factor (PLGF)-based testing\n\nCarry out PLGF-based testing on 1\xa0occasion (in accordance with NICE guidance, see recommendation 1.4.4) if there is suspicion of pre-eclampsia\n\nCarry out PLGF-based testing on 1\xa0occasion (in accordance with NICE guidance, see recommendation 1.4.4) if there is suspicion of pre-eclampsia\n\nFetal assessment\n\nOffer fetal heart auscultation at every antenatal appointment\n\nCarry out ultrasound assessment of the fetus at diagnosis and, if normal, repeat every 2\xa0to 4\xa0weeks, if clinically indicated\n\nCarry out a cardiotocography (CTG) only if clinically indicated\n\n(For advice, see the section on fetal monitoring)\n\nOffer fetal heart auscultation at every antenatal appointment\n\nCarry out ultrasound assessment of the fetus at diagnosis and, if normal, repeat every 2\xa0weeks, if severe hypertension persists\n\nCarry out a CTG at diagnosis and then only if clinically indicated\n\n(For advice, see the section on fetal monitoring\n\nOffer placental growth factor (PLGF)-based testing to help rule out pre-eclampsia in women presenting with suspected pre-eclampsia (for example, with gestational hypertension) between 20\xa0weeks and 36 weeks and 6\xa0days of pregnancy. (See the NICE diagnostics guidance on PLGF-based testing to help diagnose suspected preterm pre-eclampsia.) [2019, amended 2023]\n\nConsider labetalol to treat gestational hypertension. Consider nifedipine for women in whom labetalol is not suitable, and methyldopa if labetalol or nifedipine are not suitable. Base the choice on side-effect profiles, risk (including fetal effects) and the woman's preferences. [2010, amended 2019]At the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines.\n\nDo not offer bed rest in hospital as a treatment for gestational hypertension. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on monitoring and treatment of gestational hypertension\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: monitoring gestational hypertension.\n\nLoading. Please wait.\n\n## Timing of birth\n\nDo not offer planned early birth before 37\xa0weeks to women with gestational hypertension whose blood pressure is lower than 160/110\xa0mmHg, unless there are other medical indications. [2010, amended 2019]\n\nFor women with gestational hypertension whose blood pressure is lower than 160/110\xa0mmHg after 37\xa0weeks, timing of birth, and maternal and fetal indications for birth should be agreed between the woman and the senior obstetrician. [2010, amended 2019]\n\nIf planned early birth is necessary (see recommendation\xa01.5.7 in the section on timing of birth), offer a course of antenatal corticosteroids and magnesium sulfate if indicated, in line with the NICE guideline on preterm labour and birth. [2010, amended 2019]\n\n## Postnatal investigation, monitoring and treatment\n\nIn women with gestational hypertension who have given birth, measure blood pressure:\n\ndaily for the first 2\xa0days after birth\n\nat least once between day\xa03 and day\xa05 after birth\n\nas clinically indicated if antihypertensive treatment is changed after birth. \n\nIn women with gestational hypertension who have given birth:\n\ncontinue antihypertensive treatment if required (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding)\n\nadvise women that the duration of their postnatal antihypertensive treatment will usually be similar to the duration of their antenatal treatment (but may be longer)\n\nreduce antihypertensive treatment if their blood pressure falls below 130/80\xa0mmHg. [2010, amended 2019]\n\nIf a woman has taken methyldopa to treat gestational hypertension, stop within 2\xa0days after the birth and change to an alternative treatment if necessary (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding). [2010, amended 2019]\n\nFor women with gestational hypertension who did not take antihypertensive treatment and have given birth, start antihypertensive treatment if their blood pressure is 150/100\xa0mmHg or higher. [2010, amended 2019]\n\nWrite a care plan for women with gestational hypertension who have given birth and are being transferred to community care that includes all of the following:\n\nwho will provide follow‑up care, including medical review if needed\n\nfrequency of blood pressure monitoring needed\n\nthresholds for reducing or stopping treatment\n\nindications for referral to primary care for blood pressure review. \n\nOffer women who have had gestational hypertension and who remain on antihypertensive treatment, a medical review with their GP or specialist 2\xa0weeks after transfer to community care. [2010, amended 2019]\n\nOffer all women who have had gestational hypertension a medical review with their GP or specialist 6\xa0to 8\xa0weeks after the birth. [2010, amended 2019]\n\n# Management of pre-eclampsia\n\n## Assessing pre-eclampsia\n\nAssessment of women with pre-eclampsia should be performed by a healthcare professional trained in the management of hypertensive disorders of pregnancy. [2010, amended 2019]\n\nCarry out a full clinical assessment at each antenatal appointment for women with pre-eclampsia, and offer admission to hospital for surveillance and any interventions needed if there are concerns for the wellbeing of the woman or baby. Concerns could include any of the following:\n\nsustained systolic blood pressure of 160\xa0mmHg or higher\n\nany maternal biochemical or haematological investigations that cause concern, for example, a new and persistent:\n\n\n\nrise in creatinine (90\xa0micromol/litre or more, 1\xa0mg/100\xa0ml or more) or\n\nrise in alanine transaminase (over 70\xa0IU/litre, or twice upper limit of normal range) or\n\nfall in platelet count (under 150,000/microlitre)\n\n\n\nsigns of impending eclampsia\n\nsigns of impending pulmonary oedema\n\nother signs of severe pre-eclampsia\n\nsuspected fetal compromise\n\nany other clinical signs that cause concern. \n\nConsider using either the fullPIERS or PREP-S validated risk prediction models to help guide decisions about the most appropriate place of care (such as the need for in\xa0utero\xa0transfer) and thresholds for intervention. \n\nWhen using a risk prediction model, take into account that:\n\nfullPIERS is intended for use at any time during pregnancy\n\nPREP-S is intended for use only up to 34\xa0weeks of pregnancy\n\nfullPIERS and PREP‑S models do not predict outcomes for babies. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessment of women with pre-eclampsia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: prediction of complications in pre-eclampsia.\n\nLoading. Please wait.\n\n## Treatment of pre-eclampsia\n\nOffer women with pre-eclampsia the tests and treatments listed in table\xa02. \n\nManagement\n\nHypertension:\n\nblood pressure (BP) of 140/90 to 159/109\xa0mmHg\n\nSevere hypertension:\n\nblood pressure of 160/110\xa0mmHg or more\n\nAdmission to hospital\n\nAdmit if any clinical concerns for the wellbeing of the woman or baby (see recommendation 1.5.2) or if high risk of adverse events suggested by the fullPIERS or PREP‑S risk prediction models\n\nAdmit, but if BP falls below 160/110\xa0mmHg, then manage as for hypertension\n\nAntihypertensive pharmacological treatment\n\nOffer pharmacological treatment if BP remains above 140/90\xa0mmHg\n\nOffer pharmacological treatment to all women\n\nTarget blood pressure once on antihypertensive treatment\n\nAim for BP of 135/85\xa0mmHg or less\n\nAim for BP of 135/85\xa0mmHg or less\n\nBlood pressure measurement\n\nAt least every 48\xa0hours, and more frequently if the woman is admitted to hospital\n\nEvery 15 to 30\xa0minutes until BP is less than 160/110\xa0mmHg, then at least 4\xa0times daily while the woman is an inpatient, depending on clinical circumstances\n\nDipstick proteinuria testing\n\n(Use an automated reagent-strip reading device for dipstick screening for proteinuria in a secondary care setting)\n\nOnly repeat if clinically indicated, for example, if new symptoms and signs develop or if there is uncertainty over diagnosis\n\nOnly repeat if clinically indicated, for example, if new symptoms and signs develop or if there is uncertainty over diagnosis\n\nBlood tests\n\nMeasure full blood count, liver function and renal function twice a week\n\nMeasure full blood count, liver function and renal function 3\xa0times a week\n\nFetal assessment\n\nOffer fetal heart auscultation at every antenatal appointment\n\nCarry out ultrasound assessment of the fetus at diagnosis and, if normal, repeat every 2\xa0weeks\n\nCarry out a cardiotocography (CTG) at diagnosis and then only if clinically indicated\n\n(For advice, see the section on fetal monitoring)\n\nOffer fetal heart auscultation at every antenatal appointment\n\nCarry out ultrasound assessment of the fetus at diagnosis and, if normal, repeat every 2\xa0weeks\n\nCarry out a CTG at diagnosis and then only if clinically indicated\n\n(For advice, see the section on fetal monitoring)\n\nOffer labetalol to treat hypertension in pregnant women with pre-eclampsia. Offer nifedipine for women in whom labetalol is not suitable, and methyldopa if labetalol or nifedipine are not suitable. Base the choice on any pre-existing treatment, side-effect profiles, risks (including fetal effects) and the woman's preference. [2010, amended 2019]At the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines.\n\n## Timing of birth\n\nRecord maternal and fetal thresholds for planned early birth before 37\xa0weeks in women with pre-eclampsia. Thresholds for considering planned early birth could include (but are not limited to) any of the following known features of severe pre-eclampsia:\n\ninability to control maternal blood pressure despite using 3\xa0or more classes of antihypertensives in appropriate doses\n\nmaternal pulse oximetry less than 90%\n\nprogressive deterioration in liver function, renal function, haemolysis, or platelet count\n\nongoing neurological features, such as severe intractable headache, repeated visual scotomata, or eclampsia\n\nplacental abruption\n\nreversed end-diastolic flow in the umbilical artery doppler velocimetry, a non-reassuring cardiotocograph, or stillbirth. Other features not listed above may also be considered in the decision to plan early birth. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nInvolve a senior obstetrician in any decisions on timing of birth for women with pre-eclampsia. [2010, amended 2019]\n\nDiscuss with the anaesthetic team if birth is planned in a woman with pre-eclampsia. [2010, amended 2019]\n\nDiscuss with the neonatal team if birth is planned in a woman with pre-eclampsia, and neonatal complications are anticipated. [2010, amended 2019]\n\nOffer intravenous magnesium sulfate and a course of antenatal corticosteroids if indicated, if early birth is planned for women with preterm pre-eclampsia, in line with the NICE guideline on preterm labour and birth. [2010, amended 2019]\n\nDecide on timing of birth in women with pre-eclampsia as recommended in table\xa03. \n\nWeeks of pregnancy\n\nTiming of birth\n\nBefore 34\xa0weeks\n\nContinue surveillance unless there are indications (see recommendation\xa01.5.7 in the section on timing of birth) for planned early birth. Offer intravenous magnesium sulfate and a course of antenatal corticosteroids in line with the NICE guideline on preterm labour and birth.\n\nFrom 34 weeks to 36 weeks plus 6 days\n\nContinue surveillance unless there are indications (see recommendation\xa01.5.7 in the section on timing of birth) for planned early birth.\n\nWhen considering the option of planned early birth, take into account the woman's and baby's condition, risk factors (such as maternal comorbidities, multi-fetal pregnancy) and availability of neonatal unit beds. Consider a course of antenatal corticosteroids in line with the NICE guideline on preterm labour and birth.\n\nweeks onwards\n\nInitiate birth within 24 to 48\xa0hours.\n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on monitoring and treatment of pre-eclampsia and timing of birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: interventions for pre-eclampsia.\n\nLoading. Please wait.\n\n## Postnatal investigation, monitoring and treatment (including after discharge from critical care)\n\nIn women with pre-eclampsia who did not take antihypertensive treatment and have given birth, measure blood pressure:\n\nat least 4\xa0times a day while the woman is an inpatient\n\nat least once between day\xa03 and day\xa05 after birth\n\non alternate days until normal, if blood pressure was abnormal on days\xa03\xa0to\xa05. \n\nIn women with pre-eclampsia who did not take antihypertensive treatment and have given birth, start antihypertensive treatment if blood pressure is 150/100\xa0mmHg or higher. \n\nAsk women with pre-eclampsia who have given birth about severe headache and epigastric pain each time blood pressure is measured. \n\nIn women with pre-eclampsia who took antihypertensive treatment and have given birth, measure blood pressure:\n\nat least 4\xa0times a day while the woman is an inpatient\n\nevery 1 to 2\xa0days for up to 2\xa0weeks after transfer to community care until the woman is off treatment and has no hypertension. \n\nFor women with pre-eclampsia who have taken antihypertensive treatment and have given birth:\n\ncontinue antihypertensive treatment (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding)\n\nconsider reducing antihypertensive treatment if their blood pressure falls below 140/90\xa0mmHg\n\nreduce antihypertensive treatment if their blood pressure falls below 130/80\xa0mmHg. [2010, amended 2019]\n\nIf a woman has taken methyldopa to treat pre-eclampsia, stop within 2\xa0days after the birth and change to an alternative treatment if necessary (for choice of antihypertensive during the postnatal period, see the section on antihypertensive treatment during the postnatal period, including during breastfeeding). [2010, amended 2019]\n\nOffer women with pre-eclampsia who have given birth transfer to community care if all of the following criteria have been met:\n\nthere are no symptoms of pre-eclampsia\n\nblood pressure, with or without treatment, is 150/100\xa0mmHg or less\n\nblood test results are stable or improving. [2010, amended 2019]\n\nWrite a care plan for women with pre-eclampsia who have given birth and are being transferred to community care that includes all of the following:\n\nwho will provide follow‑up care, including medical review if needed\n\nfrequency of blood pressure monitoring\n\nthresholds for reducing or stopping treatment\n\nindications for referral to primary care for blood pressure review\n\nself-monitoring for symptoms. \n\nOffer women who have had pre-eclampsia and who remain on antihypertensive treatment, a medical review with their GP or specialist 2\xa0weeks after transfer to community care. [2010, amended 2019]\n\nOffer all women who have had pre-eclampsia a medical review with their GP or specialist 6\xa0to 8\xa0weeks after the birth. [2010, amended 2019]\n\nIn women who have pre-eclampsia with mild or moderate hypertension, or after step-down from critical care:\n\nmeasure platelet count, transaminases and serum creatinine 48\xa0to 72\xa0hours after birth or step-down\n\ndo not repeat platelet count, transaminases or serum creatinine measurements if results are normal at 48\xa0to 72\xa0hours. \n\nIf biochemical and haematological indices are outside the reference range in women with pre-eclampsia who have given birth, repeat platelet count, transaminases and serum creatinine measurements as clinically indicated until results return to normal. [2010, amended 2019]\n\nIn women with pre-eclampsia who have given birth, carry out a urinary reagent-strip test 6\xa0to 8\xa0weeks after the birth. \n\nOffer women who had pre-eclampsia and still have proteinuria (1+ or more) at 6\xa0to 8\xa0weeks after the birth, a further review with their GP or specialist at 3\xa0months after the birth to assess kidney function. [2010, amended 2019]\n\nConsider referring women with an abnormal kidney function assessment at 3\xa0months for a specialist kidney assessment in line with the NICE guideline on chronic kidney disease. [2010, amended 2019]\n\n# Fetal monitoring\n\n## Fetal monitoring in chronic hypertension\n\nIn women with chronic hypertension, carry out an ultrasound for fetal growth and amniotic fluid volume assessment, and umbilical artery doppler velocimetry at 28\xa0weeks, 32\xa0weeks and 36\xa0weeks. [2010, amended 2019]\n\nIn women with chronic hypertension, only carry out cardiotocography if clinically indicated. [2010, amended 2019]\n\n## Fetal monitoring in gestational hypertension\n\nIn women with gestational hypertension, carry out an ultrasound for fetal growth and amniotic fluid volume assessment and umbilical artery doppler velocimetry at diagnosis and if normal repeat every 2\xa0to\xa04\xa0weeks, if clinically indicated. [2010, amended 2019]\n\nIn women with gestational hypertension, only carry out cardiotocography if clinically indicated. [2010, amended 2019]\n\n## Fetal monitoring in pre-eclampsia or severe gestational hypertension\n\nCarry out cardiotocography at diagnosis of pre-eclampsia or severe gestational hypertension. \n\nIf conservative management of pre-eclampsia or severe gestational hypertension is planned, carry out all the following tests at diagnosis:\n\nultrasound for fetal growth and amniotic fluid volume assessment\n\numbilical artery doppler velocimetry. \n\nIf the results of all fetal monitoring are normal in women with pre-eclampsia or severe gestational hypertension, do not routinely repeat cardiotocography unless clinically indicated. [2010, amended 2019]\n\nIn women with pre-eclampsia or severe gestational hypertension, repeat cardiotocography if any of the following occur:\n\nthe woman reports a change in fetal movement\n\nvaginal bleeding\n\nabdominal pain\n\ndeterioration in maternal condition. \n\nIn women with pre-eclampsia or severe gestational hypertension, repeat ultrasound for fetal growth and amniotic fluid volume assessment or umbilical artery doppler velocimetry every 2\xa0weeks, with subsequent surveillance and monitoring determined by the findings of these scans. [2010, amended 2019]\n\nFor women with pre-eclampsia or severe gestational hypertension, write a care plan that includes all of the following:\n\nthe timing and nature of future fetal monitoring\n\nfetal indications for birth and if and when antenatal corticosteroids should be given\n\nplans for discussion with neonatal paediatricians and obstetric anaesthetists. [2010, amended 2019]\n\n## Women who need additional fetal monitoring\n\nCarry out an ultrasound for fetal growth and amniotic fluid volume assessment and umbilical artery doppler velocimetry starting at between 28\xa0and 30\xa0weeks (or at least 2\xa0weeks before previous gestational age of onset if earlier than 28\xa0weeks) and repeating 4\xa0weeks later in women with previous:\n\nsevere pre-eclampsia\n\npre-eclampsia that resulted in birth before 34\xa0weeks\n\npre-eclampsia with a baby whose birth weight was less than the 10th\xa0centile\n\nintrauterine death\n\nplacental abruption. \n\nIn women who need additional fetal monitoring (see recommendation 1.6.11), carry out cardiotocography only if clinically indicated. [2010, amended 2019]\n\n# Intrapartum care\n\nGive advice and treatment to women with hypertensive disorders of pregnancy in line with the NICE guideline on intrapartum care, unless there are recommendations in this guideline on the same topic. Offer care in accordance with the NICE guideline on intrapartum care for women with hypertension whether treated or untreated, and not just on the basis of blood pressure in labour. [2010, amended 2019]\n\nGive women with chronic hypertension advice and care in line with the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies. \n\n## Blood pressure\n\nDuring labour, measure blood pressure:\n\nhourly, in women with hypertension\n\nevery 15 to 30\xa0minutes until blood pressure is less than 160/110\xa0mmHg in women with severe hypertension. [2010, amended 2019]\n\nContinue use of antenatal antihypertensive treatment during labour. \n\n## Haematological and biochemical monitoring\n\nDetermine the need for haematological and biochemical tests during labour in women with hypertension using the same criteria as in the antenatal period even if regional analgesia is being considered. \n\n## Care during epidural analgesia\n\nDo not preload women who have severe pre-eclampsia with intravenous fluids before establishing low-dose epidural analgesia or combined spinal epidural analgesia. [2010, amended 2019]\n\n## Management of second stage of labour\n\nDo not routinely limit the duration of the second stage of labour in women with controlled hypertension. [2010, amended 2019]\n\nConsider operative or assisted birth in the second stage of labour for women with severe hypertension whose hypertension has not responded to initial treatment. [2010, amended 2019]\n\n# Medical management of severe hypertension, severe pre-eclampsia or eclampsia in a critical care setting\n\n## Anticonvulsants\n\nIf a woman in a critical care setting who has severe hypertension or severe pre-eclampsia has or previously had an eclamptic fit, give intravenous magnesium sulfate. \n\nConsider giving intravenous magnesium sulfate to women with severe pre-eclampsia who are in a critical care setting if birth is planned within 24\xa0hours. \n\nConsider the need for magnesium sulfate treatment, if 1\xa0or more of the following features of severe pre-eclampsia is present:\n\nongoing or recurring severe headaches\n\nvisual scotomata\n\nnausea or vomiting\n\nepigastric pain\n\noliguria and severe hypertension\n\nprogressive deterioration in laboratory blood tests (such as rising creatinine or liver transaminases, or falling platelet count). [2010, amended 2019]\n\nUse the Collaborative Eclampsia Trial regimen for administration of magnesium sulfate:\n\nA loading dose of 4\xa0g should be given intravenously over 5\xa0to\xa015\xa0minutes, followed by an infusion of 1\xa0g/hour maintained for 24\xa0hours. If the woman has had an eclamptic fit, the infusion should be continued for 24\xa0hours after the last fit.\n\nRecurrent fits should be treated with a further dose of 2\xa0g to 4\xa0g given intravenously over 5\xa0to\xa015\xa0minutes. [2010, amended 2019]The MHRA has issued a warning about the\xa0risk of skeletal adverse effects in the neonate following prolonged or repeated use of magnesium sulfate in pregnancy. Maternal administration of magnesium sulfate for longer than 5\xa0to 7\xa0days in pregnancy has been associated with skeletal adverse effects and hypocalcaemia and hypermagnesemia in neonates. If use of magnesium sulfate in pregnancy is prolonged or repeated, consider monitoring of neonates for abnormal calcium and magnesium levels and skeletal adverse effects.\n\nDo not use diazepam, phenytoin or other anticonvulsants as an alternative to magnesium sulfate in women with eclampsia. [2010, amended 2019]\n\n## Antihypertensives\n\nTreat women with severe hypertension who are in critical care during pregnancy or after birth immediately with 1\xa0of the following:\n\nlabetalol (oral or intravenous)\n\noral nifedipine\n\nintravenous hydralazine. [2010, amended 2019]At the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details. See NICE's information on prescribing medicines.\n\nIn women with severe hypertension who are in critical care, monitor their response to treatment:\n\nto ensure that their blood pressure falls\n\nto identify adverse effects for both the woman and the baby\n\nto modify treatment according to response. \n\nConsider using up to 500\xa0ml crystalloid fluid before or at the same time as the first dose of intravenous hydralazine in the antenatal period. \n\n## Corticosteroids for fetal lung maturation\n\nIf early birth is considered likely within 7\xa0days in women with pre-eclampsia, offer a course of antenatal corticosteroids in line with the NICE guideline on preterm labour and birth. [2010, amended 2019]\n\n## Corticosteroids to manage HELLP syndrome\n\nDo not use dexamethasone or betamethasone for the treatment of HELLP syndrome. \n\n## Fluid balance and volume expansion\n\nDo not use volume expansion in women with severe pre-eclampsia unless hydralazine is the antenatal antihypertensive. \n\nIn women with severe pre-eclampsia, limit maintenance fluids to 80\xa0ml/hour unless there are other ongoing fluid losses (for example, haemorrhage). \n\n## Caesarean section versus induction of labour\n\nChoose mode of birth for women with severe hypertension, severe pre-eclampsia or eclampsia according to the clinical circumstances and the woman's preference. \n\n## Referral to critical care\n\nRefer women with severe hypertension or severe pre-eclampsia to the appropriate critical care setting using the criteria in table\xa04. \n\nCritical\xa0care\xa0level\n\nClinical criteria\n\nLevel 3 care\n\nSevere pre-eclampsia and needing ventilation\n\nLevel 2 care\n\nStep-down from level\xa03 or severe pre-eclampsia with any of the following complications:\n\neclampsia\n\nHELLP syndrome\n\nhaemorrhage\n\nhyperkalaemia\n\nsevere oliguria\n\ncoagulation support\n\nintravenous antihypertensive treatment\n\ninitial stabilisation of severe hypertension\n\nevidence of cardiac failure\n\nabnormal neurology\n\nLevel 1 care\n\nPre-eclampsia with hypertension\n\nOngoing conservative antenatal management of severe preterm hypertension\n\nStep-down treatment after the birth\n\n# Antihypertensive treatment during the postnatal period, including during breastfeeding\n\nFor the indications in recommendations 1.9.4, 1.9.6 and 1.9.8, in 2009, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update on ACE inhibitors and angiotensin II receptor antagonists: recommendations on how to use during breastfeeding, and a subsequent clarification was issued in 2014 stating that 'although ACE inhibitors and angiotensin\xa0II receptor antagonists are generally not recommended for use by breastfeeding mothers, they are not absolutely contraindicated. Healthcare professionals may prescribe these medicines during breastfeeding if they consider that this treatment is essential for the lactating mother. In mothers who are breastfeeding older infants, the use of captopril, enalapril, or quinapril may be considered if an ACE inhibitor is necessary for the mother. Careful follow-up of the infant for possible signs of hypotension is recommended'.\n\nFor the indications in recommendations 1.9.5 and 1.9.6, at the time of publication (June 2019), some brands of nifedipine were specifically contraindicated during pregnancy by the manufacturer in its summary of product characteristics. Refer to the individual summaries of product characteristics for each preparation of nifedipine for further details.\n\nSee NICE's information on prescribing medicines.\n\nAdvise women with hypertension who wish to breastfeed that their treatment can be adapted to accommodate breastfeeding, and that the need to take antihypertensive medication does not prevent them from breastfeeding. \n\nExplain to women with hypertension who wish to breastfeed that:\n\nantihypertensive medicines can pass into breast milk\n\nmost antihypertensive medicines taken while breastfeeding only lead to very low levels in breast milk, so the amounts taken in by babies are very small and would be unlikely to have any clinical effect\n\nmost medicines are not tested in pregnant or breastfeeding women, so disclaimers in the manufacturer's information are not because of any specific safety concerns or evidence of harm.Make decisions on treatment together with the woman, based on her preferences. \n\nAs antihypertensive agents have the potential to transfer into breast milk:\n\nconsider monitoring the blood pressure of babies, especially those born preterm, who have symptoms of low blood pressure for the first few weeks\n\nwhen discharged home, advise women to monitor their babies for drowsiness, lethargy, pallor, cold peripheries or poor feeding. \n\nOffer enalapril to treat hypertension in women during the postnatal period, with appropriate monitoring of maternal renal function and maternal serum potassium. \n\nFor women of black African or Caribbean family origin with hypertension during the postnatal period, consider antihypertensive treatment with:\n\nnifedipine\xa0or\n\namlodipine if the woman has previously used this to successfully control her blood pressure. \n\nFor women with hypertension in the postnatal period, if blood pressure is not controlled with a single medicine, consider a combination of nifedipine (or amlodipine) and enalapril. If this combination is not tolerated or is ineffective, consider either:\n\nadding atenolol or labetalol to the combination treatment or\n\nswapping 1\xa0of the medicines already being used for atenolol or labetalol. \n\nWhen treating women with antihypertensive medication during the postnatal period, use medicines that are taken once daily when possible. \n\nWhere possible, avoid using diuretics or angiotensin receptor blockers to treat hypertension in women in the postnatal period who are breastfeeding or expressing milk. [2010, amended 2019]\n\nTreat women with hypertension in the postnatal period who are not breastfeeding and who are not planning to breastfeed in line with the NICE guideline on hypertension in adults. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on antihypertensive treatment during breastfeeding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: postnatal management of hypertension.\n\nLoading. Please wait.\n\n# Advice and follow-up at transfer to community care\n\n## Risk of recurrence of hypertensive disorders of pregnancy\n\nAdvise women with hypertensive disorders of pregnancy that the overall risk of recurrence in future pregnancies is approximately 1\xa0in\xa05 (see table\xa05). \n\nPrevalence of hypertensive disorder in a future pregnancy\n\nAny hypertension in previous or current pregnancy\n\nPre-eclampsia in previous or current pregnancy\n\nGestational hypertension in previous or current pregnancy\n\nAny hypertension\n\nApproximately 21% (1 in 5 women)\n\nApproximately 20%\n\n(1 in 5 women)\n\nApproximately 22% (1 in 5 women)\n\nPre-eclampsia\n\nApproximately 14% (1 in 7 women)\n\nUp to approximately 16% (1 in 6 women)\n\n\n\nIf birth was at 28 to 34 weeks: approximately 33% (1 in 3 women)\n\n(No evidence was identified for women who gave birth at less than 28 weeks, but the committee agreed that the risk was likely to be at least as high, if not higher, than that for women who gave birth between 28 and 34 weeks)\n\n\n\nIf birth was at 34 to 37 weeks: approximately 23% (1 in 4 women)\n\nApproximately 7% (1 in 14 women)\n\nGestational hypertension\n\nApproximately 9%\n\n(1 in 11 women)\n\nBetween approximately 6 and 12% (up to 1 in 8 women)\n\nBetween approximately 11% and 15% (up to 1 in 7 women)\n\nChronic hypertension\n\nNot applicable\n\nApproximately 2% (up to 1 in 50 women)\n\nApproximately 3% (up to 1 in 34 women)\n\n## Long-term risk of cardiovascular disease\n\nAdvise women who have had a hypertensive disorder of pregnancy that this is associated with an increased risk of hypertension and cardiovascular disease in later life (see table\xa06). \n\nRisk of future cardiovascular disease\n\nAny hypertension in current or previous pregnancy\n\nPre-eclampsia in current or previous pregnancy\n\nGestational hypertension in current or previous pregnancy\n\nChronic hypertension in current or previous pregnancy\n\nMajor adverse cardiovascular event\n\nRisk increased\n\n(up to approximately 2 times)\n\nRisk increased\n\n(approximately 1.5 to 3 times)\n\nRisk increased\n\n(approximately 1.5 to 3 times)\n\nRisk increased\n\n(approximately 1.7 times)\n\nCardiovascular mortality\n\nRisk increased\n\n(up to approximately 2 times)\n\nRisk increased\n\n(approximately 2 times)\n\n(no data)\n\n(no data)\n\nStroke\n\nRisk increased\n\n(up to approximately 1.5 times)\n\nRisk increased\n\n(approximately 2 to 3 times)\n\nRisk may be increased\n\nRisk increased\n\n(approximately 1.8 times)\n\nHypertension\n\nRisk increased\n\n(approximately 2 to 4 times)\n\nRisk increased\n\n(approximately 2 to 5 times)\n\nRisk increased\n\n(approximately 2 to 4 times)\n\n(not applicable)\n\nNotes: Risks described are overall estimates, summarised from risk ratios, odds ratios and hazard ratios.\n\nIncreased risk is compared to the background risk in women who did not have hypertensive disorders during pregnancy. Absolute risks are not reported, because these will vary considerably, depending on the follow-up time (range from 1 to 40 years postpartum).\n\nAdvise women who have had a hypertensive disorder of pregnancy to discuss how to reduce their risk of cardiovascular disease, including hypertensive disorders, with their GP or specialist. This may include:\n\navoiding smoking, as recommended in the NICE guideline on tobacco\n\nmaintaining a healthy lifestyle, as recommended in the NICE guideline on cardiovascular disease\n\nmaintaining a healthy weight, as recommended in the NICE guideline on obesity. \n\nIn women who have had pre-eclampsia or hypertension with early birth before 34\xa0weeks, consider pre-pregnancy counselling to discuss possible risks of recurrent hypertensive disorders of pregnancy, and how to lower them for any future pregnancies. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see rationale and impact section on risk of recurrence of hypertensive disorders of pregnancy and long-term cardiovascular disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: advice at discharge.\n\nLoading. Please wait.\n\n## Body mass index and recurrence of hypertensive disorders of pregnancy\n\nAdvise women who have had pre-eclampsia to achieve and keep a BMI within the healthy range before their next pregnancy (18.5\xa0to 24.9\xa0kg/m2). See also the NICE guideline on obesity. [2010, amended 2019]\n\n## Inter-pregnancy interval and recurrence of hypertensive disorders of pregnancy\n\nAdvise women who have had pre-eclampsia that the likelihood of recurrence increases with an inter-pregnancy interval greater than 10\xa0years. [2010, amended 2019]\n\n## Long-term risk of end-stage kidney disease\n\nTell women with a history of pre-eclampsia who have no proteinuria and no hypertension at the postnatal review (6 to 8\xa0weeks after the birth) that although the relative risk of end-stage kidney disease is increased, the absolute risk is low and no further follow‑up is necessary. \n\n## Thrombophilia and the risk of pre-eclampsia\n\nDo not routinely perform screening for thrombophilia in women who have had pre-eclampsia. \n\n# Terms used in this guideline\n\n## Chronic hypertension\n\nHypertension that is present at the booking visit, or before 20\xa0weeks, or if the woman is already taking antihypertensive medication when referred to maternity services. It can be primary or secondary in aetiology.\n\n## Eclampsia\n\nA convulsive condition associated with pre-eclampsia.\n\n## Gestational hypertension\n\nNew hypertension presenting after 20\xa0weeks of pregnancy without significant proteinuria.\n\n## HELLP syndrome\n\nHaemolysis, elevated liver enzymes and low platelet count.\n\n## Hypertension\n\nBlood pressure of 140\xa0mmHg systolic or higher, or 90\xa0mmHg diastolic or higher. \n\n## Multi-fetal pregnancy\n\nA pregnancy with more than 1\xa0baby (such as twins, triplets).\n\n## Pre-eclampsia\n\nNew onset of hypertension (over 140\xa0mmHg systolic or over 90\xa0mmHg diastolic) after 20\xa0weeks of pregnancy and the coexistence of 1\xa0or more of the following new-onset conditions:\n\nproteinuria (urine protein:creatinine ratio of 30\xa0mg/mmol or more or albumin:creatinine ratio of 8\xa0mg/mmol or more, or at least 1\xa0g/litre [2+] on dipstick testing) or\n\nother maternal organ dysfunction:\n\n\n\nrenal insufficiency (creatinine 90\xa0micromol/litre or more, 1.02\xa0mg/100\xa0ml or more)\n\nliver involvement (elevated transaminases [alanine aminotransferase or aspartate aminotransferase over 40\xa0IU/litre] with or without right upper quadrant or epigastric abdominal pain)\n\nneurological complications such as eclampsia, altered mental status, blindness, stroke, clonus, severe headaches or persistent visual scotomata\n\nhaematological complications such as thrombocytopenia (platelet count below 150,000/microlitre), disseminated intravascular coagulation or haemolysis\n\n\n\nuteroplacental dysfunction such as fetal growth restriction, abnormal umbilical artery doppler waveform analysis, or stillbirth.\n\n## Severe hypertension\n\nBlood pressure over 160\xa0mmHg systolic or over 110\xa0mmHg diastolic.\n\n## Severe pre-eclampsia\n\nPre-eclampsia with severe hypertension that does not respond to treatment or is associated with ongoing or recurring severe headaches, visual scotomata, nausea or vomiting, epigastric pain, oliguria and severe hypertension, as well as progressive deterioration in laboratory blood tests such as rising creatinine or liver transaminases or falling platelet count, or failure of fetal growth or abnormal doppler findings.", 'Recommendations for research': "As part of the 2019 update, the guideline committee made 6\xa0research recommendations on the management of pregnancy with chronic hypertension, pre-eclampsia, fetal monitoring, the use of antihypertensives in breastfeeding and advice and follow‑up. A research recommendation from the 2010 guideline which was superseded by these new research recommendations was deleted, and 3\xa0research recommendations where research was now underway or had been completed were also deleted.\n\n# Key recommendations for research\n\n## Management of chronic hypertension in pregnancy\n\nIn women who need treatment for chronic hypertension in pregnancy, what is the effectiveness and safety of antihypertensive agents (compared in head-to-head trials) in improving maternal and perinatal outcomes? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and impact section on pre-eclampsia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: interventions for chronic hypertension.\n\nLoading. Please wait.\n\n## Management of hypertension in pregnancy\n\nIn women who need treatment for hypertension in pregnancy, what are the adverse neonatal outcomes associated with maternal use of beta blockers (or mixed alpha-beta blockers)? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and impact section on chronic hypertension\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: interventions for chronic hypertension.\n\nLoading. Please wait.\n\n## Management of pre-eclampsia\n\nIn which women with pre-eclampsia is inpatient management associated with better outcomes for women and babies? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and impact section on pre-eclampsia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: monitoring gestational hypertension.\n\nLoading. Please wait.\n\n## Antihypertensive treatment during the postnatal period\n\nIn women who need treatment for high blood pressure after birth, what is the effectiveness and safety (including in breastfeeding women) of antihypertensive agents in achieving adequate blood pressure control? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and impact section on antihypertensive treatment during breastfeeding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: postnatal management of hypertension.\n\nLoading. Please wait.\n\n## Fetal monitoring\n\nIn women with hypertensive disorders of pregnancy, what is the optimal fetal monitoring strategy to detect small for gestational age infants? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and impact section on fetal monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: monitoring gestational hypertension.\n\nLoading. Please wait.\n\n## Advice and follow-up at transfer to community care\n\nIn women who have had hypertension during pregnancy, what interventions reduce the risk of a) recurrent hypertensive disorders of pregnancy, and b) subsequent cardiovascular disease? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale and impact section on follow up after hypertensive disorders of pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: advice at discharge.\n\nLoading. Please wait.\n\n# Other recommendations for research (from 2010 guideline)\n\n## Haematological and biochemical monitoring in women with gestational hypertension\n\nWhat is the role of assessing haematological or biochemical parameters at diagnosis of gestational hypertension and during surveillance of gestational hypertension? ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Assessment of proteinuria\n\nRecommendations 1.2.1 to 1.2.7\n\n## Why the committee made the recommendations\n\nThe committee were aware that there is often over-reliance on a proteinuria result in the diagnosis of pre-eclampsia, and agreed that healthcare professionals should use the results of a full clinical review, including severity of hypertension and other signs and symptoms, before making a diagnosis of pre-eclampsia.\n\nThe committee amended the recommendation on automated dipstick tests from the 2010 guideline to emphasise that this should be used as a screening tool for proteinuria. The committee highlighted the importance of using automated dipstick analysis in secondary care rather than visual analysis, which they were aware from their experience has a higher error rate.\n\nProtein:creatinine ratio (PCR) and albumin:creatinine ratio (ACR) were both shown to have high specificity and high sensitivity at the chosen thresholds (30\xa0mg/mmol and 8\xa0mg/mmol respectively), and therefore either could be used depending on local availability. The committee agreed that using both tests together did not have any additional diagnostic benefit.\n\nThere was some evidence that using the first morning urine void in assessment of proteinuria can lead to lower diagnostic accuracy, and so the committee recommended against using this.\n\nAs PCR and ACR show very high diagnostic accuracy, they should be used in place of 24‑hour urine collection, which is awkward for women and could delay identification of proteinuria. However, there are rare occasions when it might be more appropriate to use 24‑hour collection (for example, women with renal complications), and so the committee agreed it should not be ruled out entirely.\n\nThere was good evidence that a PCR of 30\xa0mg/mmol had good diagnostic accuracy, showing high sensitivity and specificity and should be used as the threshold for significant proteinuria. However, the committee recommended retesting for results above 30\xa0mg/mmol if there is still diagnostic uncertainty (for example, the woman has no other clinical signs or symptoms of pre-eclampsia) because there is large variation in protein excretion during the day and from day to day. The committee agreed that this would prevent women being diagnosed with pre-eclampsia on the basis of a single raised PCR result.\n\nEvidence from a single study showed high sensitivity and specificity for an ACR result of 8\xa0mg/mmol to diagnose proteinuria. However, the committee were also aware of further results from a large, UK‑based study, which provided further evidence for the efficacy of a threshold of 8\xa0mg/mmol in the diagnosis of severe pre-eclampsia. The committee were aware that this threshold is different to that used for detection of microalbuminuria in the non-pregnant population. However, they agreed that, on the basis of the evidence reviewed, it was appropriate to use a threshold of 8\xa0mg/mmol for pregnant women.\n\nAs with PCR, the committee were aware that women are sometimes diagnosed with pre-eclampsia on the basis of a single raised ACR, and that this may lead to over-diagnosis. Therefore, they made a recommendation to consider repeating the ACR measurement if there was ongoing clinical uncertainty about the diagnosis.\n\nNo evidence was reviewed that examined the timing of repeat testing for either ACR or PCR, and so no recommendations could be made regarding this.\n\n## How the recommendations might affect practice\n\nThe recommendation to take account of other clinical features when assessing women for suspected pre-eclampsia might lead to an increased need for follow‑up and surveillance. However, this will also reduce the chance that a diagnosis of pre-eclampsia is missed by raising awareness of the multi-system nature of the disease, and so could reduce the number of women who go on to develop complications from undiagnosed pre-eclampsia.\n\nNot all secondary care units currently use automated dipstick analysis to screen for proteinuria, so the recommendations might increase the need for automated reagent-strip reading devices. However, the accuracy and reliability of screening will be improved, reducing the need for further investigations for some women and correctly identifying more women who need further testing or investigations.\n\nMoving from 24‑hour urine collection to spot urine ACR or PCR will save time, with potential for faster diagnosis, and a reduction in inaccuracies because of incomplete samples. It is also likely to improve quality of life, as the process of completing a 24‑hour urine collection is time-consuming and awkward.\n\nA PCR of 30\xa0mg/mmol is already used routinely as a diagnostic threshold and therefore should not change practice. Currently units may use different ACR levels for diagnosis and so the recommendation to use 8\xa0mg/mmol will standardise practice.\n\nRecommendations have been made for the use of either ACR or PCR allowing local decisions to use whichever test is available, so this should not affect practice.\n\nRepeating the PCR or ACR test may incur a small additional cost. However, this should reduce the false positive rate, and mean some women will avoid unnecessary follow‑up or intensive monitoring (such as hospital admission) if their proteinuria resolves and is shown to be transient.\n\nReturn to recommendations\n\n# Treatment of chronic hypertension\n\nRecommendations 1.3.6 to 1.3.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that pregnant woman with chronic hypertension should be offered lifestyle advice similar to other adults with hypertension, and in line with the NICE guideline on hypertension in adults.\n\nThere was very little evidence available on treatment initiation thresholds for chronic hypertension in pregnancy, so the committee based their recommendations on the values specified in the recent Control of Hypertension in Pregnancy Study (CHIPS) and the NICE guideline on hypertension in adults. There was evidence for target blood pressure levels from the large CHIPS trial, so the committee made recommendations based on this.\n\nThere was some very limited evidence of both benefits and harms for different antihypertensive medicines. However, there was not enough evidence to recommend one treatment over another. As labetalol, nifedipine and methyldopa had been recommended in the previous guideline (for gestational hypertension and pre-eclampsia), and these medicines had been used for many years in pregnancy, the committee agreed they should be preferred treatment options for chronic hypertension in pregnancy. Labetalol is specifically licensed for use in pregnancy and so is suggested as the first-line option, with nifedipine as the next alternative, and methyldopa as the third option (as it may lead to more side effects and be the least effective option of the\xa03).\n\nThere was some very limited evidence for the benefits of aspirin in reducing preterm births and neonatal unit admissions, so the committee retained the recommendation on aspirin from the previous guideline, but incorporated it into the section on the treatment of chronic hypertension in pregnancy. The committee noted that the studies used different doses of aspirin (ranging from 50\xa0mg to 150\xa0mg daily), and that common practice in the UK was to offer 75\xa0mg to 150\xa0mg, therefore this dose range was recommended.\n\nThe committee were aware of the link between chronic hypertension and both pre-existing and gestational diabetes, therefore they made an overarching recommendation at the beginning of the guideline to cross-refer to the existing NICE guideline on diabetes in pregnancy.\n\nThe committee made a new recommendation referring to the NICE diagnostics guidance on placental growth factor (PLGF) testing as this may be applicable to women with chronic hypertension.\n\nAs there is currently a lack of evidence on the difference in outcomes between different antihypertensive medications, and concerns about possible adverse neonatal events from beta blockers, the committee made research recommendations on these topics.\n\n## How the recommendations might affect practice\n\nBased on these recommendations, a clear blood pressure target should now be set for women with chronic hypertension in pregnancy who need antihypertensive treatment to improve consistency of treatment targets.\n\nStarting treatment for hypertension and offering aspirin to women with chronic hypertension who are pregnant are standard care, so these recommendations are not expected to change practice significantly.\n\nReturn to recommendations\n\n# Monitoring and treatment of gestational hypertension\n\nRecommendations 1.4.3 and 1.4.4\n\n## Why the committee made the recommendations\n\nThe committee updated the table from the previous guideline on the management of pregnancy with gestational hypertension. There was very little evidence available on treatment initiation thresholds for gestational hypertension in pregnancy, so the committee made recommendations using the values specified in the recent Control of Hypertension in Pregnancy Study (CHIPS). There was evidence for target blood pressure levels from the large CHIPS trial, so the committee made recommendations based on this. The committee made a new recommendation referring to the NICE diagnostics guidance on placental growth factor (PLGF) testing as this is applicable to women with gestational hypertension.\n\nThe committee were aware of the link between gestational hypertension and both pre-existing and gestational diabetes, therefore they made an overarching recommendation at the beginning of the guideline to cross-refer to the existing NICE guideline on diabetes in pregnancy.\n\nThere was no evidence on fetal monitoring in gestational hypertension, so the committee made a research recommendation on the optimal fetal monitoring strategy to detect small for gestational age infants.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current clinical practice in many units, but may help standardise practice across the NHS for units that currently use other blood pressure targets.\n\nReturn to recommendations\n\n# Assessment of women with pre-eclampsia\n\nRecommendations 1.5.2 to 1.5.4\n\n## Why the committee made the recommendations\n\nThe committee agreed, based on their clinical expertise, that women with pre-eclampsia should have a full clinical assessment at every antenatal appointment and should be admitted to hospital if there are any concerns about the wellbeing of the woman or her baby. The committee agreed that this would include (but was not limited to) reasons such as severe hypertension or other features of pre-eclampsia indicating increased risk of adverse outcomes.\n\nThere was some evidence that the fullPIERS and PREP‑S models can help identify women at different risks of adverse outcomes because of pre-eclampsia. There was more extensive validation of the fullPIERS model, and the validation studies were conducted in populations from a range of healthcare settings. The PREP‑S model had been developed using a UK population, and validated using data from similar multinational settings. It was noted that further validation of PREP‑S was unlikely to be conducted, because of the cost of conducting these studies. The committee therefore agreed that both models could be considered as options, in addition to a full clinical assessment, to help guide decisions relating to interventions and place of care.\n\nThe tools predict adverse outcomes in women, but are not designed to predict outcomes for babies. The committee agreed it was important to highlight this.\n\n## How the recommendations might affect practice\n\nThe use of a full clinical assessment and validated models to predict risk may improve consistency in current practice with regard to admission to hospital for women with pre-eclampsia. Some centres offer admission to all women with pre-eclampsia, whereas others only offer it to a small proportion of women. The guidance might increase the number of women who are admitted to hospital in some centres if admission is not currently routine, but might decrease admission in other centres, thus standardising practice.\n\nReturn to recommendations\n\n# Monitoring and treatment of pre-eclampsia and timing of birth\n\nRecommendations 1.5.5, 1.5.7 and 1.5.12\n\n## Why the committee made the recommendations\n\nThe committee updated the table from the previous guideline on the management of pregnancy with pre-eclampsia. There was limited evidence on the best place of treatment for women with pre-eclampsia. Because of this, the committee made recommendations based on other evidence they reviewed (see evidence review\xa0C), which showed that women should be admitted if there were concerns for the wellbeing of the woman or her baby, or a high risk of complications of pre-eclampsia predicted using the fullPIERS or PREP‑S model. (See the section of the guideline on assessing pre-eclampsia and evidence review\xa0C for more details on the use of the fullPIERS and PREP‑S models.)\n\nThere was no evidence on treatment initiation thresholds or target blood pressure levels for pre-eclampsia, so the committee based their recommendations on the NICE guideline on hypertension in adults and the values specified in the Control of Hypertension In Pregnancy Study (CHIPS; see evidence review\xa0A), which included women with chronic or gestational hypertension.\n\nThere was some very limited evidence of both benefits and harms for different pharmacological interventions. However, as there was not enough evidence to recommend one treatment over another, the committee adopted the choices from the previous guideline and recommended choosing a treatment based on previous treatments, side-effect profiles and the woman's preferences. Labetalol is specifically licensed for use in pregnancy and so is suggested as the first-line option, with nifedipine as the next alternative, and methyldopa as the third option (as it may lead to more side effects and be the least effective option of the\xa03).\n\nThere was limited evidence on the benefits and harms of planned early birth compared with expectant management of pregnancy in women with pre-eclampsia, so the committee recommended that decisions about timing of birth should be based on whether the woman and baby are at risk of adverse outcomes if pregnancy is prolonged. These recommendations were based on those from the previous guideline, and expanded based on international guidelines, which were used by the committee in their clinical practice. Based on the data from HYPITAT‑II study, the committee also agreed that pregnancies in women with pre-eclampsia could be managed with continued surveillance to 37\xa0weeks, unless there were specific concerns or indications to offer a planned early birth before then.\n\nThere was limited evidence to guide the best place of care for women with pre-eclampsia and their babies, so the committee made a research recommendation.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current best clinical practice, so are unlikely to cause a significant change in practice.\n\nCurrently, some units admit all women with pre-eclampsia routinely, some only admit women who they believe to be at a high risk of complications, and some admit very few. Standardising practice could therefore increase or reduce the number of women who will be admitted, depending on a unit's current practice, but is likely to reduce unwanted variance between units.\n\nReturn to recommendations\n\n# Antihypertensive treatment during the postnatal period, including during breastfeeding\n\nRecommendations 1.9.1 to 1.9.7 and 1.9.9\n\n## Why the committee made the recommendations\n\nThere was very little evidence on the efficacy and safety of antihypertensive agents in postnatal women, so the committee made recommendations based on the NICE guideline on hypertension in adults, with adaptations based on the potential effects of medicines on the baby. The committee therefore recommended the use of an angiotensin converting enzyme (ACE) inhibitor as first-line treatment, except in women of African or Caribbean family origin, in whom a calcium-channel blocker would be used first line. The choice of second-line medicine was modified from the NICE guideline on hypertension in adults as angiotensin receptor blockers, thiazide and thiazide-like diuretics are not recommended during breastfeeding. Therefore, the committee agreed that beta-blockers should be used as the second-line antihypertensive agent. The committee also agreed that the medicines with once-daily administration should be used wherever possible and for this reason the committee recommended enalapril in preference to captopril (which is taken 3\xa0times daily) and atenolol as an alternative to labetalol (which is taken 2\xa0to\xa04\xa0times daily).\n\nBased on their experience, the committee made recommendations on advice for women who wish to breastfeed while taking antihypertensives, and on the monitoring of babies whose mothers are taking antihypertensives.\n\nAs there was very little evidence on the effectiveness and safety of antihypertensives for postnatal use, the committee revised the research recommendation made in the 2010 guideline.\n\n## How the recommendations might affect practice\n\nThere is currently wide variation in practice over use of antihypertensive treatment in the postnatal period, and these recommendations may reduce variation in practice. The recommendations could lead to an increase in the use of atenolol instead of labetalol in the postnatal period.\n\nReturn to recommendations\n\n# Risk of recurrence of hypertensive disorders of pregnancy and long-term cardiovascular disease\n\nRecommendations 1.10.1 to 1.10.4\n\n## Why the committee made the recommendations\n\nLong-term follow‑up studies of women who have experienced hypertensive disorders during pregnancy showed an increased risk of long-term cardiovascular disease and a higher prevalence of hypertensive disorders in subsequent pregnancies compared with women unaffected by hypertensive disorders.\n\nThere was no evidence on which interventions could reduce the risk of recurrence of hypertensive disorders of pregnancy or future cardiovascular disease, so the committee made a research recommendation.\n\n## How the recommendations might affect practice\n\nProviding guidance and advice to women on future risks and signposting appropriate care and lifestyle advice may be an additional activity for some healthcare professionals, compared with current practice.\n\nReturn to recommendations", 'Context': 'Hypertensive disorders during pregnancy affect around 8% to 10% of all pregnant women and can be associated with substantial complications for the woman and the baby. Women can have hypertension before pregnancy or it can be diagnosed in the first 20\xa0weeks (known as chronic hypertension), new onset of hypertension occurring in the second half of pregnancy (gestational hypertension) or new hypertension with features of multi-organ involvement (pre-eclampsia).\n\nAlthough the proportion of women with pregnancy hypertensive disorders overall appears to have stayed reasonably stable, maternal mortality from hypertensive causes has fallen dramatically: less than 1\xa0woman in every million who gives birth now dies from pre-eclampsia. There is consensus that introduction of the 2010 NICE evidence-based guidelines, together with the findings from the confidential enquiry into maternal deaths, has made a pivotal contribution to this fall in maternal mortality. However, hypertension in pregnancy continues to cause substantial maternal morbidity, stillbirths and neonatal deaths, and perinatal morbidity. Women with hypertension in pregnancy are also at increased risk of cardiovascular disease later in life.\n\nVariations in care contribute to inequity in adverse outcomes. Adoption and implementation of evidence-based national guidelines have a central role in reducing this variance and improving care and outcomes across the maternity service. Research that has been done since publication of the previous guideline has addressed areas of uncertainty and highlighted where the recommendations can be updated. A surveillance report from 2017 identified new studies in the following areas:\n\nmanagement of pregnancy with chronic hypertension\n\nmanagement of pregnancy with gestational hypertension\n\nmanagement of pregnancy with pre-eclampsia\n\nbreastfeeding\n\nadvice and follow‑up care at transfer to community care.\n\nThe scope of this update was limited to these sections; it did not include other areas being looked at by other groups (for example, screening strategies for pre-eclampsia, which is being evaluated by the UK National Screening Committee), and did not look into alternative approaches to categorisation of hypertension in pregnancy (for example, looking at treatment for all types of pregnancy hypertension together, rather than within the subdivisions of chronic hypertension, gestational hypertension and pre-eclampsia). This update has also clarified the basis for the current definition of pre-eclampsia, in order to better align with the stated aims of the 2010 guideline to be consistent with those agreed by the International Society for the Study of Hypertension in Pregnancy (ISSHP).\n\nThe aim of the 2019 guideline is to present updated evidence-based recommendations, relevant to practising clinicians, while identifying outstanding areas of uncertainty that need further research. There is a strong argument for uptake of these new guidelines into clinical practice, in order to minimise unnecessary variance and provide optimal care for women and their babies. In doing this, low rates of maternal mortality should be maintained, and progress on reduction of maternal morbidity and perinatal morbidity and mortality can be pursued.'}	https://www.nice.org.uk/guidance/ng133	This guideline covers diagnosing and managing hypertension (high blood pressure), including pre-eclampsia, during pregnancy, labour and birth. It also includes advice for women with hypertension who wish to conceive and women who have had a pregnancy complicated by hypertension. It aims to improve care during pregnancy, labour and birth for women and their babies.
f51f250e4958cc960b0a0ef09dfaef2efa2405fa	nice	AposHealth for knee osteoarthritis	AposHealth for knee osteoarthritis Evidence-based recommendations on AposHealth for knee osteoarthritis. # Recommendations AposHealth is recommended as a cost-saving option to manage knee osteoarthritis in adults only if: non-surgical standard care has not worked well enough and their condition meets the referral criteria for total knee replacement surgery but they do not want surgery and data is collected on the person's quality of life, health resource use and if they have knee replacement surgery in the long term. Further research is recommended on AposHealth for: people with knee osteoarthritis that meets the referral criteria for total knee replacement surgery but who cannot have surgery because it would be unsafe people whose condition does not meet the referral criteria for total knee replacement surgery.Find out more in the further research section in this guidance. Why the committee made these recommendations Clinical evidence from a high-quality trial shows that AposHealth improves scores for measuring pain, stiffness and function when compared with a sham device in people with symptomatic knee osteoarthritis. But it is uncertain whether the improvements are clinically meaningful in terms of reducing symptoms. Two studies compared AposHealth with a sham device. There is a lack of evidence directly comparing AposHealth with standard care, but this comparison is difficult because standard care is hard to define for this condition. There is limited clinical evidence for people who cannot have surgery because it would be unsafe, such as people who are frail and at a high risk of falls. The evidence from studies that did not compare AposHealth with another treatment or sham device suggests that it improves pain, stiffness and function compared with before using AposHealth. Clinical and patient experience of using AposHealth agreed with this. There is a lack of comparative evidence looking at knee surgery delay. Non-comparative clinical evidence also suggests that AposHealth may delay the need for knee surgery, but the length of this delay is uncertain. The delay seen in the evidence reflects the real-world experience of clinicians and patients who are using the technology in the NHS. Cost-comparison analyses show that the potential cost savings from AposHealth mainly come from reduced standard care costs and reduced knee replacement surgeries. The analyses also suggest that AposHealth is cost saving by £1,958 per person when compared with standard care if knee surgery is delayed for 5 years. Because the evidence for the potential cost savings is limited, further data collection is recommended to understand if cost savings are made once AposHealth is used in the NHS. There are no knee replacement costs for people who cannot have surgery because it would be unsafe, so both the potential cost saving and clinical benefit are uncertain. Therefore, AposHealth is not recommended for people who cannot have surgery, and more research is recommended.# The technology # Technology AposHealth (AposHealth, previously AposTherapy) is a non-invasive device worn on the feet. The device consists of a pair of AposHealth shoes with 2 curved pods (pertupods) on the heel and forefoot of each shoe. The pertupods are securely attached to tracks on the bottom of the shoe with screws. Positioning of the pertupods is done by trained healthcare professionals and can be aided by gait analysis software or hardware. The AposHealth 4‑step treatment plan lasts 1 year and consists of an initial patient assessment, personalisation of the device, at-home treatment and ongoing monitoring. The at-home treatment step involves the person wearing the device for short periods of time during daily activities, for a total of up to 60 minutes per day. People should be offered 1 to 2 follow ups per year after the treatment plan as part of ongoing monitoring if continuing to use AposHealth. # Care pathway Treatment of knee osteoarthritis depends on the severity of symptoms. Current treatment options include pharmacological and non-pharmacological treatments. Non-pharmacological core treatments for osteoarthritis are therapeutic exercise and weight loss (if appropriate), along with information and support. NICE's guideline on the diagnosis and management of osteoarthritis recommends tailoring information to the individual needs of people with osteoarthritis, their families and carers, ensuring it is in an accessible format. Other non-pharmacological treatment options include manual therapy (such as manipulation, mobilisation or soft tissue techniques) and devices (such as walking aids). Pharmacological treatment options include topical and oral non-steroidal anti-inflammatories to relieve pain and inflammation. Intra-articular corticosteroid injections should be considered when other pharmacological treatments are ineffective or unsuitable, or to support therapeutic exercise. However, these treatments only provide short-term relief and may become less effective as the severity of knee osteoarthritis increases. NICE's interventional procedures guidance on platelet-rich plasma injections for knee osteoarthritis says that this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Referral for knee surgery should be considered for people who experience joint symptoms (such as pain, stiffness, reduced function or progressive joint deformity) that have a substantial impact on their quality of life, and if non-surgical management is ineffective or unsuitable. Clinical assessment should be used when deciding to refer someone for joint replacement, instead of systems that numerically score severity of disease. # Innovative aspects AposHealth is intended to improve biomechanics by redistributing pressure away from affected areas and reducing knee pain. On a neuromuscular level, it is designed to re-educate muscles and correct abnormal gait patterns, which can extend to when the person is not actively wearing the device. # Intended use AposHealth is intended for use by adults with knee osteoarthritis who have had non-surgical standard care that has not worked well enough. # Costs AposHealth costs £875 (excluding VAT) per treatment programme for both knees. The treatment programme includes: AposHealth shoes and unlimited parts access for healthcare professionals to standardised outcome measures on the AposHealth clinical tracking system training for healthcare professionals (typically consisting of 6 hours of theory training, and 5 to 10 observed calibrations delivered as part of routine service provision).For more details, see the AposHealth website.# Evidence NICE commissioned an external assessment group (EAG) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website. # Clinical evidence ## The main clinical evidence comprises 29 publications, including 1 randomised controlled trial (RCT) The main clinical evidence includes 29 publications (15 full-text papers, 9 abstracts associated with the included full texts, and 5 additional abstracts), covering a total of 19 unique studies. The full-text papers comprise 1 RCT, 1 prospective comparative study with a 2‑year follow-up study and 12 non-comparative studies. Drew et al. (2022) reported clinical information from a comparative group at baseline only, so the study was treated as a single-arm observational study and the results were extracted from the AposHealth arm only. The full-text publications include a total of 3,767 people. For full details of the clinical evidence, see the clinical evidence section of the assessment report in the supporting documentation. ## Comparative evidence is lacking There is a lack of evidence comparing AposHealth with non-surgical standard care treatments. The EAG acknowledged that this may be driven by uncertainties in the care pathway, making it difficult to design and do comparative studies. Both the RCT and prospective comparative study, with a 2‑year follow-up study, compared AposHealth with a sham device. The EAG considered the RCT to be of high quality with a low risk of bias. The prospective comparative study allowed people to cross over between the groups after 8 weeks. The EAG stated that the unclear description of this crossover undermined the robustness of the results. The other 12 studies are observational and have a high risk of bias. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, 36-item short form (SF‑36) questionnaire results and gait outcomes were frequently reported, and the EAG acknowledged that the outcomes reported across the studies were consistent. ## Improved pain, function and stiffness When AposHealth is compared with a control group, the differences in pain, function and stiffness measured by the WOMAC score are statistically significant and show better outcomes for the AposHealth group. But the EAG noted that it is uncertain whether the improvement shown in the RCT is clinically meaningful. The EAG also noted that the WOMAC scores reported in the studies were not all on the same scale and advised caution when comparing WOMAC scores between studies and interpreting the evidence. Clinical evidence from non-comparative studies shows a consistent improvement in pain, function and stiffness after using AposHealth when compared with baseline and measured by the WOMAC score. ## Knee replacement surgery might be delayed or avoided, but the evidence is limited Two non-comparative studies included by the EAG had knee replacement surgery as a primary outcome, and only 1 of the studies was based in the UK. The UK-based study reported that 84% of people (305 of 365) using AposHealth whose condition met the criteria for total knee replacement surgery referral did not progress to total knee replacement surgery at 2 years. The other (US-based) study reported that 86% of people (204 of 237) using AposHealth did not progress to total knee replacement surgery at 2 years. ## Quality of life, in particular the physical aspects, may be improved There is some evidence that AposHealth may improve quality of life, with stronger evidence for improvement to physical aspects. The RCT found no difference between the active and control groups in SF‑36 scores. The prospective comparative study reported a significant difference in the physical component summary and total score of the SF‑36 questionnaire but reported no difference in the mental component summary. In non-comparative studies, SF‑36 scores from baseline to post-treatment follow up for AposHealth showed significant improvements in some sub-scores, but improvements varied between studies. ## Standard care resource use might be reduced, but the evidence is limited There is limited, low-quality evidence that AposHealth results in reduced standard care resource use. The RCT reported no difference in rates of analgesic use between the active and control groups, and the prospective comparative study reported that the control group used more rescue medication (647 tablets) than the active group (273 tablets). The company submission also included unpublished survey and audit data that suggested AposHealth resulted in a reduction in health resource use. # Cost evidence ## AposHealth is cost saving compared with non-surgical standard care at 5 and 10 years according to the company's model The company submitted a Markov decision model comparing standard care with and without AposHealth. The model is based on movement of people from standard care (with or without AposHealth) to total knee replacement surgery, and then to total knee replacement surgery of the other knee. The model results were originally reported at a 2‑year and 5‑year time horizon. However, after queries from the EAG, the company submitted an additional model with an extended 10‑year time horizon. The company model assumes that all people will have 2 follow ups per year in years 2 to 5, and 1 follow up in years 5 to 10. The company's base case showed a cost saving of £1,886 at 5 years and £247 at 10 years. For full details of the cost evidence, see the economic evidence section of the assessment report in the supporting documentation. ## The company's model structure is appropriate, with changes to certain parameters Key clinical parameters in the company model are the rate of total knee replacement, subsequent total knee replacement on the other knee, postoperative complications and mortality. The EAG added a starting age of 68 years to the model, based on data from the National Joint Registry annual report (2021). The company model assumes the rate of subsequent total knee replacement on the other knee as 0.5% per month, and the rate of total knee replacement revisions as 0.34% per month. The EAG's model includes a slightly lower rate of 0.395% for total knee replacement on the other knee, using the value from Sanders (2017). It also included a lower rate of 0.32% per month for total knee replacement revisions from an alternate data source and added a variable mortality rate as the cohort passes through the model. Total knee replacement costs in the company model are taken from NHS best practice tariffs. But the EAG used alternative NHS reference cost data from 2019 to 2020 (to avoid the impact of COVID‑19) and inflated to 2022 to 2023. ## AposHealth is cost saving at 5 years, but the model results should be treated with caution The EAG base case is that AposHealth is cost saving compared with standard care by £1,958 per person at 5 years, and cost incurring by £46 per person at 10 years. The EAG extended the model further and reported that AposHealth is also cost incurring by £2,032 at 20 years. The EAG noted that cost savings primarily come from a reduction in total knee replacement and reduced subsequent complications and follow up. So, the EAG felt that the model results should be treated with caution because existing evidence for delay to surgery is limited, as described in the clinical evidence (see the section on knee replacement surgery delay). ## Key cost drivers in the model are standard care costs and reduction in standard care because of AposHealth The company did a deterministic sensitivity analysis with one-way and two-way tables for key parameters, which were varied by 20%. The EAG repeated this with the amended model and extended it to 20 years. The cost of standard care uses parameter variations based on lower costs from Cole (2022) and a 20% increase from the base-case input. Lower standard care costs before knee surgery are likely to lead to cost savings because fewer costs are accumulated by people who are delaying having surgery. The cost of standard care before total knee replacement is the only parameter that makes the one-way sensitivity analysis cost saving at 20 years. The EAG also emphasised the importance of the reduction to standard care costs because of AposHealth. The EAG reiterated the uncertainty about this evidence, as described in the section on standard care resource use. ## AposHealth may be cost saving for people who cannot have knee surgery if standard care costs are reduced by 20% The EAG considered an exploratory scenario for people who are unable to have total knee replacement by setting movement of people having surgery in the model to 0%. With the assumption of a 15% reduction in standard care costs, AposHealth is cost incurring by £538 at 5 years and £40 at 20 years. But, if there is a 20% reduction in standard care costs, AposHealth becomes cost saving by £259 at 5 years and £701 at 20 years.# Committee discussion # Clinical effectiveness overview ## Pain, function and stiffness are improved, but there are uncertainties The committee noted that the authors of the randomised controlled trial (RCT) publication said that there was uncertainty in whether the improvements were clinically important. But the committee was reassured by the clinical and patient expert advisers reporting very positive outcomes. A patient expert adviser said that they continue to use the technology effectively as pain relief. The committee acknowledged that the rest of the evidence base is limited in methodological quality, but the outcomes reported across the evidence base are consistent. The committee concluded that AposHealth may lead to improvements in pain, function and stiffness for people with knee osteoarthritis. ## Total knee replacement surgery may be delayed, but it is uncertain for how long The EAG reported that 2 non-comparative studies based in the US and UK included the rate of total knee replacement as a primary outcome. Drew (2022) and Greene (2022) reported an 86% and 84% rate, respectively, of total knee replacement avoidance for people using AposHealth at 2 years. The clinical and patient expert advisers agreed that these rates reflected their experience of using the technology in the NHS for up to 7 years. The committee noted that the rate of surgery avoidance reported in Greene (2022) may be an overestimation. This is because the study follow up overlapped with the COVID‑19 pandemic, when elective surgeries were often put on hold. The committee acknowledged that the clinical evidence was non-comparative and uncertain but accepted the support from clinical and patient expert advisers. # NHS considerations ## People referred for AposHealth should meet the referral criteria for total knee replacement surgery The committee discussed patient selection and the position of AposHealth in the care pathway. It noted that the clinical evidence does not specify a clear place or patient population for AposHealth in the care pathway. Clinical expert advisers using the technology stated that AposHealth is usually delivered as part of the musculoskeletal secondary care service. They also explained that people must have tried other non-surgical standard care and have met the referral criteria for a total knee replacement. The committee concluded that the appropriate population and place in the care pathway should be if non-surgical standard care has not worked well enough and the person's condition meets the referral criteria for total knee replacement surgery. ## AposHealth is an option if a person does not want surgery The decision to undergo knee surgery is a shared decision and there are multiple factors involved (see NICE's guidance on shared decision making). A patient expert adviser felt that surgery was not their preferred treatment option because of their young age and negative past experiences in their family. Clinical expert advisers agreed that a person's age, social and economic factors, comorbidities and understanding of the procedure may all influence their decision to have surgery. The committee acknowledged that there are many reasons people may not want surgery, and more strategies to manage symptoms for this group, such as AposHealth, are necessary. ## AposHealth may not be suitable for some people, but this is assessed on an individual basis The committee discussed patient eligibility and monitoring for AposHealth. It noted that AposHealth may be contraindicated for people with balance issues or especially severe osteoporosis. Clinical expert advisers explained that eligibility for AposHealth is reviewed on an individual basis. This is to ensure people are not put at risk of falls and can control the instability of the shoes. They also noted that healthcare professionals trained in using AposHealth, such as physiotherapists or podiatrists, continue to assess people's eligibility during follow-up visits through clinical assessment and observational gait analysis. The committee acknowledged that the technology may not be suitable for some people but accepted that healthcare professionals will use clinical judgement when referring and assessing people for AposHealth. # Adherence ## Adherence could be improved with AposHealth because of immediate symptom relief Clinical expert advisers said they rarely find that people do not use AposHealth as recommended. People are advised to wear the technology at home or at work for short periods of time. A patient expert adviser said that wearing the technology at home was convenient, and that they are eager to wear the device because of an immediate relief of symptoms. Clinical expert advisers noted that the instant symptom relief experienced by people can lead to overuse, which may result in muscle stiffness or soreness if not monitored appropriately. The committee noted that current users are selectively sampled and there is no data on adherence in a wider NHS setting. But it accepted that it is unlikely that people may not use AposHealth as recommended. ## AposHealth needs continued use for ongoing benefits Clinical experts stated that using the technology daily improves muscle activity around the joint, which can lead to benefits when not actively wearing the technology. After the initial programme, people are advised to use the technology 2 to 4 times a week to remain stable. A patient expert adviser confirmed that wearing the technology as instructed has enabled them to do more exercise outside of the treatment programme. Now they only use the technology in response to acute joint pain or stiffness. The committee acknowledged that AposHealth may become less effective over time if use is stopped. # Other patient benefits or issues ## Other lower limb joints may benefit from AposHealth Clinical expert advisers noted that people with knee osteoarthritis often have comorbidities, such as back pain. Clinical expert advisers confirmed that they assess the impact of AposHealth on other lower limb joints during the initial AposHealth assessment to ensure the calibration of the technology is beneficial to all joints. The company noted that there is clinical evidence available for people with lower back and hip pain. This evidence was not presented to the committee or reviewed by the EAG, but the committee was reassured that AposHealth was unlikely to have adverse effects on other joints. # Decision modelling overview ## Limited data makes the economic modelling uncertain The EAG reported that AposHealth was cost saving at 5 years but became cost incurring at 10 years. The committee accepted that the main cost savings come from reduced total knee replacement surgery. The committee noted that there is limited evidence for reduced total knee replacement beyond 2 years. But it acknowledged that clinical expert advisers who have up to 7 years of experience using the technology also support the plausibility of reduced knee replacement surgery sustained over time. Clinical expert advisers also noted that AposHealth continues to be funded in their local area. The committee concluded that there are still uncertainties about the evidence for delaying total knee replacement surgery, but accepted the potential cost savings for the technology up to 5 years. ## Reduced standard care costs is a key driver in the economic model The EAG's sensitivity analysis showed that the reduced standard care costs when using AposHealth is one of the main drivers for increasing cost savings in the model. The EAG explained that the assumption of a 15% reduction in standard care costs comes from published clinical evidence showing reduced pain and increased function, and unpublished audit data from the US and UK suggesting a decrease in resource use. A patient expert adviser noted that they have not needed further help from their local service and have used less medication since using the technology. The committee acknowledged that the experience of clinical and patient experts also suggests AposHealth may reduce use of healthcare resources. # Further research ## Long-term real-world data is needed on AposHealth's clinical effectiveness and cost benefit The committee suggested that real-world data could be collected to determine the clinical effectiveness and cost benefit of AposHealth for people whose condition meets the criteria for surgery but who do not want it over a longer time horizon. The committee noted that there is already a high-quality RCT comparing AposHealth with a sham device and acknowledged that there are difficulties in designing comparative studies because of the uncertainties in the standard care pathway. The committee supported the use of the technology in the NHS alongside the collection of high-quality real-world data, with outcomes including standard care resource use, health-related quality of life, and long-term outcomes such as rates of total knee replacement. The committee suggested that this data could be collected through a high-quality national registry (such as the National Joint Registry). The committee agreed that long-term data collection over 5 to 10 years will help establish the cost benefits of AposHealth. The committee recommended that further research is needed for people whose condition meets the referral criteria for knee replacement surgery, but who cannot have surgery because it would be unsafe, and for the wider population of people with knee osteoarthritis because of the uncertainty around the clinical and cost evidence. The committee agreed that research with outcomes including standard care resource use, health-related quality of life, and long-term outcomes such as rates of total knee replacement should be collected. It noted that health-related quality of life data may be collected using standardised patient-reported outcome measures, such as the EQ‑5D.	{'Recommendations': "AposHealth is recommended as a cost-saving option to manage knee osteoarthritis in adults only if:\n\nnon-surgical standard care has not worked well enough and\n\ntheir condition meets the referral criteria for total knee replacement surgery but they do not want surgery and\n\ndata is collected on the person's quality of life, health resource use and if they have knee replacement surgery in the long term.\n\nFurther research is recommended on AposHealth for:\n\npeople with knee osteoarthritis that meets the referral criteria for total knee replacement surgery but who cannot have surgery because it would be unsafe\n\npeople whose condition does not meet the referral criteria for total knee replacement surgery.Find out more in the further research section in this guidance.\n\nWhy the committee made these recommendations\n\nClinical evidence from a high-quality trial shows that AposHealth improves scores for measuring pain, stiffness and function when compared with a sham device in people with symptomatic knee osteoarthritis. But it is uncertain whether the improvements are clinically meaningful in terms of reducing symptoms. Two studies compared AposHealth with a sham device. There is a lack of evidence directly comparing AposHealth with standard care, but this comparison is difficult because standard care is hard to define for this condition. There is limited clinical evidence for people who cannot have surgery because it would be unsafe, such as people who are frail and at a high risk of falls.\n\nThe evidence from studies that did not compare AposHealth with another treatment or sham device suggests that it improves pain, stiffness and function compared with before using AposHealth. Clinical and patient experience of using AposHealth agreed with this.\n\nThere is a lack of comparative evidence looking at knee surgery delay. Non-comparative clinical evidence also suggests that AposHealth may delay the need for knee surgery, but the length of this delay is uncertain. The delay seen in the evidence reflects the real-world experience of clinicians and patients who are using the technology in the NHS.\n\nCost-comparison analyses show that the potential cost savings from AposHealth mainly come from reduced standard care costs and reduced knee replacement surgeries. The analyses also suggest that AposHealth is cost saving by £1,958 per person when compared with standard care if knee surgery is delayed for 5\xa0years. Because the evidence for the potential cost savings is limited, further data collection is recommended to understand if cost savings are made once AposHealth is used in the NHS.\n\nThere are no knee replacement costs for people who cannot have surgery because it would be unsafe, so both the potential cost saving and clinical benefit are uncertain. Therefore, AposHealth is not recommended for people who cannot have surgery, and more research is recommended.", 'The technology': "# Technology\n\nAposHealth (AposHealth, previously AposTherapy) is a non-invasive device worn on the feet. The device consists of a pair of AposHealth shoes with 2\xa0curved pods (pertupods) on the heel and forefoot of each shoe. The pertupods are securely attached to tracks on the bottom of the shoe with screws. Positioning of the pertupods is done by trained healthcare professionals and can be aided by gait analysis software or hardware.\n\nThe AposHealth 4‑step treatment plan lasts 1\xa0year and consists of an initial patient assessment, personalisation of the device, at-home treatment and ongoing monitoring. The at-home treatment step involves the person wearing the device for short periods of time during daily activities, for a total of up to 60\xa0minutes per day. People should be offered 1\xa0to\xa02 follow ups per year after the treatment plan as part of ongoing monitoring if continuing to use AposHealth.\n\n# Care pathway\n\nTreatment of knee osteoarthritis depends on the severity of symptoms. Current treatment options include pharmacological and non-pharmacological treatments.\n\nNon-pharmacological core treatments for osteoarthritis are therapeutic exercise and weight loss (if appropriate), along with information and support. NICE's guideline on the diagnosis and management of osteoarthritis recommends tailoring information to the individual needs of people with osteoarthritis, their families and carers, ensuring it is in an accessible format. Other non-pharmacological treatment options include manual therapy (such as manipulation, mobilisation or soft tissue techniques) and devices (such as walking aids).\n\nPharmacological treatment options include topical and oral non-steroidal anti-inflammatories to relieve pain and inflammation. Intra-articular corticosteroid injections should be considered when other pharmacological treatments are ineffective or unsuitable, or to support therapeutic exercise. However, these treatments only provide short-term relief and may become less effective as the severity of knee osteoarthritis increases. NICE's interventional procedures guidance on platelet-rich plasma injections for knee osteoarthritis says that this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.\n\nReferral for knee surgery should be considered for people who experience joint symptoms (such as pain, stiffness, reduced function or progressive joint deformity) that have a substantial impact on their quality of life, and if non-surgical management is ineffective or unsuitable. Clinical assessment should be used when deciding to refer someone for joint replacement, instead of systems that numerically score severity of disease.\n\n# Innovative aspects\n\nAposHealth is intended to improve biomechanics by redistributing pressure away from affected areas and reducing knee pain. On a neuromuscular level, it is designed to re-educate muscles and correct abnormal gait patterns, which can extend to when the person is not actively wearing the device.\n\n# Intended use\n\nAposHealth is intended for use by adults with knee osteoarthritis who have had non-surgical standard care that has not worked well enough.\n\n# Costs\n\nAposHealth costs £875 (excluding VAT) per treatment programme for both knees. The treatment programme includes:\n\nAposHealth shoes and unlimited parts\n\naccess for healthcare professionals to standardised outcome measures on the AposHealth clinical tracking system\n\ntraining for healthcare professionals (typically consisting of 6\xa0hours of theory training, and 5\xa0to\xa010 observed calibrations delivered as part of routine service provision).For more details, see the AposHealth website.", 'Evidence': "NICE commissioned an external assessment group (EAG) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 29 publications, including 1 randomised controlled trial (RCT)\n\nThe main clinical evidence includes 29\xa0publications (15\xa0full-text papers, 9\xa0abstracts associated with the included full texts, and 5\xa0additional abstracts), covering a total of 19\xa0unique studies. The full-text papers comprise 1\xa0RCT, 1\xa0prospective comparative study with a 2‑year follow-up study and 12\xa0non-comparative studies. Drew et al. (2022) reported clinical information from a comparative group at baseline only, so the study was treated as a single-arm observational study and the results were extracted from the AposHealth arm only. The full-text publications include a total of 3,767\xa0people. For full details of the clinical evidence, see the clinical evidence section of the assessment report in the supporting documentation.\n\n## Comparative evidence is lacking\n\nThere is a lack of evidence comparing AposHealth with non-surgical standard care treatments. The EAG acknowledged that this may be driven by uncertainties in the care pathway, making it difficult to design and do comparative studies. Both the RCT and prospective comparative study, with a 2‑year follow-up study, compared AposHealth with a sham device. The EAG considered the RCT to be of high quality with a low risk of bias. The prospective comparative study allowed people to cross over between the groups after 8\xa0weeks. The EAG stated that the unclear description of this crossover undermined the robustness of the results.\n\nThe other 12\xa0studies are observational and have a high risk of bias. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, 36-item short form (SF‑36) questionnaire results and gait outcomes were frequently reported, and the EAG acknowledged that the outcomes reported across the studies were consistent.\n\n## Improved pain, function and stiffness\n\nWhen AposHealth is compared with a control group, the differences in pain, function and stiffness measured by the WOMAC score are statistically significant and show better outcomes for the AposHealth group. But the EAG noted that it is uncertain whether the improvement shown in the RCT is clinically meaningful. The EAG also noted that the WOMAC scores reported in the studies were not all on the same scale and advised caution when comparing WOMAC scores between studies and interpreting the evidence. Clinical evidence from non-comparative studies shows a consistent improvement in pain, function and stiffness after using AposHealth when compared with baseline and measured by the WOMAC score.\n\n## Knee replacement surgery might be delayed or avoided, but the evidence is limited\n\nTwo non-comparative studies included by the EAG had knee replacement surgery as a primary outcome, and only 1 of the studies was based in the UK. The UK-based study reported that 84% of people (305\xa0of\xa0365) using AposHealth whose condition met the criteria for total knee replacement surgery referral did not progress to total knee replacement surgery at 2\xa0years. The other (US-based) study reported that 86% of people (204\xa0of\xa0237) using AposHealth did not progress to total knee replacement surgery at 2\xa0years.\n\n## Quality of life, in particular the physical aspects, may be improved\n\nThere is some evidence that AposHealth may improve quality of life, with stronger evidence for improvement to physical aspects. The RCT found no difference between the active and control groups in SF‑36 scores. The prospective comparative study reported a significant difference in the physical component summary and total score of the SF‑36 questionnaire but reported no difference in the mental component summary. In non-comparative studies, SF‑36 scores from baseline to post-treatment follow up for AposHealth showed significant improvements in some sub-scores, but improvements varied between studies.\n\n## Standard care resource use might be reduced, but the evidence is limited\n\nThere is limited, low-quality evidence that AposHealth results in reduced standard care resource use. The RCT reported no difference in rates of analgesic use between the active and control groups, and the prospective comparative study reported that the control group used more rescue medication (647\xa0tablets) than the active group (273\xa0tablets). The company submission also included unpublished survey and audit data that suggested AposHealth resulted in a reduction in health resource use.\n\n# Cost evidence\n\n## AposHealth is cost saving compared with non-surgical standard care at 5\xa0and 10\xa0years according to the company's model\n\nThe company submitted a Markov decision model comparing standard care with and without AposHealth. The model is based on movement of people from standard care (with or without AposHealth) to total knee replacement surgery, and then to total knee replacement surgery of the other knee. The model results were originally reported at a 2‑year and 5‑year time horizon. However, after queries from the EAG, the company submitted an additional model with an extended 10‑year time horizon. The company model assumes that all people will have 2\xa0follow ups per year in years 2\xa0to\xa05, and 1\xa0follow up in years 5\xa0to\xa010. The company's base case showed a cost saving of £1,886 at 5\xa0years and £247 at 10\xa0years. For full details of the cost evidence, see the economic evidence section of the assessment report in the supporting documentation.\n\n## The company's model structure is appropriate, with changes to certain parameters\n\nKey clinical parameters in the company model are the rate of total knee replacement, subsequent total knee replacement on the other knee, postoperative complications and mortality. The EAG added a starting age of 68\xa0years to the model, based on data from the National Joint Registry annual report (2021). The company model assumes the rate of subsequent total knee replacement on the other knee as 0.5% per month, and the rate of total knee replacement revisions as 0.34% per month. The EAG's model includes a slightly lower rate of 0.395% for total knee replacement on the other knee, using the value from Sanders (2017). It also included a lower rate of 0.32% per month for total knee replacement revisions from an alternate data source and added a variable mortality rate as the cohort passes through the model. Total knee replacement costs in the company model are taken from NHS best practice tariffs. But the EAG used alternative NHS reference cost data from 2019\xa0to\xa02020 (to avoid the impact of COVID‑19) and inflated to 2022 to 2023.\n\n## AposHealth is cost saving at 5\xa0years, but the model results should be treated with caution\n\nThe EAG base case is that AposHealth is cost saving compared with standard care by £1,958 per person at 5\xa0years, and cost incurring by £46 per person at 10\xa0years. The EAG extended the model further and reported that AposHealth is also cost incurring by £2,032 at 20\xa0years. The EAG noted that cost savings primarily come from a reduction in total knee replacement and reduced subsequent complications and follow up. So, the EAG felt that the model results should be treated with caution because existing evidence for delay to surgery is limited, as described in the clinical evidence (see the section on knee replacement surgery delay).\n\n## Key cost drivers in the model are standard care costs and reduction in standard care because of AposHealth\n\nThe company did a deterministic sensitivity analysis with one-way and two-way tables for key parameters, which were varied by 20%. The EAG repeated this with the amended model and extended it to 20\xa0years. The cost of standard care uses parameter variations based on lower costs from Cole (2022) and a 20% increase from the base-case input. Lower standard care costs before knee surgery are likely to lead to cost savings because fewer costs are accumulated by people who are delaying having surgery. The cost of standard care before total knee replacement is the only parameter that makes the one-way sensitivity analysis cost saving at 20\xa0years. The EAG also emphasised the importance of the reduction to standard care costs because of AposHealth. The EAG reiterated the uncertainty about this evidence, as described in the section on standard care resource use.\n\n## AposHealth may be cost saving for people who cannot have knee surgery if standard care costs are reduced by 20%\n\nThe EAG considered an exploratory scenario for people who are unable to have total knee replacement by setting movement of people having surgery in the model to 0%. With the assumption of a 15% reduction in standard care costs, AposHealth is cost incurring by £538 at 5\xa0years and £40 at 20\xa0years. But, if there is a 20% reduction in standard care costs, AposHealth becomes cost saving by £259 at 5\xa0years and £701 at 20\xa0years.", 'Committee discussion': "# Clinical effectiveness overview\n\n## Pain, function and stiffness are improved, but there are uncertainties\n\nThe committee noted that the authors of the randomised controlled trial (RCT) publication said that there was uncertainty in whether the improvements were clinically important. But the committee was reassured by the clinical and patient expert advisers reporting very positive outcomes. A patient expert adviser said that they continue to use the technology effectively as pain relief. The committee acknowledged that the rest of the evidence base is limited in methodological quality, but the outcomes reported across the evidence base are consistent. The committee concluded that AposHealth may lead to improvements in pain, function and stiffness for people with knee osteoarthritis.\n\n## Total knee replacement surgery may be delayed, but it is uncertain for how long\n\nThe EAG reported that 2\xa0non-comparative studies based in the US and UK included the rate of total knee replacement as a primary outcome. Drew (2022) and Greene (2022) reported an 86% and 84% rate, respectively, of total knee replacement avoidance for people using AposHealth at 2\xa0years. The clinical and patient expert advisers agreed that these rates reflected their experience of using the technology in the NHS for up to 7\xa0years. The committee noted that the rate of surgery avoidance reported in Greene (2022) may be an overestimation. This is because the study follow up overlapped with the COVID‑19 pandemic, when elective surgeries were often put on hold. The committee acknowledged that the clinical evidence was non-comparative and uncertain but accepted the support from clinical and patient expert advisers.\n\n# NHS considerations\n\n## People referred for AposHealth should meet the referral criteria for total knee replacement surgery\n\nThe committee discussed patient selection and the position of AposHealth in the care pathway. It noted that the clinical evidence does not specify a clear place or patient population for AposHealth in the care pathway. Clinical expert advisers using the technology stated that AposHealth is usually delivered as part of the musculoskeletal secondary care service. They also explained that people must have tried other non-surgical standard care and have met the referral criteria for a total knee replacement. The committee concluded that the appropriate population and place in the care pathway should be if non-surgical standard care has not worked well enough and the person's condition meets the referral criteria for total knee replacement surgery.\n\n## AposHealth is an option if a person does not want surgery\n\nThe decision to undergo knee surgery is a shared decision and there are multiple factors involved (see NICE's guidance on shared decision making). A patient expert adviser felt that surgery was not their preferred treatment option because of their young age and negative past experiences in their family. Clinical expert advisers agreed that a person's age, social and economic factors, comorbidities and understanding of the procedure may all influence their decision to have surgery. The committee acknowledged that there are many reasons people may not want surgery, and more strategies to manage symptoms for this group, such as AposHealth, are necessary.\n\n## AposHealth may not be suitable for some people, but this is assessed on an individual basis\n\nThe committee discussed patient eligibility and monitoring for AposHealth. It noted that AposHealth may be contraindicated for people with balance issues or especially severe osteoporosis. Clinical expert advisers explained that eligibility for AposHealth is reviewed on an individual basis. This is to ensure people are not put at risk of falls and can control the instability of the shoes. They also noted that healthcare professionals trained in using AposHealth, such as physiotherapists or podiatrists, continue to assess people's eligibility during follow-up visits through clinical assessment and observational gait analysis. The committee acknowledged that the technology may not be suitable for some people but accepted that healthcare professionals will use clinical judgement when referring and assessing people for AposHealth.\n\n# Adherence\n\n## Adherence could be improved with AposHealth because of immediate symptom relief\n\nClinical expert advisers said they rarely find that people do not use AposHealth as recommended. People are advised to wear the technology at home or at work for short periods of time. A patient expert adviser said that wearing the technology at home was convenient, and that they are eager to wear the device because of an immediate relief of symptoms. Clinical expert advisers noted that the instant symptom relief experienced by people can lead to overuse, which may result in muscle stiffness or soreness if not monitored appropriately. The committee noted that current users are selectively sampled and there is no data on adherence in a wider NHS setting. But it accepted that it is unlikely that people may not use AposHealth as recommended.\n\n## AposHealth needs continued use for ongoing benefits\n\nClinical experts stated that using the technology daily improves muscle activity around the joint, which can lead to benefits when not actively wearing the technology. After the initial programme, people are advised to use the technology 2\xa0to\xa04 times a week to remain stable. A patient expert adviser confirmed that wearing the technology as instructed has enabled them to do more exercise outside of the treatment programme. Now they only use the technology in response to acute joint pain or stiffness. The committee acknowledged that AposHealth may become less effective over time if use is stopped.\n\n# Other patient benefits or issues\n\n## Other lower limb joints may benefit from AposHealth\n\nClinical expert advisers noted that people with knee osteoarthritis often have comorbidities, such as back pain. Clinical expert advisers confirmed that they assess the impact of AposHealth on other lower limb joints during the initial AposHealth assessment to ensure the calibration of the technology is beneficial to all joints. The company noted that there is clinical evidence available for people with lower back and hip pain. This evidence was not presented to the committee or reviewed by the EAG, but the committee was reassured that AposHealth was unlikely to have adverse effects on other joints.\n\n# Decision modelling overview\n\n## Limited data makes the economic modelling uncertain\n\nThe EAG reported that AposHealth was cost saving at 5\xa0years but became cost incurring at 10\xa0years. The committee accepted that the main cost savings come from reduced total knee replacement surgery. The committee noted that there is limited evidence for reduced total knee replacement beyond 2\xa0years. But it acknowledged that clinical expert advisers who have up to 7\xa0years of experience using the technology also support the plausibility of reduced knee replacement surgery sustained over time. Clinical expert advisers also noted that AposHealth continues to be funded in their local area. The committee concluded that there are still uncertainties about the evidence for delaying total knee replacement surgery, but accepted the potential cost savings for the technology up to 5\xa0years.\n\n## Reduced standard care costs is a key driver in the economic model\n\nThe EAG's sensitivity analysis showed that the reduced standard care costs when using AposHealth is one of the main drivers for increasing cost savings in the model. The EAG explained that the assumption of a 15% reduction in standard care costs comes from published clinical evidence showing reduced pain and increased function, and unpublished audit data from the US and UK suggesting a decrease in resource use. A patient expert adviser noted that they have not needed further help from their local service and have used less medication since using the technology. The committee acknowledged that the experience of clinical and patient experts also suggests AposHealth may reduce use of healthcare resources.\n\n# Further research\n\n## Long-term real-world data is needed on AposHealth's clinical effectiveness and cost benefit\n\nThe committee suggested that real-world data could be collected to determine the clinical effectiveness and cost benefit of AposHealth for people whose condition meets the criteria for surgery but who do not want it over a longer time horizon. The committee noted that there is already a high-quality RCT comparing AposHealth with a sham device and acknowledged that there are difficulties in designing comparative studies because of the uncertainties in the standard care pathway. The committee supported the use of the technology in the NHS alongside the collection of high-quality real-world data, with outcomes including standard care resource use, health-related quality of life, and long-term outcomes such as rates of total knee replacement. The committee suggested that this data could be collected through a high-quality national registry (such as the National Joint Registry). The committee agreed that long-term data collection over 5\xa0to\xa010\xa0years will help establish the cost benefits of AposHealth.\n\nThe committee recommended that further research is needed for people whose condition meets the referral criteria for knee replacement surgery, but who cannot have surgery because it would be unsafe, and for the wider population of people with knee osteoarthritis because of the uncertainty around the clinical and cost evidence. The committee agreed that research with outcomes including standard care resource use, health-related quality of life, and long-term outcomes such as rates of total knee replacement should be collected. It noted that health-related quality of life data may be collected using standardised patient-reported outcome measures, such as the EQ‑5D."}	https://www.nice.org.uk/guidance/mtg76	Evidence-based recommendations on AposHealth for knee osteoarthritis.
0483c5066e5d4e35442aba33392a8cb8ef3a5077	nice	Maximal cytoreductive surgery for advanced ovarian cancer	Maximal cytoreductive surgery for advanced ovarian cancer Evidence-based recommendations on maximal cytoreductive surgery for advanced ovarian cancer. This involves removing all or almost all visible cancerous tissue. More tissue is removed than with standard surgery. The aim is to improve outcomes for people with advanced ovarian cancer. # Recommendations Evidence on the safety and efficacy of maximal cytoreductive surgery for advanced ovarian cancer is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Patient selection should be done by a specialist gynaecological cancer multidisciplinary team, which may include surgeons from other specialities. The procedure should be done by a team of surgeons with appropriate expertise. The procedure should only be done in accredited specialised units. For auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).# The condition, current treatments and procedure # The condition Early symptoms of ovarian cancer can be similar to those of other pelvic or abdominal conditions and include persistent bloating, pain in the pelvis and lower abdomen, urinary frequency and urinary urgency. Ovarian cancer is usually at stage 3 or 4 when it is diagnosed and the outcome is generally poor. The overall 5‑year survival rate for ovarian cancer is about 43%, and is lower for people with more advanced disease. The stage of the disease at diagnosis is the most important factor affecting outcome and is defined by the International Federation of Gynecology and Obstetrics (FIGO) system: Stage 1 (A to C): the tumour is confined to the ovary. Stage 2 (A, B): the tumour involves 1 or both ovaries and has extended into the pelvis. Stage 3 (A to C): the tumour involves 1 or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis, or regional lymph node metastasis (if cancer cells are found only in fluid taken from inside the abdomen the cancer is stage 2). Stage 4 (A, B): there is distant metastasis beyond the peritoneal cavity (if ovarian cancer is only found on the surface of the liver and not within the liver itself, then the cancer is stage 3). The FIGO stage does not fully take into account the tumour load and disease extent in advanced disease. # Current treatments NICE's guideline on the recognition and initial management of ovarian cancer describes the initial management options. The main treatments for advanced ovarian cancer are surgery to remove all macroscopic residual disease (residual disease is cancer left behind at the end of cytoreductive surgery; this type of surgery is also known as debulking) and chemotherapy. Standard surgery usually involves, as a minimum, bilateral salpingo-oophorectomy, total abdominal hysterectomy and omentectomy. Maximal cytoreductive surgery uses additional surgical procedures, including upper abdominal surgery, with the aim of achieving no residual disease. The most important factors affecting outcomes after surgery are responsiveness to platinum-based chemotherapy and the amount of residual disease. Conventional imaging techniques cannot accurately predict the distribution or volume of disease before surgery. Therefore, the only definitive assessment of the distribution or volume of disease found in the abdomen and pelvis is done at the time of surgery. Currently, no objective tools exist to select people for surgery and a decision for surgery will depend on many factors, including fitness, patient choice, availability of surgeons with appropriate expertise and resource levels. # The procedure The aim of maximal cytoreductive surgery for advanced ovarian cancer is to safely remove all identifiable disease, to improve survival, compared with surgery that leaves residual disease. It is a development and extension of standard surgery for ovarian cancer. The precise differences between standard, radical and maximal cytoreduction procedures are not well defined. Surgical complexity scores, such as the Aletti system, have been developed to try to quantify the complexity of surgery. Each procedure that is done during the surgery is allocated a score: total hysterectomy and bilateral salpingo-oophorectomy: 1 -mentectomy: 1 pelvic lymphadenectomy: 1 para-aortic lymphadenectomy: 1 pelvic peritoneum stripping: 1 abdominal peritoneum stripping: 1 rectosigmoidectomy anastomosis: 3 large bowel resection: 2 diaphragm stripping or resection: 2 splenectomy: 2 liver resection: 2 small bowel resection: 1.The total score can then be used to categorise the surgery into low complexity (1 to 3), intermediate complexity (4 to 7) or high complexity (8 and above).	{'Recommendations': "Evidence on the safety and efficacy of maximal cytoreductive surgery for advanced ovarian cancer is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a specialist gynaecological cancer multidisciplinary team, which may include surgeons from other specialities.\n\nThe procedure should be done by a team of surgeons with appropriate expertise. The procedure should only be done in accredited specialised units.\n\nFor auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).", 'The condition, current treatments and procedure': "# The condition\n\nEarly symptoms of ovarian cancer can be similar to those of other pelvic or abdominal conditions and include persistent bloating, pain in the pelvis and lower abdomen, urinary frequency and urinary urgency. Ovarian cancer is usually at stage\xa03 or\xa04 when it is diagnosed and the outcome is generally poor. The overall 5‑year survival rate for ovarian cancer is about 43%, and is lower for people with more advanced disease. The stage of the disease at diagnosis is the most important factor affecting outcome and is defined by the International Federation of Gynecology and Obstetrics (FIGO) system:\n\nStage\xa01 (A to C): the tumour is confined to the ovary.\n\nStage\xa02 (A, B): the tumour involves 1 or both ovaries and has extended into the pelvis.\n\nStage\xa03 (A to C): the tumour involves 1 or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis, or regional lymph node metastasis (if cancer cells are found only in fluid taken from inside the abdomen the cancer is stage\xa02).\n\nStage\xa04 (A, B): there is distant metastasis beyond the peritoneal cavity (if ovarian cancer is only found on the surface of the liver and not within the liver itself, then the cancer is stage\xa03).\n\nThe FIGO stage does not fully take into account the tumour load and disease extent in advanced disease.\n\n# Current treatments\n\nNICE's guideline on the recognition and initial management of ovarian cancer describes the initial management options. The main treatments for advanced ovarian cancer are surgery to remove all macroscopic residual disease (residual disease is cancer left behind at the end of cytoreductive surgery; this type of surgery is also known as debulking) and chemotherapy. Standard surgery usually involves, as a minimum, bilateral salpingo-oophorectomy, total abdominal hysterectomy and omentectomy. Maximal cytoreductive surgery uses additional surgical procedures, including upper abdominal surgery, with the aim of achieving no residual disease. The most important factors affecting outcomes after surgery are responsiveness to platinum-based chemotherapy and the amount of residual disease.\n\nConventional imaging techniques cannot accurately predict the distribution or volume of disease before surgery. Therefore, the only definitive assessment of the distribution or volume of disease found in the abdomen and pelvis is done at the time of surgery. Currently, no objective tools exist to select people for surgery and a decision for surgery will depend on many factors, including fitness, patient choice, availability of surgeons with appropriate expertise and resource levels.\n\n# The procedure\n\nThe aim of maximal cytoreductive surgery for advanced ovarian cancer is to safely remove all identifiable disease, to improve survival, compared with surgery that leaves residual disease. It is a development and extension of standard surgery for ovarian cancer.\n\nThe precise differences between standard, radical and maximal cytoreduction procedures are not well defined. Surgical complexity scores, such as the Aletti system, have been developed to try to quantify the complexity of surgery. Each procedure that is done during the surgery is allocated a score:\n\ntotal hysterectomy and bilateral salpingo-oophorectomy: 1\n\nomentectomy: 1\n\npelvic lymphadenectomy: 1\n\npara-aortic lymphadenectomy: 1\n\npelvic peritoneum stripping: 1\n\nabdominal peritoneum stripping: 1\n\nrectosigmoidectomy anastomosis: 3\n\nlarge bowel resection: 2\n\ndiaphragm stripping or resection: 2\n\nsplenectomy: 2\n\nliver resection: 2\n\nsmall bowel resection: 1.The total score can then be used to categorise the surgery into low complexity (1 to 3), intermediate complexity (4 to 7) or high complexity (8 and above)."}	https://www.nice.org.uk/guidance/ipg757	Evidence-based recommendations on maximal cytoreductive surgery for advanced ovarian cancer. This involves removing all or almost all visible cancerous tissue. More tissue is removed than with standard surgery. The aim is to improve outcomes for people with advanced ovarian cancer.
00b1fba8a35bd7853972eedc5f5459ef8e01f5e5	nice	Percutaneous thoracic duct embolisation for persistent chyle leak	Percutaneous thoracic duct embolisation for persistent chyle leak Evidence-based recommendations on percutaneous thoracic duct embolisation for persistent chyle leak. In this procedure, under general anaesthesia, ultrasound and X-rays are used to create an image of the thoracic duct and find the leak. Then, using a needle, a tube is inserted through the abdominal wall (percutaneous) and guided into the thoracic duct. Small metal coils and medical glue are inserted through the tube and used to plug the leak (embolisation). The aim is to stop the leak. # Recommendations Evidence on the safety and efficacy of percutaneous thoracic duct embolisation for persistent chyle leak is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do percutaneous thoracic duct embolisation for persistent chyle leak should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a team experienced in managing the condition, including a dietitian. The procedure should only be done in specialist centres by clinicians with specific training and experience in this procedure. NICE encourages further research into percutaneous thoracic duct embolisation for persistent chyle leak. Research should include details of patient selection, size and position of the leak, approaches used, and short- and long-term efficacy and safety outcomes.# The condition, current treatments and procedure # The condition Chyle leak or discharge can occur as a result of thoracic duct injury (injury to the structure that returns lymph and chyle from the lower half of the body). Injury can happen during surgery, from trauma or from disease such as cancer. Chyle leak can cause delayed wound healing, dehydration, malnutrition, electrolyte imbalance, breathing problems and immunosuppression. # Current treatments Small chyle leaks are usually treated with medicines and by managing nutrition (including by modifying diet or with total parenteral nutrition) to reduce chyle secretion and relieve symptoms. Persistent high-volume leaks may need drainage or percutaneous or open surgical repair (such as thoracic duct ligation). # The procedure Thoracic duct embolisation is a percutaneous image-guided closure of the thoracic duct and is done under general or local anaesthesia. It is a 3‑step process consisting of intranodal inguinal lymphangiography followed by percutaneous transabdominal catheterisation of the thoracic duct or cisterna chyli and then embolisation of the thoracic duct. Under fluoroscopic or ultrasound guidance, an oil-based contrast medium is injected into inguinal lymph nodes. This progresses slowly through the network of pelvic and retroperitoneal lymphatic vessels and allows the thoracic duct and cisterna chyli to be visualised. Then, through transabdominal access under imaging guidance, the target thoracic duct or cisterna chyli is accessed with a guidewire using a needle. A microcatheter is advanced over the guidewire into the thoracic duct, then the guidewire is removed. Contrast medium is injected through the catheter to define the source of the leak and the thoracic duct anatomy. The target thoracic duct and its branches are embolised proximally to the leak with a combination of microcoils and cyanoacrylate glue.	{'Recommendations': "Evidence on the safety and efficacy of percutaneous thoracic duct embolisation for persistent chyle leak is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do percutaneous thoracic duct embolisation for persistent chyle leak should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a team experienced in managing the condition, including a dietitian.\n\nThe procedure should only be done in specialist centres by clinicians with specific training and experience in this procedure.\n\nNICE encourages further research into percutaneous thoracic duct embolisation for persistent chyle leak. Research should include details of patient selection, size and position of the leak, approaches used, and short- and long-term efficacy and safety outcomes.", 'The condition, current treatments and procedure': '# The condition\n\nChyle leak or discharge can occur as a result of thoracic duct injury (injury to the structure that returns lymph and chyle from the lower half of the body). Injury can happen during surgery, from trauma or from disease such as cancer. Chyle leak can cause delayed wound healing, dehydration, malnutrition, electrolyte imbalance, breathing problems and immunosuppression.\n\n# Current treatments\n\nSmall chyle leaks are usually treated with medicines and by managing nutrition (including by modifying diet or with total parenteral nutrition) to reduce chyle secretion and relieve symptoms. Persistent high-volume leaks may need drainage or percutaneous or open surgical repair (such as thoracic duct ligation).\n\n# The procedure\n\nThoracic duct embolisation is a percutaneous image-guided closure of the thoracic duct and is done under general or local anaesthesia. It is a 3‑step process consisting of intranodal inguinal lymphangiography followed by percutaneous transabdominal catheterisation of the thoracic duct or cisterna chyli and then embolisation of the thoracic duct.\n\nUnder fluoroscopic or ultrasound guidance, an oil-based contrast medium is injected into inguinal lymph nodes. This progresses slowly through the network of pelvic and retroperitoneal lymphatic vessels and allows the thoracic duct and cisterna chyli to be visualised. Then, through transabdominal access under imaging guidance, the target thoracic duct or cisterna chyli is accessed with a guidewire using a needle. A microcatheter is advanced over the guidewire into the thoracic duct, then the guidewire is removed. Contrast medium is injected through the catheter to define the source of the leak and the thoracic duct anatomy. The target thoracic duct and its branches are embolised proximally to the leak with a combination of microcoils and cyanoacrylate glue.'}	https://www.nice.org.uk/guidance/ipg755	Evidence-based recommendations on percutaneous thoracic duct embolisation for persistent chyle leak. In this procedure, under general anaesthesia, ultrasound and X-rays are used to create an image of the thoracic duct and find the leak. Then, using a needle, a tube is inserted through the abdominal wall (percutaneous) and guided into the thoracic duct. Small metal coils and medical glue are inserted through the tube and used to plug the leak (embolisation). The aim is to stop the leak.
d60459a3456b32f961281227013b6a6eb8992d8a	nice	Radiofrequency ablation for palliation of painful spinal metastases	Radiofrequency ablation for palliation of painful spinal metastases Evidence-based recommendations on radiofrequency ablation for palliation of painful spinal metastases. This involves inserting a needle-like probe containing an electrode into the spinal metastases. This produces an electrical current that aims to relieve pain and other symptoms. # Recommendations Evidence on the safety and efficacy of radiofrequency ablation for palliation of painful spinal metastases is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do radiofrequency ablation for palliation of painful spinal metastases should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people and their families and carers understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a multidisciplinary team. The procedure should only be done by clinicians with training and expertise in vertebral interventions. NICE encourages further research into the procedure. This should report details of patient selection, type of tumour and interventional procedures used.# The condition, current treatments and procedure # The condition Spinal metastases can affect quality of life by causing severe pain, functional impairment, vertebral fractures, nerve root impingement, spinal cord compression and hypercalcaemia. # Current treatments Treatment for spinal metastases is always palliative. It aims to reduce pain, improve and maintain function, provide mechanical stability, and prevent further local tumour progression. Current treatment options include a combination of medical therapies (such as analgesics, systemic therapies including osteoclastic inhibitors such as bisphosphonates and denosumab, chemotherapy or hormone therapy), orthotic support, radiation therapy (external beam radiotherapy or stereotactic body radiotherapy), and minimally invasive localised percutaneous procedures such as cryoablation, photodynamic therapy, microwave ablation and radiofrequency ablation. These techniques may also be used with kyphoplasty or vertebroplasty to improve structural or mechanical stabilisation after tumour ablation. Open surgery (or surgery combined with radiotherapy) may be suitable for some people with spinal cord compression and vertebral fractures. # The procedure Radiofrequency ablation is a procedure for palliative treatment of spinal metastases. It is usually done in a day-case setting using a transpedicular or parapedicular approach under general anaesthesia or local anaesthesia with sedation. The approach is either percutaneous, endoscopic or surgical. Under imaging guidance (fluoroscopy, CT or MRI), a radiofrequency probe is inserted into the spinal tumour. The radiofrequency probe is attached to a radiofrequency generator, which creates high-frequency alternating current pulses that heat and destroy the tumour. Radiofrequency ablation is not usually done if the spinal metastases are close to neurological structures because of the risk of neurological injury. This is a standalone radiofrequency ablation procedure and not an adjunct to vertebroplasty or kyphoplasty.	{'Recommendations': "Evidence on the safety and efficacy of radiofrequency ablation for palliation of painful spinal metastases is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do radiofrequency ablation for palliation of painful spinal metastases should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people and their families and carers understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team. The procedure should only be done by clinicians with training and expertise in vertebral interventions.\n\nNICE encourages further research into the procedure. This should report details of patient selection, type of tumour and interventional procedures used.", 'The condition, current treatments and procedure': '# The condition\n\nSpinal metastases can affect quality of life by causing severe pain, functional impairment, vertebral fractures, nerve root impingement, spinal cord compression and hypercalcaemia.\n\n# Current treatments\n\nTreatment for spinal metastases is always palliative. It aims to reduce pain, improve and maintain function, provide mechanical stability, and prevent further local tumour progression. Current treatment options include a combination of medical therapies (such as analgesics, systemic therapies including osteoclastic inhibitors such as bisphosphonates and denosumab, chemotherapy or hormone therapy), orthotic support, radiation therapy (external beam radiotherapy or stereotactic body radiotherapy), and minimally invasive localised percutaneous procedures such as cryoablation, photodynamic therapy, microwave ablation and radiofrequency ablation. These techniques may also be used with kyphoplasty or vertebroplasty to improve structural or mechanical stabilisation after tumour ablation. Open surgery (or surgery combined with radiotherapy) may be suitable for some people with spinal cord compression and vertebral fractures.\n\n# The procedure\n\nRadiofrequency ablation is a procedure for palliative treatment of spinal metastases. It is usually done in a day-case setting using a transpedicular or parapedicular approach under general anaesthesia or local anaesthesia with sedation. The approach is either percutaneous, endoscopic or surgical.\n\nUnder imaging guidance (fluoroscopy, CT or MRI), a radiofrequency probe is inserted into the spinal tumour. The radiofrequency probe is attached to a radiofrequency generator, which creates high-frequency alternating current pulses that heat and destroy the tumour.\n\nRadiofrequency ablation is not usually done if the spinal metastases are close to neurological structures because of the risk of neurological injury.\n\nThis is a standalone radiofrequency ablation procedure and not an adjunct to vertebroplasty or kyphoplasty.'}	https://www.nice.org.uk/guidance/ipg758	Evidence-based recommendations on radiofrequency ablation for palliation of painful spinal metastases. This involves inserting a needle-like probe containing an electrode into the spinal metastases. This produces an electrical current that aims to relieve pain and other symptoms.
96081965be5630a2cd4f3d5a18f9a90828299d41	nice	Focal therapy using high-intensity focused ultrasound for localised prostate cancer	Focal therapy using high-intensity focused ultrasound for localised prostate cancer Evidence-based recommendations on focal therapy using high-intensity focused ultrasound for localised prostate cancer. This involves using high-intensity focused ultrasound to heat up and destroy only the areas of the prostate with cancer (focal therapy). The aim is to destroy the cancer while reducing damage to healthy prostate tissue. # Recommendations Evidence on the safety of focal therapy using high-intensity focused ultrasound for localised prostate cancer is adequate, but evidence on its efficacy is limited. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do high-intensity focused ultrasound for localised prostate cancer should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public. Use the recommendations in NICE's guideline on diagnosing and managing prostate cancer for information on treatment options and decision support. Ensure that people (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be done by a multidisciplinary team. Further research could include registry data or randomised trials. It should include details of patient selection, including size and classification of tumour, technique used and long-term outcomes such as quality of life.# The condition, current treatments and procedure # The condition Prostate cancer can cause some lower urinary tract symptoms such as frequency, urgency, hesitancy, terminal dribbling and an overactive bladder. Localised prostate cancer is confined to the prostate and has not spread to nearby tissues or other parts of the body. # Current treatments NICE's guideline on prostate cancer describes how to diagnose and manage prostate cancer. Decisions on treatment are based on imaging, tumour staging, risk assessment and prostate-specific antigen (PSA) levels. For some people, localised prostate cancer grows slowly or not at all, and treatment may not be necessary. In such cases, watchful waiting or active surveillance strategies may be appropriate. If treatment is needed, several options are available. These include radical treatments (such as radical prostatectomy, external beam radiotherapy and radical brachytherapy), focal treatments (such as focal high-intensity focused ultrasound , focal cryoablation, irreversible electroporation, focal laser ablation and focal brachytherapy) and adjunctive treatments (such as chemotherapy and androgen deprivation therapy). # The procedure Imaging and biopsy mapping are used to confirm that the tumour is suitable for focal therapy and to show its precise location. With the person under spinal or general anaesthesia, the bladder is catheterised using a urethral or supra-pubic catheter and the HIFU probe is inserted transrectally. Ultrasound imaging guidance is used to position the probe and to monitor the procedure. Pulses of HIFU are directed at the targeted part of the prostate, inducing tumour necrosis by a thermal effect and causing cavitation (which can be visualised by ultrasound to assess the adequacy of treatment) until satisfactory ablation of the target area is judged to have occurred. This procedure differs from standard whole-gland HIFU in that only some of the prostate is treated. Transurethral resection of the prostate may be done at the same time as focal HIFU to reduce urinary symptoms.	{'Recommendations': "Evidence on the safety of focal therapy using high-intensity focused ultrasound for localised prostate cancer is adequate, but evidence on its efficacy is limited. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do high-intensity focused ultrasound for localised prostate cancer should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public. Use the recommendations in NICE's guideline on diagnosing and managing prostate cancer for information on treatment options and decision support.\n\nEnsure that people (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team.\n\nFurther research could include registry data or randomised trials. It should include details of patient selection, including size and classification of tumour, technique used and long-term outcomes such as quality of life.", 'The condition, current treatments and procedure': "# The condition\n\nProstate cancer can cause some lower urinary tract symptoms such as frequency, urgency, hesitancy, terminal dribbling and an overactive bladder. Localised prostate cancer is confined to the prostate and has not spread to nearby tissues or other parts of the body.\n\n# Current treatments\n\nNICE's guideline on prostate cancer describes how to diagnose and manage prostate cancer. Decisions on treatment are based on imaging, tumour staging, risk assessment and prostate-specific antigen (PSA) levels. For some people, localised prostate cancer grows slowly or not at all, and treatment may not be necessary. In such cases, watchful waiting or active surveillance strategies may be appropriate. If treatment is needed, several options are available. These include radical treatments (such as radical prostatectomy, external beam radiotherapy and radical brachytherapy), focal treatments (such as focal high-intensity focused ultrasound [HIFU], focal cryoablation, irreversible electroporation, focal laser ablation and focal brachytherapy) and adjunctive treatments (such as chemotherapy and androgen deprivation therapy).\n\n# The procedure\n\nImaging and biopsy mapping are used to confirm that the tumour is suitable for focal therapy and to show its precise location. With the person under spinal or general anaesthesia, the bladder is catheterised using a urethral or supra-pubic catheter and the HIFU probe is inserted transrectally. Ultrasound imaging guidance is used to position the probe and to monitor the procedure. Pulses of HIFU are directed at the targeted part of the prostate, inducing tumour necrosis by a thermal effect and causing cavitation (which can be visualised by ultrasound to assess the adequacy of treatment) until satisfactory ablation of the target area is judged to have occurred. This procedure differs from standard whole-gland HIFU in that only some of the prostate is treated. Transurethral resection of the prostate may be done at the same time as focal HIFU to reduce urinary symptoms."}	https://www.nice.org.uk/guidance/ipg756	Evidence-based recommendations on focal therapy using high-intensity focused ultrasound for localised prostate cancer. This involves using high-intensity focused ultrasound to heat up and destroy only the areas of the prostate with cancer (focal therapy). The aim is to destroy the cancer while reducing damage to healthy prostate tissue.
fb01e158090525aef8421d738a7eb3a24eea7586	nice	Radiofrequency ablation as an adjunct to balloon kyphoplasty or percutaneous vertebroplasty for palliation of painful spinal metastases	Radiofrequency ablation as an adjunct to balloon kyphoplasty or percutaneous vertebroplasty for palliation of painful spinal metastases Evidence-based recommendations on radiofrequency ablation as an adjunct to balloon kyphoplasty or percutaneous vertebroplasty for palliation of painful spinal metastases. This involves inserting a needle-like probe containing an electrode into the spinal metastases. This produces an electrical current that aims to relieve pain and other symptoms. # Recommendations Evidence on the safety and efficacy of radiofrequency ablation as an adjunct to balloon kyphoplasty or percutaneous vertebroplasty for palliation of painful spinal metastases is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. For auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Patient selection should be done by a multidisciplinary team. The procedure should only be done by clinicians with training and expertise in kyphoplasty or vertebroplasty techniques.# The condition, current treatments and procedure # The condition Spinal metastases can affect quality of life by causing severe pain, functional impairment, vertebral fractures, nerve root impingement, spinal cord compression and hypercalcaemia. # Current treatments Treatment for spinal metastases is always palliative. It aims to reduce pain, improve and maintain function, provide mechanical stability and prevent further local tumour progression. Current treatment options include a combination of medical therapies (such as analgesics, systemic therapies including osteoclastic inhibitors such as bisphosphonates and denosumab, chemotherapy or hormone therapy), orthotic support, radiation therapy (external beam radiotherapy or stereotactic body radiotherapy) and minimally invasive localised percutaneous procedures such as cryoablation, photodynamic therapy, microwave ablation and radiofrequency ablation. These techniques may also be used with kyphoplasty or vertebroplasty to improve structural or mechanical stabilisation after tumour ablation. Open surgery (or surgery combined with radiotherapy) may be suitable for some people with spinal cord compression and vertebral fractures. # The procedure Radiofrequency ablation is a procedure for palliative treatment of spinal metastases. It is usually done in a day-case setting using a transpedicular or parapedicular approach under general anaesthesia or local anaesthesia with sedation. The approach is either percutaneous, endoscopic or surgical. Under imaging guidance (fluoroscopy, CT or MRI), a radiofrequency probe is inserted into the spinal tumour. The radiofrequency probe is attached to a radiofrequency generator, which creates high-frequency, alternating current pulses that heat and destroy the tumour. This creates a cavity in the vertebral body. In this procedure, percutaneous vertebroplasty or balloon kyphoplasty is done at the same time with the aim of preventing subsequent fractures in the treated vertebrae. Radiofrequency ablation is not usually done if the spinal metastases are close to neurological structures because of the risk of neurological injury.	{'Recommendations': "Evidence on the safety and efficacy of radiofrequency ablation as an adjunct to balloon kyphoplasty or percutaneous vertebroplasty for palliation of painful spinal metastases is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nFor auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nPatient selection should be done by a multidisciplinary team. The procedure should only be done by clinicians with training and expertise in kyphoplasty or vertebroplasty techniques.", 'The condition, current treatments and procedure': '# The condition\n\nSpinal metastases can affect quality of life by causing severe pain, functional impairment, vertebral fractures, nerve root impingement, spinal cord compression and hypercalcaemia.\n\n# Current treatments\n\nTreatment for spinal metastases is always palliative. It aims to reduce pain, improve and maintain function, provide mechanical stability and prevent further local tumour progression. Current treatment options include a combination of medical therapies (such as analgesics, systemic therapies including osteoclastic inhibitors such as bisphosphonates and denosumab, chemotherapy or hormone therapy), orthotic support, radiation therapy (external beam radiotherapy or stereotactic body radiotherapy) and minimally invasive localised percutaneous procedures such as cryoablation, photodynamic therapy, microwave ablation and radiofrequency ablation. These techniques may also be used with kyphoplasty or vertebroplasty to improve structural or mechanical stabilisation after tumour ablation. Open surgery (or surgery combined with radiotherapy) may be suitable for some people with spinal cord compression and vertebral fractures.\n\n# The procedure\n\nRadiofrequency ablation is a procedure for palliative treatment of spinal metastases. It is usually done in a day-case setting using a transpedicular or parapedicular approach under general anaesthesia or local anaesthesia with sedation. The approach is either percutaneous, endoscopic or surgical.\n\nUnder imaging guidance (fluoroscopy, CT or MRI), a radiofrequency probe is inserted into the spinal tumour. The radiofrequency probe is attached to a radiofrequency generator, which creates high-frequency, alternating current pulses that heat and destroy the tumour. This creates a cavity in the vertebral body. In this procedure, percutaneous vertebroplasty or balloon kyphoplasty is done at the same time with the aim of preventing subsequent fractures in the treated vertebrae.\n\nRadiofrequency ablation is not usually done if the spinal metastases are close to neurological structures because of the risk of neurological injury.'}	https://www.nice.org.uk/guidance/ipg759	Evidence-based recommendations on radiofrequency ablation as an adjunct to balloon kyphoplasty or percutaneous vertebroplasty for palliation of painful spinal metastases. This involves inserting a needle-like probe containing an electrode into the spinal metastases. This produces an electrical current that aims to relieve pain and other symptoms.
109e3ef87423ca49f84ec04918104bedab56f895	nice	UrgoStart for treating diabetic foot ulcers and leg ulcers	UrgoStart for treating diabetic foot ulcers and leg ulcers Evidence-based recommendations on UrgoStart for treating diabetic foot ulcers and leg ulcers. # Recommendations UrgoStart is recommended as a cost saving option to treat diabetic foot ulcers and venous leg ulcers. There is not enough evidence to support the case for routine adoption of UrgoStart for non-venous leg ulcers. Why the committee made these recommendations UrgoStart is a range of dressings which can improve wound healing for diabetic foot ulcers and improve the rate of wound healing for venous leg ulcers. Cost modelling shows that UrgoStart is cost saving compared with standard care dressings in these groups. UrgoStart should therefore be considered as an option for people with diabetic foot ulcers or venous leg ulcers after any modifiable factors such as infection have been treated. There is less evidence for non-venous leg ulcers so, although clinical benefits are possible, further evidence is needed to make a recommendation.# The technology # Technology UrgoStart (Urgo Medical) is an interactive dressing for treating diabetic foot ulcers and leg ulcers. It consists of a layer of open-weave polyester mesh impregnated with hydrocolloid polymers within a petroleum jelly known as technology lipido-colloid (TLC). It also contains nano-oligosaccharide factor (NOSF) and has an absorbent pad and a semi-permeable backing. There are 5 formats of the dressing and each comes in different sizes: UrgoStart Contact Layer, UrgoStart Non-Adhesive, UrgoStart Plus Pad, UrgoStart Border and UrgoStart Plus Border. # Innovative aspects The TLC-NOSF layer is a combination of the patented TLC technology, which is intended to create a moist protective wound healing environment, and the NOSF, which inhibits protease activity, specifically matrix metalloproteinases, and this is claimed to accelerate healing. # Intended use UrgoStart is intended for treating chronic wounds. The indications addressed in this evaluation are leg ulcers and diabetic foot ulcers. # Costs UrgoStart has a typical list price of £4.28 per dressing.For more details, see the Urgo Medical website.# Evidence # Clinical evidence ## Relevant evidence comes from 5 studies, 3 of which are randomised controlled trials Of the 5 studies that met the inclusion criteria defined in the scope, 2 were randomised controlled trials in venous and mixed leg ulcers and 1 was a randomised controlled trial in diabetic foot ulcers. There is also a non-comparative study in diabetic foot ulcers and a pooled analysis of non-comparative observational studies, which included both patient groups. For full details of the clinical evidence, see section 3 of the assessment report. ## Results from EXPLORER show an increase in wound closure for diabetic foot ulcers The multicentre, double-blind, international randomised controlled trial EXPLORER (n=240; 20‑week follow-up) compared UrgoStart with UrgoTul, a non-interactive dressing (Edmonds et al. 2018). The results reported a statistically significant increase in complete wound closure in favour of UrgoStart (p=0.002), as well as a statistically significant increase in absolute wound area reduction (p=0.022). Adverse effects and quality of life were similar in the 2 groups. The external assessment centre (EAC) noted that this was a European international study with some patients recruited from UK centres, but the number of patients recruited per centre was low (median=3) and the study only included patients with neuro-ischaemic ulcers. ## Results from CHALLENGE show an increase in wound area reduction in the first 8 weeks for venous leg ulcers The multicentre, double-blind, international randomised controlled trial CHALLENGE (n=187; 8‑week study period) compared UrgoStart with UrgoTul Absorb, a non-interactive dressing (Meaume et al. 2012 and Meaume et al. 2017). Compression therapy was used in both the intervention and control groups (more than 96% at week 6). The results reported a statistically significant increase in relative wound area reduction (p=0.002) and in absolute wound area reduction (p=0.003) in favour of UrgoStart. Use of UrgoStart also resulted in a statistically significant improvement in the pain and discomfort dimensions of the EQ‑5D (p=0.022). Adverse effects and patient acceptance were similar in the 2 groups. The EAC noted that the follow-up period of 8 weeks was potentially too short to assess healing in complex wounds, and only 13 wounds in total were completely healed by the end of the study (equally spread across the 2 treatment arms). No UK sites were included in this study, and there was a small number of patients per centre (mean=4.2). ## A pooled analysis of non-observational studies broadly supports the evidence from the randomised controlled trials Evidence from a pooled analysis of non-comparative data from 8 observational studies (Munter et al. 2017) supported the healing rates of diabetic foot and venous leg ulcers seen with UrgoStart in the randomised controlled trials. The analysis included more than 10,000 patients with chronic wounds, of whom 7,903 had venous leg ulcers and 1,306 had diabetic foot ulcers. However, the EAC noted that there were a range of follow-up periods (4 to 20 weeks), outcome measures and distributions of ulcer type in the included studies. ## guidance review As part of the guidance surveillance process, new clinical evidence for UrgoStart was reviewed. A total of 22 eligible new clinical studies were identified. The EAG did not identify any evidence that contradicts the current NICE guidance for the UrgoStart range. Three studies noted that wound duration at baseline was an important predictor of outcome following UrgoStart use, with a shorter wound duration leading to better wound healing outcomes. There was still not enough evidence to recommend UrgoStart for non-venous leg ulcers because of a lack of new evidence explicitly in this population. For more on the new evidence, see the review report. # Cost evidence ## The company's models for both leg ulcers and diabetic foot ulcers show cost savings with UrgoStart The company presented separate de novo cost-effectiveness models for leg ulcers and diabetic foot ulcers. The leg ulcer model was a Markov model with a 1‑week cycle length, which incorporated 3 health states. The diabetic foot ulcer model was more complicated and included 6 health states. The company presented base-case results with a time horizon of 1 year. The results showed that compared with non-interactive dressings, UrgoStart was associated with savings of £274.25 per patient per year for leg ulcers and £666.51 per patient per year for diabetic foot ulcers. ## The EAC's changes to the model parameters and its calibrations more accurately reflect NHS costs and consequences The EAC considered that both model structures presented by the company adequately captured all the relevant health states, and that the assumptions were valid and reasonable. However, it changed some parameter values with which it did not agree. The EAC also calibrated the models to align with the healing outcomes and resource use from published UK studies (Guest et al. 2018a and 2018b). In its changes to the models, the EAC assumed that: diabetic foot ulcers would not heal in 20% of patients and treatment would continue for 1.4 months (6.09 weeks) on average before the dressing was changed to a different product leg ulcers would not heal in 37.6% of patients and treatment would continue for 1.9 months (8.26 weeks) on average before the dressing was changed to a different product. ## The EAC's updated models show that UrgoStart is likely to be cost saving Results from the EAC's base-case analysis showed that UrgoStart compared with standard care was associated with cost savings of £541 per patient per year for leg ulcers and £342 per patient per year for diabetic foot ulcers. The main drivers of the savings were the cost of dressings, the transition parameters for healing and infection or complications, and the cost of community nursing and hospital visits. Sensitivity analyses showed that UrgoStart was always cost saving for leg ulcers, but that it became cost incurring for diabetic foot ulcers if the healing rate was assumed to be half of that reported in the EXPLORER trial. For full details of the cost evidence, see section 4 of the assessment report.# Committee discussion # Clinical-effectiveness overview ## Results from the EXPLORER trial show faster complete healing with UrgoStart dressings in diabetic foot ulcers The committee concluded that the EXPLORER study provided convincing evidence that UrgoStart dressings improve complete wound healing in patients with diabetic foot ulcers. It noted the external assessment centre (EAC) conclusions that there was a low risk of bias in this study, and that the reported benefits associated with UrgoStart were also supported by the pooled analysis of non-comparative observational data. Although most of the evidence came from patients with neuro-ischaemic ulcers, a clinical expert advised that similar care is used for both neuropathic and neuro-ischaemic diabetic foot ulcers. The committee concluded that the use of UrgoStart, when used as part of overall management, improves wound healing in people with diabetic foot ulcers. ## Results from the CHALLENGE study show a faster rate of early healing with UrgoStart dressings in venous leg ulcers The committee concluded that the results of the CHALLENGE study showed an increase in the rate of early wound healing with UrgoStart in patients with venous leg ulcers compared with standard treatment. It noted, however, that the study period of 8 weeks was relatively short, and that the observed treatment benefit was based on measuring increased wound area reduction rather than complete wound closure. The clinical experts confirmed that rapid wound area reduction in the first 8 weeks is a good surrogate for ultimately complete wound closure, but that this is not definitive. The experts stated that venous leg ulcers typically heal completely within 18 to 24 weeks. The committee noted the EAC conclusion that there was a low risk of bias in this study, and also that the benefits associated with UrgoStart were supported by the observational data. It concluded that UrgoStart improves wound healing in venous leg ulcers when used as part of overall management including compression therapy, although it was uncertain if this would be translated into complete wound closure. ## UrgoStart may lead to benefits that are important in improving day-to-day living in people with diabetic foot or venous leg ulcers The committee recognised how severely diabetic foot and venous leg ulcers affect people's quality of life. However, it concluded that there was limited published evidence to support any quality-of-life benefits directly as a result of using UrgoStart. The clinical experts explained that increases in wound closure and in the rate of wound area reduction are likely to be associated with improvements in day-to-day living. For people with diabetic foot ulcers, complete wound closure is usually necessary for them to return to unhindered walking. For people with venous leg ulcers, a reduction in the wound area may translate into important benefits including earlier transition to less cumbersome dressings and treatment in the community. The experts' comments were corroborated by a small sample of people who have used UrgoStart dressings and reported quality-of-life benefits associated with improved wound healing. The committee concluded that it was plausible that UrgoStart leads to benefits that are important in improving day-to-day living in people with diabetic foot or venous leg ulcers. # Relevance to the NHS ## The evidence for UrgoStart is broadly generalisable to the NHS Only a small proportion of the patients with diabetic foot ulcers in the EXPLORER study were recruited from a UK centre. There were no patients from the UK in any of the studies that investigated the benefits of UrgoStart in patients with leg ulcers. Clinical experts stated that the demographics of patients and the fundamentals of wound care are likely to be similar across Europe. However, the experts also explained that some differences in care may exist including, for example, the type of health professional giving the treatment and the compression pressure used to treat venous leg ulcers. The committee concluded that the evidence for UrgoStart was broadly generalisable to the NHS. ## There is insufficient evidence to recommend UrgoStart for non-venous leg ulcers The committee noted that most of the evidence of UrgoStart providing benefit in patients with leg ulcers was specifically for venous leg ulcers. The clinical experts confirmed that about 70% of leg ulcers are caused by venous disease. They also stated that compression is an important part of standard care for venous leg ulcers, but that treatment of non-venous leg ulcers relies on dressings alone. The committee concluded that even though it is plausible that there are benefits from using UrgoStart for non-venous leg ulcers, there was insufficient evidence to make a definitive recommendation about the use of UrgoStart in this group. # NHS considerations ## UrgoStart can be incorporated in care pathways by including it on local formularies The clinical experts explained that diabetic foot care, including ulcer management, varies across the NHS. Diabetic foot care usually involves a multi-disciplinary team; patients move between GP practice, secondary care and community care depending on their needs. Venous leg ulcers, on the other hand, are mostly treated in a community setting. New and novel dressings are usually incorporated into local care pathways through their inclusion in dressing formularies. The committee did not consider that the use of UrgoStart should be restricted to any particular setting in the NHS, but understood that the decision to use it would usually be made by a multi-disciplinary team or a tissue viability specialist. ## UrgoStart should be considered for patients with non-infected ulcers The clinical experts confirmed that UrgoStart would only be used after a thorough wound and patient assessment, and after interventions to control other modifiable factors including debridement and treatment of wound infection. The experts also agreed that if using UrgoStart dressings did not lead to progress in wound healing, they would change to a different product. The committee concluded that UrgoStart should be recommended for patients with non-infected diabetic foot ulcers or venous leg ulcers. # Cost-modelling overview ## The EAC's updated models are more plausible than the company's models and most appropriate for decision making The committee expressed concerns about the variability seen in wound healing rates, and questioned whether this was correctly reflected in the models. The EAC explained that it had calibrated the models to better reflect this, recognising that not all wounds will improve with treatment and in these instances UrgoStart would be replaced by a different dressing (6.09 weeks for diabetic foot ulcers and 8.26 weeks for venous leg ulcers). The calibration process included using data from the Guest et al. (2018a) and Guest et al. (2018b) papers, which summarised resource-use data taken from an electronic database of patients in 562 GP practices across the UK. These data were used to estimate the proportion of patients whose ulcers had not healed after 1 year in the comparator arms of both analyses. The committee agreed that the EAC's updated models were most appropriate for decision making. # Main cost drivers ## Estimates of cost savings are likely to be robust for treating diabetic foot ulcers but are less certain for treating venous leg ulcers The committee noted the importance of healing-rate parameters in the cost modelling. It was confident that UrgoStart improved complete wound healing, but was uncertain about the reliability of using an extrapolation method to derive complete wound healing rates from partial healing at 8 weeks in people with venous leg ulcers. In view of this, the committee concluded that the estimates of cost savings are likely to be robust when UrgoStart is used to treat diabetic foot ulcers, but that uncertainty remains about the cost savings when UrgoStart is used to treat venous leg ulcers. # Cost savings ## UrgoStart is likely to be cost saving compared with standard care but there are uncertainties in the size of these savings in people with venous leg ulcers The EAC's did deterministic sensitivity analyses that varied parameters in both cost models. Results showed that the technology remained cost saving in most cases. The committee concluded that, based on the published evidence, cost modelling and expert opinion, UrgoStart is likely to be cost saving compared with non-interactive dressings. For diabetic foot ulcers, the committee agreed with the estimate from the EAC's updated model of a £342 saving per patient per year with UrgoStart. For venous leg ulcers, it accepted that use of UrgoStart is likely to be cost saving but considered any estimates to be less certain, because of the uncertainty in the evidence for complete wound healing.	{'Recommendations': 'UrgoStart is recommended as a cost saving option to treat diabetic foot ulcers and venous leg ulcers.\n\nThere is not enough evidence to support the case for routine adoption of UrgoStart for non-venous leg ulcers.\n\nWhy the committee made these recommendations\n\nUrgoStart is a range of dressings which can improve wound healing for diabetic foot ulcers and improve the rate of wound healing for venous leg ulcers. Cost modelling shows that UrgoStart is cost saving compared with standard care dressings in these groups.\n\nUrgoStart should therefore be considered as an option for people with diabetic foot ulcers or venous leg ulcers after any modifiable factors such as infection have been treated.\n\nThere is less evidence for non-venous leg ulcers so, although clinical benefits are possible, further evidence is needed to make a recommendation.', 'The technology': '# Technology\n\nUrgoStart (Urgo Medical) is an interactive dressing for treating diabetic foot ulcers and leg ulcers. It consists of a layer of open-weave polyester mesh impregnated with hydrocolloid polymers within a petroleum jelly known as technology lipido-colloid (TLC). It also contains nano-oligosaccharide factor (NOSF) and has an absorbent pad and a semi-permeable backing.\n\nThere are 5\xa0formats of the dressing and each comes in different sizes: UrgoStart Contact Layer, UrgoStart Non-Adhesive, UrgoStart Plus Pad, UrgoStart Border and UrgoStart Plus Border.\n\n# Innovative aspects\n\nThe TLC-NOSF layer is a combination of the patented TLC technology, which is intended to create a moist protective wound healing environment, and the NOSF, which inhibits protease activity, specifically matrix metalloproteinases, and this is claimed to accelerate healing.\n\n# Intended use\n\nUrgoStart is intended for treating chronic wounds. The indications addressed in this evaluation are leg ulcers and diabetic foot ulcers.\n\n# Costs\n\nUrgoStart has a typical list price of £4.28\xa0per\xa0dressing.For more details, see the Urgo Medical website.', 'Evidence': "# Clinical evidence\n\n## Relevant evidence comes from 5\xa0studies, 3\xa0of which are randomised controlled trials\n\nOf the 5\xa0studies that met the inclusion criteria defined in the scope, 2\xa0were randomised controlled trials in venous and mixed leg ulcers and 1\xa0was a randomised controlled trial in diabetic foot ulcers. There is also a non-comparative study in diabetic foot ulcers and a pooled analysis of non-comparative observational studies, which included both patient groups. For full details of the clinical evidence, see section 3 of the assessment report.\n\n## Results from EXPLORER show an increase in wound closure for diabetic foot ulcers\n\nThe multicentre, double-blind, international randomised controlled trial EXPLORER (n=240; 20‑week\xa0follow-up) compared UrgoStart with UrgoTul, a non-interactive dressing (Edmonds\xa0et\xa0al. 2018). The results reported a statistically significant increase in complete wound closure in favour of UrgoStart (p=0.002), as well as a statistically significant increase in absolute wound area reduction (p=0.022). Adverse effects and quality of life were similar in the 2\xa0groups. The external assessment centre (EAC) noted that this was a European international study with some patients recruited from UK centres, but the number of patients recruited\xa0per\xa0centre was low (median=3) and the study only included patients with neuro-ischaemic ulcers.\n\n## Results from CHALLENGE show an increase in wound area reduction in the first 8\xa0weeks for venous leg ulcers\n\nThe multicentre, double-blind, international randomised controlled trial CHALLENGE (n=187; 8‑week\xa0study period) compared UrgoStart with UrgoTul Absorb, a non-interactive dressing (Meaume\xa0et\xa0al. 2012 and Meaume\xa0et\xa0al. 2017). Compression therapy was used in both the intervention and control groups (more than 96% at week\xa06). The results reported a statistically significant increase in relative wound area reduction (p=0.002) and in absolute wound area reduction (p=0.003) in favour of UrgoStart. Use of UrgoStart also resulted in a statistically significant improvement in the pain and discomfort dimensions of the EQ‑5D (p=0.022). Adverse effects and patient acceptance were similar in the 2\xa0groups. The EAC noted that the follow-up period of 8\xa0weeks was potentially too short to assess healing in complex wounds, and only 13\xa0wounds in total were completely healed by the end of the study (equally spread across the 2\xa0treatment arms). No UK sites were included in this study, and there was a small number of patients\xa0per\xa0centre (mean=4.2).\n\n## A pooled analysis of non-observational studies broadly supports the evidence from the randomised controlled trials\n\nEvidence from a pooled analysis of non-comparative data from 8\xa0observational studies (Munter\xa0et\xa0al. 2017) supported the healing rates of diabetic foot and venous leg ulcers seen with UrgoStart in the randomised controlled trials. The analysis included more than 10,000 patients with chronic wounds, of whom 7,903 had venous leg ulcers and 1,306 had diabetic foot ulcers. However, the EAC noted that there were a range of follow-up periods (4 to 20\xa0weeks), outcome measures and distributions of ulcer type in the included studies.\n\n## guidance review\n\nAs part of the guidance surveillance process, new clinical evidence for UrgoStart was reviewed. A total of 22 eligible new clinical studies were identified. The EAG did not identify any evidence that contradicts the current NICE guidance for the UrgoStart range. Three studies noted that wound duration at baseline was an important predictor of outcome following UrgoStart use, with a shorter wound duration leading to better wound healing outcomes. There was still not enough evidence to recommend UrgoStart for non-venous leg ulcers because of a lack of new evidence explicitly in this population. For more on the new evidence, see the review report. \n\n# Cost evidence\n\n## The company's models for both leg ulcers and diabetic foot ulcers show cost savings with UrgoStart\n\nThe company presented separate de novo cost-effectiveness models for leg ulcers and diabetic foot ulcers. The leg ulcer model was a Markov model with a 1‑week\xa0cycle length, which incorporated 3\xa0health states. The diabetic foot ulcer model was more complicated and included 6\xa0health states. The company presented base-case results with a time horizon of 1\xa0year. The results showed that compared with non-interactive dressings, UrgoStart was associated with savings of £274.25\xa0per\xa0patient\xa0per\xa0year for leg ulcers and £666.51\xa0per\xa0patient\xa0per\xa0year for diabetic foot ulcers.\n\n## The EAC's changes to the model parameters and its calibrations more accurately reflect NHS costs and consequences\n\nThe EAC considered that both model structures presented by the company adequately captured all the relevant health states, and that the assumptions were valid and reasonable. However, it changed some parameter values with which it did not agree. The EAC also calibrated the models to align with the healing outcomes and resource use from published UK studies (Guest\xa0et\xa0al. 2018a and 2018b). In its changes to the models, the EAC assumed that:\n\ndiabetic foot ulcers would not heal in 20% of patients and treatment would continue for 1.4 months (6.09\xa0weeks) on average before the dressing was changed to a different product\n\nleg ulcers would not heal in 37.6% of patients and treatment would continue for 1.9 months (8.26\xa0weeks) on average before the dressing was changed to a different product.\n\n## The EAC's updated models show that UrgoStart is likely to be cost saving\n\nResults from the EAC's base-case analysis showed that UrgoStart compared with standard care was associated with cost savings of £541\xa0per\xa0patient\xa0per\xa0year for leg ulcers and £342\xa0per\xa0patient\xa0per\xa0year for diabetic foot ulcers. The main drivers of the savings were the cost of dressings, the transition parameters for healing and infection or complications, and the cost of community nursing and hospital visits. Sensitivity analyses showed that UrgoStart was always cost saving for leg ulcers, but that it became cost incurring for diabetic foot ulcers if the healing rate was assumed to be half of that reported in the EXPLORER trial. For full details of the cost evidence, see section 4 of the assessment report.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Results from the EXPLORER trial show faster complete healing with UrgoStart dressings in diabetic foot ulcers\n\nThe committee concluded that the EXPLORER study provided convincing evidence that UrgoStart dressings improve complete wound healing in patients with diabetic foot ulcers. It noted the external assessment centre (EAC) conclusions that there was a low risk of bias in this study, and that the reported benefits associated with UrgoStart were also supported by the pooled analysis of non-comparative observational data. Although most of the evidence came from patients with neuro-ischaemic ulcers, a clinical expert advised that similar care is used for both neuropathic and neuro-ischaemic diabetic foot ulcers. The committee concluded that the use of UrgoStart, when used as part of overall management, improves wound healing in people with diabetic foot ulcers.\n\n## Results from the CHALLENGE study show a faster rate of early healing with UrgoStart dressings in venous leg ulcers\n\nThe committee concluded that the results of the CHALLENGE study showed an increase in the rate of early wound healing with UrgoStart in patients with venous leg ulcers compared with standard treatment. It noted, however, that the study period of 8\xa0weeks was relatively short, and that the observed treatment benefit was based on measuring increased wound area reduction rather than complete wound closure. The clinical experts confirmed that rapid wound area reduction in the first 8\xa0weeks is a good surrogate for ultimately complete wound closure, but that this is not definitive. The experts stated that venous leg ulcers typically heal completely within 18\xa0to\xa024\xa0weeks. The committee noted the EAC conclusion that there was a low risk of bias in this study, and also that the benefits associated with UrgoStart were supported by the observational data. It concluded that UrgoStart improves wound healing in venous leg ulcers when used as part of overall management including compression therapy, although it was uncertain if this would be translated into complete wound closure.\n\n## UrgoStart may lead to benefits that are important in improving day-to-day living in people with diabetic foot or venous leg ulcers\n\nThe committee recognised how severely diabetic foot and venous leg ulcers affect people's quality of life. However, it concluded that there was limited published evidence to support any quality-of-life benefits directly as a result of using UrgoStart. The clinical experts explained that increases in wound closure and in the rate of wound area reduction are likely to be associated with improvements in day-to-day living. For people with diabetic foot ulcers, complete wound closure is usually necessary for them to return to unhindered walking. For people with venous leg ulcers, a reduction in the wound area may translate into important benefits including earlier transition to less cumbersome dressings and treatment in the community. The experts' comments were corroborated by a small sample of people who have used UrgoStart dressings and reported quality-of-life benefits associated with improved wound healing. The committee concluded that it was plausible that UrgoStart leads to benefits that are important in improving day-to-day living in people with diabetic foot or venous leg ulcers.\n\n# Relevance to the NHS\n\n## The evidence for UrgoStart is broadly generalisable to the NHS\n\nOnly a small proportion of the patients with diabetic foot ulcers in the EXPLORER study were recruited from a UK centre. There were no patients from the UK in any of the studies that investigated the benefits of UrgoStart in patients with leg ulcers. Clinical experts stated that the demographics of patients and the fundamentals of wound care are likely to be similar across Europe. However, the experts also explained that some differences in care may exist including, for example, the type of health professional giving the treatment and the compression pressure used to treat venous leg ulcers. The committee concluded that the evidence for UrgoStart was broadly generalisable to the NHS.\n\n## There is insufficient evidence to recommend UrgoStart for non-venous leg ulcers\n\nThe committee noted that most of the evidence of UrgoStart providing benefit in patients with leg ulcers was specifically for venous leg ulcers. The clinical experts confirmed that about 70% of leg ulcers are caused by venous disease. They also stated that compression is an important part of standard care for venous leg ulcers, but that treatment of non-venous leg ulcers relies on dressings alone. The committee concluded that even though it is plausible that there are benefits from using UrgoStart for non-venous leg ulcers, there was insufficient evidence to make a definitive recommendation about the use of UrgoStart in this group.\n\n# NHS considerations\n\n## UrgoStart can be incorporated in care pathways by including it on local formularies\n\nThe clinical experts explained that diabetic foot care, including ulcer management, varies across the NHS. Diabetic foot care usually involves a multi-disciplinary team; patients move between GP practice, secondary care and community care depending on their needs. Venous leg ulcers, on the other hand, are mostly treated in a community setting. New and novel dressings are usually incorporated into local care pathways through their inclusion in dressing formularies. The committee did not consider that the use of UrgoStart should be restricted to any particular setting in the NHS, but understood that the decision to use it would usually be made by a multi-disciplinary team or a tissue viability specialist.\n\n## UrgoStart should be considered for patients with non-infected ulcers\n\nThe clinical experts confirmed that UrgoStart would only be used after a thorough wound and patient assessment, and after interventions to control other modifiable factors including debridement and treatment of wound infection. The experts also agreed that if using UrgoStart dressings did not lead to progress in wound healing, they would change to a different product. The committee concluded that UrgoStart should be recommended for patients with non-infected diabetic foot ulcers or venous leg ulcers.\n\n# Cost-modelling overview\n\n## The EAC's updated models are more plausible than the company's models and most appropriate for decision making\n\nThe committee expressed concerns about the variability seen in wound healing rates, and questioned whether this was correctly reflected in the models. The EAC explained that it had calibrated the models to better reflect this, recognising that not all wounds will improve with treatment and in these instances UrgoStart would be replaced by a different dressing (6.09\xa0weeks for diabetic foot ulcers and 8.26\xa0weeks for venous leg ulcers). The calibration process included using data from the Guest\xa0et\xa0al. (2018a) and Guest\xa0et\xa0al. (2018b) papers, which summarised resource-use data taken from an electronic database of patients in\xa0562 GP practices across the UK. These data were used to estimate the proportion of patients whose ulcers had not healed after 1\xa0year in the comparator arms of both analyses. The committee agreed that the EAC's updated models were most appropriate for decision making.\n\n# Main cost drivers\n\n## Estimates of cost savings are likely to be robust for treating diabetic foot ulcers but are less certain for treating venous leg ulcers\n\nThe committee noted the importance of healing-rate parameters in the cost modelling. It was confident that UrgoStart improved complete wound healing, but was uncertain about the reliability of using an extrapolation method to derive complete wound healing rates from partial healing at 8\xa0weeks in people with venous leg ulcers. In view of this, the committee concluded that the estimates of cost savings are likely to be robust when UrgoStart is used to treat diabetic foot ulcers, but that uncertainty remains about the cost savings when UrgoStart is used to treat venous leg ulcers.\n\n# Cost savings\n\n## UrgoStart is likely to be cost saving compared with standard care but there are uncertainties in the size of these savings in people with venous leg ulcers\n\nThe EAC's did deterministic sensitivity analyses that varied parameters in both cost models. Results showed that the technology remained cost saving in most cases. The committee concluded that, based on the published evidence, cost modelling and expert opinion, UrgoStart is likely to be cost saving compared with non-interactive dressings. For diabetic foot ulcers, the committee agreed with the estimate from the EAC's updated model of a £342 saving\xa0per\xa0patient\xa0per\xa0year with UrgoStart. For venous leg ulcers, it accepted that use of UrgoStart is likely to be cost saving but considered any estimates to be less certain, because of the uncertainty in the evidence for complete wound healing."}	https://www.nice.org.uk/guidance/mtg42	Evidence-based recommendations on UrgoStart for treating diabetic foot ulcers and leg ulcers.
de4a560d5cdc65ba6c03435207b4125ee28e6242	nice	Finerenone for treating chronic kidney disease in type 2 diabetes	Finerenone for treating chronic kidney disease in type 2 diabetes Evidence-based recommendations on finerenone (Kerendia) for stage 3 and 4 chronic kidney disease (with albuminuria) associated with type 2 diabetes in adults. # Recommendations Finerenone is recommended as an option for treating stage 3 and 4 chronic kidney disease (with albuminuria) associated with type 2 diabetes in adults. It is recommended only if: it is an add-on to optimised standard care; this should include, unless they are unsuitable, the highest tolerated licensed doses of: angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) and sodium–glucose cotransporter‑2 (SGLT2) inhibitors and the person has an estimated glomerular filtration rate (eGFR) of 25 ml/min/1.73 m2 or more. This recommendation is not intended to affect treatment with finerenone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard care for chronic kidney disease in people with type 2 diabetes includes ACE inhibitors and ARBs, with SGLT2 inhibitors being added if needed. Finerenone would be added to ACE inhibitors and ARBs if they are not working well enough. It could be offered before, after, or with SGLT2 inhibitors. The clinical evidence suggests that finerenone improves kidney function and helps to slow the worsening of the disease compared with placebo (both plus standard care, with and without SGLT2 inhibitors). There are no direct comparisons of finerenone against SGLT2 inhibitors when used as an add-on to standard care (without SGLT2 inhibitors). The cost-effectiveness estimates are uncertain, but they are all within the range that NICE considers an acceptable use of NHS resources. Because finerenone has not been compared directly with SGLT2 inhibitors as an add-on to standard care (without SGLT2 inhibitors), it cannot be recommended instead of them. So, finerenone is recommended as an add-on to standard care, when standard care includes SGLT2 inhibitors.# Information about finerenone # Marketing authorisation indication Finerenone (Kerendia, Bayer) is indicated 'for the treatment of chronic kidney disease (stage 3 and 4 with albuminuria) associated with type 2 diabetes in adults'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for finerenone. # Price The list price of finerenone is £36.68 for 28 tablets, for both the 10‑mg and 20‑mg doses. The daily cost of treatment is £1.31 (BNF online, accessed January 2023). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion The appraisal committee considered evidence submitted by Bayer, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## There is an unmet need for treatment options for chronic kidney disease associated with type 2 diabetes Chronic kidney disease (CKD) is a long-term condition involving abnormal kidney function or structure. It is affected by comorbidities, particularly type 2 diabetes. The excess glucose in type 2 diabetes can further affect kidney function and accelerate CKD progression. In severe cases, people can sometimes need dialysis or transplant. It is estimated that around 3 million people have type 2 diabetes in the UK and around 20% of these will need kidney disease treatment. The clinical experts commented that people with CKD and type 2 diabetes have significant additional risk of morbidity (including end-stage renal disease) and premature mortality compared with people with CKD alone. This is particularly because they are at higher risk of cardiovascular disease. The clinical experts added that the aim of treatment is to slow progression of disease. They described current treatments, which focus on lifestyle changes, using angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), as well as increasing use of sodium–glucose cotransporter‑2 (SGLT2) inhibitors because of the recent recommendations in the NICE guideline on the management of type 2 diabetes in adults (NG28) and NICE technology appraisal guidance on dapagliflozin for treating chronic kidney disease (TA775). The clinical experts emphasised the need for additional therapies for people with CKD and type 2 diabetes because of the residual risk of progressive deterioration in kidney function, despite current therapies. They also highlighted the need for managing complications such as foot ulcers and amputations caused by peripheral vascular disease. There is an increased risk of developing peripheral vascular disease in diabetes, which is further exacerbated by CKD, in addition to needing dialysis or transplants. The clinical experts explained that comorbidities can prevent people from having dialysis. The patient expert submission highlighted the limited treatment options in this disease area, especially when SGLT2 inhibitors are not suitable, and that new options would be welcomed. The committee also acknowledged that younger people and people from certain family backgrounds were at increased risk of disease progression. The committee concluded that there is an unmet need for additional therapies for CKD associated with type 2 diabetes. # Treatment pathway ## Finerenone is likely to be prescribed in secondary care to begin with, but will eventually be prescribed in primary care The clinical experts expected that people with type 2 diabetes and proteinuria (which is elevated protein in the urine, indicating that the kidneys may be damaged) would be seen by nephrologists in secondary care. They stated that new treatments are usually prescribed in secondary care initially, and, as familiarity with the treatment increases, they eventually transition to primary care. But they noted that people who may be eligible for finerenone treatment may not always be receiving care in secondary care settings. The committee noted that the setting in which finerenone is prescribed is important when considering the confidential discounts of treatments used in standard care, and therefore the cost-effectiveness estimates. This is because some confidential discounts may not be available in primary care. The committee concluded that finerenone may initially be prescribed in secondary care, but will likely be prescribed in primary care once experience grows. ## Finerenone would be offered as an add-on after ACE inhibitors and ARBs, but its positioning relative to SGLT2 inhibitors is unclear Finerenone is indicated for stage 3 and 4 CKD with albuminuria (with albuminuria defined in the marketing authorisation as a minimum urine albumin to creatinine ratio of 3 mg/mmol). People with stage 3 or stage 4 CKD with albuminuria usually receive ACE inhibitors or ARBs, at the maximum tolerated licensed dose, as first-line therapy. Second-line SGLT2 inhibitors can be added, in line with NG28 and TA775. The company explained that it did not expect finerenone to replace existing therapies, because it has a different mode of action. Rather, it expands on current treatment options. The company also did not view SGLT2 inhibitors as established treatments in the NHS. So, the company submission focused on finerenone as a second-line treatment which would be added to first-line ACE inhibitors and ARBs. The clinical experts stated that although SGLT2 inhibitors were only recently recommended by NICE, their use is expected to increase, although this could take time. They also noted that a range of therapies is needed to target different causes of kidney damage, and that all of these treatments will likely work together for better renal protection than any of them alone. The committee agreed that finerenone and SGLT2 inhibitors would be used after the maximum tolerated dose of ACE inhibitors and ARBs, but noted that which treatment would be chosen first was unclear. The clinical experts agreed that finerenone and SGLT2 inhibitors would be positioned sequentially in the treatment pathway, with the second treatment (after first-line ACE inhibitors and ARBs) depending on tolerance and proteinuria incidence. They agreed that which treatment would be chosen first is unclear, because both are new. But they would not both be started at the same time. The clinical experts described instances in which SGLT2 inhibitors may be preferred, for example in hyperkalaemia, and instances in which finerenone may be preferred, for example if there was a risk of diabetic ketoacidosis and foot disease. During consultation, the company highlighted clinical expert advice it had received suggesting that finerenone would not replace SGLT2 inhibitors. The advice suggested that SGLT2 inhibitors would form part of standard care; that is, finerenone would be used in combination with SGLT2 inhibitors, or offered to people for whom SGLT2 inhibitors are unsuitable. The committee concluded that in practice, finerenone could be given before or with SGLT2 inhibitors, depending on people's individual circumstances. But clinical and cost-effectiveness analyses comparing finerenone with SGLT2 inhibitors would further inform this decision (see section 3.4). ## SGLT2 inhibitors are a relevant comparator The company did not include SGLT2 inhibitors as a comparator in its decision problem, because it did not view SGLT2 inhibitors as established NHS practice. The company referenced a low percentage market share by volume of SGLT2 inhibitors compared with oral or parenteral hypoglycaemics, and uncertainty about the proportions that are used for CKD associated with type 2 diabetes. The committee noted that in the FIGARO‑DKD study, the proportion of people taking SGLT2 inhibitors was higher than in the FIDELIO‑DKD study, which was completed a year earlier (see section 3.5), suggesting increased use of SGLT2 inhibitors. But the company and clinical experts noted that in this case, the SGLT2 inhibitors were used for lowering glucose. The committee recognised that SGLT2 inhibitors were not established NHS treatment for CKD during the FIDELIO‑DKD and FIGARO‑DKD trials, but could still be considered a relevant comparator. It noted that the recent NICE recommendations will likely increase uptake at a faster rate. The clinical experts agreed that SGLT2 inhibitor use is likely to increase, and that finerenone and SGLT2 inhibitors would be used in combination, sequentially, unless either drug is not tolerated (see section 3.3). The ERG suggested that, because of the multiple potential places of finerenone in the pathway, multiple approaches could be used to compare finerenone with SGLT2 inhibitors. This could include an indirect treatment comparison, with finerenone as an alternative to SGLT2 inhibitors, or a comparison involving adding finerenone to standard care including SGLT2 inhibitors using trial data (although the sample sizes would be small). The ERG noted that the trial and model were not informative enough to allow such comparisons as they were. Spironolactone, a steroidal mineralocorticoid receptor antagonist, was also discussed, but the committee did not consider it relevant for CKD associated with type 2 diabetes. This was because there was a lack of comparative trial evidence and the clinical experts agreed that finerenone and spironolactone are different and are used in different contexts. During consultation, the company highlighted that it primarily expects finerenone to be offered to people for whom SGLT2 inhibitors are unsuitable, or as an add-on to SGLT2 inhibitors in people who remain at high risk of deteriorating kidney function. So, it considered that a comparison of finerenone with SGLT2 inhibitors in an SGLT2 inhibitor-naive population was not appropriate. Instead, it compared finerenone plus standard care (including SGLT2 inhibitors) with standard care alone (including SGLT2 inhibitors) in scenario analyses (see section 3.10). The committee agreed that SGLT2 inhibitor use will increase and become incorporated into standard practice. It recalled that, in practice, finerenone could be given before or with SGLT2 inhibitors in the treatment pathway (see section 3.3). The committee concluded that SGLT2 inhibitors are a relevant comparator. But it noted that the comparison of finerenone with SGLT2 inhibitors was still missing. So, finerenone could only be considered as an option in addition to SGLT2 inhibitors, or when these are unsuitable. # Clinical evidence ## Clinical evidence from FIDELIO-DKD is relevant The clinical effectiveness evidence for finerenone was from the FIDELIO‑DKD trial. This was a phase 3, randomised, double-blind, multicentre, placebo-controlled trial that enrolled over 5,000 adults with CKD and type 2 diabetes in the full analysis set. The inclusion criteria included: an albumin to creatinine ratio of 3.4 mg/mmol to less than 33.9 mg/mmol, an estimated glomerular filtration rate (eGFR) of 25 ml/min/1.73 m2 to less than 60 ml/min/1.73 m2, and diabetic retinopathy, or an albumin to creatinine ratio of 33.9 mg/mmol to 565 mg/mmol, and an eGFR of 25 ml/min/1.73 m2 to less than 75 ml/min/1.73 m2.People took 10 mg or the target 20‑mg dose of finerenone once daily in addition to standard care. In the full analysis set, 14 people (0.25%) were not receiving any ACE inhibitors or ARBs at baseline. Follow up was every 4 months including after discontinuation, with the final follow up being 4 weeks and 5 days after the last dose of the study drug. The primary outcome was the time to the first event of a composite end point consisting of: onset of kidney failure, a sustained decrease of eGFR of 40% or more from baseline over at least 4 weeks, or renal death. The results from the population covered by the marketing authorisation (approximately 90% of the study population) were presented to the committee. But the committee noted that the trial was powered for the full analysis set rather than the marketing authorisation population. The clinical experts were satisfied that the baseline characteristics reflected the population that would be seen in the NHS, in particular noting a good balance of family backgrounds including a significant number of people from Asian family backgrounds. In the full analysis set, the proportions of ACE inhibitors and ARBs at baseline were in line with the marketing authorisation population. So, the committee agreed that the company's proposed positioning of finerenone was in line with the marketing authorisation population (see section 3.3). There was a relatively low proportion of people using SGLT2 inhibitors at baseline, which the clinical experts suggested was because, at the time of study, SGLT2 inhibitors were used for glycaemic control only, and, at the beginning of the trial, were contraindicated for people with an eGFR of less than 60 ml/min/1.73 m2 (this restriction no longer exists in NHS practice). So, SGLT2 inhibitors would have been actively discouraged for the marketing authorisation population because it included people with an eGFR of less than 60 ml/min/1.73 m2. The committee concluded that the clinical evidence from FIDELIO‑DKD was relevant. ## Additional clinical evidence from FIGARO-DKD and FIDELITY is also appropriate The committee was aware of the FIGARO‑DKD phase 3 trial, which the company excluded from its evidence base because the full data was not available at the time of the submission. The primary outcome in FIGARO‑DKD was a composite cardiovascular end point, and the key secondary end point matched the primary end point in FIDELIO-DKD. There were some differences in the inclusion criteria between the trials, with more early-stage CKD allowed in FIGARO‑DKD. The clinical experts agreed that, although the trial populations were different, there was significant overlap, so that some patients could have entered either study. A meta-analysis called FIDELITY pooled results from FIDELIO‑DKD and FIGARO‑DKD. The committee thought that a similar analysis would provide additional insight into the marketing authorisation population. A clinical expert commented that they would feel confident using data from FIDELIO‑DKD if this was the only trial available, but the committee felt that not all the potentially relevant evidence had been presented. This was because the results from FIDELIO‑DKD were underpowered for the marketing authorisation population, and evidence from additional trials could give further supportive evidence and reduce uncertainty (see section 3.8). In response to consultation, the company highlighted that the marketing authorisation population represents approximately 90% of the FIDELIO‑DKD population. It suggested that combining FIDELIO‑DKD and FIGARO‑DKD data for the marketing authorisation population was not prespecified and was questionable from a statistical point of view. But the company did provide scenario analyses using additional evidence from FIDELITY. The committee concluded that, although FIDELIO-DKD, the key clinical trial, was relevant, further clinical evidence from FIGARO‑DKD and FIDELITY were also relevant and appropriate for decision making. ## The eGFR ranges in the marketing authorisation are appropriate The marketing authorisation population submitted by the company included patients with stage 3 and stage 4 CKD with an eGFR of 25 ml/min/1.73 m2 or greater. This is narrower than the definition of stage 3 and stage 4 CKD used by the NHS, which is an eGFR of 15 ml/min/1.73 m2 to less than 60 ml/min/1.73 m2. The clinical experts explained that in practice, each decline in eGFR is looked at individually, rather than as CKD stages. In addition, the clinical experts reported that from a patient perspective, the percentage of kidney function is the main concern. They were therefore satisfied with the CKD stages defined in the marketing authorisation. The ERG noted a lack of clarity about finerenone use when the eGFR is between 15 ml/min/1.73 m2 and 25 ml/min/1.73 m2 because people in this category have CKD stage 4, and the company's submission did not include an analysis of this population. The company explained that the trial only enrolled people with an eGFR of 25 ml/min/1.73 m2 and above, and although 2.4% of people in the trial had an eGFR below this, their eGFR had deteriorated in the time between screening and randomisation. The ERG was satisfied with the analyses presented at technical engagement. The committee noted that the marketing authorisation does not recommend starting finerenone with an eGFR of less than 25 ml/min/1.73 m2, but: it allows continuation if the eGFR drops below this if the eGFR is 15 ml/min/1.73 m2 or more, finerenone use can continue with dose adjustment according to serum potassium if the eGFR falls below 15 ml/min/1.73 m2, that is end-stage CKD, and finerenone should be stopped because of limited data.The clinical experts did not expect the eGFR ranges in which SGLT2 inhibitors would be used would influence the treatment pathway, because they expected SGLT2 inhibitors to be used widely because of their many indications. The finerenone marketing authorisation specifies that people must have albuminuria, which the company defined as at least 3 mg/mmol urine albumin, because this was the cut-off used in FIDELIO-DKD. But the degree of albuminuria does not affect finerenone use. The clinical experts commented that the greater the degree of albuminuria, the more potential benefit a person will have from additional therapies. The committee concluded that, although the marketing authorisation population submitted by the company did not cover all of the stage 3 and stage 4 CKD as defined by the NHS, the eGFR ranges specified by the company were appropriate for likely finerenone use. ## The primary composite outcome is appropriate, but further evidence from FIGARO-DKD would help supplement the data The components of the primary composite outcome of FIDELIO‑DKD (see section 3.5) were kidney failure (and its subcomponents: end-stage renal disease and a sustained decrease in eGFR of less than 15 ml/min/1.73 m2), a sustained decrease in eGFR of 40% or more from baseline, and death from renal causes. The committee noted that of these components, only 1 result was statistically significant. But the company emphasised that the study was not powered for the components of the primary composite outcome – it was only powered for the primary composite outcome for the full analysis set. The ERG accepted that the primary composite outcome was clinically relevant. At technical engagement, the company did statistical analyses to assess heterogeneity (that is, the interaction between components of the composite end point), and did not identify any heterogeneity. But the ERG stated that the company's test for heterogeneity would also be underpowered if the trial itself was underpowered for individual components. So, the committee acknowledged that all outcomes presented were underpowered because the marketing authorisation is based on a subset of the population, and the trial was only powered for the full population. Despite this, the clinical experts and committee acknowledged that numerically, if not always statistically, the components of the composite outcome were consistent in favouring finerenone. The clinical experts explained that the trial would have to be a lot longer for all the components to be individually powered. They further clarified that death from renal causes is a rare outcome in clinical trials because it only occurs in people who do not have dialysis. The committee understood that the composite outcome components are not mutually exclusive, so each component is a smaller subset of the same people. It also understood that wider confidence intervals are expected for rarer events. The clinical experts agreed that the primary composite outcome was clinically relevant. The committee agreed that renal outcomes from FIGARO‑DKD (see section 3.5) would have been useful, but acknowledged that some of the FIGARO‑DKD population was not relevant in this disease area. The committee noted that the Kaplan–Meier curves had a lot of censoring and not many events, and that the company had not provided confidence intervals. This emphasised the importance of using additional data from FIGARO‑DKD for a better powered analysis. The committee concluded that the primary composite outcome of FIDELIO‑DKD is clinically relevant, but further evidence from FIGARO‑DKD would help supplement the data. ## Additional evidence from FIGARO-DKD supports the results of the primary composite outcome, but has limitations During consultation, the company provided a scenario analysis, in which clinical evidence from FIDELITY, matching the population in the marketing authorisation for finerenone, was used to update the cost-effectiveness analysis. The company highlighted that the population in FIGARO-DKD included some people with less marked albuminuria (even at the same level of eGFR) than in FIDELITY. So, it said that including these people would dilute the effect seen in FIDELIO-DKD. But the committee noted that people in both trials had some degree of albuminuria, in line with finerenone's marketing authorisation. At the second committee meeting, the clinical experts emphasised that, in NHS practice, prescribers would want to offer finerenone to people who met either definition of albuminuria. So the committee considered that the best evidence to estimate the effectiveness of finerenone in practice would be the pooled data from people in FIDELIO‑DKD and FIGARO-DKD who met the criteria in the marketing authorisation. The ERG noted that the presentation of data from FIDELITY was limited and lacking in transparency, preventing a clear assessment of the scenario analysis results. It agreed with the company's view that this scenario analysis was subject to limitations (see section 3.6). But it could not rule out using additional evidence from FIGARO-DKD to inform the model instead of relying solely on the more optimistic evidence from FIDELIO-DKD. The committee concluded that additional evidence from FIGARO-DKD supports the results of the primary analysis from FIDELIO-DKD, but has limitations. ## Results from modelling standard care including SGLT2 inhibitors with and without finerenone are uncertain During consultation, the company provided scenario analyses to estimate the cost effectiveness of finerenone as an add-on to standard care including SGLT2 inhibitors. It used evidence on the effectiveness of an SGLT2 inhibitor (dapagliflozin) in delaying transitions for time to end-stage renal disease, time to dialysis and time to a cardiovascular event. It calculated how these outcomes would be affected in FIDELIO‑DKD and FIGARO-DKD for the proportion of people taking SGLT2 inhibitors. This allowed estimation of outcomes in a population in which 100% of people take SGLT2 inhibitors and finerenone. The company assumed that the effects of finerenone and SGLT2 inhibitors are independent and additive. This was based on evidence from FIDELIO-DKD, which suggested that background SGLT2 inhibitors use did not reduce the benefit of finerenone. The ERG highlighted that the company had provided insufficient details to allow an informed critique of the approach, and noted that it was uncertain whether the effects of finerenone and SGLT2 inhibitors would actually be additive. It explained that, although there is some evidence that combining finerenone and SGLT2 inhibitors may provide more benefit than SGLT2 inhibitors alone (an 'additional' effect), this is not necessarily the same as the combined benefit being the sum of both independent benefits (an 'additive' effect). The committee concluded that the company's attempt to model standard care including SGLT2 inhibitors with and without finerenone was uncertain. Because it could not know whether the effects were truly additive, the committee considered that the analyses provided a useful upper bound to the likely cost effectiveness of finerenone in that setting. ## Hyperkalaemia is the main adverse event associated with finerenone, but overall the adverse events are not concerning The main adverse event in FIDELIO‑DKD associated with finerenone was hyperkalaemia. But the committee acknowledged that it seemed to be mild in most cases. The clinical experts agreed that the adverse events were not unexpected and noted that in the FIDELIO‑DKD protocol, finerenone and placebo were withheld when serum potassium levels were greater than 5.5 mmol/litre. But they agreed that in clinical practice, the level would be allowed to go slightly above this in some circumstances. Hospitalisation rates were around 1% higher in the finerenone arm than in the placebo arm, but the clinical experts did not see this as being a significant concern if these hospitalisations were for short durations. The committee concluded that hyperkalaemia is an important adverse event to consider, but overall, the adverse events results from FIDELIO‑DKD were not particularly concerning. # Cost effectiveness ## The structure of the company's model is appropriate for decision making The company presented a cohort-level, state-transition Markov model to estimate the cost effectiveness of finerenone plus standard care compared with placebo plus standard care. A representative treatment from each relevant class of therapy in standard care was used in the model, at its maximum dose. The ERG agreed with this approach. The clinical experts agreed that the treatments used were typical of NHS practice, but also agreed with stakeholder comments that some of the doses were lower than expected. But if the average or most common dose was assumed, then they were not unreasonable. The committee acknowledged that any inaccuracies were likely to have a minor impact on results because they applied to both arms of the model. The health states used were CKD stage 1 or 2, CKD stage 3, CKD stage 4, CKD stage 5 without dialysis, dialysis, transplant, and death. These health states were all duplicated into 2 sub-models for before and after a cardiovascular event. The model had a cycle length of 4 months, in line with data collection in the trial, and a lifetime time horizon of 34.2 years. Originally, the utilities used in the model were 5-level EQ-5D (EQ-5D-5L) values from the trial mapped onto the EQ-5D-3L. But after technical engagement, the company updated these to utilities from the literature (see section 3.18). No treatment waning effects were included in the model (see section 3.15). The committee noted that the model showed possible large jumps in progression, for example from CKD stage 3 to CKD stage 5, and from CKD stage 3 to dialysis or transplant. The clinical experts considered this to be plausible because in clinical practice, people with CKD associated with type 2 diabetes can move between health states, rather progress linearly. The committee noted that a shorter cycle length may have showed more intermediate states. Overall, the committee concluded that structurally, the company's model was suitable for decision making. ## The modelled health state-transition probabilities are uncertain The individual health states in the model were empirically based on FIDELIO‑DKD and applied as a 4-month probability for the whole of the model. So, the probability of transitioning from 1 state to another was repeated for the duration of the model. The ERG was concerned that assuming constant transition probabilities over time may have been an over-simplification. It added that the large FIDELIO‑DKD dataset could allow for more complex transitions in the model. The company agreed, but explained that its experts had advised against this approach. The company clarified that time-varying risks are accounted for (albeit in a simplified way) because cardiovascular risk over time varies by age. The company used this approach to minimise interference with trial data, and because its health economists and clinicians had advised that its method of validating progression was reasonable. It added that its model structure was common in modelling CKD progression, and clinical expert advice was that current eGFR level is the main predictor for progression, so the same rates of cardiovascular events were applied for all people with the same CKD state. Mortality was also accounted for separately because of competing risks. The ERG agreed that the model captured the additional risk linked with age. But overall CKD progression between health states did not vary with time, and the ERG determined that the model was oversimplified. To validate its approach, the company compared its model with the Study of Heart and Renal Protection (SHARP)-CKD-CVD Markov model. This validation compared the cumulative probabilities per 1,000 participants at 5 and 10 years, with 95% confidence intervals around the company model results, and ranges around the SHARP-CKD-CVD model. The company concluded that its model results were within the ranges shown by SHARP-CKD-CVD. But the ERG explained that although the company's model results may have been within the ranges of the SHARP-CKD-CVD model, these ranges were extremes rather than confidence intervals. So, they could be obtained from varying inputs. The ERG highlighted that it was important to consider how the results were obtained, for example how events accrued over time. It noted that the tight confidence intervals observed around the company's model results in the cross validation were because of the time-invariant transition probabilities used. The ERG noted that although the SHARP-CKD-CVD model could inform some parts of the company's model, this was limited because it was built for a different purpose and the populations could not be exactly matched. For example, there were more renal replacement events in the SHARP-CKD-CVD model, but fewer people with relatively mild CKD, because the minimum CKD stage was 3b. The ERG explained that the effect of time-invariant transitions on the model output was uncertain. This was because it was not possible to assess CKD over time. The company also clarified that it had not compared transitions with the trial data. The ERG felt that validating the distribution of outputs over a time period would have been a better approach. The committee considered that the effects of using time-invariant transition probabilities were uncertain; a comparison of transitions over time with the trial data would be informative. In particular, the committee would have liked to see modelling predictions of time to various events, for example cardiovascular or renal replacement therapy events, compared with empirical Kaplan–Meier curves from the relevant populations in FIDELIO‑DKD and FIGARO‑DKD. The committee concluded that the modelled health state-transition probabilities were uncertain. ## The updated health state-transition probabilities are also uncertain During consultation, the company updated its transition probabilities for the finerenone arm by applying hazard ratios to the standard care transition probabilities corresponding to the 'CKD5 without dialysis' and 'CKD5 without dialysis to dialysis' health states. The ERG and the committee noted that for the finerenone arm, no direct effect of finerenone was reflected on transitions in the earlier stages of CKD, but instead transitions associated with CKD5 were amended. The ERG highlighted that 2 possible sets of transitions were explicitly modelled to differ by arms through applying a simple hazard ratio, 1 of which was for a different outcome (that is, progression to CKD5 without dialysis rather than 'onset of eGFR decrease less than 15 ml/min sustained over at least 4 weeks'). Furthermore, the transitions and the effect of finerenone remained time-invariant. Also during consultation, the company did an external validation of the cost-effectiveness model to ensure that its results were in line with the FIDELIO‑DKD outcomes. It compared incidence of first cardiovascular events, cardiovascular deaths and the number of people having dialysis with the model predictions. The model results reflected the incidence of the first cardiovascular event, cardiovascular mortality and incidence of dialysis observed in the FIDELIO‑DKD trial. The ERG noted that because the validation used input data from the same study, it did not represent a true 'external' validation. The ERG highlighted that the analyses supported the expectation that cardiovascular events and onset of dialysis could be accurately reflected by the model over a 4‑year time horizon. But the model projected outcomes over a 34‑year time horizon, and so for the remaining 30 years, all probabilities were assumed fixed. The committee acknowledged that the company addressed its request to provide analyses comparing model outputs with empirical data from the trial. For both outcomes considered (time to dialysis and time to a cardiovascular event), the model outputs closely approximated the observed data. The committee was reassured that the model provided a reasonable representation of expected outcomes and, in particular, that using time-invariant transitions did not compromise the model's validity, at least over the 4 years for which empirical data was available. The committee noted that the ERG's scenario analyses that used both the company's original approach and revised approach to estimating transition probabilities were useful for decision making. But only the latter allowed for consideration of parameter uncertainty in the probabilistic sensitivity analyses. The committee concluded that the updated transition probabilities were also uncertain. ## Treatment effects beyond 4 years are uncertain In the model, the company assumed that people would stop taking finerenone at the rate observed in FIDELIO-DKD. After this, people accrued the costs and effectiveness of standard care. The company did not explore treatment effect waning because it claimed that in the trial, the relative effect of finerenone was almost constant over 4 years. The company also assumed that in clinical practice, finerenone would be stopped (see section 3.16) if there was no treatment effect. The clinical experts thought that finerenone benefit is likely to be maintained over time. They added that at more advanced CKD stages, it takes fewer events to progress to dialysis, with a large impact on quality of life. So there may be a greater absolute benefit of finerenone in more advanced CKD. During consultation, the company provided scenario analyses assuming the effect of finerenone waning over a period of 16 years, that is, decreasing by 25% every 4 years until it dissipated entirely by 16 years. It provided 2 further scenario analyses in which finerenone was stopped before the point at which finerenone's constant effect was extrapolated to end after the trial period. These assumed finerenone would be stopped after 7 years, based on a median of 7.5 years spent in stages 3 and 4 CKD (Wilson et al. 2012), and 9 years, based on the average time without renal replacement therapy in the economic model. Although the ERG considered the 16‑year waning scenario an arbitrary assumption, it highlighted that the finerenone discontinuation scenarios (7 years and 9 years) were potentially informative. The committee acknowledged that uncertainty around the treatment waning effect was inherent beyond the trial period. It concluded that extrapolating relative treatment effects beyond the 4 years seen in the trial was uncertain, but that the company had made a reasonable attempt to explore this. ## Finerenone is stopped after renal replacement therapy starts In the company's model, finerenone was stopped after starting renal replacement therapy. The ERG did not have a preference about whether finerenone should be stopped or continued after renal replacement therapy is started. The clinical experts stated that finerenone would be stopped if a person's eGFR dropped below 15 ml/min/1.73 m2 (see section 3.7), which would occur before renal replacement therapy was started. The stopping rule decreased the incremental cost-effectiveness ratio (ICER) in a scenario analysis. The committee concluded that finerenone would be stopped after renal replacement therapy is started. ## Modelling of previous cardiovascular disease remains an outstanding area of uncertainty The ERG explained that some people in FIDELIO‑DKD would have had at least 1 previous cardiovascular event. This is because, although people were excluded if they experienced cardiovascular events in the 30 days before the screening visit, the exclusion criterion did not cover cardiovascular events that happened before this. The ERG and company agreed that 45.9% of people entered the model with a history of cardiovascular disease. The company preferred to model this proportion of people from the point of entering FIDELIO‑DKD (that is, to use the simplifying assumption that no patients had experienced a cardiovascular event before entering the model), whereas the ERG preferred to model this using the total patient history. The ERG explained that the company used external evidence to inform mortality and that this had a substantial effect on the cost-effectiveness estimates. So, there was a risk that estimates would be biased if the proportion of people with a history of cardiovascular disease was not accurate. The company explained that the model was structured in a way that meant that if it included total cardiovascular history, a considerable part of any cardiovascular protective benefit of finerenone would be lost. The ERG suggested that it would be ideal to have 3 sub-models, reflecting: people with no cardiovascular history people entering the model with cardiovascular history but yet to experience a further cardiovascular event people who experienced a cardiovascular event in the model.The committee agreed that in the company's 2 sub-models, the company and the ERG had valid reasons to support the different approaches, and that neither approach was optimal. It agreed that it would not be fair to lose any cardiovascular benefit of finerenone, but noted that this benefit was not statistically significant in the trial. The committee also noted that any limitations in the company's sensitivity analyses (see section 3.19) meant that uncertainties around this benefit could not be analysed with a valid probabilistic sensitivity analysis. The committee considered that the company's approach likely resulted in optimistic cost-effectiveness results, and recommended that restructuring the model into 3 sub-models would reduce uncertainty. During consultation, the company updated its model to account for the impact of recorded cardiovascular history on costs, utilities and mortality. The company felt that the 3 sub-model approach suggested by the committee would not be informative. Despite this, it created the sub-models and provided the results as scenario analyses. The ERG highlighted that the company's approach to the 3 sub-models did not align with the committee's request; the company's approach did not track patients over time in each of the 3 subgroups, but instead modelled 3 independent populations over time. The ERG did not consider these scenario analyses relevant to decision making. The committee concluded that modelling of previous cardiovascular disease remains an outstanding area of uncertainty. ## Utility values used in the company's updated model are appropriate The company initially used empirical data from FIDELIO‑DKD to inform the utilities in its model because they were trial-based and it considered them to be conservative. But after technical engagement, the company decided to use utility sources from the literature. This was because the ERG was concerned about an apparent increase in utility from CKD stages 1 to 2, to CKD stage 3. The company still used FIDELIO‑DKD to inform CKD stage 1 to 2 utilities, but used disutilities for all other CKD health states to be consistent with NICE's technology appraisal guidance on tolvaptan for treating autosomal dominant polycystic kidney disease (TA358). This was because it included the necessary utilities for the health states, and it was previously accepted by NICE. The ERG noted that it had merely raised questions about some utility values used in the company's submission, and it had not directed the company to completely revise its approach. It noted that the CKD-based health utilities from TA358 were from a study from 2005, with a small relevant population, and it did not use the EQ-5D. The company reviewed relevant literature in its submission that included more recent studies to inform comparable health states in the NICE guideline on type 2 diabetes in adults: management (NG28), acute kidney injury: prevention, detection and management (NG148) and chronic kidney disease (NG203). But it did not appear to have used them to inform its model. The ERG preferred using modified trial-based utilities, despite some imperfections. The utilities from the trial and updated utilities from the literature were similar for CKD stages 3 and 4, but lower for the subsequent stages from TA358. The company acknowledged that the CKD health states were taken from TA358, which evaluated a different indication, but it had advice from clinicians that it is not CKD stage 5 and dialysis, but being on dialysis itself, that has a large impact on quality of life. The clinical experts explained that there is not a large difference in the quality of life between CKD stage 1 to 2 and CKD stage 3, because CKD stages 3a and 3b are generally asymptomatic, although renal function is affected physiologically. But the clinical experts noted that with CKD and type 2 diabetes, there are more comorbidities, with a greater burden, and therefore a lower quality of life. In addition, in people with CKD and type 2 diabetes, their CKD tends to progress through stages at a faster rate for any given eGFR level. The ERG and the committee acknowledged that in the trial, the utilities for dialysis, post-dialysis and transplant were higher than expected. The committee considered that both approaches to utilities in the model have advantages and disadvantages, so a base case with trial-based utilities, and another with utilities from more recent and relevant literature sources than those currently used in the model, such as utilities from NG28, would be informative. During consultation, the company updated the model's utility values for dialysis and kidney transplant and cardiovascular events to reflect those in NG28. The ERG accepted the updated utility values. The committee concluded that the utility values used in the company's updated model were appropriate. ## The updated sensitivity analyses should still be interpreted with caution The ERG described the company's sensitivity analyses as having multifaceted issues. These included issues of grouping parameters, having wide parameter bounds, parameters being sampled from user-specified limits, and the overestimation of uncertainty in utility values. Moreover, the critical transition probabilities were not only time-invariant, they were also not subject to any form of sensitivity analysis. The company attempted to address these uncertainties and its rationale during technical engagement. It explained that certain parameters were grouped to account for a higher utility being observed for CKD stage 3 than for CKD stage 1 to 2. But the company changed its utility source in the model (see section 3.18). The ERG did not agree with the approach because the differences in values in the probabilistic sensitivity analysis were not shown, only whether the values were all high or all low. The ERG highlighted that using very wide parameter bounds stress tests the deterministic sensitivity analyses to implausible limits. The company acknowledged that not including the uncertainty from its time-invariant transition probabilities was a limitation, but also that this concerned the impact of finerenone in delaying CKD progression, which was significant in the trial. The company described how the probabilistic sensitivity analysis could include the statistical impact of finerenone to translate to an improvement in benefit when randomisation occurs. The company acknowledged the limitations in the sensitivity analyses and mentioned that it would not be able to resolve all the problems, in particular those to do with utilities. During consultation, it updated the transition probabilities to account for parameter uncertainty in the probabilistic sensitivity analysis. Transition probabilities for the standard care arm were sampled in the probabilistic sensitivity analysis from the Dirichlet distribution. The ERG questioned why this approach was not considered for the finerenone arm as well. The committee recalled the ERG's concerns with both the original and updated approaches to estimating transition probabilities and that only the latter approach allowed for parameter uncertainty in the probabilistic sensitivity analyses (see section 3.14). It considered that, although the updated approach to sensitivity analyses was an improvement, the outputs of these remained uncertain. The committee concluded that the results of the updated sensitivity analyses should be interpreted with caution. # Cost-effectiveness estimates ## Finerenone is cost effective compared with standard care The committee considered the cost-effectiveness estimates for finerenone compared with standard care. It acknowledged that, since the first committee meeting, the company had attempted to reduce the uncertainty in the clinical and cost-effectiveness evidence. But it noted the outstanding areas of uncertainty: missing comparison for finerenone use with SGLT2 inhibitors (see section 3.4) estimation of transition probabilities (see section 3.13 and section 3.14) treatment effect waning of finerenone (see section 3.15) modelling of previous cardiovascular disease (see section 3.17) sensitivity analyses results (see section 3.19).For finerenone plus standard care compared with standard care alone (when standard care did not include SGLT2 inhibitors), the committee noted that the company's and the ERG's base-case ICERs were relatively low. It also noted that in all the company's scenario analyses, in which standard care included SGLT2 inhibitors, the ICER was less than £30,000 per quality-adjusted life year (QALY) gained. So, despite the uncertainties, it agreed that the most plausible ICER was within the range NICE normally considers an acceptable use of NHS resources. The committee concluded that finerenone is a cost-effective use of NHS resources compared with standard care with or without SGLT2 inhibitors. # Other factors ## There are no equality issues No equality or social value judgement issues were identified that were not captured in the modelling. # Conclusion ## Finerenone is recommended as an add-on to optimised standard care including ACE inhibitors or ARBs, and SGLT2 inhibitors, unless these are unsuitable For CKD associated with type 2 diabetes, finerenone is clinically effective compared with placebo, and improves outcomes when added to standard care (with or without SGLT2 inhibitors). Despite uncertainty in the economic modelling, the committee agreed that the most plausible ICER for finerenone plus standard care compared with standard care alone was within the range NICE normally considers to be a cost-effective use of NHS resources. It also took into account that finerenone had not been compared with SGLT2 inhibitors, so it could not be recommended instead of them. So the committee concluded that finerenone is recommended for stage 3 and 4 CKD (with albuminuria) associated with type 2 diabetes only as an add-on to optimised standard care including ACE inhibitors or ARBs, and SGLT2 inhibitors, unless these are unsuitable.	{'Recommendations': 'Finerenone is recommended as an option for treating stage\xa03 and 4 chronic kidney disease (with albuminuria) associated with type\xa02 diabetes in adults. It is recommended only if:\n\nit is an add-on to optimised standard care; this should include, unless they are unsuitable, the highest tolerated licensed doses of:\n\n\n\nangiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) and\n\nsodium–glucose cotransporter‑2 (SGLT2) inhibitors and\n\n\n\nthe person has an estimated glomerular filtration rate (eGFR) of 25\xa0ml/min/1.73\xa0m2 or more.\n\nThis recommendation is not intended to affect treatment with finerenone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for chronic kidney disease in people with type\xa02 diabetes includes ACE inhibitors and ARBs, with SGLT2 inhibitors being added if needed. Finerenone would be added to ACE inhibitors and ARBs if they are not working well enough. It could be offered before, after, or with SGLT2 inhibitors.\n\nThe clinical evidence suggests that finerenone improves kidney function and helps to slow the worsening of the disease compared with placebo (both plus standard care, with and without SGLT2 inhibitors). There are no direct comparisons of finerenone against SGLT2 inhibitors when used as an add-on to standard care (without SGLT2 inhibitors).\n\nThe cost-effectiveness estimates are uncertain, but they are all within the range that NICE considers an acceptable use of NHS resources. Because finerenone has not been compared directly with SGLT2 inhibitors as an add-on to standard care (without SGLT2 inhibitors), it cannot be recommended instead of them. So, finerenone is recommended as an add-on to standard care, when standard care includes SGLT2 inhibitors.', 'Information about finerenone': "# Marketing authorisation indication\n\nFinerenone (Kerendia, Bayer) is indicated 'for the treatment of chronic kidney disease (stage\xa03 and 4 with albuminuria) associated with type\xa02 diabetes in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for finerenone.\n\n# Price\n\nThe list price of finerenone is £36.68 for 28\xa0tablets, for both the 10‑mg and 20‑mg doses. The daily cost of treatment is £1.31 (BNF online, accessed January 2023). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bayer, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## There is an unmet need for treatment options for chronic kidney disease associated with type 2 diabetes\n\nChronic kidney disease (CKD) is a long-term condition involving abnormal kidney function or structure. It is affected by comorbidities, particularly type\xa02 diabetes. The excess glucose in type\xa02 diabetes can further affect kidney function and accelerate CKD progression. In severe cases, people can sometimes need dialysis or transplant. It is estimated that around 3\xa0million people have type\xa02 diabetes in the UK and around 20% of these will need kidney disease treatment. The clinical experts commented that people with CKD and type\xa02 diabetes have significant additional risk of morbidity (including end-stage renal disease) and premature mortality compared with people with CKD alone. This is particularly because they are at higher risk of cardiovascular disease. The clinical experts added that the aim of treatment is to slow progression of disease. They described current treatments, which focus on lifestyle changes, using angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), as well as increasing use of sodium–glucose cotransporter‑2 (SGLT2) inhibitors because of the recent recommendations in the NICE guideline on the management of type 2 diabetes in adults (NG28) and NICE technology appraisal guidance on dapagliflozin for treating chronic kidney disease (TA775). The clinical experts emphasised the need for additional therapies for people with CKD and type\xa02 diabetes because of the residual risk of progressive deterioration in kidney function, despite current therapies. They also highlighted the need for managing complications such as foot ulcers and amputations caused by peripheral vascular disease. There is an increased risk of developing peripheral vascular disease in diabetes, which is further exacerbated by CKD, in addition to needing dialysis or transplants. The clinical experts explained that comorbidities can prevent people from having dialysis. The patient expert submission highlighted the limited treatment options in this disease area, especially when SGLT2 inhibitors are not suitable, and that new options would be welcomed. The committee also acknowledged that younger people and people from certain family backgrounds were at increased risk of disease progression. The committee concluded that there is an unmet need for additional therapies for CKD associated with type\xa02 diabetes.\n\n# Treatment pathway\n\n## Finerenone is likely to be prescribed in secondary care to begin with, but will eventually be prescribed in primary care\n\nThe clinical experts expected that people with type\xa02 diabetes and proteinuria (which is elevated protein in the urine, indicating that the kidneys may be damaged) would be seen by nephrologists in secondary care. They stated that new treatments are usually prescribed in secondary care initially, and, as familiarity with the treatment increases, they eventually transition to primary care. But they noted that people who may be eligible for finerenone treatment may not always be receiving care in secondary care settings. The committee noted that the setting in which finerenone is prescribed is important when considering the confidential discounts of treatments used in standard care, and therefore the cost-effectiveness estimates. This is because some confidential discounts may not be available in primary care. The committee concluded that finerenone may initially be prescribed in secondary care, but will likely be prescribed in primary care once experience grows.\n\n## Finerenone would be offered as an add-on after ACE inhibitors and ARBs, but its positioning relative to SGLT2 inhibitors is unclear\n\nFinerenone is indicated for stage\xa03 and 4 CKD with albuminuria (with albuminuria defined in the marketing authorisation as a minimum urine albumin to creatinine ratio of 3\xa0mg/mmol). People with stage\xa03 or stage\xa04 CKD with albuminuria usually receive ACE inhibitors or ARBs, at the maximum tolerated licensed dose, as first-line therapy. Second-line SGLT2 inhibitors can be added, in line with NG28 and TA775. The company explained that it did not expect finerenone to replace existing therapies, because it has a different mode of action. Rather, it expands on current treatment options. The company also did not view SGLT2 inhibitors as established treatments in the NHS. So, the company submission focused on finerenone as a second-line treatment which would be added to first-line ACE inhibitors and ARBs. The clinical experts stated that although SGLT2 inhibitors were only recently recommended by NICE, their use is expected to increase, although this could take time. They also noted that a range of therapies is needed to target different causes of kidney damage, and that all of these treatments will likely work together for better renal protection than any of them alone. The committee agreed that finerenone and SGLT2 inhibitors would be used after the maximum tolerated dose of ACE inhibitors and ARBs, but noted that which treatment would be chosen first was unclear. The clinical experts agreed that finerenone and SGLT2 inhibitors would be positioned sequentially in the treatment pathway, with the second treatment (after first-line ACE inhibitors and ARBs) depending on tolerance and proteinuria incidence. They agreed that which treatment would be chosen first is unclear, because both are new. But they would not both be started at the same time. The clinical experts described instances in which SGLT2 inhibitors may be preferred, for example in hyperkalaemia, and instances in which finerenone may be preferred, for example if there was a risk of diabetic ketoacidosis and foot disease. During consultation, the company highlighted clinical expert advice it had received suggesting that finerenone would not replace SGLT2 inhibitors. The advice suggested that SGLT2 inhibitors would form part of standard care; that is, finerenone would be used in combination with SGLT2 inhibitors, or offered to people for whom SGLT2 inhibitors are unsuitable. The committee concluded that in practice, finerenone could be given before or with SGLT2 inhibitors, depending on people's individual circumstances. But clinical and cost-effectiveness analyses comparing finerenone with SGLT2 inhibitors would further inform this decision (see section 3.4).\n\n## SGLT2 inhibitors are a relevant comparator\n\nThe company did not include SGLT2 inhibitors as a comparator in its decision problem, because it did not view SGLT2 inhibitors as established NHS practice. The company referenced a low percentage market share by volume of SGLT2 inhibitors compared with oral or parenteral hypoglycaemics, and uncertainty about the proportions that are used for CKD associated with type\xa02 diabetes. The committee noted that in the FIGARO‑DKD study, the proportion of people taking SGLT2 inhibitors was higher than in the FIDELIO‑DKD study, which was completed a year earlier (see section 3.5), suggesting increased use of SGLT2 inhibitors. But the company and clinical experts noted that in this case, the SGLT2 inhibitors were used for lowering glucose. The committee recognised that SGLT2 inhibitors were not established NHS treatment for CKD during the FIDELIO‑DKD and FIGARO‑DKD trials, but could still be considered a relevant comparator. It noted that the recent NICE recommendations will likely increase uptake at a faster rate. The clinical experts agreed that SGLT2 inhibitor use is likely to increase, and that finerenone and SGLT2 inhibitors would be used in combination, sequentially, unless either drug is not tolerated (see section 3.3). The ERG suggested that, because of the multiple potential places of finerenone in the pathway, multiple approaches could be used to compare finerenone with SGLT2 inhibitors. This could include an indirect treatment comparison, with finerenone as an alternative to SGLT2 inhibitors, or a comparison involving adding finerenone to standard care including SGLT2 inhibitors using trial data (although the sample sizes would be small). The ERG noted that the trial and model were not informative enough to allow such comparisons as they were. Spironolactone, a steroidal mineralocorticoid receptor antagonist, was also discussed, but the committee did not consider it relevant for CKD associated with type\xa02 diabetes. This was because there was a lack of comparative trial evidence and the clinical experts agreed that finerenone and spironolactone are different and are used in different contexts. During consultation, the company highlighted that it primarily expects finerenone to be offered to people for whom SGLT2 inhibitors are unsuitable, or as an add-on to SGLT2 inhibitors in people who remain at high risk of deteriorating kidney function. So, it considered that a comparison of finerenone with SGLT2 inhibitors in an SGLT2 inhibitor-naive population was not appropriate. Instead, it compared finerenone plus standard care (including SGLT2 inhibitors) with standard care alone (including SGLT2 inhibitors) in scenario analyses (see section 3.10). The committee agreed that SGLT2 inhibitor use will increase and become incorporated into standard practice. It recalled that, in practice, finerenone could be given before or with SGLT2 inhibitors in the treatment pathway (see section 3.3). The committee concluded that SGLT2 inhibitors are a relevant comparator. But it noted that the comparison of finerenone with SGLT2 inhibitors was still missing. So, finerenone could only be considered as an option in addition to SGLT2 inhibitors, or when these are unsuitable.\n\n# Clinical evidence\n\n## Clinical evidence from FIDELIO-DKD is relevant\n\nThe clinical effectiveness evidence for finerenone was from the FIDELIO‑DKD trial. This was a phase\xa03, randomised, double-blind, multicentre, placebo-controlled trial that enrolled over 5,000 adults with CKD and type\xa02 diabetes in the full analysis set. The inclusion criteria included:\n\nan albumin to creatinine ratio of 3.4\xa0mg/mmol to less than 33.9\xa0mg/mmol, an estimated glomerular filtration rate (eGFR) of 25\xa0ml/min/1.73\xa0m2 to less than 60\xa0ml/min/1.73\xa0m2, and diabetic retinopathy, or\n\nan albumin to creatinine ratio of 33.9\xa0mg/mmol to 565\xa0mg/mmol, and an eGFR of 25\xa0ml/min/1.73\xa0m2 to less than 75\xa0ml/min/1.73\xa0m2.People took 10\xa0mg or the target 20‑mg dose of finerenone once daily in addition to standard care. In the full analysis set, 14 people (0.25%) were not receiving any ACE inhibitors or ARBs at baseline. Follow\xa0up was every 4\xa0months including after discontinuation, with the final follow\xa0up being 4\xa0weeks and 5\xa0days after the last dose of the study drug. The primary outcome was the time to the first event of a composite end point consisting of: onset of kidney failure, a sustained decrease of eGFR of 40% or more from baseline over at least 4\xa0weeks, or renal death. The results from the population covered by the marketing authorisation (approximately 90% of the study population) were presented to the committee. But the committee noted that the trial was powered for the full analysis set rather than the marketing authorisation population. The clinical experts were satisfied that the baseline characteristics reflected the population that would be seen in the NHS, in particular noting a good balance of family backgrounds including a significant number of people from Asian family backgrounds. In the full analysis set, the proportions of ACE inhibitors and ARBs at baseline were in line with the marketing authorisation population. So, the committee agreed that the company's proposed positioning of finerenone was in line with the marketing authorisation population (see section 3.3). There was a relatively low proportion of people using SGLT2 inhibitors at baseline, which the clinical experts suggested was because, at the time of study, SGLT2 inhibitors were used for glycaemic control only, and, at the beginning of the trial, were contraindicated for people with an eGFR of less than 60\xa0ml/min/1.73\xa0m2 (this restriction no longer exists in NHS practice). So, SGLT2 inhibitors would have been actively discouraged for the marketing authorisation population because it included people with an eGFR of less than 60\xa0ml/min/1.73\xa0m2. The committee concluded that the clinical evidence from FIDELIO‑DKD was relevant.\n\n## Additional clinical evidence from FIGARO-DKD and FIDELITY is also appropriate\n\nThe committee was aware of the FIGARO‑DKD phase\xa03 trial, which the company excluded from its evidence base because the full data was not available at the time of the submission. The primary outcome in FIGARO‑DKD was a composite cardiovascular end point, and the key secondary end point matched the primary end point in FIDELIO-DKD. There were some differences in the inclusion criteria between the trials, with more early-stage CKD allowed in FIGARO‑DKD. The clinical experts agreed that, although the trial populations were different, there was significant overlap, so that some patients could have entered either study. A meta-analysis called FIDELITY pooled results from FIDELIO‑DKD and FIGARO‑DKD. The committee thought that a similar analysis would provide additional insight into the marketing authorisation population. A clinical expert commented that they would feel confident using data from FIDELIO‑DKD if this was the only trial available, but the committee felt that not all the potentially relevant evidence had been presented. This was because the results from FIDELIO‑DKD were underpowered for the marketing authorisation population, and evidence from additional trials could give further supportive evidence and reduce uncertainty (see section 3.8). In response to consultation, the company highlighted that the marketing authorisation population represents approximately 90% of the FIDELIO‑DKD population. It suggested that combining FIDELIO‑DKD and FIGARO‑DKD data for the marketing authorisation population was not prespecified and was questionable from a statistical point of view. But the company did provide scenario analyses using additional evidence from FIDELITY. The committee concluded that, although FIDELIO-DKD, the key clinical trial, was relevant, further clinical evidence from FIGARO‑DKD and FIDELITY were also relevant and appropriate for decision making.\n\n## The eGFR ranges in the marketing authorisation are appropriate\n\nThe marketing authorisation population submitted by the company included patients with stage\xa03 and stage\xa04 CKD with an eGFR of 25\xa0ml/min/1.73\xa0m2 or greater. This is narrower than the definition of stage\xa03 and stage\xa04 CKD used by the NHS, which is an eGFR of 15\xa0ml/min/1.73\xa0m2 to less than 60\xa0ml/min/1.73\xa0m2. The clinical experts explained that in practice, each decline in eGFR is looked at individually, rather than as CKD stages. In addition, the clinical experts reported that from a patient perspective, the percentage of kidney function is the main concern. They were therefore satisfied with the CKD stages defined in the marketing authorisation. The ERG noted a lack of clarity about finerenone use when the eGFR is between 15\xa0ml/min/1.73\xa0m2 and 25\xa0ml/min/1.73\xa0m2 because people in this category have CKD stage\xa04, and the company's submission did not include an analysis of this population. The company explained that the trial only enrolled people with an eGFR of 25\xa0ml/min/1.73\xa0m2 and above, and although 2.4% of people in the trial had an eGFR below this, their eGFR had deteriorated in the time between screening and randomisation. The ERG was satisfied with the analyses presented at technical engagement. The committee noted that the marketing authorisation does not recommend starting finerenone with an eGFR of less than 25\xa0ml/min/1.73\xa0m2, but:\n\nit allows continuation if the eGFR drops below this\n\nif the eGFR is 15\xa0ml/min/1.73\xa0m2 or more, finerenone use can continue with dose adjustment according to serum potassium\n\nif the eGFR falls below 15\xa0ml/min/1.73\xa0m2, that is end-stage CKD, and finerenone should be stopped because of limited data.The clinical experts did not expect the eGFR ranges in which SGLT2 inhibitors would be used would influence the treatment pathway, because they expected SGLT2 inhibitors to be used widely because of their many indications. The finerenone marketing authorisation specifies that people must have albuminuria, which the company defined as at least 3\xa0mg/mmol urine albumin, because this was the cut-off used in FIDELIO-DKD. But the degree of albuminuria does not affect finerenone use. The clinical experts commented that the greater the degree of albuminuria, the more potential benefit a person will have from additional therapies. The committee concluded that, although the marketing authorisation population submitted by the company did not cover all of the stage\xa03 and stage\xa04 CKD as defined by the NHS, the eGFR ranges specified by the company were appropriate for likely finerenone use.\n\n## The primary composite outcome is appropriate, but further evidence from FIGARO-DKD would help supplement the data\n\nThe components of the primary composite outcome of FIDELIO‑DKD (see section 3.5) were kidney failure (and its subcomponents: end-stage renal disease and a sustained decrease in eGFR of less than 15\xa0ml/min/1.73\xa0m2), a sustained decrease in eGFR of 40% or more from baseline, and death from renal causes. The committee noted that of these components, only 1 result was statistically significant. But the company emphasised that the study was not powered for the components of the primary composite outcome – it was only powered for the primary composite outcome for the full analysis set. The ERG accepted that the primary composite outcome was clinically relevant. At technical engagement, the company did statistical analyses to assess heterogeneity (that is, the interaction between components of the composite end point), and did not identify any heterogeneity. But the ERG stated that the company's test for heterogeneity would also be underpowered if the trial itself was underpowered for individual components. So, the committee acknowledged that all outcomes presented were underpowered because the marketing authorisation is based on a subset of the population, and the trial was only powered for the full population. Despite this, the clinical experts and committee acknowledged that numerically, if not always statistically, the components of the composite outcome were consistent in favouring finerenone. The clinical experts explained that the trial would have to be a lot longer for all the components to be individually powered. They further clarified that death from renal causes is a rare outcome in clinical trials because it only occurs in people who do not have dialysis. The committee understood that the composite outcome components are not mutually exclusive, so each component is a smaller subset of the same people. It also understood that wider confidence intervals are expected for rarer events. The clinical experts agreed that the primary composite outcome was clinically relevant. The committee agreed that renal outcomes from FIGARO‑DKD (see section 3.5) would have been useful, but acknowledged that some of the FIGARO‑DKD population was not relevant in this disease area. The committee noted that the Kaplan–Meier curves had a lot of censoring and not many events, and that the company had not provided confidence intervals. This emphasised the importance of using additional data from FIGARO‑DKD for a better powered analysis. The committee concluded that the primary composite outcome of FIDELIO‑DKD is clinically relevant, but further evidence from FIGARO‑DKD would help supplement the data.\n\n## Additional evidence from FIGARO-DKD supports the results of the primary composite outcome, but has limitations\n\nDuring consultation, the company provided a scenario analysis, in which clinical evidence from FIDELITY, matching the population in the marketing authorisation for finerenone, was used to update the cost-effectiveness analysis. The company highlighted that the population in FIGARO-DKD included some people with less marked albuminuria (even at the same level of eGFR) than in FIDELITY. So, it said that including these people would dilute the effect seen in FIDELIO-DKD. But the committee noted that people in both trials had some degree of albuminuria, in line with finerenone's marketing authorisation. At the second committee meeting, the clinical experts emphasised that, in NHS practice, prescribers would want to offer finerenone to people who met either definition of albuminuria. So the committee considered that the best evidence to estimate the effectiveness of finerenone in practice would be the pooled data from people in FIDELIO‑DKD and FIGARO-DKD who met the criteria in the marketing authorisation. The ERG noted that the presentation of data from FIDELITY was limited and lacking in transparency, preventing a clear assessment of the scenario analysis results. It agreed with the company's view that this scenario analysis was subject to limitations (see section 3.6). But it could not rule out using additional evidence from FIGARO-DKD to inform the model instead of relying solely on the more optimistic evidence from FIDELIO-DKD. The committee concluded that additional evidence from FIGARO-DKD supports the results of the primary analysis from FIDELIO-DKD, but has limitations.\n\n## Results from modelling standard care including SGLT2 inhibitors with and without finerenone are uncertain\n\nDuring consultation, the company provided scenario analyses to estimate the cost effectiveness of finerenone as an add-on to standard care including SGLT2 inhibitors. It used evidence on the effectiveness of an SGLT2 inhibitor (dapagliflozin) in delaying transitions for time to end-stage renal disease, time to dialysis and time to a cardiovascular event. It calculated how these outcomes would be affected in FIDELIO‑DKD and FIGARO-DKD for the proportion of people taking SGLT2 inhibitors. This allowed estimation of outcomes in a population in which 100% of people take SGLT2 inhibitors and finerenone. The company assumed that the effects of finerenone and SGLT2 inhibitors are independent and additive. This was based on evidence from FIDELIO-DKD, which suggested that background SGLT2 inhibitors use did not reduce the benefit of finerenone. The ERG highlighted that the company had provided insufficient details to allow an informed critique of the approach, and noted that it was uncertain whether the effects of finerenone and SGLT2 inhibitors would actually be additive. It explained that, although there is some evidence that combining finerenone and SGLT2 inhibitors may provide more benefit than SGLT2 inhibitors alone (an 'additional' effect), this is not necessarily the same as the combined benefit being the sum of both independent benefits (an 'additive' effect). The committee concluded that the company's attempt to model standard care including SGLT2 inhibitors with and without finerenone was uncertain. Because it could not know whether the effects were truly additive, the committee considered that the analyses provided a useful upper bound to the likely cost effectiveness of finerenone in that setting.\n\n## Hyperkalaemia is the main adverse event associated with finerenone, but overall the adverse events are not concerning\n\nThe main adverse event in FIDELIO‑DKD associated with finerenone was hyperkalaemia. But the committee acknowledged that it seemed to be mild in most cases. The clinical experts agreed that the adverse events were not unexpected and noted that in the FIDELIO‑DKD protocol, finerenone and placebo were withheld when serum potassium levels were greater than 5.5\xa0mmol/litre. But they agreed that in clinical practice, the level would be allowed to go slightly above this in some circumstances. Hospitalisation rates were around 1% higher in the finerenone arm than in the placebo arm, but the clinical experts did not see this as being a significant concern if these hospitalisations were for short durations. The committee concluded that hyperkalaemia is an important adverse event to consider, but overall, the adverse events results from FIDELIO‑DKD were not particularly concerning.\n\n# Cost effectiveness\n\n## The structure of the company's model is appropriate for decision making\n\nThe company presented a cohort-level, state-transition Markov model to estimate the cost effectiveness of finerenone plus standard care compared with placebo plus standard care. A representative treatment from each relevant class of therapy in standard care was used in the model, at its maximum dose. The ERG agreed with this approach. The clinical experts agreed that the treatments used were typical of NHS practice, but also agreed with stakeholder comments that some of the doses were lower than expected. But if the average or most common dose was assumed, then they were not unreasonable. The committee acknowledged that any inaccuracies were likely to have a minor impact on results because they applied to both arms of the model. The health states used were CKD stage\xa01 or 2, CKD stage\xa03, CKD stage\xa04, CKD stage\xa05 without dialysis, dialysis, transplant, and death. These health states were all duplicated into 2 sub-models for before and after a cardiovascular event. The model had a cycle length of 4\xa0months, in line with data collection in the trial, and a lifetime time horizon of 34.2\xa0years. Originally, the utilities used in the model were 5-level EQ-5D (EQ-5D-5L) values from the trial mapped onto the EQ-5D-3L. But after technical engagement, the company updated these to utilities from the literature (see section 3.18). No treatment waning effects were included in the model (see section 3.15). The committee noted that the model showed possible large jumps in progression, for example from CKD stage\xa03 to CKD stage\xa05, and from CKD stage\xa03 to dialysis or transplant. The clinical experts considered this to be plausible because in clinical practice, people with CKD associated with type\xa02 diabetes can move between health states, rather progress linearly. The committee noted that a shorter cycle length may have showed more intermediate states. Overall, the committee concluded that structurally, the company's model was suitable for decision making.\n\n## The modelled health state-transition probabilities are uncertain\n\nThe individual health states in the model were empirically based on FIDELIO‑DKD and applied as a 4-month probability for the whole of the model. So, the probability of transitioning from 1 state to another was repeated for the duration of the model. The ERG was concerned that assuming constant transition probabilities over time may have been an over-simplification. It added that the large FIDELIO‑DKD dataset could allow for more complex transitions in the model. The company agreed, but explained that its experts had advised against this approach. The company clarified that time-varying risks are accounted for (albeit in a simplified way) because cardiovascular risk over time varies by age. The company used this approach to minimise interference with trial data, and because its health economists and clinicians had advised that its method of validating progression was reasonable. It added that its model structure was common in modelling CKD progression, and clinical expert advice was that current eGFR level is the main predictor for progression, so the same rates of cardiovascular events were applied for all people with the same CKD state. Mortality was also accounted for separately because of competing risks. The ERG agreed that the model captured the additional risk linked with age. But overall CKD progression between health states did not vary with time, and the ERG determined that the model was oversimplified. To validate its approach, the company compared its model with the Study of Heart and Renal Protection (SHARP)-CKD-CVD Markov model. This validation compared the cumulative probabilities per 1,000 participants at 5 and 10\xa0years, with 95% confidence intervals around the company model results, and ranges around the SHARP-CKD-CVD model. The company concluded that its model results were within the ranges shown by SHARP-CKD-CVD. But the ERG explained that although the company's model results may have been within the ranges of the SHARP-CKD-CVD model, these ranges were extremes rather than confidence intervals. So, they could be obtained from varying inputs. The ERG highlighted that it was important to consider how the results were obtained, for example how events accrued over time. It noted that the tight confidence intervals observed around the company's model results in the cross validation were because of the time-invariant transition probabilities used. The ERG noted that although the SHARP-CKD-CVD model could inform some parts of the company's model, this was limited because it was built for a different purpose and the populations could not be exactly matched. For example, there were more renal replacement events in the SHARP-CKD-CVD model, but fewer people with relatively mild CKD, because the minimum CKD stage was 3b. The ERG explained that the effect of time-invariant transitions on the model output was uncertain. This was because it was not possible to assess CKD over time. The company also clarified that it had not compared transitions with the trial data. The ERG felt that validating the distribution of outputs over a time period would have been a better approach. The committee considered that the effects of using time-invariant transition probabilities were uncertain; a comparison of transitions over time with the trial data would be informative. In particular, the committee would have liked to see modelling predictions of time to various events, for example cardiovascular or renal replacement therapy events, compared with empirical Kaplan–Meier curves from the relevant populations in FIDELIO‑DKD and FIGARO‑DKD. The committee concluded that the modelled health state-transition probabilities were uncertain.\n\n## The updated health state-transition probabilities are also uncertain\n\nDuring consultation, the company updated its transition probabilities for the finerenone arm by applying hazard ratios to the standard care transition probabilities corresponding to the 'CKD5 without dialysis' and 'CKD5 without dialysis to dialysis' health states. The ERG and the committee noted that for the finerenone arm, no direct effect of finerenone was reflected on transitions in the earlier stages of CKD, but instead transitions associated with CKD5 were amended. The ERG highlighted that 2 possible sets of transitions were explicitly modelled to differ by arms through applying a simple hazard ratio, 1 of which was for a different outcome (that is, progression to CKD5 without dialysis rather than 'onset of eGFR decrease less than 15\xa0ml/min sustained over at least 4\xa0weeks'). Furthermore, the transitions and the effect of finerenone remained time-invariant. Also during consultation, the company did an external validation of the cost-effectiveness model to ensure that its results were in line with the FIDELIO‑DKD outcomes. It compared incidence of first cardiovascular events, cardiovascular deaths and the number of people having dialysis with the model predictions. The model results reflected the incidence of the first cardiovascular event, cardiovascular mortality and incidence of dialysis observed in the FIDELIO‑DKD trial. The ERG noted that because the validation used input data from the same study, it did not represent a true 'external' validation. The ERG highlighted that the analyses supported the expectation that cardiovascular events and onset of dialysis could be accurately reflected by the model over a 4‑year time horizon. But the model projected outcomes over a 34‑year time horizon, and so for the remaining 30\xa0years, all probabilities were assumed fixed. The committee acknowledged that the company addressed its request to provide analyses comparing model outputs with empirical data from the trial. For both outcomes considered (time to dialysis and time to a cardiovascular event), the model outputs closely approximated the observed data. The committee was reassured that the model provided a reasonable representation of expected outcomes and, in particular, that using time-invariant transitions did not compromise the model's validity, at least over the 4\xa0years for which empirical data was available. The committee noted that the ERG's scenario analyses that used both the company's original approach and revised approach to estimating transition probabilities were useful for decision making. But only the latter allowed for consideration of parameter uncertainty in the probabilistic sensitivity analyses. The committee concluded that the updated transition probabilities were also uncertain.\n\n## Treatment effects beyond 4 years are uncertain\n\nIn the model, the company assumed that people would stop taking finerenone at the rate observed in FIDELIO-DKD. After this, people accrued the costs and effectiveness of standard care. The company did not explore treatment effect waning because it claimed that in the trial, the relative effect of finerenone was almost constant over 4\xa0years. The company also assumed that in clinical practice, finerenone would be stopped (see section 3.16) if there was no treatment effect. The clinical experts thought that finerenone benefit is likely to be maintained over time. They added that at more advanced CKD stages, it takes fewer events to progress to dialysis, with a large impact on quality of life. So there may be a greater absolute benefit of finerenone in more advanced CKD. During consultation, the company provided scenario analyses assuming the effect of finerenone waning over a period of 16\xa0years, that is, decreasing by 25% every 4\xa0years until it dissipated entirely by 16\xa0years. It provided 2 further scenario analyses in which finerenone was stopped before the point at which finerenone's constant effect was extrapolated to end after the trial period. These assumed finerenone would be stopped after 7\xa0years, based on a median of 7.5\xa0years spent in stages\xa03 and 4 CKD (Wilson et al. 2012), and 9\xa0years, based on the average time without renal replacement therapy in the economic model. Although the ERG considered the 16‑year waning scenario an arbitrary assumption, it highlighted that the finerenone discontinuation scenarios (7\xa0years and 9\xa0years) were potentially informative. The committee acknowledged that uncertainty around the treatment waning effect was inherent beyond the trial period. It concluded that extrapolating relative treatment effects beyond the 4\xa0years seen in the trial was uncertain, but that the company had made a reasonable attempt to explore this.\n\n## Finerenone is stopped after renal replacement therapy starts\n\nIn the company's model, finerenone was stopped after starting renal replacement therapy. The ERG did not have a preference about whether finerenone should be stopped or continued after renal replacement therapy is started. The clinical experts stated that finerenone would be stopped if a person's eGFR dropped below 15\xa0ml/min/1.73\xa0m2 (see section 3.7), which would occur before renal replacement therapy was started. The stopping rule decreased the incremental cost-effectiveness ratio (ICER) in a scenario analysis. The committee concluded that finerenone would be stopped after renal replacement therapy is started.\n\n## Modelling of previous cardiovascular disease remains an outstanding area of uncertainty\n\nThe ERG explained that some people in FIDELIO‑DKD would have had at least 1 previous cardiovascular event. This is because, although people were excluded if they experienced cardiovascular events in the 30\xa0days before the screening visit, the exclusion criterion did not cover cardiovascular events that happened before this. The ERG and company agreed that 45.9% of people entered the model with a history of cardiovascular disease. The company preferred to model this proportion of people from the point of entering FIDELIO‑DKD (that is, to use the simplifying assumption that no patients had experienced a cardiovascular event before entering the model), whereas the ERG preferred to model this using the total patient history. The ERG explained that the company used external evidence to inform mortality and that this had a substantial effect on the cost-effectiveness estimates. So, there was a risk that estimates would be biased if the proportion of people with a history of cardiovascular disease was not accurate. The company explained that the model was structured in a way that meant that if it included total cardiovascular history, a considerable part of any cardiovascular protective benefit of finerenone would be lost. The ERG suggested that it would be ideal to have 3 sub-models, reflecting:\n\npeople with no cardiovascular history\n\npeople entering the model with cardiovascular history but yet to experience a further cardiovascular event\n\npeople who experienced a cardiovascular event in the model.The committee agreed that in the company's 2 sub-models, the company and the ERG had valid reasons to support the different approaches, and that neither approach was optimal. It agreed that it would not be fair to lose any cardiovascular benefit of finerenone, but noted that this benefit was not statistically significant in the trial. The committee also noted that any limitations in the company's sensitivity analyses (see section 3.19) meant that uncertainties around this benefit could not be analysed with a valid probabilistic sensitivity analysis. The committee considered that the company's approach likely resulted in optimistic cost-effectiveness results, and recommended that restructuring the model into 3 sub-models would reduce uncertainty. During consultation, the company updated its model to account for the impact of recorded cardiovascular history on costs, utilities and mortality. The company felt that the 3 sub-model approach suggested by the committee would not be informative. Despite this, it created the sub-models and provided the results as scenario analyses. The ERG highlighted that the company's approach to the 3 sub-models did not align with the committee's request; the company's approach did not track patients over time in each of the 3 subgroups, but instead modelled 3 independent populations over time. The ERG did not consider these scenario analyses relevant to decision making. The committee concluded that modelling of previous cardiovascular disease remains an outstanding area of uncertainty.\n\n## Utility values used in the company's updated model are appropriate\n\nThe company initially used empirical data from FIDELIO‑DKD to inform the utilities in its model because they were trial-based and it considered them to be conservative. But after technical engagement, the company decided to use utility sources from the literature. This was because the ERG was concerned about an apparent increase in utility from CKD stages\xa01 to 2, to CKD stage\xa03. The company still used FIDELIO‑DKD to inform CKD stage\xa01 to 2 utilities, but used disutilities for all other CKD health states to be consistent with NICE's technology appraisal guidance on tolvaptan for treating autosomal dominant polycystic kidney disease (TA358). This was because it included the necessary utilities for the health states, and it was previously accepted by NICE. The ERG noted that it had merely raised questions about some utility values used in the company's submission, and it had not directed the company to completely revise its approach. It noted that the CKD-based health utilities from TA358 were from a study from 2005, with a small relevant population, and it did not use the EQ-5D. The company reviewed relevant literature in its submission that included more recent studies to inform comparable health states in the NICE guideline on type 2 diabetes in adults: management (NG28), acute kidney injury: prevention, detection and management (NG148) and chronic kidney disease (NG203). But it did not appear to have used them to inform its model. The ERG preferred using modified trial-based utilities, despite some imperfections. The utilities from the trial and updated utilities from the literature were similar for CKD stages\xa03 and 4, but lower for the subsequent stages from TA358. The company acknowledged that the CKD health states were taken from TA358, which evaluated a different indication, but it had advice from clinicians that it is not CKD stage\xa05 and dialysis, but being on dialysis itself, that has a large impact on quality of life. The clinical experts explained that there is not a large difference in the quality of life between CKD stage\xa01 to 2 and CKD stage\xa03, because CKD stages 3a and 3b are generally asymptomatic, although renal function is affected physiologically. But the clinical experts noted that with CKD and type\xa02 diabetes, there are more comorbidities, with a greater burden, and therefore a lower quality of life. In addition, in people with CKD and type\xa02 diabetes, their CKD tends to progress through stages at a faster rate for any given eGFR level. The ERG and the committee acknowledged that in the trial, the utilities for dialysis, post-dialysis and transplant were higher than expected. The committee considered that both approaches to utilities in the model have advantages and disadvantages, so a base case with trial-based utilities, and another with utilities from more recent and relevant literature sources than those currently used in the model, such as utilities from NG28, would be informative. During consultation, the company updated the model's utility values for dialysis and kidney transplant and cardiovascular events to reflect those in NG28. The ERG accepted the updated utility values. The committee concluded that the utility values used in the company's updated model were appropriate.\n\n## The updated sensitivity analyses should still be interpreted with caution\n\nThe ERG described the company's sensitivity analyses as having multifaceted issues. These included issues of grouping parameters, having wide parameter bounds, parameters being sampled from user-specified limits, and the overestimation of uncertainty in utility values. Moreover, the critical transition probabilities were not only time-invariant, they were also not subject to any form of sensitivity analysis. The company attempted to address these uncertainties and its rationale during technical engagement. It explained that certain parameters were grouped to account for a higher utility being observed for CKD stage\xa03 than for CKD stage\xa01 to 2. But the company changed its utility source in the model (see section 3.18). The ERG did not agree with the approach because the differences in values in the probabilistic sensitivity analysis were not shown, only whether the values were all high or all low. The ERG highlighted that using very wide parameter bounds stress tests the deterministic sensitivity analyses to implausible limits. The company acknowledged that not including the uncertainty from its time-invariant transition probabilities was a limitation, but also that this concerned the impact of finerenone in delaying CKD progression, which was significant in the trial. The company described how the probabilistic sensitivity analysis could include the statistical impact of finerenone to translate to an improvement in benefit when randomisation occurs. The company acknowledged the limitations in the sensitivity analyses and mentioned that it would not be able to resolve all the problems, in particular those to do with utilities. During consultation, it updated the transition probabilities to account for parameter uncertainty in the probabilistic sensitivity analysis. Transition probabilities for the standard care arm were sampled in the probabilistic sensitivity analysis from the Dirichlet distribution. The ERG questioned why this approach was not considered for the finerenone arm as well. The committee recalled the ERG's concerns with both the original and updated approaches to estimating transition probabilities and that only the latter approach allowed for parameter uncertainty in the probabilistic sensitivity analyses (see section 3.14). It considered that, although the updated approach to sensitivity analyses was an improvement, the outputs of these remained uncertain. The committee concluded that the results of the updated sensitivity analyses should be interpreted with caution.\n\n# Cost-effectiveness estimates\n\n## Finerenone is cost effective compared with standard care\n\nThe committee considered the cost-effectiveness estimates for finerenone compared with standard care. It acknowledged that, since the first committee meeting, the company had attempted to reduce the uncertainty in the clinical and cost-effectiveness evidence. But it noted the outstanding areas of uncertainty:\n\nmissing comparison for finerenone use with SGLT2 inhibitors (see section 3.4)\n\nestimation of transition probabilities (see section 3.13 and section 3.14)\n\ntreatment effect waning of finerenone (see section 3.15)\n\nmodelling of previous cardiovascular disease (see section 3.17)\n\nsensitivity analyses results (see section 3.19).For finerenone plus standard care compared with standard care alone (when standard care did not include SGLT2 inhibitors), the committee noted that the company's and the ERG's base-case ICERs were relatively low. It also noted that in all the company's scenario analyses, in which standard care included SGLT2 inhibitors, the ICER was less than £30,000 per quality-adjusted life year (QALY) gained. So, despite the uncertainties, it agreed that the most plausible ICER was within the range NICE normally considers an acceptable use of NHS resources. The committee concluded that finerenone is a cost-effective use of NHS resources compared with standard care with or without SGLT2 inhibitors.\n\n# Other factors\n\n## There are no equality issues\n\nNo equality or social value judgement issues were identified that were not captured in the modelling.\n\n# Conclusion\n\n## Finerenone is recommended as an add-on to optimised standard care including ACE inhibitors or ARBs, and SGLT2 inhibitors, unless these are unsuitable\n\nFor CKD associated with type\xa02 diabetes, finerenone is clinically effective compared with placebo, and improves outcomes when added to standard care (with or without SGLT2 inhibitors). Despite uncertainty in the economic modelling, the committee agreed that the most plausible ICER for finerenone plus standard care compared with standard care alone was within the range NICE normally considers to be a cost-effective use of NHS resources. It also took into account that finerenone had not been compared with SGLT2 inhibitors, so it could not be recommended instead of them. So the committee concluded that finerenone is recommended for stage\xa03 and 4 CKD (with albuminuria) associated with type\xa02 diabetes only as an add-on to optimised standard care including ACE inhibitors or ARBs, and SGLT2 inhibitors, unless these are unsuitable."}	https://www.nice.org.uk/guidance/ta877	Evidence-based recommendations on finerenone (Kerendia) for stage 3 and 4 chronic kidney disease (with albuminuria) associated with type 2 diabetes in adults.
73ce0901e3be650662a13f3e9a9cc6f218371341	nice	Nivolumab with chemotherapy for neoadjuvant treatment of resectable non-small-cell lung cancer	Nivolumab with chemotherapy for neoadjuvant treatment of resectable non-small-cell lung cancer Evidence-based recommendations on nivolumab (Opdivo) with chemotherapy for neoadjuvant treatment of resectable non-small-cell lung cancer in adults. # Recommendations Nivolumab with chemotherapy is recommended, within its marketing authorisation, as an option for the neoadjuvant treatment of resectable (tumours at least 4 cm or node positive) non-small-cell lung cancer (NSCLC) in adults. It is only recommended if the company provides it according to the commercial arrangement. Why the committee made this recommendation Standard care for NSCLC that can be surgically removed (resectable) is surgery. Sometimes chemoradiotherapy before (neoadjuvant) or chemotherapy after (adjuvant) surgery is also used. There is no clinical trial evidence directly comparing neoadjuvant nivolumab plus chemotherapy with standard care but an indirect comparison suggests it is more effective. The cost-effectiveness estimates for neoadjuvant nivolumab with chemotherapy compared with standard care are within the range NICE normally considers an acceptable use of NHS resources. So, neoadjuvant nivolumab with chemotherapy is recommended.# Information about nivolumab with chemotherapy # Marketing authorisation indication Nivolumab (Opdivo, Bristol-Myers Squibb) with chemotherapy is indicated for 'the neoadjuvant treatment of resectable (tumours ≥ 4 cm or node positive) non-small cell lung cancer in adults'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for nivolumab. # Price The list price for nivolumab is £439.00 for a (10 mg/ml) 4‑ml vial (excluding VAT; BNF online, accessed January 2023). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Bristol-Myers Squibb, a review of this submission by the external assessment group (EAG), and submissions from stakeholders. See the committee papers for full details of the evidence considered. # The condition ## Unmet need Standard care for resectable non-small-cell lung cancer (NSCLC) is surgical resection. Treatment options in addition to surgery are limited. Neoadjuvant chemoradiotherapy or adjuvant chemotherapy may be considered with the aim of improving long-term outcomes. Some people choose not to have adjuvant chemotherapy because of the associated serious adverse events and some may not be fit enough to tolerate it after surgery. The patient organisation submission highlighted that the 5‑year survival rate after surgical resection with curative intent is about 50%, with relapses in distant sites. It explained that symptoms of recurrent NSCLC, such as breathlessness, cough and weight loss, are often difficult to manage without active treatment. It also highlighted that neoadjuvant treatment is well established in other cancers, such as breast cancer, as a promising approach for prolonging survival and increasing the chance of cure for people with potentially resectable NSCLC. A professional organisation submission highlighted that NSCLC has a very poor prognosis in the UK. It explained that only a small proportion of people have NSCLC that can be cured at an early stage and a substantial proportion have recurrence. So, it is important that new treatment options are made available to ensure the best chance of cure. This submission noted that nivolumab plus chemotherapy increases the potential of good outcomes for the small proportion of people who have potentially curable NSCLC. There are limited treatment options for resectable NSCLC after surgery, and outcomes with available treatments are poor. Also, there is a need for a new treatment option, particularly in the neoadjuvant setting. The committee concluded that there is an unmet need for treatments for resectable NSCLC, and neoadjuvant nivolumab plus chemotherapy would be welcomed. ## Comparators In its submission, the company compared neoadjuvant nivolumab plus chemotherapy with neoadjuvant chemoradiotherapy, surgery alone and adjuvant chemotherapy. The company highlighted that surgery alone represents the active monitoring comparator as per the NICE scope. It further explained that, in its economic model, people in the neoadjuvant chemoradiotherapy arm had chemotherapy plus radiotherapy then surgery. Some people had adjuvant treatment. In the surgery alone arm, people had surgery and did not have neoadjuvant or adjuvant treatment, but had monitoring after surgery. In the adjuvant chemotherapy arm people had surgery and a subsequent course of chemotherapy. The EAG noted that the comparators included in the company's economic evaluation were in line with the NICE scope and representative of NHS clinical practice. The committee concluded that the comparators included in the company submission were appropriate. # Clinical effectiveness ## CheckMate-816 trial evidence The clinical-effectiveness evidence for neoadjuvant nivolumab plus chemotherapy came from CheckMate‑816. This is an ongoing phase 3, multicentre, randomised, open-label, clinical trial. It is comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant chemotherapy alone in adults with resectable stage 1B to 3A NSCLC. In the interim analysis 1 (October 2021), there was a median follow up of 29.5 months. Results from this analysis showed that neoadjuvant nivolumab plus chemotherapy improved event-free and overall survival. They also showed that the odds of pathological complete response were higher compared with neoadjuvant chemotherapy alone. The EAG highlighted that its clinical advice suggested that NSCLC disease stage is the main prognostic factor. It did subgroup analyses for disease stage, which showed that neoadjuvant nivolumab plus chemotherapy was less effective for stage 1B to 2 NSCLC than for stage 3 NSCLC. The result was less precise for stage 1B to 2 NSCLC, indicating that the analysis was underpowered. The EAG noted that more people in CheckMate‑816 had cisplatin-based chemotherapy than carboplatin-based chemotherapy, consistent with clinical advice it had received. But clinical advice also suggested carboplatin-based chemotherapy could be paired with nivolumab. Clinical advice to the EAG further suggested that cisplatin plus vinorelbine would be the most commonly used chemotherapy regimen in the UK. But this combination was only used in the neoadjuvant chemotherapy alone arm of CheckMate‑816. The EAG considered that, when assessed in the overall population, neoadjuvant nivolumab plus chemotherapy is more effective for stage 1B to 3A resectable NSCLC compared with neoadjuvant chemotherapy alone. It also thought that, although neoadjuvant nivolumab plus chemotherapy may be less effective for the stage 1B to 2 NSCLC subgroup (compared with the stage 3A NSCLC subgroup), its effectiveness in the overall resectable stage 1B to 3A NSCLC population is more relevant. The committee concluded that neoadjuvant nivolumab plus chemotherapy is more effective for stage 1B to 3A resectable NSCLC compared with neoadjuvant chemotherapy alone. ## CheckMate-816 generalisability The EAG noted that CheckMate‑816 has not recruited anyone from the UK, and that about 50% of people in the study had an Asian family background. So, it considered that generalisability of the trial to NHS clinical practice is questionable. The EAG also noted that the characteristics of the North American and European family background subgroups from CheckMate‑816 may be more applicable to NHS clinical practice. The EAG's subgroup analyses by family background showed that neoadjuvant nivolumab plus chemotherapy was less effective in the North American and European populations compared with the Asian population. In CheckMate‑816, 59.1% of people in the neoadjuvant nivolumab plus chemotherapy arm and 63.0% of people in the neoadjuvant chemotherapy alone arm had thoracotomy. Also, 16.8% of people in the neoadjuvant nivolumab plus chemotherapy arm and 25.2% in the neoadjuvant chemotherapy alone arm had pneumonectomy. But clinical advice to the EAG suggested that minimally invasive surgery is more common in NHS clinical practice. In CheckMate‑816 only 29.5% of people in the neoadjuvant nivolumab plus chemotherapy arm and 21.5% in the neoadjuvant chemotherapy alone arm had minimally invasive surgery. Clinical advice to the EAG also suggested that pneumonectomy is now very uncommon for NSCLC resection in NHS clinical practice. So, the EAG considered that the main resection types used in CheckMate‑816 may not reflect NHS clinical practice. But it is unclear if resection type is associated with different recurrence rates and health-related quality of life. The EAG considered that all other baseline characteristics were well balanced between treatment arms in CheckMate‑816. The committee acknowledged that there were differences in demographics between the trial and NHS clinical practice, and noted that neoadjuvant nivolumab plus chemotherapy is less effective in some subgroups. But it considered that the trial is likely representative of NHS clinical practice and that most baseline characteristics between the CheckMate‑816 treatment arms were well balanced. So, the committee concluded that clinical evidence from CheckMate‑816 was uncertain but suitable for decision making. ## Indirect comparison There was no evidence directly comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant chemoradiotherapy, surgery alone or adjuvant chemotherapy. So, the company presented an indirect treatment comparison informed by network meta-analyses. These provided comparative effectiveness evidence for neoadjuvant nivolumab plus chemotherapy compared with all the relevant comparators and neoadjuvant chemotherapy alone. The primary outcomes assessed in the network meta-analyses were event-free survival and overall survival. The secondary outcomes assessed were time to locoregional recurrence (TTLR), time to distant metastasis, pathological complete response and safety. The results of the network meta-analyses showed that neoadjuvant nivolumab plus chemotherapy was more effective at improving survival outcomes compared with neoadjuvant chemotherapy alone, neoadjuvant chemoradiotherapy, surgery alone and adjuvant chemotherapy. Results for secondary outcomes were considered confidential by the company, so cannot be reported here. The EAG noted that some studies in the network meta-analyses only included people with an Asian family background, while about 50% of people in CheckMate‑816 had an Asian family background. Also, it noted that, although its clinical advice suggested disease stage is the main prognostic factor, only CheckMate‑816 included stage 1B to 3A NSCLC. Subgroup analyses conducted by the EAG contained data that the company considered confidential, so cannot be reported here. Despite the differences between the studies included in the network meta-analyses, it was considered that the company had sufficiently responded to the EAG's requests at the clarification stage to explore these uncertainties. It was also decided that little more could be done to further address the uncertainties. So, the network meta-analyses were deemed sufficient, and the results considered acceptable for decision making. Because the marketing authorisation for nivolumab plus chemotherapy is not restricted by disease stage, the results of the network meta-analyses for neoadjuvant nivolumab plus chemotherapy for the overall resectable stage 1B to 3A NSCLC population were considered appropriate. The committee concluded that neoadjuvant nivolumab plus chemotherapy is more effective than all the relevant comparators. ## Survival extrapolation The parametric models used to extrapolate time to any progression (TTaP) and TTLR beyond CheckMate‑816 follow up played an important role in determining the efficacy of the intervention. There is considerable uncertainty around the extrapolation of the TTaP and TTLR curves. The company's and EAG's approaches to modelling long-term TTLR and event-free mortality was uncertain. But both were considered plausible and produced cost-effectiveness estimates that were well below NICE's cost-effectiveness threshold. The committee concluded that the optimal approach to modelling survival was uncertain. # Economic model ## Model structure The company presented a 4‑state semi-Markov model to estimate the cost effectiveness of neoadjuvant nivolumab plus chemotherapy compared with neoadjuvant chemoradiotherapy, surgery alone and adjuvant chemotherapy. The 4 health states were event-free, locoregional recurrence, distant metastasis and death. The model used a lifetime horizon and a cycle length of 3 weeks. The model assumed distant metastasis was an absorbing state and applied a one-off cost, and life-year and quality-adjusted life-year (QALY) pay-off upon transitions to the distant metastasis health state. Utility values in the locoregional recurrence state were assumed to be lower than in the event-free state and lower still in the distant metastasis state. A short-term disutility was included to reflect grade 3 and grade 4 adverse events associated with adjuvant treatment during the first cycle of the model. The EAG noted the model structure was consistent with previous economic models for lung cancer. It considered the approach to modelling the distant metastasis state was pragmatic, reduced the complexity of the model and was consistent with previous NICE technology appraisals for lung cancer. The committee concluded that the company's model was appropriate based on the available evidence for this appraisal. ## Cure assumption In its economic model, the company applied a 'cure assumption'. The EAG considered that there was no convincing clinical evidence to support how the cure assumption had been modelled. It was noted that there is generally a consensus among clinical experts that cure occurs between years 5 and 8. But there is no consensus on the rates of cure, and the empirical evidence to support this assumption is lacking. The company's and the EAG's scenario analysis removing the cure assumption only had a small effect on the cost-effectiveness results. The committee concluded that the cure assumption applied was uncertain. ## Utility values The health-state utility values used in the cost-effectiveness model were associated with a degree of uncertainty. This was mainly because the utility values for both the event-free and locoregional recurrence health states were higher than what would be expected in a population with NSCLC. Other minor issues included: using overall rather than treatment-specific utilities from CheckMate‑816 using linear mixed models when analysing non-linear EQ‑5D‑3L data the age-sex adjustment process implemented in the model.But these issues would be difficult to resolve given the lack of evidence. The EAG presented 4 scenarios to explore this uncertainty. The committee concluded that, given the available evidence, the uncertainty had been sufficiently explored. ## Retreatment restrictions In its model, the company applied immuno-oncology therapy retreatment restrictions for people who had neoadjuvant nivolumab plus chemotherapy as their initial treatment and whose NSCLC progressed within 6 months. These people were not considered eligible for further immuno-oncology treatment. Data from CheckMate‑816 was used to adjust the distribution of treatment in the distant metastasis health state to account for the proportion of people in the neoadjuvant nivolumab plus chemotherapy arm who had an event while on treatment. So, these people were not eligible for further treatment with immuno-oncology therapy for 6 months, and their treatments were redistributed across the remaining treatment options. The EAG considered there was uncertainty in the proportion of people ineligible for retreatment with immuno-oncology therapy and the timelines of these restrictions. But it noted that the company had done a scenario analysis with retreatment restriction extended to 12 months, and that the percentage of those not considered for further immuno-oncology retreatment was increased. A further scenario analysis was done by both the company and the EAG in which the retreatment restriction was not included. The EAG did additional scenario analyses by assuming the distribution of chemotherapies in the distant metastasis health state were the same for immuno-oncology and non-immuno-oncology treatments. It was noted that further evidence on the distribution of chemotherapies used for immuno-oncology and non-immuno-oncology treatments in the distant metastasis health state would help address this uncertainty. The committee concluded that the application of retreatment restrictions in the economic model was uncertain. # Cost-effectiveness estimates ## Results When commercial arrangements for nivolumab plus chemotherapy and all the comparators were included, the company's and EAG's base-case incremental cost-effectiveness ratios (ICERs) compared with neoadjuvant chemoradiotherapy, surgery alone and adjuvant chemotherapy were all below £20,000 per QALY gained. The exact ICERs are considered confidential and cannot be reported here. Outstanding areas of uncertainty were considered, including: long-term survival modelling beyond CheckMate‑816 trial follow up (see section 3.6) application of a cure assumption (see section 3.8) utility values for event-free and locoregional recurrence health states (see section 3.9) application of retreatment restrictions (see section 3.10).The committee considered that key uncertainties had been explored sufficiently by both the company and EAG. It noted that almost all of the ICERs remained within the range that is normally considered by NICE as a cost-effective use of NHS resources. So, the likelihood of decision error in this appraisal was assessed to be minimal. The committee concluded that neoadjuvant nivolumab plus chemotherapy for neoadjuvant treatment of resectable NSCLC is likely to be a cost-effective use of NHS resources. # Other factors ## Equality issues No equality issues were identified. NICE's advice about conditions with a high degree of severity did not apply. ## Innovation It was considered whether neoadjuvant nivolumab plus chemotherapy is innovative. No additional benefits of nivolumab plus chemotherapy were identified that were not captured in the economic modelling. So, the committee concluded that all additional benefits of neoadjuvant nivolumab plus chemotherapy had already been taken into account. # Conclusion ## Recommendation All the ICERs considered were in the range normally considered by NICE to be a cost-effective use of NHS resources. So, nivolumab plus chemotherapy is recommended for the neoadjuvant treatment of resectable NSCLC.	{'Recommendations': 'Nivolumab with chemotherapy is recommended, within its marketing authorisation, as an option for the neoadjuvant treatment of resectable (tumours at least 4\xa0cm or node positive) non-small-cell lung cancer (NSCLC) in adults. It is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nStandard care for NSCLC that can be surgically removed (resectable) is surgery. Sometimes chemoradiotherapy before (neoadjuvant) or chemotherapy after (adjuvant) surgery is also used.\n\nThere is no clinical trial evidence directly comparing neoadjuvant nivolumab plus chemotherapy with standard care but an indirect comparison suggests it is more effective.\n\nThe cost-effectiveness estimates for neoadjuvant nivolumab with chemotherapy compared with standard care are within the range NICE normally considers an acceptable use of NHS resources. So, neoadjuvant nivolumab with chemotherapy is recommended.', 'Information about nivolumab with chemotherapy': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol-Myers Squibb) with chemotherapy is indicated for 'the neoadjuvant treatment of resectable (tumours ≥ 4 cm or node positive) non-small cell lung cancer in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for nivolumab.\n\n# Price\n\nThe list price for nivolumab is £439.00 for a (10\xa0mg/ml) 4‑ml vial (excluding VAT; BNF online, accessed January\xa02023).\n\nThe company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Bristol-Myers Squibb, a review of this submission by the external assessment group (EAG), and submissions from stakeholders. See the committee papers for full details of the evidence considered.\n\n# The condition\n\n## Unmet need\n\nStandard care for resectable non-small-cell lung cancer (NSCLC) is surgical resection. Treatment options in addition to surgery are limited. Neoadjuvant chemoradiotherapy or adjuvant chemotherapy may be considered with the aim of improving long-term outcomes. Some people choose not to have adjuvant chemotherapy because of the associated serious adverse events and some may not be fit enough to tolerate it after surgery. The patient organisation submission highlighted that the 5‑year survival rate after surgical resection with curative intent is about 50%, with relapses in distant sites. It explained that symptoms of recurrent NSCLC, such as breathlessness, cough and weight loss, are often difficult to manage without active treatment. It also highlighted that neoadjuvant treatment is well established in other cancers, such as breast cancer, as a promising approach for prolonging survival and increasing the chance of cure for people with potentially resectable NSCLC. A professional organisation submission highlighted that NSCLC has a very poor prognosis in the UK. It explained that only a small proportion of people have NSCLC that can be cured at an early stage and a substantial proportion have recurrence. So, it is important that new treatment options are made available to ensure the best chance of cure. This submission noted that nivolumab plus chemotherapy increases the potential of good outcomes for the small proportion of people who have potentially curable NSCLC. There are limited treatment options for resectable NSCLC after surgery, and outcomes with available treatments are poor. Also, there is a need for a new treatment option, particularly in the neoadjuvant setting. The committee concluded that there is an unmet need for treatments for resectable NSCLC, and neoadjuvant nivolumab plus chemotherapy would be welcomed.\n\n## Comparators\n\nIn its submission, the company compared neoadjuvant nivolumab plus chemotherapy with neoadjuvant chemoradiotherapy, surgery alone and adjuvant chemotherapy. The company highlighted that surgery alone represents the active monitoring comparator as per the NICE scope. It further explained that, in its economic model, people in the neoadjuvant chemoradiotherapy arm had chemotherapy plus radiotherapy then surgery. Some people had adjuvant treatment. In the surgery alone arm, people had surgery and did not have neoadjuvant or adjuvant treatment, but had monitoring after surgery. In the adjuvant chemotherapy arm people had surgery and a subsequent course of chemotherapy. The EAG noted that the comparators included in the company's economic evaluation were in line with the NICE scope and representative of NHS clinical practice. The committee concluded that the comparators included in the company submission were appropriate.\n\n# Clinical effectiveness\n\n## CheckMate-816 trial evidence\n\nThe clinical-effectiveness evidence for neoadjuvant nivolumab plus chemotherapy came from CheckMate‑816. This is an ongoing phase\xa03, multicentre, randomised, open-label, clinical trial. It is comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant chemotherapy alone in adults with resectable stage 1B\xa0to 3A\xa0NSCLC. In the interim analysis\xa01 (October\xa02021), there was a median follow up of 29.5\xa0months. Results from this analysis showed that neoadjuvant nivolumab plus chemotherapy improved event-free and overall survival. They also showed that the odds of pathological complete response were higher compared with neoadjuvant chemotherapy alone. The EAG highlighted that its clinical advice suggested that NSCLC disease stage is the main prognostic factor. It did subgroup analyses for disease stage, which showed that neoadjuvant nivolumab plus chemotherapy was less effective for stage 1B\xa0to 2\xa0NSCLC than for stage\xa03 NSCLC. The result was less precise for stage 1B\xa0to 2\xa0NSCLC, indicating that the analysis was underpowered. The EAG noted that more people in CheckMate‑816 had cisplatin-based chemotherapy than carboplatin-based chemotherapy, consistent with clinical advice it had received. But clinical advice also suggested carboplatin-based chemotherapy could be paired with nivolumab. Clinical advice to the EAG further suggested that cisplatin plus vinorelbine would be the most commonly used chemotherapy regimen in the UK. But this combination was only used in the neoadjuvant chemotherapy alone arm of CheckMate‑816. The EAG considered that, when assessed in the overall population, neoadjuvant nivolumab plus chemotherapy is more effective for stage\xa01B to\xa03A resectable NSCLC compared with neoadjuvant chemotherapy alone. It also thought that, although neoadjuvant nivolumab plus chemotherapy may be less effective for the stage\xa01B to\xa02 NSCLC subgroup (compared with the stage\xa03A NSCLC subgroup), its effectiveness in the overall resectable stage\xa01B to\xa03A NSCLC population is more relevant. The committee concluded that neoadjuvant nivolumab plus chemotherapy is more effective for stage\xa01B to\xa03A resectable NSCLC compared with neoadjuvant chemotherapy alone.\n\n## CheckMate-816 generalisability\n\nThe EAG noted that CheckMate‑816 has not recruited anyone from the UK, and that about 50% of people in the study had an Asian family background. So, it considered that generalisability of the trial to NHS clinical practice is questionable. The EAG also noted that the characteristics of the North American and European family background subgroups from CheckMate‑816 may be more applicable to NHS clinical practice. The EAG's subgroup analyses by family background showed that neoadjuvant nivolumab plus chemotherapy was less effective in the North American and European populations compared with the Asian population. In CheckMate‑816, 59.1% of people in the neoadjuvant nivolumab plus chemotherapy arm and 63.0% of people in the neoadjuvant chemotherapy alone arm had thoracotomy. Also, 16.8% of people in the neoadjuvant nivolumab plus chemotherapy arm and 25.2% in the neoadjuvant chemotherapy alone arm had pneumonectomy. But clinical advice to the EAG suggested that minimally invasive surgery is more common in NHS clinical practice. In CheckMate‑816 only 29.5% of people in the neoadjuvant nivolumab plus chemotherapy arm and 21.5% in the neoadjuvant chemotherapy alone arm had minimally invasive surgery. Clinical advice to the EAG also suggested that pneumonectomy is now very uncommon for NSCLC resection in NHS clinical practice. So, the EAG considered that the main resection types used in CheckMate‑816 may not reflect NHS clinical practice. But it is unclear if resection type is associated with different recurrence rates and health-related quality of life. The EAG considered that all other baseline characteristics were well balanced between treatment arms in CheckMate‑816. The committee acknowledged that there were differences in demographics between the trial and NHS clinical practice, and noted that neoadjuvant nivolumab plus chemotherapy is less effective in some subgroups. But it considered that the trial is likely representative of NHS clinical practice and that most baseline characteristics between the CheckMate‑816 treatment arms were well balanced. So, the committee concluded that clinical evidence from CheckMate‑816 was uncertain but suitable for decision making.\n\n## Indirect comparison\n\nThere was no evidence directly comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant chemoradiotherapy, surgery alone or adjuvant chemotherapy. So, the company presented an indirect treatment comparison informed by network meta-analyses. These provided comparative effectiveness evidence for neoadjuvant nivolumab plus chemotherapy compared with all the relevant comparators and neoadjuvant chemotherapy alone. The primary outcomes assessed in the network meta-analyses were event-free survival and overall survival. The secondary outcomes assessed were time to locoregional recurrence (TTLR), time to distant metastasis, pathological complete response and safety. The results of the network meta-analyses showed that neoadjuvant nivolumab plus chemotherapy was more effective at improving survival outcomes compared with neoadjuvant chemotherapy alone, neoadjuvant chemoradiotherapy, surgery alone and adjuvant chemotherapy. Results for secondary outcomes were considered confidential by the company, so cannot be reported here. The EAG noted that some studies in the network meta-analyses only included people with an Asian family background, while about 50% of people in CheckMate‑816 had an Asian family background. Also, it noted that, although its clinical advice suggested disease stage is the main prognostic factor, only CheckMate‑816 included stage\xa01B to\xa03A NSCLC. Subgroup analyses conducted by the EAG contained data that the company considered confidential, so cannot be reported here. Despite the differences between the studies included in the network meta-analyses, it was considered that the company had sufficiently responded to the EAG's requests at the clarification stage to explore these uncertainties. It was also decided that little more could be done to further address the uncertainties. So, the network meta-analyses were deemed sufficient, and the results considered acceptable for decision making. Because the marketing authorisation for nivolumab plus chemotherapy is not restricted by disease stage, the results of the network meta-analyses for neoadjuvant nivolumab plus chemotherapy for the overall resectable stage\xa01B to\xa03A NSCLC population were considered appropriate. The committee concluded that neoadjuvant nivolumab plus chemotherapy is more effective than all the relevant comparators.\n\n## Survival extrapolation\n\nThe parametric models used to extrapolate time to any progression (TTaP) and TTLR beyond CheckMate‑816 follow up played an important role in determining the efficacy of the intervention. There is considerable uncertainty around the extrapolation of the TTaP and TTLR curves. The company's and EAG's approaches to modelling long-term TTLR and event-free mortality was uncertain. But both were considered plausible and produced cost-effectiveness estimates that were well below NICE's cost-effectiveness threshold. The committee concluded that the optimal approach to modelling survival was uncertain.\n\n# Economic model\n\n## Model structure\n\nThe company presented a 4‑state semi-Markov model to estimate the cost effectiveness of neoadjuvant nivolumab plus chemotherapy compared with neoadjuvant chemoradiotherapy, surgery alone and adjuvant chemotherapy. The 4\xa0health states were event-free, locoregional recurrence, distant metastasis and death. The model used a lifetime horizon and a cycle length of 3\xa0weeks. The model assumed distant metastasis was an absorbing state and applied a one-off cost, and life-year and quality-adjusted life-year (QALY) pay-off upon transitions to the distant metastasis health state. Utility values in the locoregional recurrence state were assumed to be lower than in the event-free state and lower still in the distant metastasis state. A short-term disutility was included to reflect grade\xa03 and grade\xa04 adverse events associated with adjuvant treatment during the first cycle of the model. The EAG noted the model structure was consistent with previous economic models for lung cancer. It considered the approach to modelling the distant metastasis state was pragmatic, reduced the complexity of the model and was consistent with previous NICE technology appraisals for lung cancer. The committee concluded that the company's model was appropriate based on the available evidence for this appraisal.\n\n## Cure assumption\n\nIn its economic model, the company applied a 'cure assumption'. The EAG considered that there was no convincing clinical evidence to support how the cure assumption had been modelled. It was noted that there is generally a consensus among clinical experts that cure occurs between years\xa05 and\xa08. But there is no consensus on the rates of cure, and the empirical evidence to support this assumption is lacking. The company's and the EAG's scenario analysis removing the cure assumption only had a small effect on the cost-effectiveness results. The committee concluded that the cure assumption applied was uncertain.\n\n## Utility values\n\nThe health-state utility values used in the cost-effectiveness model were associated with a degree of uncertainty. This was mainly because the utility values for both the event-free and locoregional recurrence health states were higher than what would be expected in a population with NSCLC. Other minor issues included:\n\nusing overall rather than treatment-specific utilities from CheckMate‑816\n\nusing linear mixed models when analysing non-linear EQ‑5D‑3L data\n\nthe age-sex adjustment process implemented in the model.But these issues would be difficult to resolve given the lack of evidence. The EAG presented 4\xa0scenarios to explore this uncertainty. The committee concluded that, given the available evidence, the uncertainty had been sufficiently explored.\n\n## Retreatment restrictions\n\nIn its model, the company applied immuno-oncology therapy retreatment restrictions for people who had neoadjuvant nivolumab plus chemotherapy as their initial treatment and whose NSCLC progressed within 6\xa0months. These people were not considered eligible for further immuno-oncology treatment. Data from CheckMate‑816 was used to adjust the distribution of treatment in the distant metastasis health state to account for the proportion of people in the neoadjuvant nivolumab plus chemotherapy arm who had an event while on treatment. So, these people were not eligible for further treatment with immuno-oncology therapy for 6\xa0months, and their treatments were redistributed across the remaining treatment options. The EAG considered there was uncertainty in the proportion of people ineligible for retreatment with immuno-oncology therapy and the timelines of these restrictions. But it noted that the company had done a scenario analysis with retreatment restriction extended to 12\xa0months, and that the percentage of those not considered for further immuno-oncology retreatment was increased. A further scenario analysis was done by both the company and the EAG in which the retreatment restriction was not included. The EAG did additional scenario analyses by assuming the distribution of chemotherapies in the distant metastasis health state were the same for immuno-oncology and non-immuno-oncology treatments. It was noted that further evidence on the distribution of chemotherapies used for immuno-oncology and non-immuno-oncology treatments in the distant metastasis health state would help address this uncertainty. The committee concluded that the application of retreatment restrictions in the economic model was uncertain.\n\n# Cost-effectiveness estimates\n\n## Results\n\nWhen commercial arrangements for nivolumab plus chemotherapy and all the comparators were included, the company's and EAG's base-case incremental cost-effectiveness ratios (ICERs) compared with neoadjuvant chemoradiotherapy, surgery alone and adjuvant chemotherapy were all below £20,000 per QALY gained. The exact ICERs are considered confidential and cannot be reported here. Outstanding areas of uncertainty were considered, including:\n\nlong-term survival modelling beyond CheckMate‑816 trial follow up (see section\xa03.6)\n\napplication of a cure assumption (see section\xa03.8)\n\nutility values for event-free and locoregional recurrence health states (see section 3.9)\n\napplication of retreatment restrictions (see section 3.10).The committee considered that key uncertainties had been explored sufficiently by both the company and EAG. It noted that almost all of the ICERs remained within the range that is normally considered by NICE as a cost-effective use of NHS resources. So, the likelihood of decision error in this appraisal was assessed to be minimal. The committee concluded that neoadjuvant nivolumab plus chemotherapy for neoadjuvant treatment of resectable NSCLC is likely to be a cost-effective use of NHS resources.\n\n# Other factors\n\n## Equality issues\n\nNo equality issues were identified. NICE's advice about conditions with a high degree of severity did not apply.\n\n## Innovation\n\nIt was considered whether neoadjuvant nivolumab plus chemotherapy is innovative. No additional benefits of nivolumab plus chemotherapy were identified that were not captured in the economic modelling. So, the committee concluded that all additional benefits of neoadjuvant nivolumab plus chemotherapy had already been taken into account.\n\n# Conclusion\n\n## Recommendation\n\nAll the ICERs considered were in the range normally considered by NICE to be a cost-effective use of NHS resources. So, nivolumab plus chemotherapy is recommended for the neoadjuvant treatment of resectable NSCLC."}	https://www.nice.org.uk/guidance/ta876	Evidence-based recommendations on nivolumab (Opdivo) with chemotherapy for neoadjuvant treatment of resectable non-small-cell lung cancer in adults.
fcdabda62280254fe6bc8ef1133b39a5ea8ccde6	nice	Lung cancer: diagnosis and management	Lung cancer: diagnosis and management This guideline covers diagnosing and managing non-small-cell and small-cell lung cancer. It aims to improve outcomes for patients by ensuring that the most effective tests and treatments are used, and that people have access to suitable palliative care and follow-up. # Access to services and referral People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # The importance of early diagnosis The public needs to be better informed of the symptoms and signs that are characteristic of lung cancer, through coordinated campaigning to raise awareness. ## Referral and indications for chest radiography For guidance on referral, see the recommendations on referral for suspected lung cancer in the NICE guideline on suspected cancer. # Communication # Helping people understand their condition and the tests and treatments available Find out what the person knows about their condition without assuming a level of knowledge. Provide them with the opportunity to discuss tests and treatment options in a private environment, with the support of family members or carers (as appropriate), and give them time to make an informed choice. Ensure that a lung cancer clinical nurse specialist is available at all stages of care to support people and (as appropriate) their family members or carers. Offer accurate and easy-to-understand information to people and their family members or carers (as appropriate). Explain the tests and treatment options, including potential survival benefits, side effects and effect on symptoms. Consider tailor-made decision aids to help people to: understand the probable outcomes of treatment options think about the personal value they place on benefits versus harms of treatment options feel supported in decision making move through the steps towards making a decision take part in decisions about their healthcare. Offer people a record of all discussions that have taken place with them and a copy of any correspondence with other healthcare professionals. Ensure all communications are worded in such a way to assist understanding. Respect the person's choice if they do not wish to confront future issues. Avoid giving people unexpected bad news in writing. Only give unexpected bad news by phone in exceptional circumstances. Offer to discuss end-of-life care with the person sensitively and when appropriate. Wherever possible, avoid leaving this discussion until the terminal stages of the illness. Document discussions with the person about end-of-life care. In particular, document: their specific concerns their understanding of their illness and its prognosis important values or personal goals for care their preferences for the types of care or treatment that may be beneficial in the future and their availability. Share information between healthcare professionals about: any problems the person has the management plan what the person has been told what the person has understood (if possible) the involvement of other agencies any advance decision made by the person. # Diagnosis and staging # Effectiveness of diagnostic and staging investigations Only use sputum cytology for investigation in people with suspected lung cancer who have centrally placed nodules or masses and who decline or cannot tolerate bronchoscopy or other invasive tests. Offer people with known or suspected lung cancer a contrast-enhanced chest CT scan to further the diagnosis and stage the disease. Include the liver, adrenals and lower neck in the scan. The guideline committee also recognised that contrast medium should only be given with caution to people with known renal impairment. When assessing mediastinal and chest wall invasion: be aware that CT alone may not be reliable consider other techniques such as ultrasound if there is doubt be aware that surgical assessment may be necessary if there are no contraindications to resection. Ensure that all people with lung cancer who could potentially have treatment with curative intent are offered positron-emission tomography CT (PET‑CT) before treatment. Every cancer alliance should have a system of rapid access to PET‑CT scanning for eligible people. Do not routinely use MRI to assess the stage of the primary tumour (T‑stage) in non-small-cell lung cancer (NSCLC). Use MRI when necessary to assess the extent of disease, for people with superior sulcus tumours. Offer endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for biopsy of paratracheal and peri-bronchial intra-parenchymal lung lesions. Every cancer alliance should have at least 1 centre with EBUS and/or endoscopic ultrasound (EUS) to ensure timely access. Audit the local test performance of EBUS-TBNA and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). When taking samples, ensure they are adequate (without unacceptable risk to the person) to permit pathological diagnosis, including tumour subtyping and assessment of predictive markers. For guidance on EGFR-TK mutation testing, see the NICE diagnostics guidance on EGFR‑TK mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on effectiveness of diagnostic and staging investigations . Full details of the evidence and the committee's discussion are in evidence review A: Investigations for staging the mediastinum. Loading. Please wait. ## Sequence of investigations Choose investigations that give the most information about diagnosis and staging with the least risk to the person. Think carefully before performing a test that gives only diagnostic pathology when information on staging is also needed to guide treatment. Perform contrast-enhanced CT of the chest, liver adrenals and lower neck before any biopsy procedure. Offer image-guided biopsy to people with peripheral lung lesions when treatment can be planned on the basis of this test. Biopsy any enlarged intrathoracic nodes (10 mm or larger maximum short axis on CT) or other lesions in preference to the primary lesion if determination of nodal stage affects treatment. Some people with lung cancer will not be well enough for treatment with curative intent. This needs to be taken into account when choosing diagnostic and staging investigations. Offer flexible bronchoscopy to people with central lesions on CT if nodal staging does not influence treatment. Offer PET-CT as the preferred first test after CT with a low probability of nodal malignancy (lymph nodes below 10 mm maximum short axis on CT), for people with lung cancer who could potentially have treatment with curative intent. Offer PET-CT (if not already done), followed by EBUS‑TBNA and/or EUS‑FNA, to people with suspected lung cancer who have enlarged intrathoracic lymph nodes (lymph nodes greater than or equal to 10 mm short axis on CT) and who could potentially have treatment with curative intent. Evaluate PET-CT-positive or enlarged intrathoracic nodes using a systematic approach (sampling any suspicious node on CT, PET or USS) with EBUS‑TBNA and/or EUS‑FNA if nodal status would affect the treatment plan. Consider surgical mediastinal staging for people with a negative EBUS‑TBNA or EUS‑FNA if clinical suspicion of nodal malignancy is high and nodal status would affect their treatment plan. We have produced an algorithm on intrathoracic nodal staging of non-small cell lung cancer in patients being considered for radical treatment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on EBUS-TBNA and EUS-FNA . Full details of the evidence and the committee's discussion are in evidence review A: Investigations for staging the mediastinum. Loading. Please wait. Confirm the presence of isolated distant metastases/synchronous tumours by biopsy or further imaging (for example, MRI or PET-CT) in people being considered for treatment with curative intent. Do not offer dedicated brain imaging to people with clinical stage I NSCLC who have no neurological symptoms and are having treatment with curative intent. Offer contrast-enhanced brain CT to people with clinical stage II NSCLC who are having treatment with curative intent. If CT shows suspected brain metastases, offer contrast-enhanced brain MRI. Offer contrast-enhanced brain MRI for people with stage III NSCLC who are having treatment with curative intent. Offer people with clinical features suggestive of intracranial pathology CT of the head followed by MRI if normal, or MRI as an initial test. Perform an X-ray as the first test for people with localised signs or symptoms of bone metastasis. If the results are negative or inconclusive, offer bone scintigraphy or an MRI scan. Avoid bone scintigraphy when PET-CT has not shown bone metastases. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on brain imaging for people having treatment with curative intent . Full details of the evidence and the committee's discussion are in evidence review B: Brain imaging for people with NSCLC selected for treatment with curative intent. Loading. Please wait. ## Organisational factors relevant to diagnosis and staging Provide treatment without undue delay for people who have lung cancer that is suitable for radical treatment or chemotherapy, or who need radiotherapy or ablative treatment for relief of symptoms. Refer all people with a suspected diagnosis of lung cancer to a member of a lung cancer multidisciplinary team (usually a chest physician). The care of all people with a working diagnosis of lung cancer should be discussed at a lung cancer multidisciplinary team meeting. Provide fast-track lung cancer clinics (previously known as early diagnosis clinics and rapid access clinics) for investigating suspected lung cancer, because they are associated with faster diagnosis and less anxiety. All cancer units/centres should have one or more trained lung cancer clinical nurse specialists to: see people before, at the time of and after diagnosis provide continuing support facilitate communication between the secondary care team (including the multidisciplinary team), the person's GP, the community team and the person with lung cancer help people access advice and support whenever they need it. # Treatment # Stop smoking interventions and services Inform people that smoking increases the risk of pulmonary complications after lung cancer surgery. Advise people to stop smoking as soon as the diagnosis of lung cancer is suspected and tell them why this is important. Offer nicotine replacement therapy and other therapies to help people to stop smoking in line with the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence and the NICE technology appraisal guidance on varenicline for smoking cessation. Do not postpone surgery for lung cancer to allow people to stop smoking. # Assessing people with non-small-cell lung cancer for treatment with curative intent ## Perioperative mortality When evaluating surgery as an option for people with NSCLC, consider using a global risk score such as Thoracoscore to estimate the risk of death. Ensure the person is aware of the risk before they give consent for surgery. ## Cardiovascular function Avoid surgery within 30 days of myocardial infarction. Seek a cardiology review in people with an active cardiac condition, or 3 or more risk factors, or poor cardiac functional capacity. Offer surgery without further investigations to people with 2 or fewer risk factors and good cardiac functional capacity. Optimise any primary cardiac treatment and begin secondary prophylaxis for coronary disease as soon as possible. Continue anti-ischaemic treatment in the perioperative period, including aspirin, statins and beta‑blockers. For people with coronary stents, discuss perioperative anti-platelet treatment with a cardiologist. Consider revascularisation (percutaneous intervention or coronary artery bypass grafting) before surgery for people with chronic stable angina and conventional indications for revascularisation. ## Lung function Perform spirometry and transfer factor (TLCO) in all people being considered for treatment with curative intent. Offer people surgery if they have a forced expiratory volume in 1 second (FEV1) within normal limits and good exercise tolerance. When considering surgery perform a functional segment count to predict postoperative lung function. Offer people with predicted postoperative FEV1 or TLCO below 30% the option of treatment with curative intent if they accept the risks of dyspnoea and associated complications. Consider using shuttle walk testing (using a distance walked of more than 400 m as a cut-off for good function) to assess the fitness of people with moderate to high risk of postoperative dyspnoea. Consider cardiopulmonary exercise testing to measure oxygen uptake (VO2 max) and assess lung function in people with moderate to high risk of postoperative dyspnoea, using more than 15 ml/kg/minute as a cut-off for good function. ## Assessment before radiotherapy with curative intent A clinical oncologist specialising in thoracic oncology should determine suitability for radiotherapy with curative intent, taking into account performance status and comorbidities. # Surgery and radiotherapy with curative intent for non-small-cell lung cancer ## Surgery For people with NSCLC who are well enough and for whom treatment with curative intent is suitable, offer lobectomy (either open or thoracoscopic). Offer more extensive surgery (bronchoangioplastic surgery, bilobectomy, pneumonectomy) only when needed to obtain clear margins. Perform hilar and mediastinal lymph node sampling or en bloc resection for all people having surgery with curative intent. For people with T3 NSCLC with chest wall involvement who are having surgery, aim for complete resection of the tumour using either extrapleural or en bloc chest wall resection. ## Surgery or radiotherapy for people not having lobectomy For people with stage I–IIA (T1a–T2b, N0, M0) NSCLC who decline lobectomy or in whom it is contraindicated, offer radical radiotherapy with stereotactic ablative radiotherapy (SABR) or sublobar resection. ## Radical radiotherapy for people not having surgery All people should have pulmonary function tests (including lung volumes and transfer factor) before radical radiotherapy for NSCLC. People receiving radiotherapy with curative intent should be part of a national quality assurance programme. For people with stage I–IIA (T1a–T2b, N0, M0) NSCLC who decline surgery or in whom any surgery is contraindicated, offer SABR. If SABR is contraindicated, offer either conventional or hyperfractionated radiotherapy. For eligible people with stage IIIA NSCLC who cannot tolerate or who decline chemoradiotherapy (with or without surgery), consider radical radiotherapy (either conventional or hyperfractionated). For eligible people with stage IIIB NSCLC who cannot tolerate or who decline chemoradiotherapy, consider radical radiotherapy (either conventional or hyperfractionated). ## Radiotherapy fractionation If using SABR, follow the SABR Consortium guidance on fractionation. If conventionally fractionated radical radiotherapy is used, offer either: Gy in 20 fractions over 4 weeks or –66 Gy in 30–33 fractions over 6–6½ weeks. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgery and radiotherapy with curative intent for non-small-cell lung cancer . Full details of the evidence and the committee's discussion are in evidence review D: Radiotherapy with curative intent for NSCLC. Loading. Please wait. # Combination treatment for non-small-cell lung cancer Consider chemoradiotherapy for people with stage II or III NSCLC that are not suitable for or decline surgery. Balance potential benefit in survival with the risk of additional toxicities. Ensure that all people for whom multimodality treatment is potentially suitable (surgery, radiotherapy and chemotherapy in any combination) are assessed by a thoracic oncologist and by a thoracic surgeon. Offer postoperative chemotherapy to people with good performance status (WHO 0 or 1) and T1a–4, N1–2, M0 NSCLC. Consider postoperative chemotherapy for people with good performance status (WHO 0 or 1) and T2b–4, N0, M0 NSCLC with tumours greater than 4 cm in diameter. Offer a cisplatin-based combination chemotherapy regimen for adjuvant chemotherapy. For people with stage I–II NSCLC that are suitable for surgery, do not offer neo-adjuvant treatment outside a clinical trial. Ensure eligible people have the benefit of detailed discussion of the risks and benefits of adjuvant chemotherapy. Treat Pancoast tumours in the same way as other types of NSCLC. Offer multimodality therapy according to resectability, stage of the tumour and performance status of the person. For people with operable stage IIIA–N2 NSCLC who can have surgery and are well enough for multimodality therapy, consider chemoradiotherapy with surgery. Discuss the benefits and risks with the person before starting chemoradiotherapy with surgery, including that: chemoradiotherapy with surgery improves progression-free survival chemoradiotherapy with surgery may improve overall survival. For people with stage IIIA–N2 NSCLC who are having chemoradiotherapy and surgery, ensure that their surgery is scheduled for 3 to 5 weeks after the chemoradiotherapy. Multidisciplinary teams that provide chemoradiotherapy with surgery should have expertise in the combined therapy and in all of the individual components. Centres performing lung resections for lung cancer should validate their data for the Royal College of Physicians Lung Cancer Clinical Outcomes publication and the National Lung Cancer Audit. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management of operable stage IIIA–N2 non-small-cell lung cancer . Full details of the evidence and the committee's discussion are in evidence review C: Management of NSCLC stage IIIA-N2. Loading. Please wait. # Systemic anti-cancer therapy (SACT) for advanced non-small-cell lung cancer We have produced treatment pathways bringing together NICE recommended treatment options from this guideline and relevant technology appraisal guidance on advanced non-small-cell lung cancer (squamous and non-squamous). The treatment pathways cover the recommended treatment options at each decision point. These are available to view as individual pathways (linked below), or grouped together in a single interactive PDF of all treatment pathways for squamous and non-squamous advanced non-small-cell lung cancer. We have also produced fully accessible summaries of the treatment pathways. ## Squamous non-small-cell lung cancer Systemic anti-cancer therapy: treatment options for people with squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with RET fusion positive squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with RET fusion positive squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with RET fusion positive squamous non-small-cell lung cancer, with PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with RET fusion positive squamous non-small-cell lung cancer, with PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with NTRK fusion positive squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with NTRK fusion positive squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with NTRK fusion positive squamous non-small-cell lung cancer, with PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with NTRK fusion positive squamous non-small-cell lung cancer, with PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with KRAS G12C positive squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with KRAS G12C positive squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with KRAS G12C positive squamous non-small-cell lung cancer, with PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with KRAS G12C positive squamous non-small-cell lung cancer, with PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration squamous non-small-cell lung cancer, with PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration squamous non-small-cell lung cancer, with PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with EGFRex 20 insertion positive squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with EGFRex 20 insertion positive squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with EGFRex 20 insertion positive squamous non-small-cell lung cancer, with PD-L1 50% or higher Fully accessible summary of systemic anti-cancer therapy: treatment options for people with EGFRex 20 insertion positive squamous non-small-cell lung cancer, with PD-L1 50% or higher ## Non-squamous non-small-cell lung cancer Systemic anti-cancer therapy: treatment options for people with non-squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with non-squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with non-squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with non-squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with EGFR-TK positive non-squamous non-small-cell lung cancer Fully accessible summary of systemic anti-cancer therapy: treatment options for people with EGFR-TK positive non-squamous non-small-cell lung cancer Systemic anti-cancer therapy: treatment options for people with ALK positive non-squamous non-small-cell lung cancer Fully accessible summary of systemic anti-cancer therapy: treatment options for people with ALK positive non-squamous non-small-cell lung cancer Systemic anti-cancer therapy: treatment options for people with ROS-1 positive non-squamous non-small-cell lung cancer Fully accessible summary of systemic anti-cancer therapy: treatment options for people with ROS-1 positive non-squamous non-small-cell lung cancer Systemic anti-cancer therapy: treatment options for people with RET fusion positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with RET fusion positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with RET fusion positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with RET fusion positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with NTRK fusion positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with NTRK fusion positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with NTRK fusion positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with NTRK fusion positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with KRAS G12C positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with KRAS G12C positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with KRAS G12C positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with KRAS G12C positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration non-squamous non-small-cell lung cancer, with PD-L1 less than 50% Fully accessible summary of systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration non-squamous non-small-cell lung cancer, with PD-L1 less than 50% Systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration non-squamous non-small-cell lung cancer, with PD-L1 50% or more Fully accessible summary of systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration non-squamous non-small-cell lung cancer, with PD-L1 50% or more Systemic anti-cancer therapy: treatment options for people with EGFRex20 insertion positive non-squamous non-small-cell lung cancer Fully accessible summary of systemic anti-cancer therapy: treatment options for people with EGFRex20 insertion positive non-squamous non-small-cell lung cancer # Assessing people with small-cell lung cancer Arrange for people with small-cell lung cancer (SCLC) to have an assessment by a thoracic oncologist within 1 week of deciding to recommend treatment. # First-line treatment for limited-stage disease small-cell lung cancer Offer people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) 4 to 6 cycles of cisplatin-based combination chemotherapy. Consider substituting carboplatin in people with impaired renal function, poor performance status (WHO 2 or more) or significant comorbidity. Offer twice-daily radiotherapy with concurrent chemotherapy to people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) and a WHO performance status of 0 or 1, if they present with disease that can be encompassed in a radical thoracic radiotherapy volume. Start the radiotherapy during the first or second cycle of chemotherapy. If the person declines or is unable to have twice-daily radiotherapy, offer once-daily radiotherapy. Offer sequential radical thoracic radiotherapy to people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) who are not well enough for concurrent chemoradiotherapy but who respond to chemotherapy. Offer prophylactic cranial irradiation at a dose of 25 Gy in 10 fractions to people with limited-stage disease SCLC and WHO performance status 0 to 2, if their disease has not progressed on first-line treatment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on first-line treatment for limited-stage disease SCLC . Full details of the evidence and the committee's discussion are in evidence review F: Chemoradiotherapy for limited stage SCLC. Loading. Please wait. # Surgery for small-cell lung cancer Consider surgery in people with early-stage SCLC (T1–2a, N0, M0). # First-line treatment for extensive-stage disease small-cell lung cancer Offer platinum-based combination chemotherapy to people with extensive-stage disease SCLC (broadly corresponding to T1–4, N0–3, M1a/b – including cerebral metastases) if they are fit enough. Assess the person's condition before each cycle of chemotherapy for extensive-stage disease SCLC (broadly corresponding to T1–4, N0–3, M1a/b) and offer up to a maximum of 6 cycles, depending on response and toxicity. Consider thoracic radiotherapy with prophylactic cranial irradiation for people with extensive‑stage disease SCLC who have had a partial or complete response to chemotherapy within the thorax and at distant sites. Consider prophylactic cranial irradiation for people with extensive-stage disease SCLC and WHO performance status 0 to 2, if their disease has responded to first-line treatment. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on thoracic radiotherapy and prophylactic cranial irradiation in SCLC . Full details of the evidence and the committee's discussion are in evidence review G: Thoracic radiotherapy for extensive stage SCLC and evidence review H: Prophylactic cranial irradiation for extensive stage SCLC. Loading. Please wait. # Maintenance treatment for small-cell lung cancer Only offer maintenance treatment to people with SCLC in the context of a clinical trial. # Second-line treatment for small-cell lung cancer that has relapsed after first-line treatment Offer people with SCLC that has relapsed after first-line treatment assessment by a thoracic oncologist. Inform people whose disease has not responded to first-line treatment that there is very limited evidence that second-line chemotherapy will be of benefit. Offer people with relapsed SCLC in whom chemotherapy is suitable treatment with an anthracycline-containing regimen or further treatment with a platinum-based regimen to a maximum of 6 cycles. Offer radiotherapy for palliation of local symptoms to people with SCLC that has relapsed after first-line treatment. ## Topotecan Refer to the NICE technology appraisal guidance on topotecan for the treatment of relapsed small-cell lung cancer. # Palliative interventions and supportive and palliative care # Providing palliative care Supportive and palliative care of the person should be provided by general and specialist palliative care providers in line with the NICE guidance on improving supportive and palliative care for adults with cancer. Identify and refer people who may benefit from specialist palliative care services without delay. # Palliative radiotherapy Provide palliative radiotherapy, either as symptoms arise or immediately, for eligible people who cannot be offered curative treatment. # Managing endobronchial obstruction When people have large airway involvement, monitor (clinically and radiologically) for endobronchial obstruction to ensure treatment is offered early. Offer external beam radiotherapy and/or endobronchial debulking or stenting to people with impending endobronchial obstruction. Every cancer alliance should ensure that people have rapid access to a team capable of providing interventional endobronchial treatments. # Other palliative treatments Perform pleural aspiration or drainage in an attempt to relieve the symptoms of a pleural effusion. Patients who benefit symptomatically from aspiration or drainage of fluid should be offered talc pleurodesis for longer-term benefit. Consider non-drug interventions based on psychosocial support, breathing control and coping strategies for people with breathlessness. Non-drug interventions for breathlessness should be delivered by a multidisciplinary group, coordinated by a professional with an interest in breathlessness and expertise in the techniques (for example, a nurse, physiotherapist or occupational therapist). Although this support may be provided in a breathlessness clinic, people should have access to it in all care settings. Consider opioids, such as codeine or morphine, to reduce cough. Refer people with troublesome hoarseness due to recurrent laryngeal nerve palsy to an ear, nose and throat specialist for advice. Offer people who present with superior vena cava obstruction chemotherapy and radiotherapy according to the stage of disease and performance status. Consider stent insertion for the immediate relief of severe symptoms of superior vena caval obstruction or following failure of earlier treatment. # Managing brain metastases Offer dexamethasone to people with symptomatic brain metastases and reduce to the minimum necessary maintenance dose for symptomatic response. For guidance on management of brain metastases, see the section on management of confirmed brain metastases in the NICE guideline on brain tumours. # Bone metastases Administer single-fraction radiotherapy to people with bone metastasis who need palliation and for whom standard analgesic treatments are inadequate. For more guidance on preventing complications from bone metastases, see the NICE technology appraisal guidance on denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours. # Managing other symptoms: weight loss, loss of appetite, difficulty swallowing, fatigue and depression Other symptoms, including weight loss, loss of appetite, depression and difficulty swallowing, should be managed by multidisciplinary groups that include supportive and palliative care professionals. # Follow-up and patient perspectives # Organising follow-up and collecting information on patient experience Offer all people with lung cancer an initial specialist follow-up appointment within 6 weeks of completing treatment to discuss ongoing care. Offer regular appointments after this, rather than relying on the person requesting appointments when they experience symptoms. Offer protocol-driven follow-up led by a lung cancer clinical nurse specialist as an option for people with a life expectancy of more than 3 months. Ensure that people know how to contact the lung cancer clinical nurse specialist involved in their care between their scheduled hospital visits. The opinions and experiences of people with lung cancer and their family members or carers (as appropriate) should be collected and used to improve the delivery of lung cancer services. People should receive feedback on any action taken as a result of such surveys. # Recommendations for research The guideline committee has made the following recommendations for research. # Immunotherapy after multimodality treatment What is the effectiveness and cost effectiveness of immunotherapy in people with stage IIIA-N2 non‑small‑cell lung cancer following multimodality treatment including surgery? For a short explanation of why the committee made the recommendation for research, see the rationale on management of operable stage IIIA–N2 non-small-cell lung cancer . Full details of the evidence and the committee's discussion are in evidence review C: Management of NSCLC stage IIIA-N2. Loading. Please wait. # Stereotactic ablative radiotherapy compared with surgery What is the effectiveness and cost effectiveness of stereotactic ablative radiotherapy (SABR) compared with surgery (for example, sublobar, wedge resection, lobectomy) for people with non-small-cell lung cancer (stage I and IIA) in whom surgery is suitable? For a short explanation of why the committee made the recommendation for research, see the rationale on surgery and radiotherapy with curative intent for non-small-cell lung cancer . Full details of the evidence and the committee's discussion are in evidence review D: Radiotherapy with curative intent for NSCLC. Loading. Please wait. # Routine contrast-enhanced brain CT What is the effectiveness and cost effectiveness of routinely performing contrast-enhanced brain CT at the time of initial diagnosis and/or staging CT? For a short explanation of why the committee made the recommendation for research, see the rationale on brain imaging for people having treatment with curative intent . Full details of the evidence and the committee's discussion are in evidence review B: Brain imaging for people with NSCLC selected for treatment with curative intent. Loading. Please wait. # Prophylactic cranial irradiation compared with routine MRI follow-up in extensive-stage small-cell lung cancer What is the effectiveness and cost effectiveness of prophylactic cranial irradiation compared with routine MRI follow-up in people with extensive-stage small-cell lung cancer without brain metastases? For a short explanation of why the committee made the recommendation for research, see the rationale on thoracic radiotherapy and prophylactic cranial irradiation in SCLC . Full details of the evidence and the committee's discussion are in evidence review G: Thoracic radiotherapy for extensive stage SCLC and evidence review H: Prophylactic cranial irradiation for extensive stage SCLC. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect services. They link to details of the evidence and a full description of the committee's discussion. # Diagnosis and staging ## Why the committee made the recommendations Recommendation 1.3.10 Clinical audit is an important tool for maintaining high standards in the use of endobronchial ultrasound‑guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound‑guided fine‑needle aspiration (EUS-FNA). This is consistent with the British Thoracic Society guideline and quality standards (which are accredited by NICE). Recommendations 1.3.19 to 1.3.21 The recommendations cover: initial invasive investigations for people with an intermediate probability of mediastinal malignancy subsequent investigations for people with a high probability of mediastinal malignancy, when neck ultrasound and biopsy are negative. In these circumstances, when compared with alternative investigations, EBUS-TBNA and EUS-FNA: produce a diagnosis and stage faster than bronchoscopy or CT-guided biopsy are more acceptable to patients than surgery reduce the need for further investigations and hospital visits compared with bronchoscopy. Recommendation 1.3.21 There is evidence that surgical staging is useful when EBUS-TBNA and/or EUS-FNA are negative but clinical suspicion of mediastinal malignancy is high. While there are potential harms from the invasive nature of surgical staging, there is no evidence that these outweigh the benefits in this population. Transthoracic needle biopsy, bronchoscopy and non-ultrasound-guided TBNA are no longer recommended for staging lung cancer in intrathoracic lymph nodes because: bronchoscopy and non-ultrasound-guided TBNA are unlikely to reach the minimum sensitivity required by the British Thoracic quality standards and they may discourage people from having more effective procedures (such as EBUS-TBNA) and subsequent investigations. The word 'fibreoptic' has been removed because bronchoscopy can be fibreoptic, video or hybrid. ## How the recommendations might affect practice The recommendations on PET-CT reflect current practice, so will not incur an extra cost. The recommendations on EBUS-TBNA and EUS-FNA will reinforce best practice and result in a more streamlined diagnostic service with more timely diagnosis and staging. The surgical mediastinal staging recommendation will also reinforce best practice and restrict this procedure to people most likely to benefit. Return to recommendations # Brain imaging for people having treatment with curative intent Recommendations 1.3.23 to 1.3.25 ## Why the committee made the recommendations Brain imaging is helpful before starting treatment with curative intent, because if brain metastases are detected then the treatment plan is likely to change. However, routine brain imaging is expensive, and the evidence showed that it does not always offer a good balance of benefits and costs. In people with stage II and IIIA disease, the benefits of brain imaging outweigh the costs because: brain metastases are more common than in stage I disease people can start early treatment for metastases if they are identified, which improves prognosis some people with brain metastases will not have radical treatment (depending on factors such as the number of metastases, prognosis and patient preference), and this reduces costs. In people with clinical stage I NSCLC and no neurological symptoms, the prevalence of detectable brain metastases is fairly low (around 4%) compared with people with stage II or IIIA disease. People with stage I NSCLC who do have brain metastases often still have radical lung treatment, which is much more rarely the case for people with stage IIIA NSCLC. Overall, the lower prevalence of metastases and smaller reduction in numbers of people having radical treatment mean that the benefits of brain imaging in this population are too low to justify the costs. The 2018 review only examined the clinical and cost effectiveness of imaging after the treatment plan has been decided, but the committee noted that it could be more efficient to conduct CT brain imaging alongside initial staging CT. With this in mind, the committee made a recommendation for research on routine brain imaging with CT at initial diagnosis and/or staging. ## How the recommendations might affect practice Practice in this area is variable. The committee estimated that the recommendations will increase the number of people who have brain imaging. In turn, they thought this should prevent the use of treatment options (such as lobectomy and sublobar resection) in some patients for whom it is not expected to be beneficial. The recommendations may also lead to an increase in radical radiotherapy, stereotactic radiosurgery and brain surgery. These treatments would be expected to improve the person's prognosis, although each treatment would carry its own risks and side effects. Return to recommendations # Surgery and radiotherapy with curative intent for non-small-cell lung cancer Recommendations 1.6.1 and 1.6.5 to 1.6.12 ## Why the committee made the recommendations For people with non-small-cell lung cancer (NSCLC) who are well enough and for whom treatment with curative intent is suitable, the evidence showed that lobectomy provides better survival outcomes than stereotactic ablative radiotherapy (SABR). Lobectomy is a good compromise between preserving pulmonary function and being more likely to remove cancerous cells compared with sublobar resection. For people with stage I–IIA (T1a–T2b, N0, M0) NSCLC, the evidence showed that: if they decline lobectomy or it is contraindicated, sublobar resection and SABR both provide better survival outcomes than conventionally fractionated radiotherapy, although it is not clear which of these 2 is better if they decline any surgery or it is contraindicated, SABR provides better survival outcomes than conventionally fractionated radiotherapy, and people often prefer it because it involves fewer hospital visits if surgery and SABR are contraindicated, conventionally fractionated radiotherapy provides better survival outcomes than no radiotherapy. For people with stage IIIA or IIIB NSCLC who cannot tolerate chemoradiotherapy or who decline it, the evidence was not strong enough to recommend conventional radiotherapy over hyper-fractionated regimens or vice versa. However, people who cannot tolerate chemoradiotherapy may also be unable to tolerate radical radiotherapy, so this will not be an option for everyone with stage IIIA or IIIB NSCLC. For an explanation of the recommendations covering surgery in this group, see the rationale on management of stage IIIA-N2 NSCLC . Gy in 20 fractions is the most common conventional radical radiotherapy regimen in the UK. If conventionally fractionated radiotherapy is used, a total radiation dose of 60 Gy provides better survival outcomes and fewer adverse events than 74 Gy. A total dose of 60 to 66 Gy is also normal NHS practice. There are not many randomised controlled trials comparing SABR with surgery (lobectomy or sublobar resection). SABR is non-invasive, so if it is as effective as surgery then it may be a preferable option for many people with lung cancer. There are also various factors that may make SABR less costly than surgery. For example, it is usually delivered as outpatient treatment. There might also be subgroups for whom different forms of surgery or SABR might be the most cost-effective options. The committee made a recommendation for research on SABR compared with surgery to investigate these uncertainties. Loading. Please wait. ## How the recommendations might affect practice The new recommendations on SABR are a change from the 2011 guideline and improve choice for people with NSCLC. However, practice has also changed since 2011, and SABR is now widely used, so implementing the recommendations may not involve a significant change in practice. The remaining changes to the recommendations reflect current practice. Return to recommendations # Management of operable stage IIIA–N2 non-small-cell lung cancer Recommendations 1.7.9 to 1.7.13 ## Why the committee made the recommendations The available evidence showed that chemoradiotherapy and surgery are more effective than chemoradiotherapy alone in people who are well enough for surgery and when the disease is operable. For chemotherapy and surgery, there was no evidence that survival outcomes were better than for chemoradiotherapy, so the additional costs of including surgery outweighed the benefits. The key benefit associated with chemoradiotherapy and surgery is the longer progression‑free survival time. An analysis of multiple trials showed improved progression-free survival and cost effectiveness for chemoradiotherapy with surgery, compared with chemoradiotherapy alone. There was an 89% probability that chemoradiotherapy and surgery improved average overall survival time compared with chemoradiotherapy. However, the evidence in favour of chemoradiotherapy and surgery involved indirect comparisons, and no head-to-head trials showed meaningful differences in overall survival for any of the interventions. And as with any major surgery, there is a perioperative mortality risk for people who have chemoradiotherapy and surgery. The 3 to 5 week wait for surgery is recommended to give people time to recover from the chemoradiotherapy. Chemoradiotherapy with surgery is not often offered in current practice. In addition, there are specific factors to take into account when offering all these treatments together. Therefore, multidisciplinary teams providing it should have expertise both in the combined therapy, and in all the individual components. Immunotherapy has been shown to be effective in a variety of NSCLC indications but there is currently no evidence on whether it is clinically or cost effective for people with stage IIIA-N2 NSCLC following surgery. The committee made a recommendation for research on immunotherapy after multimodality treatment to address this. ## How the recommendations might affect practice The committee felt that chemoradiotherapy and surgery is offered far less often than chemoradiotherapy alone or chemotherapy and surgery for people with NSCLC stage IIIA-N2. Therefore, these recommendations could lead to a change in current practice. Return to recommendations # First-line treatment for limited-stage disease small-cell lung cancer Recommendations 1.10.1 to 1.10.5 ## Why the committee changed the recommendations The evidence showed a survival benefit from twice-daily radiotherapy compared with once-daily. However, the committee agreed that some people with small-cell lung cancer will not be well enough to tolerate twice-daily radiotherapy, so they recommended giving people the option of once-daily radiotherapy. The committee noted that, in practice, radiotherapy is not started in chemotherapy cycle 1, because this is when planning for the radiotherapy often takes place (see the recommendation on twice-daily radiotherapy with concurrent chemotherapy in the section on first-line treatment for limited-stage disease small-cell lung cancer). However, there was no new evidence on when to start radiotherapy, so the 2019 recommendation on this is the same as the original 2011 recommendation. There were limited data available on whether continuous radiotherapy with concurrent chemotherapy was more effective than alternating radiotherapy and chemotherapy. Because of the limited data, and the committee's experience that people prefer to complete treatment as quickly as possible, the 2019 recommendation on concurrent therapy (see the recommendation on twice-daily radiotherapy with concurrent chemotherapy) is the same as the 2011 recommendation. Return to recommendations # Thoracic radiotherapy and prophylactic cranial irradiation in small-cell lung cancer Recommendations 1.12.3 and 1.12.4 ## Why the committee made the recommendations There was some uncertainty in the evidence. However, the study most relevant to UK practice showed that thoracic radiotherapy improves long-term survival for people who have had a partial or complete response to chemotherapy, if they live longer than 1 year after the radiotherapy. The committee specified that thoracic radiotherapy should be given alongside prophylactic cranial irradiation. This is to match recommendation 1.4.55. In addition, the reviewed clinical trials gave thoracic radiotherapy alongside prophylactic cranial irradiation. The evidence showed that prophylactic cranial irradiation improves survival versus best supportive care. Prophylactic cranial irradiation can adversely affect quality of life, and the survival benefits are limited. There is also some evidence from a study outside the UK that routine MRI follow-up may be more cost effective. The committee made a recommendation for research on prophylactic cranial irradiation compared with routine MRI follow-up in extensive-stage SCLC, to provide evidence more relevant to the UK and to see if MRI could identify people who need whole-brain radiotherapy and so reduce the number of people having unnecessary treatment. ## How the recommendations might affect practice The 2011 recommendation only recommended thoracic radiotherapy for people with a complete response to chemotherapy at distant sites. Therefore, this recommendation could increase the number of people who are given thoracic radiotherapy. It is likely that the recommendation reflects current clinical practice. Return to recommendations# Context Over 46,000 people were diagnosed with lung cancer in the UK in 2015. An estimated 89% of lung cancers are preventable, with 86% of these linked to smoking, 13% to occupational exposure, 9% to dietary factors and 7.8% to air pollution. Lung cancer can be linked to more than one cause. In 2015 in the UK, over 35,000 people died from lung cancer. The overall mortality rate from lung cancer has decreased by 9% over the last decade. However, while there has been a decrease of 19% in mortality rates in men, there has been an increase of 2% in women. This is linked to lifestyle factors such as smoking and is driven by an increased incidence of lung cancer in older women. In the UK, lung cancer is more common in people of European family origin than in people of African or Asian family origin. It is strongly linked to socioeconomic deprivation. There are many risk factors for lung cancer, including age, genetics, lifestyle (especially smoking) and occupation. Lung cancer is estimated to cost the UK economy £2.4 billion per year. Note: all statistics in this section are from Cancer Research UK's Lung Cancer Statistics. Lung cancer is diagnosed and staged using a variety of tests, including chest X‑rays, CT or positron-emission tomography CT (PET‑CT). Lung cancer samples are commonly acquired for diagnosis using bronchoscopy, endobronchial ultrasound (EBUS) or a percutaneous procedure (guided by CT or ultrasound). Lung cancer has 2 main types: non-small-cell lung cancer (NSCLC), which is more common and spreads more slowly small-cell lung cancer (SCLC), which is rarer and spreads more quickly. Treatment depends on the type, size, position and stage of the cancer, and the person's health. Possible treatments include radiotherapy, systemic anti-cancer therapies, surgery, supportive care cryotherapy, photodynamic therapy and ablation. Since 2011, when the NICE lung cancer guideline was last updated, there have been changes in the way that lung cancer is diagnosed and treated. The Royal College of Physicians' National Lung Cancer Audit annual report 2016 identified that only 72% of people have pathological confirmation of their lung cancer. There is also inconsistency in the availability of molecular testing in lung cancer diagnosis. NHS England has taken steps to shorten the time to treatment, as well as improve access to and uptake of radiotherapy, and stereotactic ablative radiotherapy (SABR) is routinely used for certain subgroups of people with early-stage NSCLC. There are now a variety of licensed immunotherapies and biological targeted therapies for treating advanced NSCLC, and NICE has published technology appraisals covering many of these.	{'Access to services and referral': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# The importance of early diagnosis\n\nThe public needs to be better informed of the symptoms and signs that are characteristic of lung cancer, through coordinated campaigning to raise awareness. \n\n## Referral and indications for chest radiography\n\nFor guidance on referral, see the recommendations on referral for suspected lung cancer in the NICE guideline on suspected cancer. ", 'Communication': "# Helping people understand their condition and the tests and treatments available\n\nFind out what the person knows about their condition without assuming a level of knowledge. Provide them with the opportunity to discuss tests and treatment options in a private environment, with the support of family members or carers (as appropriate), and give them time to make an informed choice. \n\nEnsure that a lung cancer clinical nurse specialist is available at all stages of care to support people and (as appropriate) their family members or carers. \n\nOffer accurate and easy-to-understand information to people and their family members or carers (as appropriate). Explain the tests and treatment options, including potential survival benefits, side effects and effect on symptoms. \n\nConsider tailor-made decision aids to help people to:\n\nunderstand the probable outcomes of treatment options\n\nthink about the personal value they place on benefits versus harms of treatment options\n\nfeel supported in decision making\n\nmove through the steps towards making a decision\n\ntake part in decisions about their healthcare. \n\nOffer people a record of all discussions that have taken place with them and a copy of any correspondence with other healthcare professionals. Ensure all communications are worded in such a way to assist understanding. \n\nRespect the person's choice if they do not wish to confront future issues. \n\nAvoid giving people unexpected bad news in writing. Only give unexpected bad news by phone in exceptional circumstances. \n\nOffer to discuss end-of-life care with the person sensitively and when appropriate. Wherever possible, avoid leaving this discussion until the terminal stages of the illness. \n\nDocument discussions with the person about end-of-life care. In particular, document:\n\ntheir specific concerns\n\ntheir understanding of their illness and its prognosis\n\nimportant values or personal goals for care\n\ntheir preferences for the types of care or treatment that may be beneficial in the future and their availability. \n\nShare information between healthcare professionals about:\n\nany problems the person has\n\nthe management plan\n\nwhat the person has been told\n\nwhat the person has understood (if possible)\n\nthe involvement of other agencies\n\nany advance decision made by the person. ", 'Diagnosis and staging': "# Effectiveness of diagnostic and staging investigations\n\nOnly use sputum cytology for investigation in people with suspected lung cancer who have centrally placed nodules or masses and who decline or cannot tolerate bronchoscopy or other invasive tests. \n\nOffer people with known or suspected lung cancer a contrast-enhanced chest CT scan to further the diagnosis and stage the disease. Include the liver, adrenals and lower neck in the scan. The guideline committee also recognised that contrast medium should only be given with caution to people with known renal impairment. [2005, amended 2019]\n\nWhen assessing mediastinal and chest wall invasion:\n\nbe aware that CT alone may not be reliable\n\nconsider other techniques such as ultrasound if there is doubt\n\nbe aware that surgical assessment may be necessary if there are no contraindications to resection. \n\nEnsure that all people with lung cancer who could potentially have treatment with curative intent are offered positron-emission tomography CT (PET‑CT) before treatment. \n\nEvery cancer alliance should have a system of rapid access to PET‑CT scanning for eligible people. [2005, amended 2019]\n\nDo not routinely use MRI to assess the stage of the primary tumour (T‑stage) in non-small-cell lung cancer (NSCLC). \n\nUse MRI when necessary to assess the extent of disease, for people with superior sulcus tumours. \n\nOffer endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for biopsy of paratracheal and peri-bronchial intra-parenchymal lung lesions. \n\nEvery cancer alliance should have at least 1 centre with EBUS and/or endoscopic ultrasound (EUS) to ensure timely access. \n\nAudit the local test performance of EBUS-TBNA and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). [2011, amended 2019]\n\nWhen taking samples, ensure they are adequate (without unacceptable risk to the person) to permit pathological diagnosis, including tumour subtyping and assessment of predictive markers. [2011, amended 2019]\n\nFor guidance on EGFR-TK mutation testing, see the NICE diagnostics guidance on EGFR‑TK mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on effectiveness of diagnostic and staging investigations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: Investigations for staging the mediastinum.\n\nLoading. Please wait.\n\n## Sequence of investigations\n\nChoose investigations that give the most information about diagnosis and staging with the least risk to the person. Think carefully before performing a test that gives only diagnostic pathology when information on staging is also needed to guide treatment. \n\nPerform contrast-enhanced CT of the chest, liver adrenals and lower neck before any biopsy procedure. [2005, amended 2019]\n\nOffer image-guided biopsy to people with peripheral lung lesions when treatment can be planned on the basis of this test. [2011, amended 2019]\n\nBiopsy any enlarged intrathoracic nodes (10\xa0mm or larger maximum short axis on CT) or other lesions in preference to the primary lesion if determination of nodal stage affects treatment. Some people with lung cancer will not be well enough for treatment with curative intent. This needs to be taken into account when choosing diagnostic and staging investigations. [2011, amended 2019]\n\nOffer flexible bronchoscopy to people with central lesions on CT if nodal staging does not influence treatment. [2011, amended 2019]\n\nOffer PET-CT as the preferred first test after CT with a low probability of nodal malignancy (lymph nodes below 10\xa0mm maximum short axis on CT), for people with lung cancer who could potentially have treatment with curative intent. [2011, amended 2019]\n\nOffer PET-CT (if not already done), followed by EBUS‑TBNA and/or EUS‑FNA, to people with suspected lung cancer who have enlarged intrathoracic lymph nodes (lymph nodes greater than or equal to 10\xa0mm short axis on CT) and who could potentially have treatment with curative intent. \n\nEvaluate PET-CT-positive or enlarged intrathoracic nodes using a systematic approach (sampling any suspicious node on CT, PET or USS) with EBUS‑TBNA and/or EUS‑FNA if nodal status would affect the treatment plan. \n\nConsider surgical mediastinal staging for people with a negative EBUS‑TBNA or EUS‑FNA if clinical suspicion of nodal malignancy is high and nodal status would affect their treatment plan. \n\nWe have produced an algorithm on intrathoracic nodal staging of non-small cell lung cancer in patients being considered for radical treatment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on EBUS-TBNA and EUS-FNA\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: Investigations for staging the mediastinum.\n\nLoading. Please wait.\n\nConfirm the presence of isolated distant metastases/synchronous tumours by biopsy or further imaging (for example, MRI or PET-CT) in people being considered for treatment with curative intent. \n\nDo not offer dedicated brain imaging to people with clinical stage\xa0I NSCLC who have no neurological symptoms and are having treatment with curative intent. \n\nOffer contrast-enhanced brain CT to people with clinical stage\xa0II NSCLC who are having treatment with curative intent. If CT shows suspected brain metastases, offer contrast-enhanced brain MRI. \n\nOffer contrast-enhanced brain MRI for people with stage\xa0III NSCLC who are having treatment with curative intent. \n\nOffer people with clinical features suggestive of intracranial pathology CT of the head followed by MRI if normal, or MRI as an initial test. \n\nPerform an X-ray as the first test for people with localised signs or symptoms of bone metastasis. If the results are negative or inconclusive, offer bone scintigraphy or an MRI scan. \n\nAvoid bone scintigraphy when PET-CT has not shown bone metastases. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on brain imaging for people having treatment with curative intent\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: Brain imaging for people with NSCLC selected for treatment with curative intent.\n\nLoading. Please wait.\n\n## Organisational factors relevant to diagnosis and staging\n\nProvide treatment without undue delay for people who have lung cancer that is suitable for radical treatment or chemotherapy, or who need radiotherapy or ablative treatment for relief of symptoms. [2005, amended 2019]\n\nRefer all people with a suspected diagnosis of lung cancer to a member of a lung cancer multidisciplinary team (usually a chest physician). \n\nThe care of all people with a working diagnosis of lung cancer should be discussed at a lung cancer multidisciplinary team meeting. \n\nProvide fast-track lung cancer clinics (previously known as early diagnosis clinics and rapid access clinics) for investigating suspected lung cancer, because they are associated with faster diagnosis and less anxiety. \n\nAll cancer units/centres should have one or more trained lung cancer clinical nurse specialists to:\n\nsee people before, at the time of and after diagnosis\n\nprovide continuing support\n\nfacilitate communication between the secondary care team (including the multidisciplinary team), the person's GP, the community team and the person with lung cancer\n\nhelp people access advice and support whenever they need it. [2005, amended 2019]", 'Treatment': "# Stop smoking interventions and services\n\nInform people that smoking increases the risk of pulmonary complications after lung cancer surgery. \n\nAdvise people to stop smoking as soon as the diagnosis of lung cancer is suspected and tell them why this is important. \n\nOffer nicotine replacement therapy and other therapies to help people to stop smoking in line with the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence and the NICE technology appraisal guidance on varenicline for smoking cessation. \n\nDo not postpone surgery for lung cancer to allow people to stop smoking. \n\n# Assessing people with non-small-cell lung cancer for treatment with curative intent\n\n## Perioperative mortality\n\nWhen evaluating surgery as an option for people with NSCLC, consider using a global risk score such as Thoracoscore to estimate the risk of death. Ensure the person is aware of the risk before they give consent for surgery. \n\n## Cardiovascular function\n\nAvoid surgery within 30\xa0days of myocardial infarction. \n\nSeek a cardiology review in people with an active cardiac condition, or 3\xa0or more risk factors, or poor cardiac functional capacity. \n\nOffer surgery without further investigations to people with 2\xa0or fewer risk factors and good cardiac functional capacity. \n\nOptimise any primary cardiac treatment and begin secondary prophylaxis for coronary disease as soon as possible. \n\nContinue anti-ischaemic treatment in the perioperative period, including aspirin, statins and beta‑blockers. \n\nFor people with coronary stents, discuss perioperative anti-platelet treatment with a cardiologist. \n\nConsider revascularisation (percutaneous intervention or coronary artery bypass grafting) before surgery for people with chronic stable angina and conventional indications for revascularisation. \n\n## Lung function\n\nPerform spirometry and transfer factor (TLCO) in all people being considered for treatment with curative intent. [2011, amended 2019]\n\nOffer people surgery if they have a forced expiratory volume in 1\xa0second (FEV1) within normal limits and good exercise tolerance. \n\nWhen considering surgery perform a functional segment count to predict postoperative lung function. \n\nOffer people with predicted postoperative FEV1 or TLCO below 30% the option of treatment with curative intent if they accept the risks of dyspnoea and associated complications. [2011, amended 2019]\n\nConsider using shuttle walk testing (using a distance walked of more than 400\xa0m as a cut-off for good function) to assess the fitness of people with moderate to high risk of postoperative dyspnoea. \n\nConsider cardiopulmonary exercise testing to measure oxygen uptake (VO2 max) and assess lung function in people with moderate to high risk of postoperative dyspnoea, using more than 15\xa0ml/kg/minute as a cut-off for good function. \n\n## Assessment before radiotherapy with curative intent\n\nA clinical oncologist specialising in thoracic oncology should determine suitability for radiotherapy with curative intent, taking into account performance status and comorbidities. \n\n# Surgery and radiotherapy with curative intent for non-small-cell lung cancer\n\n## Surgery\n\nFor people with NSCLC who are well enough and for whom treatment with curative intent is suitable, offer lobectomy (either open or thoracoscopic). \n\nOffer more extensive surgery (bronchoangioplastic surgery, bilobectomy, pneumonectomy) only when needed to obtain clear margins. \n\nPerform hilar and mediastinal lymph node sampling or en bloc resection for all people having surgery with curative intent. \n\nFor people with T3 NSCLC with chest wall involvement who are having surgery, aim for complete resection of the tumour using either extrapleural or en bloc chest wall resection. \n\n## Surgery or radiotherapy for people not having lobectomy\n\nFor people with stage\xa0I–IIA (T1a–T2b, N0, M0) NSCLC who decline lobectomy or in whom it is contraindicated, offer radical radiotherapy with stereotactic ablative radiotherapy (SABR) or sublobar resection. \n\n## Radical radiotherapy for people not having surgery\n\nAll people should have pulmonary function tests (including lung volumes and transfer factor) before radical radiotherapy for NSCLC. \n\nPeople receiving radiotherapy with curative intent should be part of a national quality assurance programme. \n\nFor people with stage I–IIA (T1a–T2b, N0, M0) NSCLC who decline surgery or in whom any surgery is contraindicated, offer SABR. If SABR is contraindicated, offer either conventional or hyperfractionated radiotherapy. \n\nFor eligible people with stage\xa0IIIA NSCLC who cannot tolerate or who decline chemoradiotherapy (with or without surgery), consider radical radiotherapy (either conventional or hyperfractionated). \n\nFor eligible people with stage\xa0IIIB NSCLC who cannot tolerate or who decline chemoradiotherapy, consider radical radiotherapy (either conventional or hyperfractionated). \n\n## Radiotherapy fractionation\n\nIf using SABR, follow the SABR Consortium guidance on fractionation. \n\nIf conventionally fractionated radical radiotherapy is used, offer either:\n\nGy in 20\xa0fractions over 4\xa0weeks or\n\n–66 Gy in 30–33\xa0fractions over 6–6½\xa0weeks. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgery and radiotherapy with curative intent for non-small-cell lung cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: Radiotherapy with curative intent for NSCLC.\n\nLoading. Please wait.\n\n# Combination treatment for non-small-cell lung cancer\n\nConsider chemoradiotherapy for people with stage\xa0II or\xa0III NSCLC that are not suitable for or decline surgery. Balance potential benefit in survival with the risk of additional toxicities. \n\nEnsure that all people for whom multimodality treatment is potentially suitable (surgery, radiotherapy and chemotherapy in any combination) are assessed by a thoracic oncologist and by a thoracic surgeon. \n\nOffer postoperative chemotherapy to people with good performance status (WHO 0 or 1) and T1a–4, N1–2, M0 NSCLC. \n\nConsider postoperative chemotherapy for people with good performance status (WHO 0 or 1) and T2b–4, N0, M0 NSCLC with tumours greater than 4\xa0cm in diameter. \n\nOffer a cisplatin-based combination chemotherapy regimen for adjuvant chemotherapy. \n\nFor people with stage\xa0I–II NSCLC that are suitable for surgery, do not offer neo-adjuvant treatment outside a clinical trial. [2011, amended 2019]\n\nEnsure eligible people have the benefit of detailed discussion of the risks and benefits of adjuvant chemotherapy. \n\nTreat Pancoast tumours in the same way as other types of NSCLC. Offer multimodality therapy according to resectability, stage of the tumour and performance status of the person. \n\nFor people with operable stage IIIA–N2 NSCLC who can have surgery and are well enough for multimodality therapy, consider chemoradiotherapy with surgery. \n\nDiscuss the benefits and risks with the person before starting chemoradiotherapy with surgery, including that:\n\nchemoradiotherapy with surgery improves progression-free survival\n\nchemoradiotherapy with surgery may improve overall survival. \n\nFor people with stage IIIA–N2 NSCLC who are having chemoradiotherapy and surgery, ensure that their surgery is scheduled for 3\xa0to 5\xa0weeks after the chemoradiotherapy. \n\nMultidisciplinary teams that provide chemoradiotherapy with surgery should have expertise in the combined therapy and in all of the individual components. \n\nCentres performing lung resections for lung cancer should validate their data for the Royal College of Physicians Lung Cancer Clinical Outcomes publication and the National Lung Cancer Audit. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management of operable stage IIIA–N2 non-small-cell lung cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: Management of NSCLC stage IIIA-N2.\n\nLoading. Please wait.\n\n# Systemic anti-cancer therapy (SACT) for advanced non-small-cell lung cancer\n\nWe have produced treatment pathways bringing together NICE recommended treatment options from this guideline and relevant technology appraisal guidance on advanced non-small-cell lung cancer (squamous and non-squamous). The treatment pathways cover the recommended treatment options at each decision point.\n\nThese are available to view as individual pathways (linked below), or grouped together in a single interactive PDF of all treatment pathways for squamous and non-squamous advanced non-small-cell lung cancer.\n\nWe have also produced fully accessible summaries of the treatment pathways.\n\n## Squamous non-small-cell lung cancer\n\nSystemic anti-cancer therapy: treatment options for people with squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with RET fusion positive squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with RET fusion positive squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with RET fusion positive squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with RET fusion positive squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with NTRK fusion positive squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with NTRK fusion positive squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with NTRK fusion positive squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with NTRK fusion positive squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with KRAS G12C positive squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with KRAS G12C positive squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with KRAS G12C positive squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with KRAS G12C positive squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with METex14 skipping alteration squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with METex14 skipping alteration squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with EGFRex 20 insertion positive squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with EGFRex 20 insertion positive squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with EGFRex 20 insertion positive squamous non-small-cell lung cancer, with PD-L1 50% or higher\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with EGFRex 20 insertion positive squamous non-small-cell lung cancer, with PD-L1 50% or higher\n\n## Non-squamous non-small-cell lung cancer\n\nSystemic anti-cancer therapy: treatment options for people with non-squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with non-squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with non-squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with non-squamous non-small-cell lung cancer, with no targetable mutations and PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with EGFR-TK positive non-squamous non-small-cell lung cancer\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with EGFR-TK positive non-squamous non-small-cell lung cancer\n\nSystemic anti-cancer therapy: treatment options for people with ALK positive non-squamous non-small-cell lung cancer\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with ALK positive non-squamous non-small-cell lung cancer\n\nSystemic anti-cancer therapy: treatment options for people with ROS-1 positive non-squamous non-small-cell lung cancer\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with ROS-1 positive non-squamous non-small-cell lung cancer\n\nSystemic anti-cancer therapy: treatment options for people with RET fusion positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with RET fusion positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with RET fusion positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with RET fusion positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with NTRK fusion positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with NTRK fusion positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with NTRK fusion positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with NTRK fusion positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with KRAS G12C positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with KRAS G12C positive non-squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with KRAS G12C positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with KRAS G12C positive non-squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with METex14 skipping alteration non-squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration non-squamous non-small-cell lung cancer, with PD-L1 less than 50%\n\nSystemic anti-cancer therapy: treatment options for people with METex14 skipping alteration non-squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with METex14 skipping alteration non-squamous non-small-cell lung cancer, with PD-L1 50% or more\n\nSystemic anti-cancer therapy: treatment options for people with EGFRex20 insertion positive non-squamous non-small-cell lung cancer\n\nFully accessible summary of systemic anti-cancer therapy: treatment options for people with EGFRex20 insertion positive non-squamous non-small-cell lung cancer\n\n# Assessing people with small-cell lung cancer\n\nArrange for people with small-cell lung cancer (SCLC) to have an assessment by a thoracic oncologist within 1\xa0week of deciding to recommend treatment. \n\n# First-line treatment for limited-stage disease small-cell lung cancer\n\nOffer people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) 4\xa0to 6\xa0cycles of cisplatin-based combination chemotherapy. Consider substituting carboplatin in people with impaired renal function, poor performance status (WHO 2 or more) or significant comorbidity. \n\nOffer twice-daily radiotherapy with concurrent chemotherapy to people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) and a WHO performance status of 0\xa0or\xa01, if they present with disease that can be encompassed in a radical thoracic radiotherapy volume. Start the radiotherapy during the first or second cycle of chemotherapy. \n\nIf the person declines or is unable to have twice-daily radiotherapy, offer once-daily radiotherapy. \n\nOffer sequential radical thoracic radiotherapy to people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) who are not well enough for concurrent chemoradiotherapy but who respond to chemotherapy. \n\nOffer prophylactic cranial irradiation at a dose of 25\xa0Gy in 10\xa0fractions to people with limited-stage disease SCLC and WHO performance status 0\xa0to\xa02, if their disease has not progressed on first-line treatment. [2011, amended 2019]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on first-line treatment for limited-stage disease SCLC\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: Chemoradiotherapy for limited stage SCLC.\n\nLoading. Please wait.\n\n# Surgery for small-cell lung cancer\n\nConsider surgery in people with early-stage SCLC (T1–2a, N0, M0). \n\n# First-line treatment for extensive-stage disease small-cell lung cancer\n\nOffer platinum-based combination chemotherapy to people with extensive-stage disease SCLC (broadly corresponding to T1–4, N0–3, M1a/b – including cerebral metastases) if they are fit enough. \n\nAssess the person's condition before each cycle of chemotherapy for extensive-stage disease SCLC (broadly corresponding to T1–4, N0–3, M1a/b) and offer up to a maximum of 6\xa0cycles, depending on response and toxicity. \n\nConsider thoracic radiotherapy with prophylactic cranial irradiation for people with extensive‑stage disease SCLC who have had a partial or complete response to chemotherapy within the thorax and at distant sites. \n\nConsider prophylactic cranial irradiation for people with extensive-stage disease SCLC and WHO performance status 0\xa0to\xa02, if their disease has responded to first-line treatment. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on thoracic radiotherapy and prophylactic cranial irradiation in SCLC\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: Thoracic radiotherapy for extensive stage SCLC and evidence review H: Prophylactic cranial irradiation for extensive stage SCLC.\n\nLoading. Please wait.\n\n# Maintenance treatment for small-cell lung cancer\n\nOnly offer maintenance treatment to people with SCLC in the context of a clinical trial. \n\n# Second-line treatment for small-cell lung cancer that has relapsed after first-line treatment\n\nOffer people with SCLC that has relapsed after first-line treatment assessment by a thoracic oncologist. \n\nInform people whose disease has not responded to first-line treatment that there is very limited evidence that second-line chemotherapy will be of benefit. \n\nOffer people with relapsed SCLC in whom chemotherapy is suitable treatment with an anthracycline-containing regimen or further treatment with a platinum-based regimen to a maximum of 6\xa0cycles. \n\nOffer radiotherapy for palliation of local symptoms to people with SCLC that has relapsed after first-line treatment. \n\n## Topotecan\n\nRefer to the NICE technology appraisal guidance on topotecan for the treatment of relapsed small-cell lung cancer. ", 'Palliative interventions and supportive and palliative care': '# Providing palliative care\n\nSupportive and palliative care of the person should be provided by general and specialist palliative care providers in line with the NICE guidance on improving supportive and palliative care for adults with cancer. \n\nIdentify and refer people who may benefit from specialist palliative care services without delay. \n\n# Palliative radiotherapy\n\nProvide palliative radiotherapy, either as symptoms arise or immediately, for eligible people who cannot be offered curative treatment. \n\n# Managing endobronchial obstruction\n\nWhen people have large airway involvement, monitor (clinically and radiologically) for endobronchial obstruction to ensure treatment is offered early. \n\nOffer external beam radiotherapy and/or endobronchial debulking or stenting to people with impending endobronchial obstruction. \n\nEvery cancer alliance should ensure that people have rapid access to a team capable of providing interventional endobronchial treatments. \n\n# Other palliative treatments\n\nPerform pleural aspiration or drainage in an attempt to relieve the symptoms of a pleural effusion. \n\nPatients who benefit symptomatically from aspiration or drainage of fluid should be offered talc pleurodesis for longer-term benefit. \n\nConsider non-drug interventions based on psychosocial support, breathing control and coping strategies for people with breathlessness. \n\nNon-drug interventions for breathlessness should be delivered by a multidisciplinary group, coordinated by a professional with an interest in breathlessness and expertise in the techniques (for example, a nurse, physiotherapist or occupational therapist). Although this support may be provided in a breathlessness clinic, people should have access to it in all care settings. \n\nConsider opioids, such as codeine or morphine, to reduce cough. \n\nRefer people with troublesome hoarseness due to recurrent laryngeal nerve palsy to an ear, nose and throat specialist for advice. \n\nOffer people who present with superior vena cava obstruction chemotherapy and radiotherapy according to the stage of disease and performance status. \n\nConsider stent insertion for the immediate relief of severe symptoms of superior vena caval obstruction or following failure of earlier treatment. \n\n# Managing brain metastases\n\nOffer dexamethasone to people with symptomatic brain metastases and reduce to the minimum necessary maintenance dose for symptomatic response. \n\nFor guidance on management of brain metastases, see the section on management of confirmed brain metastases in the NICE guideline on brain tumours. \n\n# Bone metastases\n\nAdminister single-fraction radiotherapy to people with bone metastasis who need palliation and for whom standard analgesic treatments are inadequate. \n\nFor more guidance on preventing complications from bone metastases, see the NICE technology appraisal guidance on denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours. \n\n# Managing other symptoms: weight loss, loss of appetite, difficulty swallowing, fatigue and depression\n\nOther symptoms, including weight loss, loss of appetite, depression and difficulty swallowing, should be managed by multidisciplinary groups that include supportive and palliative care professionals. ', 'Follow-up and patient perspectives': '# Organising follow-up and collecting information on patient experience\n\nOffer all people with lung cancer an initial specialist follow-up appointment within 6\xa0weeks of completing treatment to discuss ongoing care. Offer regular appointments after this, rather than relying on the person requesting appointments when they experience symptoms. \n\nOffer protocol-driven follow-up led by a lung cancer clinical nurse specialist as an option for people with a life expectancy of more than 3\xa0months. \n\nEnsure that people know how to contact the lung cancer clinical nurse specialist involved in their care between their scheduled hospital visits. \n\nThe opinions and experiences of people with lung cancer and their family members or carers (as appropriate) should be collected and used to improve the delivery of lung cancer services. People should receive feedback on any action taken as a result of such surveys. ', 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Immunotherapy after multimodality treatment\n\nWhat is the effectiveness and cost effectiveness of immunotherapy in people with stage\xa0IIIA-N2 non‑small‑cell lung cancer following multimodality treatment including surgery?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on management of operable stage IIIA–N2 non-small-cell lung cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: Management of NSCLC stage IIIA-N2.\n\nLoading. Please wait.\n\n# Stereotactic ablative radiotherapy compared with surgery\n\nWhat is the effectiveness and cost effectiveness of stereotactic ablative radiotherapy (SABR) compared with surgery (for example, sublobar, wedge resection, lobectomy) for people with non-small-cell lung cancer (stage\xa0I and IIA) in whom surgery is suitable?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on surgery and radiotherapy with curative intent for non-small-cell lung cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: Radiotherapy with curative intent for NSCLC.\n\nLoading. Please wait.\n\n# Routine contrast-enhanced brain CT\n\nWhat is the effectiveness and cost effectiveness of routinely performing contrast-enhanced brain CT at the time of initial diagnosis and/or staging CT?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on brain imaging for people having treatment with curative intent\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: Brain imaging for people with NSCLC selected for treatment with curative intent.\n\nLoading. Please wait.\n\n# Prophylactic cranial irradiation compared with routine MRI follow-up in extensive-stage small-cell lung cancer\n\nWhat is the effectiveness and cost effectiveness of prophylactic cranial irradiation compared with routine MRI follow-up in people with extensive-stage small-cell lung cancer without brain metastases?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on thoracic radiotherapy and prophylactic cranial irradiation in SCLC\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: Thoracic radiotherapy for extensive stage SCLC and evidence review H: Prophylactic cranial irradiation for extensive stage SCLC.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect services. They link to details of the evidence and a full description of the committee's discussion.\n\n# Diagnosis and staging\n\n## Why the committee made the recommendations\n\nRecommendation 1.3.10\n\nClinical audit is an important tool for maintaining high standards in the use of endobronchial ultrasound‑guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound‑guided fine‑needle aspiration (EUS-FNA). This is consistent with the British Thoracic Society guideline and quality standards (which are accredited by NICE).\n\nRecommendations 1.3.19 to 1.3.21\n\nThe recommendations cover:\n\ninitial invasive investigations for people with an intermediate probability of mediastinal malignancy\n\nsubsequent investigations for people with a high probability of mediastinal malignancy, when neck ultrasound and biopsy are negative.\n\nIn these circumstances, when compared with alternative investigations, EBUS-TBNA and EUS-FNA:\n\nproduce a diagnosis and stage faster than bronchoscopy or CT-guided biopsy\n\nare more acceptable to patients than surgery\n\nreduce the need for further investigations and hospital visits compared with bronchoscopy.\n\nRecommendation 1.3.21\n\nThere is evidence that surgical staging is useful when EBUS-TBNA and/or EUS-FNA are negative but clinical suspicion of mediastinal malignancy is high. While there are potential harms from the invasive nature of surgical staging, there is no evidence that these outweigh the benefits in this population.\n\nTransthoracic needle biopsy, bronchoscopy and non-ultrasound-guided TBNA are no longer recommended for staging lung cancer in intrathoracic lymph nodes because:\n\nbronchoscopy and non-ultrasound-guided TBNA are unlikely to reach the minimum sensitivity required by the British Thoracic quality standards and\n\nthey may discourage people from having more effective procedures (such as EBUS-TBNA) and subsequent investigations.\n\nThe word 'fibreoptic' has been removed because bronchoscopy can be fibreoptic, video or hybrid.\n\n## How the recommendations might affect practice\n\nThe recommendations on PET-CT reflect current practice, so will not incur an extra cost.\n\nThe recommendations on EBUS-TBNA and EUS-FNA will reinforce best practice and result in a more streamlined diagnostic service with more timely diagnosis and staging.\n\nThe surgical mediastinal staging recommendation will also reinforce best practice and restrict this procedure to people most likely to benefit.\n\nReturn to recommendations\n\n# Brain imaging for people having treatment with curative intent\n\nRecommendations 1.3.23 to 1.3.25\n\n## Why the committee made the recommendations\n\nBrain imaging is helpful before starting treatment with curative intent, because if brain metastases are detected then the treatment plan is likely to change. However, routine brain imaging is expensive, and the evidence showed that it does not always offer a good balance of benefits and costs.\n\nIn people with stage\xa0II and IIIA disease, the benefits of brain imaging outweigh the costs because:\n\nbrain metastases are more common than in stage\xa0I disease\n\npeople can start early treatment for metastases if they are identified, which improves prognosis\n\nsome people with brain metastases will not have radical treatment (depending on factors such as the number of metastases, prognosis and patient preference), and this reduces costs.\n\nIn people with clinical stage\xa0I NSCLC and no neurological symptoms, the prevalence of detectable brain metastases is fairly low (around 4%) compared with people with stage\xa0II or IIIA disease. People with stage\xa0I NSCLC who do have brain metastases often still have radical lung treatment, which is much more rarely the case for people with stage\xa0IIIA NSCLC. Overall, the lower prevalence of metastases and smaller reduction in numbers of people having radical treatment mean that the benefits of brain imaging in this population are too low to justify the costs.\n\nThe 2018 review only examined the clinical and cost effectiveness of imaging after the treatment plan has been decided, but the committee noted that it could be more efficient to conduct CT brain imaging alongside initial staging CT. With this in mind, the committee made a recommendation for research on routine brain imaging with CT at initial diagnosis and/or staging.\n\n## How the recommendations might affect practice\n\nPractice in this area is variable. The committee estimated that the recommendations will increase the number of people who have brain imaging. In turn, they thought this should prevent the use of treatment options (such as lobectomy and sublobar resection) in some patients for whom it is not expected to be beneficial. The recommendations may also lead to an increase in radical radiotherapy, stereotactic radiosurgery and brain surgery. These treatments would be expected to improve the person's prognosis, although each treatment would carry its own risks and side effects.\n\nReturn to recommendations\n\n# Surgery and radiotherapy with curative intent for non-small-cell lung cancer\n\nRecommendations 1.6.1 and 1.6.5 to 1.6.12\n\n## Why the committee made the recommendations\n\nFor people with non-small-cell lung cancer (NSCLC) who are well enough and for whom treatment with curative intent is suitable, the evidence showed that lobectomy provides better survival outcomes than stereotactic ablative radiotherapy (SABR). Lobectomy is a good compromise between preserving pulmonary function and being more likely to remove cancerous cells compared with sublobar resection.\n\nFor people with stage\xa0I–IIA (T1a–T2b, N0, M0) NSCLC, the evidence showed that:\n\nif they decline lobectomy or it is contraindicated, sublobar resection and SABR both provide better survival outcomes than conventionally fractionated radiotherapy, although it is not clear which of these 2 is better\n\nif they decline any surgery or it is contraindicated, SABR provides better survival outcomes than conventionally fractionated radiotherapy, and people often prefer it because it involves fewer hospital visits\n\nif surgery and SABR are contraindicated, conventionally fractionated radiotherapy provides better survival outcomes than no radiotherapy.\n\nFor people with stage\xa0IIIA or IIIB NSCLC who cannot tolerate chemoradiotherapy or who decline it, the evidence was not strong enough to recommend conventional radiotherapy over hyper-fractionated regimens or vice versa. However, people who cannot tolerate chemoradiotherapy may also be unable to tolerate radical radiotherapy, so this will not be an option for everyone with stage IIIA or IIIB NSCLC. For an explanation of the recommendations covering surgery in this group, see the rationale on management of stage IIIA-N2 NSCLC\xa0.\n\nGy in 20\xa0fractions is the most common conventional radical radiotherapy regimen in the UK. If conventionally fractionated radiotherapy is used, a total radiation dose of 60\xa0Gy provides better survival outcomes and fewer adverse events than 74\xa0Gy. A total dose of 60\xa0to 66\xa0Gy is also normal NHS practice.\n\nThere are not many randomised controlled trials comparing SABR with surgery (lobectomy or sublobar resection). SABR is non-invasive, so if it is as effective as surgery then it may be a preferable option for many people with lung cancer. There are also various factors that may make SABR less costly than surgery. For example, it is usually delivered as outpatient treatment. There might also be subgroups for whom different forms of surgery or SABR might be the most cost-effective options. The committee made a recommendation for research on SABR compared with surgery to investigate these uncertainties.\n\nLoading. Please wait.\n\n## How the recommendations might affect practice\n\nThe new recommendations on SABR are a change from the 2011 guideline and improve choice for people with NSCLC. However, practice has also changed since 2011, and SABR is now widely used, so implementing the recommendations may not involve a significant change in practice. The remaining changes to the recommendations reflect current practice.\n\nReturn to recommendations\n\n# Management of operable stage IIIA–N2 non-small-cell lung cancer\n\nRecommendations 1.7.9 to 1.7.13\n\n## Why the committee made the recommendations\n\nThe available evidence showed that chemoradiotherapy and surgery are more effective than chemoradiotherapy alone in people who are well enough for surgery and when the disease is operable. For chemotherapy and surgery, there was no evidence that survival outcomes were better than for chemoradiotherapy, so the additional costs of including surgery outweighed the benefits.\n\nThe key benefit associated with chemoradiotherapy and surgery is the longer progression‑free survival time. An analysis of multiple trials showed improved progression-free survival and cost effectiveness for chemoradiotherapy with surgery, compared with chemoradiotherapy alone. There was an 89% probability that chemoradiotherapy and surgery improved average overall survival time compared with chemoradiotherapy. However, the evidence in favour of chemoradiotherapy and surgery involved indirect comparisons, and no head-to-head trials showed meaningful differences in overall survival for any of the interventions. And as with any major surgery, there is a perioperative mortality risk for people who have chemoradiotherapy and surgery.\n\nThe 3\xa0to 5\xa0week wait for surgery is recommended to give people time to recover from the chemoradiotherapy.\n\nChemoradiotherapy with surgery is not often offered in current practice. In addition, there are specific factors to take into account when offering all these treatments together. Therefore, multidisciplinary teams providing it should have expertise both in the combined therapy, and in all the individual components.\n\nImmunotherapy has been shown to be effective in a variety of NSCLC indications but there is currently no evidence on whether it is clinically or cost effective for people with stage IIIA-N2 NSCLC following surgery. The committee made a recommendation for research on immunotherapy after multimodality treatment to address this.\n\n## How the recommendations might affect practice\n\nThe committee felt that chemoradiotherapy and surgery is offered far less often than chemoradiotherapy alone or chemotherapy and surgery for people with NSCLC stage IIIA-N2. Therefore, these recommendations could lead to a change in current practice.\n\nReturn to recommendations\n\n# First-line treatment for limited-stage disease small-cell lung cancer\n\nRecommendations 1.10.1 to 1.10.5\n\n## Why the committee changed the recommendations\n\nThe evidence showed a survival benefit from twice-daily radiotherapy compared with once-daily. However, the committee agreed that some people with small-cell lung cancer will not be well enough to tolerate twice-daily radiotherapy, so they recommended giving people the option of once-daily radiotherapy.\n\nThe committee noted that, in practice, radiotherapy is not started in chemotherapy cycle\xa01, because this is when planning for the radiotherapy often takes place (see the recommendation on twice-daily radiotherapy with concurrent chemotherapy in the section on first-line treatment for limited-stage disease small-cell lung cancer). However, there was no new evidence on when to start radiotherapy, so the 2019 recommendation on this is the same as the original 2011 recommendation.\n\nThere were limited data available on whether continuous radiotherapy with concurrent chemotherapy was more effective than alternating radiotherapy and chemotherapy. Because of the limited data, and the committee's experience that people prefer to complete treatment as quickly as possible, the 2019 recommendation on concurrent therapy (see the recommendation\xa0on twice-daily radiotherapy with concurrent chemotherapy) is the same as the 2011 recommendation.\n\nReturn to recommendations\n\n# Thoracic radiotherapy and prophylactic cranial irradiation in small-cell lung cancer\n\nRecommendations 1.12.3 and 1.12.4\n\n## Why the committee made the recommendations\n\nThere was some uncertainty in the evidence. However, the study most relevant to UK practice showed that thoracic radiotherapy improves long-term survival for people who have had a partial or complete response to chemotherapy, if they live longer than 1\xa0year after the radiotherapy. The committee specified that thoracic radiotherapy should be given alongside prophylactic cranial irradiation. This is to match recommendation 1.4.55. In addition, the reviewed clinical trials gave thoracic radiotherapy alongside prophylactic cranial irradiation.\n\nThe evidence showed that prophylactic cranial irradiation improves survival versus best supportive care.\n\nProphylactic cranial irradiation can adversely affect quality of life, and the survival benefits are limited. There is also some evidence from a study outside the UK that routine MRI follow-up may be more cost effective. The committee made a recommendation for research on prophylactic cranial irradiation compared with routine MRI follow-up in extensive-stage SCLC, to provide evidence more relevant to the UK and to see if MRI could identify people who need whole-brain radiotherapy and so reduce the number of people having unnecessary treatment.\n\n## How the recommendations might affect practice\n\nThe 2011 recommendation only recommended thoracic radiotherapy for people with a complete response to chemotherapy at distant sites. Therefore, this recommendation could increase the number of people who are given thoracic radiotherapy.\n\nIt is likely that the recommendation reflects current clinical practice.\n\nReturn to recommendations", 'Context': "Over 46,000\xa0people were diagnosed with lung cancer in the UK in 2015. An estimated 89% of lung cancers are preventable, with 86% of these linked to smoking, 13% to occupational exposure, 9% to dietary factors and 7.8% to air pollution. Lung cancer can be linked to more than one\xa0cause.\n\nIn 2015 in the UK, over 35,000\xa0people died from lung cancer. The overall mortality rate from lung cancer has decreased by 9% over the last decade. However, while there has been a decrease of 19% in mortality rates in men, there has been an increase of 2% in women. This is linked to lifestyle factors such as smoking and is driven by an increased incidence of lung cancer in older women.\n\nIn the UK, lung cancer is more common in people of European family origin than in people of African or Asian family origin. It is strongly linked to socioeconomic deprivation. There are many risk factors for lung cancer, including age, genetics, lifestyle (especially smoking) and occupation. Lung cancer is estimated to cost the UK economy £2.4\xa0billion per year.\n\nNote: all statistics in this section are from Cancer Research UK's Lung Cancer Statistics.\n\nLung cancer is diagnosed and staged using a variety of tests, including chest X‑rays, CT or positron-emission tomography CT (PET‑CT). Lung cancer samples are commonly acquired for diagnosis using bronchoscopy, endobronchial ultrasound (EBUS) or a percutaneous procedure (guided by CT or ultrasound).\n\nLung cancer has 2 main types:\n\nnon-small-cell lung cancer (NSCLC), which is more common and spreads more slowly\n\nsmall-cell lung cancer (SCLC), which is rarer and spreads more quickly.\n\nTreatment depends on the type, size, position and stage of the cancer, and the person's health. Possible treatments include radiotherapy, systemic anti-cancer therapies, surgery, supportive care cryotherapy, photodynamic therapy and ablation.\n\nSince 2011, when the NICE lung cancer guideline was last updated, there have been changes in the way that lung cancer is diagnosed and treated. The Royal College of Physicians' National Lung Cancer Audit annual report 2016 identified that only 72% of people have pathological confirmation of their lung cancer. There is also inconsistency in the availability of molecular testing in lung cancer diagnosis.\n\nNHS England has taken steps to shorten the time to treatment, as well as improve access to and uptake of radiotherapy, and stereotactic ablative radiotherapy (SABR) is routinely used for certain subgroups of people with early-stage NSCLC. There are now a variety of licensed immunotherapies and biological targeted therapies for treating advanced NSCLC, and NICE has published technology appraisals covering many of these."}	https://www.nice.org.uk/guidance/ng122	This guideline covers diagnosing and managing non-small-cell and small-cell lung cancer. It aims to improve outcomes for patients by ensuring that the most effective tests and treatments are used, and that people have access to suitable palliative care and follow-up.
721f166e5204eed3f0c5219ae2d524208c0940db	nice	Semaglutide for managing overweight and obesity	Semaglutide for managing overweight and obesity Evidence-based recommendations on semaglutide (Wegovy) for managing overweight and obesity in adults. # Recommendations Semaglutide is recommended as an option for weight management, including weight loss and weight maintenance, alongside a reduced-calorie diet and increased physical activity in adults, only if: it is used for a maximum of 2 years, and within a specialist weight management service providing multidisciplinary management of overweight or obesity (including but not limited to tiers 3 and 4), and they have at least 1 weight-related comorbidity and: a body mass index (BMI) of at least 35.0 kg/m2, or a BMI of 30.0 kg/m2 to 34.9 kg/m2 and meet the criteria for referral to specialist weight management services in NICE's guideline on obesity: identification, assessment and management.Use lower BMI thresholds (usually reduced by 2.5 kg/m2) for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds. Consider stopping semaglutide if less than 5% of the initial weight has been lost after 6 months of treatment. These recommendations are not intended to affect treatment with semaglutide that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Management of overweight and obesity in adults includes lifestyle measures alone or with orlistat, or referral to specialist weight management services (such as tier 3 or 4), which might include liraglutide or bariatric surgery. Clinical trial evidence shows that: people lose more weight with semaglutide alongside supervised weight management support than with the support alone more weight is lost with semaglutide than with liraglutide in people with non-diabetic hyperglycaemia, semaglutide plus lifestyle measures helps normalise blood glucose more frequently than lifestyle measures alone semaglutide may decrease the risk of cardiovascular disease. People from some minority ethnic family backgrounds have an equivalent risk from obesity at a lower BMI than people from a White ethnic family background. Also, NICE's guideline on obesity recommends using lower BMI thresholds for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds when identifying the risk of developing type 2 diabetes and providing interventions to prevent it. So, a similar adjustment in the BMI threshold is appropriate when considering using semaglutide. It is appropriate to use semaglutide alongside lifestyle interventions that are provided in specialist weight management services (offered in the NHS for a limited time). This is because it is in keeping with the clinical trial, and there is no evidence of effectiveness if semaglutide is used as a single stand-alone treatment. Also, the marketing authorisation specifies use as an adjunct to a reduced-calorie diet and increased physical activity. For people who have at least 1 weight-related comorbidity and a BMI of at least 35 kg/m2 or a BMI of 30 kg/m2 to 34.9 kg/m2 and also meet the NICE criteria for referral to a specialist weight management service, the cost-effectiveness estimates for semaglutide are likely to be within what is normally considered a cost-effective use of NHS resources. For these groups, semaglutide is recommended alongside lifestyle interventions in an appropriate multidisciplinary setting.# Information about semaglutide # Marketing authorisation indication Semaglutide (Wegovy, Novo Nordisk) is 'indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of ≥30 kg/m2 (obesity), or ≥27 kg/m2 to <30 mg/kg2 (overweight) in the presence of at least one weight-related comorbidity'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for semaglutide. # Price The list price of semaglutide (Wegovy) 2.4 mg and 1.7 mg is commercial in confidence and cannot be reported here. The list price of semaglutide (Ozempic) 0.25 mg, 0.5 mg and 1.0 mg is £73.25 per pack (excluding VAT; BNF online accessed June 2022).# Committee discussion The appraisal committee considered evidence submitted by Novo Nordisk, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need ## Semaglutide would be a welcome new treatment option for people living with obesity Overweight and obesity can be physically debilitating, and may lead to severe and potentially life-limiting conditions, as well as fertility issues and symptoms such as skin infections. The social stigma associated with overweight and obesity can affect career prospects and self-confidence. The patient experts explained how obesity is a lifelong condition that needs medical intervention, can affect quality of life, and has psychological and physical effects. They also explained that the ability to lose weight and maintain weight loss is challenging and a lifelong burden. This is despite people living with obesity having knowledge about lifestyle interventions including diet and increased physical activity. The patient experts explained that access to treatment with liraglutide is limited to a specific population who have non-diabetic hyperglycaemia and a risk factor for cardiovascular disease. They thought that access to a new treatment option would provide hope for more people living with obesity. Orlistat is the only other pharmacological treatment option available but is poorly tolerated by many people and rarely used. The patient experts also explained that, even after bariatric surgery, maintaining weight loss is challenging. The committee concluded that there is a large unmet need for many people living with obesity, and that semaglutide would be a welcome new treatment option. # Current management ## Some people living with obesity are referred to specialist weight management services (usually tier 3 services) but NHS provision varies The management of overweight and obesity in the NHS is broadly structured into tiered services. Tier 1 services provide universal interventions such as population level health promotion and advice. Tier 2 services include community-based diet, nutrition, lifestyle and behaviour change advice for up to 12 weeks. Tier 3 services provide longer and more comprehensive multidisciplinary team assessment and interventions. These include dietary, lifestyle and behaviour modification advice, with or without drug therapy, and psychological support. The clinical experts explained that tier 3 services are traditionally offered in secondary care but there are equivalent services with similar multidisciplinary team support in community settings in some places. The clinical and patient experts explained that specialist weight management services such as tier 3 services are not available everywhere across England and Wales. They are normally accessed for up to 2 years by people with a body mass index (BMI) of 35 kg/m2 or more plus 1 or more comorbidities, or with a BMI of 40 kg/m2 or more with or without comorbidities. The specific nature of the comorbidities needed for referral may vary across different services. Also, the length of time they can be accessed may be shorter than 2 years in different areas of the country. The clinical experts explained that the average BMI in tier 3 is well above 35 kg/m2, at 46 kg/m2. Tier 3 services are also accessed by a small number of people with a lower BMI of 30 kg/m2 to 35 kg/m2 who have a complex comorbidity that would benefit from weight loss. The clinical experts explained that this group represents only about 1.5% of people in tier 3. However, the population prevalence of a BMI of 30 kg/m2 to 35 kg/m2 is much greater than that of a BMI of over 35 kg/m2. People with a BMI of 30 kg/m2 to 35 kg/m2 accessing tier 3 services typically have particularly complex health needs or other significant co-existing conditions, such as muscular dystrophy. The committee was aware that NICE's quality standard on obesity: clinical assessment and management states that adults with a BMI of 30 kg/m2 or more for whom tier 2 interventions have been unsuccessful should have a discussion about the choice of alternative interventions for weight management, including tier 3 referral. NICE's guideline on obesity: identification, assessment and management recommends that referral to tier 3 services is considered for people in specific circumstances. This includes, for example, when the person has a complex disease state or needs that cannot be managed adequately in tier 2. The committee noted that, in clinical practice, very few people with a BMI of 30.0 kg/m2 to 34.9 kg/m2 are referred to tier 3 services. Tier 4 services provide similar multidisciplinary team interventions to tier 3, but also manage bariatric surgery and bariatric medicine. A patient expert noted that semaglutide could be useful for treating weight regain after bariatric surgery. The committee noted the consultation comments highlighting that specialist weight management services such as tier 3 are not available in all parts of the country. Other consultation comments suggested that people with severe mental illness are excluded from accessing specialist weight management services. The committee acknowledged these comments but agreed that it was outside its remit to address the whole of the NHS weight management service provision and referral criteria. The committee noted that NHS services for overweight and obesity are under review and welcomed this, but was not aware of any planned or confirmed changes to these services. The committee concluded that, ideally, all people living with obesity eligible for specialist weight management services according to NICE's guideline on obesity should have access to these services. # Treatment setting ## Semaglutide should be used as part of a package of care provided in a specialist weight management service The marketing authorisation for semaglutide specifies that it should be used as an adjunct to a reduced-calorie diet and increased physical activity (see section 2.1). The clinical experts explained that, in the NHS, a sustained programme of lifestyle interventions, including diet and physical activity advice and management is only available in specialist weight management services such as tier 3 and 4 services. They also stated the importance of only offering semaglutide with these interventions because this was a requirement in the trial that showed favourable results. The clinical experts did not consider that semaglutide is a 'stand-alone' treatment. Although tier 2 services include diet, nutrition, lifestyle and behaviour change advice, they are only accessed for 12 weeks (see section 3.2). This is not long enough to establish treatment with semaglutide, which has an initial 16‑week dose escalation period. In addition, the marketing authorisation specifies reassessment at 6 months to see if treatment with semaglutide should be continued. Tier 2 services also do not include the support of a multidisciplinary team. The committee agreed that semaglutide should be used alongside specialist weight management interventions. These include dietary and physical activity interventions, as specified in the marketing authorisation, delivered by a multidisciplinary team, as suggested by the clinical experts. The committee noted that the clinical trial included adjunct physical activity, dietary advice and behaviour change interventions similar to the treatment provided in specialist weight management services (see section 3.6). Without the accompanying support provided by these services, the trial results used in the cost-effectiveness modelling might not be achieved in clinical practice. The committee noted that tier 2 services could not support delivery of semaglutide. It recognised that specialist weight management services such as tier 3 or 4 are not available to everyone across England and Wales (see section 3.2). However, the clinical experts explained that service provision is under review. The committee concluded that, as in the marketing authorisation and clinical trial evidence, these services are the only appropriate setting that can provide the necessary multidisciplinary specialist weight management interventions for a sustained period alongside semaglutide treatment. Therefore, the committee agreed that semaglutide should only be available within a specialist weight management service. # Population ## Semaglutide is most appropriate for the population with the highest risk for the adverse effects of obesity The NICE scope for this appraisal and semaglutide's marketing authorisation includes people with a BMI of 30 kg/m2 or more (obesity), or a BMI from 27 kg/m2 to less than 30 kg/m2 (overweight) and at least 1 weight-related comorbidity. The company presented evidence in its submission for its target population, which was a more restricted population than the full marketing authorisation. It included people with a BMI of 30 kg/m2 or more with at least 1 weight-related comorbidity. It suggested that these people may benefit most from pharmacological treatment and that they would be able to have treatment in specialist weight management services. The committee recalled that NICE's guideline on obesity recommends considering referral to tier 3 services in specific circumstances, and that referral to tier 3 services is not recommended for all people with a BMI of 30 kg/m2 or more with any weight-related comorbidity. Only rarely are referrals made for people within this population, for example, when they have a complex disease state or needs that cannot be managed adequately in tier 2 (see section 3.2). The company also presented evidence for people with a BMI of 35 kg/m2 or more with non-diabetic hyperglycaemia and high cardiovascular disease risk. This was in line with the population in NICE's technology appraisal guidance on liraglutide for managing overweight and obesity. At technical engagement, the company also presented a cost-effectiveness analysis for the full population in the NICE scope and marketing authorisation. The clinical experts explained that people with a BMI of less than 30 kg/m2 are not referred to tier 3 services. They added that these services are only rarely accessed by some people with a BMI between 30 kg/m2 and 35 kg/m2, and only if they have complex comorbidities (see section 3.2). The company agreed that it was acceptable to only consider semaglutide for people who have treatment in specialist weight management services. It agreed that the population with a BMI between 27 kg/m2 and 30 kg/m2 or with a BMI between 30 kg/m2 and 35 kg/m2 without a weight-related comorbidity did not need further consideration. The committee agreed that this population was not generally at high enough risk for semaglutide use. NHS England proposed that a further population to consider is people with a BMI of 35 kg/m2 or more and a high risk of cardiovascular disease based on risk factors. The patient experts explained that there was a potential disconnect between the needs of people living with obesity and NHS provision within the tier system. The committee discussed that NHS specialist provision is clearly focused on providing intensive support for the highest-risk population with a BMI of 35 kg/m2 or more. It noted that stratifying by risk was a reasonable strategy in terms of absolute benefit. It also noted that very few people with a BMI of 30 kg/m2 to 35 kg/m2 are referred to tier 3 services. But it agreed that people for whom tier 2 services have not been successful do have a potential route of referral based on criteria in NICE's guideline on obesity (see section 3.2), although this rarely happens. If the recommendation for considering tier 3 referral in the NICE guideline were to be used more, it is not known how the population potentially eligible for semaglutide would or would not resemble the company's target population. The committee concluded that the appropriate population for semaglutide comprises people at the highest risk for the adverse effects of obesity. This is the population eligible for specialist weight management services. # Comparators ## The comparators proposed by the company are appropriate The company suggested that diet plus exercise was the appropriate comparator for semaglutide for its target population (people with a BMI of 30 kg/m2 or more plus at least 1 weight-related comorbidity). For people with a BMI of 35 kg/m2 or more, non-diabetic hyperglycaemia and a high risk of cardiovascular disease, liraglutide alongside a reduced-calorie diet and increased physical activity is recommended in NICE's technology appraisal guidance on liraglutide for managing overweight and obesity. So, liraglutide is the appropriate comparator for this population. The company proposed that orlistat should not be considered a comparator for semaglutide because it is not often used in practice. When it is, it is offered as a first-line option in primary care and would usually be tried before semaglutide would be considered. The clinical experts agreed that orlistat use is limited and that it is not a relevant comparator for semaglutide. The committee concluded that the appropriate comparators for semaglutide were: weight management support, diet and exercise for people with a BMI of 30 kg/m2 or more and at least 1 weight-related comorbidity liraglutide plus weight management support, diet and exercise for people with a BMI of 35 kg/m2 or more, non-diabetic hyperglycaemia and a high risk of cardiovascular disease. # Clinical evidence ## The population in STEP 1 does not reflect the population distribution of overweight and obesity in the general population STEP 1 was a randomised double-blind trial that compared a semaglutide once-weekly injection with placebo. Both groups also had lifestyle interventions including counselling, a reduced-calorie diet and increased physical activity with 68‑week treatment and follow up. It included adults living with obesity (BMI of 30.0 kg/m2 or more) with or without a comorbidity, or with overweight (BMI of 27.0 kg/m2 to 29.9 kg/m2) with at least 1 weight-related comorbidity. The comorbidities included hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease. People with type 2 diabetes were excluded from the trial. In the trial, 6.0% of people were categorised as having overweight (BMI of 27.0 kg/m2 to 29.9 kg/m2), 32.8% were categorised as having obesity category 1 (BMI of 30.0 kg/m2 to 34.9 kg/m2) and 61.2% were categorised as having obesity categories 2 or 3 (BMI of at least 35.0 kg/m2). The committee noted that this was the reverse of the weight distribution in clinical practice, where many more people would have a BMI of 30.0 kg/m2 to 35.0 kg/m2 than of at least 35.0 kg/m2. The average BMI in the trial was 37.9 kg/m2. The clinical experts explained that around 80% of people in tier 3 services have a BMI of 40.0 kg/m2 or more and that 1.5% have a BMI of less than 35.0 kg/m2 (see section 3.2). The company proposed that people with a BMI of 30.0 kg/m2 or more with at least 1 comorbidity (its target population; see section 3.4) should be considered for semaglutide. This population made up 75.0% of STEP 1. The committee agreed that the company's target population was at higher risk than those outside the target population. However, it noted that only 32.8% of people in STEP 1 had a BMI of 30.0 kg/m2 to 34.9 kg/m2. So, if semaglutide were to be available for everyone with a comorbidity within this BMI range, as in the company's target population, it is highly likely that the average BMI of the population having treatment would be lower than the trial population. This is because the prevalence of a BMI of 30 kg/m2 to 35 kg/m2 in the general population is higher than the prevalence of 35 kg/m2 or more. The committee recognised that the highest-risk population should have treatment. However, as more people with a lower BMI are included within a population having treatment, the less well this population would match the trial population. The committee also noted that any large increase in the number of people having treatment in specialist weight management services (with the associated multidisciplinary support) would have implications for service delivery and design. It acknowledged that this was outside its remit. However, it appreciated that it should be confident that the trial and modelled outcomes would be delivered in clinical practice if broader eligibility were to be accepted. It also needs to be confident that it would be a cost-effective strategy for the NHS. The committee concluded that the population in STEP 1 had a larger proportion of a high-risk population. This meant it did not reflect the population distribution of overweight and obesity in the general population. It also concluded that the population in STEP 1 was unlikely to correspond with the distribution of people who could be eligible for semaglutide if everyone within the company's original target population (including anyone with a BMI of 30 kg/m2 or more with any weight-related comorbidity) was recommended. ## People with type 2 diabetes are not included in STEP 1, although they could have semaglutide for weight management The committee noted that STEP 1 did not include people with type 2 diabetes. It was aware that a lower dose of semaglutide is available for managing type 2 diabetes. The clinical experts explained that, if someone with type 2 diabetes and obesity needs specialist weight management, it would be appropriate for them to have treatment for obesity within a specialist weight management service. This would include semaglutide treatment at the higher dose indicated for managing overweight and obesity. They also explained that, based on their experience, they would expect people with type 2 diabetes to have less weight loss with semaglutide than seen in STEP 1. This was also supported by data from the STEP 2 trial, a randomised controlled trial of semaglutide compared with placebo in people with overweight or obesity and type 2 diabetes. They noted that people with type 2 diabetes would be likely to have less weight loss than people without type 2 diabetes. But they commented that a small amount of weight loss is associated with greater health gain in a higher risk population such as this. The committee concluded that STEP 1 did not include people with type 2 diabetes, so did not cover the whole population who would potentially be offered semaglutide in the NHS. The committee agreed that this introduced some uncertainty about the generalisability of the clinical effectiveness results, and may have affected the reliability of the cost-effectiveness results. ## Semaglutide is more effective than placebo for treating overweight and obesity The company presented the full trial analysis and a post-hoc subgroup analysis of STEP 1. The full trial population (n=1,961) included adults living with obesity (BMI of 30 kg/m2 or more) or overweight (BMI of 27 kg/m2 to 29.9 kg/m2) with at least 1 weight-related comorbidity. The post-hoc subgroup analysis (n=1,470) included adults with a BMI of 30 kg/m2 or more with at least 1 weight-related comorbidity. Weight-related outcomes favoured semaglutide compared with placebo in the full trial population. The difference in mean percentage change in body weight at 68 weeks was -12.4%. It also favoured semaglutide in the post-hoc subgroup analysis. The difference in mean percentage change in body weight at 68 weeks was -12.2%. There was also a large increase in the proportion of people shifting from non-diabetic hyperglycaemia to normoglycaemia from baseline to week 68 with semaglutide treatment. However, this was greater in the post-hoc subgroup analysis population than the full trial population. The proportion who shifted from non-diabetic hyperglycaemia to normoglycaemia in the full trial population was 79.8% with semaglutide compared with 39.1% with placebo (40.7% treatment difference). The proportion who shifted from non-diabetic hyperglycaemia to normoglycaemia in the post-hoc population was 79.2% with semaglutide compared with 20.0% with placebo (59.2% treatment difference). The committee concluded that this analysis showed that semaglutide was clinically effective, with benefits for weight and non-diabetic hyperglycaemia in the full trial population and the post-hoc analysis subgroup. ## Semaglutide is more effective than liraglutide for weight loss Liraglutide plus weight management support, diet and exercise is the appropriate comparator for people with a BMI of 35 kg/m2 or more, non-diabetic hyperglycaemia and a high risk of cardiovascular disease (liraglutide-eligible subgroup; see section 3.5). At the time of submission, there was no head-to-head trial data available comparing semaglutide with liraglutide. The company presented an indirect treatment comparison using individual patient data from STEP 1 and SCALE 1839 to estimate the effectiveness of semaglutide compared with liraglutide in the liraglutide-eligible subgroup. SCALE 1839 was a randomised controlled trial of liraglutide compared with placebo in people with overweight or obesity. The results of the indirect treatment comparison showed that weight-related outcomes favoured semaglutide compared with liraglutide. The difference in mean percentage change in body weight at 68 weeks was ‑5.81%. At technical engagement, the company submitted direct head-to-head data for semaglutide compared with liraglutide (both alongside a lifestyle intervention) from the STEP 8 trial. STEP 8 was a randomised controlled trial including 388 adults living with obesity (BMI of 30 kg/m2 or more) or overweight (BMI of 27 kg/m2 to 29.9 kg/m2) with at least 1 weight-related comorbidity (hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease) and without type 2 diabetes. Results for the full trial population supported the results from the indirect treatment comparison. The difference in mean percentage change in body weight at 68 weeks was -9.38%. The ERG explained that the results were for the full trial population and not the liraglutide-eligible subgroup. The company explained that the liraglutide-eligible subgroup made up a small proportion of the trial population, so a subgroup analysis was not appropriate. The committee concluded that direct trial evidence for the subgroup would have been preferred. However, it agreed that the results from both the indirect treatment comparison and the full population of STEP 8 showed that semaglutide is more effective than liraglutide for weight loss. # The company's economic model ## The company's model is suitable for decision making The company submitted a cohort-transition model with 11 health states to estimate the cost effectiveness of semaglutide in 2 subgroups: compared with weight management support, diet and exercise for people with a BMI of 30 kg/m2 or more with at least 1 weight-related comorbidity compared with liraglutide plus weight management support, diet and exercise for people with a BMI of 35 kg/m2 or more with non-diabetic hyperglycaemia and a high risk of cardiovascular disease.The treatment effects for each subgroup were sourced from the full trial population of STEP 1 and applied to the populations of interest with different baseline risks. The model was based on a previous model used for NICE's technology appraisal of liraglutide for managing overweight and obesity, and on assumptions and service use in a specialist multidisciplinary weight management setting. The model only allowed up to 3 years treatment. People entered the model in a normal glucose tolerance state (46.6%) or non-diabetic hyperglycaemic state (53.4%), based on the prevalence in STEP 1. A once-only transition was used to incorporate the proportion of people reversing from non-diabetic hyperglycaemia to normal glucose tolerance based on STEP 1 data. Transitions between health states were based on type 2 diabetes status and cardiovascular events, estimated from risk equations. The committee expressed concern about the validity of risk equations (see section 3.16) and the model only allowing treatment with semaglutide plus diet and exercise, or diet and exercise alone for up to 3 years. However, it concluded that the perspective of use in specialist weight management services was appropriate and that the model was suitable for decision making. # Assumptions in the economic model ## It is reasonable to assume that people stop treatment after 6 months if they do not have an adequate response The company included a stopping rule in the model for people who had less than 5% weight loss after 6 months. This was based on the marketing authorisation, which states that a decision on continuing treatment for these people should be made at 6 months. The clinical experts agreed that most people would not want to continue semaglutide treatment after 6 months without a meaningful weight loss, especially considering the side effects associated with it. They explained that treatment assessment at 6 months was in line with what is expected in practice and that the stopping rule was appropriate. The committee concluded that it was appropriate to include the stopping rule for people with less than 5% reduction in body weight at 6 months in the model. This was in line with the time specified for the decision on continuing treatment in the marketing authorisation. ## Semaglutide is limited to 2 years because of restricted time in specialist weight management services and lack of evidence for longer use The company included an assumption in the model that people would take semaglutide for a maximum of 2 years. The patient experts explained that obesity is a lifelong condition, and that continued treatment was important for maintaining weight loss. This is still a challenge after people have reached their target weight. They noted that having only 2 years of semaglutide treatment would not be ideal. However, they still thought it would be highly beneficial for helping weight loss over a 2‑year period. It would give people the opportunity to incorporate more physical activity into their lifestyles, with improved mobility and reduced pain. The committee agreed that treatment for other chronic conditions is not stopped after a certain period when it is tolerated and effective. But it noted that the NHS provides specialist services for obesity that is time limited. The NHS England representative suggested that the psychological impact of stopping semaglutide treatment after 2 years at the same time as being discharged from specialist weight management services could be detrimental. However, the committee agreed that semaglutide should only be used in a specialist weight management service (see section 3.3). The committee noted the clinical experts' statements that specialist weight management services such as tier 3 are usually accessed for up to 2 years. People only very exceptionally stay in tier 3 services for longer. Also, some areas offer these services for shorter periods, and many people are discharged from tier 3 services before 2 years. The committee understood that there are restrictions on time spent in specialist weight management services. It agreed that, for a long-term problem like obesity, this was not ideal (see section 3.2). However, it accepted that the company model was based on a single course of treatment of no longer than 2 years. This is in line with the clinical trial evidence and is how long, on average, specialist weight management services can be accessed. The ERG highlighted that removing the 2‑year stopping rule to model lifelong use, including maintenance of weight loss, was not possible within the company's model. However, increasing the time on treatment to 3 years increased the incremental cost-effectiveness ratio (ICER), suggesting that longer use is less likely to be cost effective. The company highlighted that the longest treatment duration studied in a clinical trial was 2 years in the STEP 5 trial (a randomised controlled trial of 2‑year treatment with semaglutide compared with placebo for people with overweight or obesity). There is no evidence for longer-term use of semaglutide available, including evidence for maintenance treatment. However, longer-term evidence may be available in the future. The ERG noted that the results of the STEP 5 trial were comparable to the results from the STEP 1 trial used in the model, supporting the efficacy of semaglutide use for up to 2 years. The committee concluded that the assumption that treatment would be stopped at 2 years was reasonable in the context of NHS specialist weight management services, which are time limited. Such services are the only appropriate setting for semaglutide treatment given the marketing authorisation and clinical evidence base. However, when further evidence becomes available, it might be possible to consider long-term use in other settings if the evidence suggests that long-term or lifetime use is clinically and cost effective. ## The assumptions for weight gain are uncertain The company included an assumption that 3 years after stopping semaglutide (with a 2‑year treatment period), the weight advantage with semaglutide would be lost. This means the average weight for people taking semaglutide would be in line with what it would be in the average population in the diet and exercise treatment arm after 5 years. The company also assumed that people whose glucose tolerance became normal on treatment would revert to having non-diabetic hyperglycaemia 3 years after treatment stopped. In response to consultation, the committee noted the suggestion that the SCALE 1839 trial showed rapid weight gain in the first 12 weeks after stopping liraglutide. It was also suggested that the SCALE 1839 trial showed that weight would return to baseline weight following liraglutide treatment after 6 to 12 months, and that similar would be expected for semaglutide. The NHS England representative also noted evidence from a pharmacokinetic modelling study of liraglutide that showed weight returned to close to baseline by 29 weeks after stopping treatment following 56 weeks of liraglutide. The clinical experts noted that the assumptions around the rate of weight gain after treatment were very uncertain. They suggested that, on average, it would be expected that the weight advantage gained with semaglutide would be lost around 2 to 3 years after stopping treatment. But they explained that some people would maintain clinically relevant weight loss for longer. A committee member with experience of using semaglutide and liraglutide for treating diabetes explained that liraglutide is a less active and less effective treatment. Therefore, less weight would be expected to be lost with liraglutide than semaglutide (see section 3.9). Because of the expected greater weight loss with semaglutide the time to regain the weight following semaglutide treatment would be longer than the time to regain the weight following liraglutide treatment. The ERG explained that the STEP 4 clinical trial provided some evidence that not all weight lost is regained 1 year after stopping semaglutide. STEP 4 was a randomised trial that included a treatment arm including semaglutide treatment for 20 weeks, followed by placebo for 48 weeks for people with overweight or obesity. A 20‑week treatment duration is less than the time in the marketing authorisation specified for reassessment of benefit (see section 3.11). Therefore, initial weight loss in STEP 4 was expected to be less than that with 2 years of semaglutide treatment in clinical practice. If initial weight loss were lower because of a shorter treatment duration, it would be expected that the time to lose the weight advantage associated with semaglutide would be shorter than if semaglutide was given for 2 years. The ERG agreed that the assumption of the loss of weight advantage over 3 years was reasonable. It also provided a scenario analysis showing a modest effect on the cost-effectiveness results when an assumption of a loss of weight advantage over 2 years was included in the model. The committee concluded that this was an area of uncertainty. It accepted that there is not yet any long-term evidence to show the true average time to lose the weight advantage after semaglutide treatment. However, it noted that including an assumption in the model of loss of weight advantage at the lower end of the clinical expert's estimation (2 years) did not have a major effect on the cost-effectiveness estimate. ## Retreatment might be appropriate for some people meeting the eligibility criteria for a rereferral to a specialist weight management service The company's model included the assumption that there would be no retreatment with semaglutide. The clinical experts explained that some people who have regained weight after weight loss with semaglutide may wish to have it again. They also noted that rereferral into specialist weight management services is not usual but does happen occasionally. The committee discussed that the cost effectiveness of retreatment with semaglutide after weight regain was unknown because this was not included in the trial or the model. However, it acknowledged that retreatment might be appropriate for some people who have lost and regained weight and who become eligible for treatment again according to the same starting criteria. ## The model assumes that all people with non-diabetic hyperglycaemia develop type 2 diabetes after a cardiovascular event The company included a simplifying assumption in the model that all people with non-diabetic hyperglycaemia who have a cardiovascular event develop type 2 diabetes within the following year. The clinical experts explained that people with non-diabetic hyperglycaemia are more likely to be diagnosed with type 2 diabetes after a cardiovascular event, but that this relationship is not causal. However, they did agree that some people with non-diabetic hyperglycaemia would be diagnosed with type 2 diabetes after a cardiovascular event. So, because the model could only include this assumption for none or all of the people in the model, they thought it was reasonable to include it. The committee noted that the ERG's scenario analysis, which removed this assumption, had minimal effect on the ICER. The committee concluded that the true proportion of people who would be diagnosed with type 2 diabetes would fall somewhere between none and all people with non-diabetic hyperglycaemia who had a cardiovascular event. ## Risk equations are the only available method for modelling long-term health outcomes The company's model used risk equations to estimate the risk of long-term cardiovascular events such as an acute coronary event or stroke, and the risk of developing type 2 diabetes. These equations were based on surrogate outcomes from STEP 1 including BMI, systolic blood pressure, total cholesterol, high density lipoprotein and HbA1c levels. The NHS England representative explained that the risk equations used had not been validated by any data showing beneficial cardiovascular outcomes with weight loss in people without diabetes. They quoted a real-world, large UK study (with a follow up of up to 6 years) that did not show a reduction in cardiovascular events related to sustained weight loss alone. The clinical experts highlighted that a reduction in cardiovascular events has been shown with GLP‑1 inhibitors (the same class of drug as semaglutide) in people with diabetes. However, they accepted this had not yet been shown in people without diabetes. The committee was also aware that risk equations were based on an assumption of a steady state. They were not designed for estimating long-term risk when using an intervention with a time-limited benefit (such as a 2‑year treatment course; see section 3.12). Also, risk equations are not prognostic on an individual basis. The ERG explained that there was no practical alternative to using risk equations in the modelling. In response to consultation comments that disagreed with using risk equations to predict long-term cardiovascular disease outcomes, the ERG conducted scenario analyses excluding the cardiovascular disease benefits alone, or in combination with diabetes outcomes from the model. These showed that excluding cardiovascular disease benefits from the model had a small upward effect on the cost-effectiveness estimate. However, excluding diabetes benefits had a larger effect. The committee accepted that there was no data available on the effect of semaglutide treatment on long-term cardiovascular outcomes. However, it agreed that even a temporary improvement in weight, diabetic status and other risk parameters seen with semaglutide in STEP 1 would have some benefit. It noted, though, that this was difficult to quantify. The company explained that there would be further evidence on the long-term cardiovascular outcomes with semaglutide from the SELECT trial. This is a randomised controlled trial comparing semaglutide with placebo for up to 5 years in people with overweight or obesity and cardiovascular disease. The committee noted that the benefits seen in STEP 1 for shifting diabetic status from non-diabetic hyperglycaemic to normoglycemic were both striking and important (see section 3.8). This suggested that the time spent without diabetes could be increased for people taking semaglutide. The committee agreed that prolonging time without diabetes was an important and highly beneficial outcome, even if this was limited in duration. It noted that removing diabetic benefits from the model had a much greater upward effect on the ICER than removing cardiovascular benefits, which only modestly increased the ICER. Despite the uncertainties associated with using risk equations, the committee concluded that they were the only method available. This was because it had not been presented with an alternative method for estimating long-term health outcomes. # Cost-effectiveness estimate ## Because of uncertainty, there needs to be a high level of confidence that the ICER is around £20,000 per quality-adjusted life year gained NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of a technology as an effective use of NHS resources will consider the degree of certainty around the ICER. The committee noted the uncertainties in the modelling assumptions, particularly: the rebound in weight gain after semaglutide is stopped (see section 3.13) the calculation of long-term benefits using risk equations based on data about a temporary benefit (see section 3.16) the possible implications for NHS delivery of services.Based on these uncertainties, the committee agreed that it needed a high level of confidence that the ICER was at the lower end of the range for acceptable cost effectiveness (£20,000 to £30,000 per QALY gained). ## The ERG's and company's assumptions are reasonable The company's base-case analysis included: a stopping rule for people who have not lost at least 5% initial body weight at 6 months (see section 3.11) a maximum treatment duration of 2 years (see section 3.12) a loss of the weight advantage gained with semaglutide, and a return to the original glycaemic state 3 years after stopping treatment (see section 3.13) no retreatment throughout the full time horizon of the model (see section 3.14) that 100% of people with non-diabetic hyperglycaemia develop type 2 diabetes after a cardiovascular event (see section 3.15).The ERG's base case included some of the same assumptions as the company's, with the following differences: people with non-diabetic hyperglycaemia do not automatically develop type 2 diabetes after a cardiovascular event (see section 3.15) there is a natural weight increase per year of 0.30 kg (compared with the company's assumption of 0.46 kg) weight no longer increases after age 66 (compared with the company's assumption of age 68) natural weight decreases by 0.30 kg after age 66 (compared with the company's assumption of weight remaining constant) the annual cost of sleep apnoea is £274 (compared with the company's assumption of £1,081).The committee concluded that the company's and the ERG's assumptions were reasonable and that, individually, none of those that differed between the analyses had a major effect on the ICER. ## Semaglutide is cost effective compared with liraglutide in both the company's and ERG's base case For the population who were eligible for liraglutide (people with a BMI of 35 kg/m2 or more with non-diabetic hyperglycaemia and high cardiovascular risk), the company's base-case ICER was dominant (that is, semaglutide is more effective and costs less than liraglutide). The ERG's base-case ICER was £600 per QALY gained. The committee concluded that semaglutide was cost effective compared with liraglutide. ## A restricted version of the company's original target population is appropriate The company presented cost-effectiveness estimates for semaglutide in comparison with diet plus exercise for people with a BMI of 30 kg/m2 or more with at least 1 weight-related comorbidity (company's original target population; see section 3.4). For this population, the company's base-case ICER was £14,827 per QALY gained and the ERG's base-case ICER was £16,337 per QALY gained. In STEP 1, 60% of people had a BMI of at least 35.0 kg/m2 and 33% had a BMI of 30.0 kg/m2 to 34.9 kg/m2, and the average BMI was 37.9 kg/m2 (see section 3.6). The company's original target population made up 75% of the STEP 1 trial population (see section 3.6). The committee questioned whether this population in the trial represented the population who, in practice, would be eligible for treatment if the company's original target population were to be recommended. This was because, in the general population, the prevalence of a BMI between 30.0 kg/m2 and 34.9 kg/m2 far exceeded that of a BMI of at least 35.0 kg/m2. In the trial and the modelled population, it was a smaller percentage (see section 3.2). Scenario analyses done by the ERG showed that, if the mean starting BMI was 32.5 kg/m2, the ICER increased from the base case of £16,337 per QALY gained (including a mean starting BMI of 38.7 kg/m2) to £22,192 per QALY gained. Therefore, expanding the population to include large numbers with a lower BMI would increase the ICER. There was additional underlying uncertainty related to model inputs. This included the time to losing the weight advantage associated with semaglutide (see section 3.13), and the percentage of people with type 2 diabetes who would have treatment in practice (see section 3.7). The ERG's scenario analysis assuming a loss of weight advantage over 2 years rather than 3 years increased the ICER to £21,060 per QALY gained. The company's scenario analysis including people with type 2 diabetes in the model increased the ICER to £21,277 per QALY gained. The committee also discussed the concern about the reliability of using risk equations to predict cardiovascular events. It noted that these were predictions alone and not based on clinical evidence (see section 3.16). However, although this remained an uncertainty, semaglutide was still cost effective if these benefits were not included in the model. It also discussed that only providing semaglutide for a maximum of 2 years was not ideal for treating a chronic condition (see section 3.12). It noted that the ICER increased when treatment duration was increased in the model because of a plateauing of the benefits seen with semaglutide. The committee was aware that referral to specialist weight management services for people with a BMI of less than 35.0 kg/m2 is only made in specific circumstances. Also, according to 1 clinical expert, the population of people with a BMI of less than 35.0 kg/m2 in tier 3 services is 1.5% (see section 3.2). There would therefore be big implications for NHS service delivery if the population were to be significantly expanded as in the company's original target population. The committee considered that it therefore needed to have a high level of confidence that this was a cost-effective strategy for the NHS. Given the high level of uncertainty, the committee agreed that it was appropriate to consider a population at the highest risk for the adverse effects of obesity and likely to gain the most benefit from semaglutide. This would increase the likelihood of semaglutide being a cost-effective treatment. Therefore, the committee concluded that it was appropriate to consider the company's original target population for treatment with semaglutide. But this was only if they also meet the criteria for treatment in specialist weight management services in line with the criteria in NICE's guideline on obesity. # Other factors ## There are likely to be uncounted benefits not included in the QALY calculation The committee considered whether there were further benefits associated with semaglutide treatment that had not been captured by the QALY calculation. It discussed that, while the long-term benefits of weight loss were modelled, some long-term benefits such as reduced risk of liver disease may not have been captured in the model. It also discussed that weight loss may have other benefits that may not have been captured in the model. Examples could include: a decreased risk of adverse events associated with respiratory infections such as COVID‑19 a reduction in social isolation and stigma associated with obesity, and related improvement in career prospects (see section 3.1) improvement in fertility or success rate for in vitro fertilisation.The committee noted that there was some uncertainty around the assumptions in the model. However, it concluded that it was also important to consider these uncounted benefits, which may positively affect the cost-effectiveness estimates if they were to be modelled. ## There are equality issues related to people from some minority ethnic family backgrounds The committee noted that people from some minority ethnic family backgrounds are at an equivalent risk of the consequences of obesity at a lower BMI than people from a White ethnic family background. Also, NICE's guideline on obesity recommends using lower BMI thresholds for South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds when identifying the risk of developing type 2 diabetes and providing interventions to prevent it. The committee agreed that a similar adjustment would be suitable when considering treatment with semaglutide. ## Specialist weight management services are not equally accessible throughout England The committee noted that specialist weight management services are not equally available throughout the country (see section 3.2). It discussed that the uneven distribution of specialist weight management services produces a postcode lottery for access to these services. It also considered comments from consultees that access to specialist weight management services is restricted for some people with severe mental illness. Because of these issues, the committee discussed whether semaglutide should be offered in different settings, such as tier 2 or mental health services. However, it considered that specialist weight management services (with a suitable duration of care) are the only appropriate setting for semaglutide treatment. This is because they can provide the necessary multidisciplinary specialist weight management interventions needed to provide semaglutide as a package of care. This is in line with the marketing authorisation for semaglutide, which specifies that it is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management. It is also in line with advice from the clinical experts that semaglutide is not a stand-alone treatment. They explained that semaglutide should only be given alongside a suitably sustained programme of lifestyle interventions with multidisciplinary input, and in line with the trial design (see section 3.3). The committee noted a consultation comment that some secondary care mental health services provide advice on and management of physical health. This includes lifestyle advice for weight management alongside treatment for mental health issues. However, the committee agreed that this is not equivalent to the setting in the trial, which included weight-loss orientated multidisciplinary treatment. It also agreed that there was no evidence that semaglutide would be effective outside this setting. The committee noted comments that even intensive diet and lifestyle interventions are ineffective in people with severe mental illness. This means that pharmacological management of obesity might be particularly important in this group. However, the committee understood that semaglutide is licensed only as an adjunct to diet and exercise, and it could not make a recommendation that was not in line with either the marketing authorisation or the evidence base for semaglutide. The committee agreed that specialist weight management services should be accessible to anyone who is eligible and able to engage with the interventions provided, regardless of comorbidities. The committee concluded that the system for obesity management is not ideal. It suggested that this system, including the referral criteria for people with severe mental illness, should be reconsidered. It welcomed any review of NHS services for overweight and obesity, which is not uniform. # Conclusion ## Semaglutide is recommended for some people living with obesity The committee noted that the estimated ICERs for the company's original target population were below what would normally be considered a cost-effective use of NHS resources. However, it discussed the high levels of uncertainty associated with these estimates, and that the population in the model may not have been representative of the company's original target population (see section 3.20). It also discussed that semaglutide should be used alongside lifestyle interventions available in specialist weight management services, in line with its marketing authorisation (see section 3.3). Therefore, the committee agreed that semaglutide, when used as part of a specialist weight management service for a maximum of 2 years, could be recommended for adults: with at least 1 weight-related comorbidity and: a BMI of at least 35.0 kg/m2, or a BMI of 30.0 kg/m2 to 34.9 kg/m2 and they meet the criteria for referral to specialist weight management services in NICE's guideline on obesity: identification, assessment and management.They noted that lower BMI thresholds (usually reduced by 2.5 kg/m2) should be used for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds. Whether semaglutide should be stopped if less than 5% of the initial weight has been lost after 6 months of treatment should be considered.	{'Recommendations': "Semaglutide is recommended as an option for weight management, including weight loss and weight maintenance, alongside a reduced-calorie diet and increased physical activity in adults, only if:\n\nit is used for a maximum of 2\xa0years, and within a specialist weight management service providing multidisciplinary management of overweight or obesity (including but not limited to tiers\xa03 and\xa04), and\n\nthey have at least 1\xa0weight-related comorbidity and:\n\n\n\na body mass index (BMI) of at least 35.0\xa0kg/m2, or\n\na BMI of 30.0\xa0kg/m2 to 34.9\xa0kg/m2 and meet the criteria for referral to specialist weight management services in NICE's guideline on obesity: identification, assessment and management.Use lower BMI thresholds (usually reduced by 2.5\xa0kg/m2) for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds.\n\n\n\nConsider stopping semaglutide if less than 5% of the initial weight has been lost after 6\xa0months of treatment.\n\nThese recommendations are not intended to affect treatment with semaglutide that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nManagement of overweight and obesity in adults includes lifestyle measures alone or with orlistat, or referral to specialist weight management services (such as tier\xa03 or\xa04), which might include liraglutide or bariatric surgery.\n\nClinical trial evidence shows that:\n\npeople lose more weight with semaglutide alongside supervised weight management support than with the support alone\n\nmore weight is lost with semaglutide than with liraglutide\n\nin people with non-diabetic hyperglycaemia, semaglutide plus lifestyle measures helps normalise blood glucose more frequently than lifestyle measures alone\n\nsemaglutide may decrease the risk of cardiovascular disease.\n\nPeople from some minority ethnic family backgrounds have an equivalent risk from obesity at a lower BMI than people from a White ethnic family background. Also, NICE's guideline on obesity recommends using lower BMI thresholds for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds when identifying the risk of developing type\xa02 diabetes and providing interventions to prevent it. So, a similar adjustment in the BMI threshold is appropriate when considering using semaglutide.\n\nIt is appropriate to use semaglutide alongside lifestyle interventions that are provided in specialist weight management services (offered in the NHS for a limited time). This is because it is in keeping with the clinical trial, and there is no evidence of effectiveness if semaglutide is used as a single stand-alone treatment. Also, the marketing authorisation specifies use as an adjunct to a reduced-calorie diet and increased physical activity.\n\nFor people who have at least 1\xa0weight-related comorbidity and a BMI of at least 35\xa0kg/m2 or a BMI of 30\xa0kg/m2 to 34.9\xa0kg/m2 and also meet the NICE criteria for referral to a specialist weight management service, the cost-effectiveness estimates for semaglutide are likely to be within what is normally considered a cost-effective use of NHS resources. For these groups, semaglutide is recommended alongside lifestyle interventions in an appropriate multidisciplinary setting.", 'Information about semaglutide': "# Marketing authorisation indication\n\nSemaglutide (Wegovy, Novo Nordisk) is 'indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of ≥30\xa0kg/m2 (obesity), or ≥27\xa0kg/m2 to <30\xa0mg/kg2 (overweight) in the presence of at least one weight-related comorbidity'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for semaglutide.\n\n# Price\n\nThe list price of semaglutide (Wegovy) 2.4\xa0mg and 1.7\xa0mg is commercial in confidence and cannot be reported here. The list price of semaglutide (Ozempic) 0.25\xa0mg, 0.5\xa0mg and 1.0\xa0mg is £73.25 per pack (excluding VAT; BNF online accessed June 2022).", 'Committee discussion': "The appraisal committee considered evidence submitted by Novo Nordisk, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## Semaglutide would be a welcome new treatment option for people living with obesity\n\nOverweight and obesity can be physically debilitating, and may lead to severe and potentially life-limiting conditions, as well as fertility issues and symptoms such as skin infections. The social stigma associated with overweight and obesity can affect career prospects and self-confidence. The patient experts explained how obesity is a lifelong condition that needs medical intervention, can affect quality of life, and has psychological and physical effects. They also explained that the ability to lose weight and maintain weight loss is challenging and a lifelong burden. This is despite people living with obesity having knowledge about lifestyle interventions including diet and increased physical activity. The patient experts explained that access to treatment with liraglutide is limited to a specific population who have non-diabetic hyperglycaemia and a risk factor for cardiovascular disease. They thought that access to a new treatment option would provide hope for more people living with obesity. Orlistat is the only other pharmacological treatment option available but is poorly tolerated by many people and rarely used. The patient experts also explained that, even after bariatric surgery, maintaining weight loss is challenging. The committee concluded that there is a large unmet need for many people living with obesity, and that semaglutide would be a welcome new treatment option.\n\n# Current management\n\n## Some people living with obesity are referred to specialist weight management services (usually tier\xa03 services) but NHS provision varies\n\nThe management of overweight and obesity in the NHS is broadly structured into tiered services. Tier\xa01 services provide universal interventions such as population level health promotion and advice. Tier\xa02 services include community-based diet, nutrition, lifestyle and behaviour change advice for up to 12\xa0weeks. Tier\xa03 services provide longer and more comprehensive multidisciplinary team assessment and interventions. These include dietary, lifestyle and behaviour modification advice, with or without drug therapy, and psychological support. The clinical experts explained that tier\xa03 services are traditionally offered in secondary care but there are equivalent services with similar multidisciplinary team support in community settings in some places. The clinical and patient experts explained that specialist weight management services such as tier\xa03 services are not available everywhere across England and Wales. They are normally accessed for up to 2\xa0years by people with a body mass index (BMI) of 35\xa0kg/m2 or more plus 1\xa0or more comorbidities, or with a BMI of 40\xa0kg/m2 or more with or without comorbidities. The specific nature of the comorbidities needed for referral may vary across different services. Also, the length of time they can be accessed may be shorter than 2\xa0years in different areas of the country. The clinical experts explained that the average BMI in tier\xa03 is well above 35\xa0kg/m2, at 46\xa0kg/m2. Tier\xa03 services are also accessed by a small number of people with a lower BMI of 30\xa0kg/m2 to 35\xa0kg/m2 who have a complex comorbidity that would benefit from weight loss. The clinical experts explained that this group represents only about 1.5% of people in tier\xa03. However, the population prevalence of a BMI of 30\xa0kg/m2 to 35\xa0kg/m2 is much greater than that of a BMI of over 35\xa0kg/m2. People with a BMI of 30\xa0kg/m2 to 35\xa0kg/m2 accessing tier\xa03 services typically have particularly complex health needs or other significant co-existing conditions, such as muscular dystrophy. The committee was aware that NICE's quality standard on obesity: clinical assessment and management states that adults with a BMI of 30\xa0kg/m2 or more for whom tier\xa02 interventions have been unsuccessful should have a discussion about the choice of alternative interventions for weight management, including tier\xa03 referral. NICE's guideline on obesity: identification, assessment and management recommends that referral to tier\xa03 services is considered for people in specific circumstances. This includes, for example, when the person has a complex disease state or needs that cannot be managed adequately in tier\xa02. The committee noted that, in clinical practice, very few people with a BMI of 30.0\xa0kg/m2 to 34.9\xa0kg/m2 are referred to tier\xa03 services. Tier\xa04 services provide similar multidisciplinary team interventions to tier\xa03, but also manage bariatric surgery and bariatric medicine. A patient expert noted that semaglutide could be useful for treating weight regain after bariatric surgery. The committee noted the consultation comments highlighting that specialist weight management services such as tier\xa03 are not available in all parts of the country. Other consultation comments suggested that people with severe mental illness are excluded from accessing specialist weight management services. The committee acknowledged these comments but agreed that it was outside its remit to address the whole of the NHS weight management service provision and referral criteria. The committee noted that NHS services for overweight and obesity are under review and welcomed this, but was not aware of any planned or confirmed changes to these services. The committee concluded that, ideally, all people living with obesity eligible for specialist weight management services according to NICE's guideline on obesity should have access to these services.\n\n# Treatment setting\n\n## Semaglutide should be used as part of a package of care provided in a specialist weight management service\n\nThe marketing authorisation for semaglutide specifies that it should be used as an adjunct to a reduced-calorie diet and increased physical activity (see section\xa02.1). The clinical experts explained that, in the NHS, a sustained programme of lifestyle interventions, including diet and physical activity advice and management is only available in specialist weight management services such as tier\xa03 and\xa04 services. They also stated the importance of only offering semaglutide with these interventions because this was a requirement in the trial that showed favourable results. The clinical experts did not consider that semaglutide is a 'stand-alone' treatment. Although tier\xa02 services include diet, nutrition, lifestyle and behaviour change advice, they are only accessed for 12\xa0weeks (see section\xa03.2). This is not long enough to establish treatment with semaglutide, which has an initial 16‑week dose escalation period. In addition, the marketing authorisation specifies reassessment at 6\xa0months to see if treatment with semaglutide should be continued. Tier\xa02 services also do not include the support of a multidisciplinary team. The committee agreed that semaglutide should be used alongside specialist weight management interventions. These include dietary and physical activity interventions, as specified in the marketing authorisation, delivered by a multidisciplinary team, as suggested by the clinical experts. The committee noted that the clinical trial included adjunct physical activity, dietary advice and behaviour change interventions similar to the treatment provided in specialist weight management services (see section\xa03.6). Without the accompanying support provided by these services, the trial results used in the cost-effectiveness modelling might not be achieved in clinical practice. The committee noted that tier\xa02 services could not support delivery of semaglutide. It recognised that specialist weight management services such as tier\xa03 or 4 are not available to everyone across England and Wales (see section\xa03.2). However, the clinical experts explained that service provision is under review. The committee concluded that, as in the marketing authorisation and clinical trial evidence, these services are the only appropriate setting that can provide the necessary multidisciplinary specialist weight management interventions for a sustained period alongside semaglutide treatment. Therefore, the committee agreed that semaglutide should only be available within a specialist weight management service.\n\n# Population\n\n## Semaglutide is most appropriate for the population with the highest risk for the adverse effects of obesity\n\nThe NICE scope for this appraisal and semaglutide's marketing authorisation includes people with a BMI of 30\xa0kg/m2 or more (obesity), or a BMI from 27\xa0kg/m2 to less than 30\xa0kg/m2 (overweight) and at least 1\xa0weight-related comorbidity. The company presented evidence in its submission for its target population, which was a more restricted population than the full marketing authorisation. It included people with a BMI of 30\xa0kg/m2 or more with at least 1\xa0weight-related comorbidity. It suggested that these people may benefit most from pharmacological treatment and that they would be able to have treatment in specialist weight management services. The committee recalled that NICE's guideline on obesity recommends considering referral to tier\xa03 services in specific circumstances, and that referral to tier\xa03 services is not recommended for all people with a BMI of 30\xa0kg/m2 or more with any weight-related comorbidity. Only rarely are referrals made for people within this population, for example, when they have a complex disease state or needs that cannot be managed adequately in tier\xa02 (see section\xa03.2). The company also presented evidence for people with a BMI of 35\xa0kg/m2 or more with non-diabetic hyperglycaemia and high cardiovascular disease risk. This was in line with the population in NICE's technology appraisal guidance on liraglutide for managing overweight and obesity. At technical engagement, the company also presented a cost-effectiveness analysis for the full population in the NICE scope and marketing authorisation. The clinical experts explained that people with a BMI of less than 30\xa0kg/m2 are not referred to tier\xa03 services. They added that these services are only rarely accessed by some people with a BMI between 30\xa0kg/m2 and 35\xa0kg/m2, and only if they have complex comorbidities (see section\xa03.2). The company agreed that it was acceptable to only consider semaglutide for people who have treatment in specialist weight management services. It agreed that the population with a BMI between 27\xa0kg/m2 and 30\xa0kg/m2 or with a BMI between 30\xa0kg/m2 and 35\xa0kg/m2 without a weight-related comorbidity did not need further consideration. The committee agreed that this population was not generally at high enough risk for semaglutide use. NHS England proposed that a further population to consider is people with a BMI of 35\xa0kg/m2 or more and a high risk of cardiovascular disease based on risk factors. The patient experts explained that there was a potential disconnect between the needs of people living with obesity and NHS provision within the tier system. The committee discussed that NHS specialist provision is clearly focused on providing intensive support for the highest-risk population with a BMI of 35\xa0kg/m2 or more. It noted that stratifying by risk was a reasonable strategy in terms of absolute benefit. It also noted that very few people with a BMI of 30\xa0kg/m2 to 35\xa0kg/m2 are referred to tier\xa03 services. But it agreed that people for whom tier\xa02 services have not been successful do have a potential route of referral based on criteria in NICE's guideline on obesity (see section\xa03.2), although this rarely happens. If the recommendation for considering tier\xa03 referral in the NICE guideline were to be used more, it is not known how the population potentially eligible for semaglutide would or would not resemble the company's target population. The committee concluded that the appropriate population for semaglutide comprises people at the highest risk for the adverse effects of obesity. This is the population eligible for specialist weight management services.\n\n# Comparators\n\n## The comparators proposed by the company are appropriate\n\nThe company suggested that diet plus exercise was the appropriate comparator for semaglutide for its target population (people with a BMI of 30\xa0kg/m2 or more plus at least 1\xa0weight-related comorbidity). For people with a BMI of 35\xa0kg/m2 or more, non-diabetic hyperglycaemia and a high risk of cardiovascular disease, liraglutide alongside a reduced-calorie diet and increased physical activity is recommended in NICE's technology appraisal guidance on liraglutide for managing overweight and obesity. So, liraglutide is the appropriate comparator for this population. The company proposed that orlistat should not be considered a comparator for semaglutide because it is not often used in practice. When it is, it is offered as a first-line option in primary care and would usually be tried before semaglutide would be considered. The clinical experts agreed that orlistat use is limited and that it is not a relevant comparator for semaglutide. The committee concluded that the appropriate comparators for semaglutide were:\n\nweight management support, diet and exercise for people with a BMI of 30\xa0kg/m2 or more and at least 1\xa0weight-related comorbidity\n\nliraglutide plus weight management support, diet and exercise for people with a BMI of 35\xa0kg/m2 or more, non-diabetic hyperglycaemia and a high risk of cardiovascular disease.\n\n# Clinical evidence\n\n## The population in STEP\xa01 does not reflect the population distribution of overweight and obesity in the general population\n\nSTEP\xa01 was a randomised double-blind trial that compared a semaglutide once-weekly injection with placebo. Both groups also had lifestyle interventions including counselling, a reduced-calorie diet and increased physical activity with 68‑week treatment and follow up. It included adults living with obesity (BMI of 30.0\xa0kg/m2 or more) with or without a comorbidity, or with overweight (BMI of 27.0\xa0kg/m2 to 29.9\xa0kg/m2) with at least 1\xa0weight-related comorbidity. The comorbidities included hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease. People with type\xa02 diabetes were excluded from the trial. In the trial, 6.0% of people were categorised as having overweight (BMI of 27.0\xa0kg/m2 to 29.9\xa0kg/m2), 32.8% were categorised as having obesity category\xa01 (BMI of 30.0\xa0kg/m2 to 34.9\xa0kg/m2) and 61.2% were categorised as having obesity categories\xa02 or\xa03 (BMI of at least 35.0\xa0kg/m2). The committee noted that this was the reverse of the weight distribution in clinical practice, where many more people would have a BMI of 30.0\xa0kg/m2 to 35.0\xa0kg/m2 than of at least 35.0\xa0kg/m2. The average BMI in the trial was 37.9\xa0kg/m2. The clinical experts explained that around 80% of people in tier\xa03 services have a BMI of 40.0\xa0kg/m2 or more and that 1.5% have a BMI of less than 35.0\xa0kg/m2 (see section\xa03.2). The company proposed that people with a BMI of 30.0\xa0kg/m2 or more with at least 1\xa0comorbidity (its target population; see section\xa03.4) should be considered for semaglutide. This population made up 75.0% of STEP\xa01. The committee agreed that the company's target population was at higher risk than those outside the target population. However, it noted that only 32.8% of people in STEP\xa01 had a BMI of 30.0\xa0kg/m2 to 34.9\xa0kg/m2. So, if semaglutide were to be available for everyone with a comorbidity within this BMI range, as in the company's target population, it is highly likely that the average BMI of the population having treatment would be lower than the trial population. This is because the prevalence of a BMI of 30\xa0kg/m2 to 35\xa0kg/m2 in the general population is higher than the prevalence of 35\xa0kg/m2 or more. The committee recognised that the highest-risk population should have treatment. However, as more people with a lower BMI are included within a population having treatment, the less well this population would match the trial population. The committee also noted that any large increase in the number of people having treatment in specialist weight management services (with the associated multidisciplinary support) would have implications for service delivery and design. It acknowledged that this was outside its remit. However, it appreciated that it should be confident that the trial and modelled outcomes would be delivered in clinical practice if broader eligibility were to be accepted. It also needs to be confident that it would be a cost-effective strategy for the NHS. The committee concluded that the population in STEP\xa01 had a larger proportion of a high-risk population. This meant it did not reflect the population distribution of overweight and obesity in the general population. It also concluded that the population in STEP\xa01 was unlikely to correspond with the distribution of people who could be eligible for semaglutide if everyone within the company's original target population (including anyone with a BMI of 30\xa0kg/m2 or more with any weight-related comorbidity) was recommended.\n\n## People with type\xa02 diabetes are not included in STEP\xa01, although they could have semaglutide for weight management\n\nThe committee noted that STEP\xa01 did not include people with type\xa02 diabetes. It was aware that a lower dose of semaglutide is available for managing type\xa02 diabetes. The clinical experts explained that, if someone with type\xa02 diabetes and obesity needs specialist weight management, it would be appropriate for them to have treatment for obesity within a specialist weight management service. This would include semaglutide treatment at the higher dose indicated for managing overweight and obesity. They also explained that, based on their experience, they would expect people with type\xa02 diabetes to have less weight loss with semaglutide than seen in STEP\xa01. This was also supported by data from the STEP\xa02 trial, a randomised controlled trial of semaglutide compared with placebo in people with overweight or obesity and type\xa02 diabetes. They noted that people with type\xa02 diabetes would be likely to have less weight loss than people without type\xa02 diabetes. But they commented that a small amount of weight loss is associated with greater health gain in a higher risk population such as this. The committee concluded that STEP\xa01 did not include people with type\xa02 diabetes, so did not cover the whole population who would potentially be offered semaglutide in the NHS. The committee agreed that this introduced some uncertainty about the generalisability of the clinical effectiveness results, and may have affected the reliability of the cost-effectiveness results.\n\n## Semaglutide is more effective than placebo for treating overweight and obesity\n\nThe company presented the full trial analysis and a post-hoc subgroup analysis of STEP\xa01. The full trial population (n=1,961) included adults living with obesity (BMI of 30\xa0kg/m2 or more) or overweight (BMI of 27\xa0kg/m2 to 29.9\xa0kg/m2) with at least 1\xa0weight-related comorbidity. The post-hoc subgroup analysis (n=1,470) included adults with a BMI of 30\xa0kg/m2 or more with at least 1\xa0weight-related comorbidity. Weight-related outcomes favoured semaglutide compared with placebo in the full trial population. The difference in mean percentage change in body weight at 68\xa0weeks was -12.4%. It also favoured semaglutide in the post-hoc subgroup analysis. The difference in mean percentage change in body weight at 68\xa0weeks was -12.2%. There was also a large increase in the proportion of people shifting from non-diabetic hyperglycaemia to normoglycaemia from baseline to week\xa068 with semaglutide treatment. However, this was greater in the post-hoc subgroup analysis population than the full trial population. The proportion who shifted from non-diabetic hyperglycaemia to normoglycaemia in the full trial population was 79.8% with semaglutide compared with 39.1% with placebo (40.7% treatment difference). The proportion who shifted from non-diabetic hyperglycaemia to normoglycaemia in the post-hoc population was 79.2% with semaglutide compared with 20.0% with placebo (59.2% treatment difference). The committee concluded that this analysis showed that semaglutide was clinically effective, with benefits for weight and non-diabetic hyperglycaemia in the full trial population and the post-hoc analysis subgroup.\n\n## Semaglutide is more effective than liraglutide for weight loss\n\nLiraglutide plus weight management support, diet and exercise is the appropriate comparator for people with a BMI of 35\xa0kg/m2 or more, non-diabetic hyperglycaemia and a high risk of cardiovascular disease (liraglutide-eligible subgroup; see section\xa03.5). At the time of submission, there was no head-to-head trial data available comparing semaglutide with liraglutide. The company presented an indirect treatment comparison using individual patient data from STEP\xa01 and SCALE\xa01839 to estimate the effectiveness of semaglutide compared with liraglutide in the liraglutide-eligible subgroup. SCALE\xa01839 was a randomised controlled trial of liraglutide compared with placebo in people with overweight or obesity. The results of the indirect treatment comparison showed that weight-related outcomes favoured semaglutide compared with liraglutide. The difference in mean percentage change in body weight at 68\xa0weeks was ‑5.81%. At technical engagement, the company submitted direct head-to-head data for semaglutide compared with liraglutide (both alongside a lifestyle intervention) from the STEP\xa08 trial. STEP\xa08 was a randomised controlled trial including 388\xa0adults living with obesity (BMI of 30\xa0kg/m2 or more) or overweight (BMI of 27\xa0kg/m2 to 29.9\xa0kg/m2) with at least 1\xa0weight-related comorbidity (hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease) and without type\xa02 diabetes. Results for the full trial population supported the results from the indirect treatment comparison. The difference in mean percentage change in body weight at 68\xa0weeks was -9.38%. The ERG explained that the results were for the full trial population and not the liraglutide-eligible subgroup. The company explained that the liraglutide-eligible subgroup made up a small proportion of the trial population, so a subgroup analysis was not appropriate. The committee concluded that direct trial evidence for the subgroup would have been preferred. However, it agreed that the results from both the indirect treatment comparison and the full population of STEP\xa08 showed that semaglutide is more effective than liraglutide for weight loss.\n\n# The company's economic model\n\n## The company's model is suitable for decision making\n\nThe company submitted a cohort-transition model with 11\xa0health states to estimate the cost effectiveness of semaglutide in 2\xa0subgroups:\n\ncompared with weight management support, diet and exercise for people with a BMI of 30\xa0kg/m2 or more with at least 1\xa0weight-related comorbidity\n\ncompared with liraglutide plus weight management support, diet and exercise for people with a BMI of 35\xa0kg/m2 or more with non-diabetic hyperglycaemia and a high risk of cardiovascular disease.The treatment effects for each subgroup were sourced from the full trial population of STEP\xa01 and applied to the populations of interest with different baseline risks. The model was based on a previous model used for NICE's technology appraisal of liraglutide for managing overweight and obesity, and on assumptions and service use in a specialist multidisciplinary weight management setting. The model only allowed up to 3\xa0years treatment. People entered the model in a normal glucose tolerance state (46.6%) or non-diabetic hyperglycaemic state (53.4%), based on the prevalence in STEP\xa01. A once-only transition was used to incorporate the proportion of people reversing from non-diabetic hyperglycaemia to normal glucose tolerance based on STEP\xa01 data. Transitions between health states were based on type\xa02 diabetes status and cardiovascular events, estimated from risk equations. The committee expressed concern about the validity of risk equations (see section\xa03.16) and the model only allowing treatment with semaglutide plus diet and exercise, or diet and exercise alone for up to 3\xa0years. However, it concluded that the perspective of use in specialist weight management services was appropriate and that the model was suitable for decision making.\n\n# Assumptions in the economic model\n\n## It is reasonable to assume that people stop treatment after 6\xa0months if they do not have an adequate response\n\nThe company included a stopping rule in the model for people who had less than 5% weight loss after 6\xa0months. This was based on the marketing authorisation, which states that a decision on continuing treatment for these people should be made at 6\xa0months. The clinical experts agreed that most people would not want to continue semaglutide treatment after 6\xa0months without a meaningful weight loss, especially considering the side effects associated with it. They explained that treatment assessment at 6\xa0months was in line with what is expected in practice and that the stopping rule was appropriate. The committee concluded that it was appropriate to include the stopping rule for people with less than 5% reduction in body weight at 6\xa0months in the model. This was in line with the time specified for the decision on continuing treatment in the marketing authorisation.\n\n## Semaglutide is limited to 2\xa0years because of restricted time in specialist weight management services and lack of evidence for longer use\n\nThe company included an assumption in the model that people would take semaglutide for a maximum of 2\xa0years. The patient experts explained that obesity is a lifelong condition, and that continued treatment was important for maintaining weight loss. This is still a challenge after people have reached their target weight. They noted that having only 2\xa0years of semaglutide treatment would not be ideal. However, they still thought it would be highly beneficial for helping weight loss over a 2‑year period. It would give people the opportunity to incorporate more physical activity into their lifestyles, with improved mobility and reduced pain. The committee agreed that treatment for other chronic conditions is not stopped after a certain period when it is tolerated and effective. But it noted that the NHS provides specialist services for obesity that is time limited. The NHS England representative suggested that the psychological impact of stopping semaglutide treatment after 2\xa0years at the same time as being discharged from specialist weight management services could be detrimental. However, the committee agreed that semaglutide should only be used in a specialist weight management service (see section\xa03.3). The committee noted the clinical experts' statements that specialist weight management services such as tier\xa03 are usually accessed for up to 2\xa0years. People only very exceptionally stay in tier\xa03 services for longer. Also, some areas offer these services for shorter periods, and many people are discharged from tier\xa03 services before 2\xa0years. The committee understood that there are restrictions on time spent in specialist weight management services. It agreed that, for a long-term problem like obesity, this was not ideal (see section\xa03.2). However, it accepted that the company model was based on a single course of treatment of no longer than 2\xa0years. This is in line with the clinical trial evidence and is how long, on average, specialist weight management services can be accessed. The ERG highlighted that removing the 2‑year stopping rule to model lifelong use, including maintenance of weight loss, was not possible within the company's model. However, increasing the time on treatment to 3\xa0years increased the incremental cost-effectiveness ratio (ICER), suggesting that longer use is less likely to be cost effective. The company highlighted that the longest treatment duration studied in a clinical trial was 2\xa0years in the STEP\xa05 trial (a randomised controlled trial of 2‑year treatment with semaglutide compared with placebo for people with overweight or obesity). There is no evidence for longer-term use of semaglutide available, including evidence for maintenance treatment. However, longer-term evidence may be available in the future. The ERG noted that the results of the STEP\xa05 trial were comparable to the results from the STEP\xa01 trial used in the model, supporting the efficacy of semaglutide use for up to 2\xa0years. The committee concluded that the assumption that treatment would be stopped at 2\xa0years was reasonable in the context of NHS specialist weight management services, which are time limited. Such services are the only appropriate setting for semaglutide treatment given the marketing authorisation and clinical evidence base. However, when further evidence becomes available, it might be possible to consider long-term use in other settings if the evidence suggests that long-term or lifetime use is clinically and cost effective.\n\n## The assumptions for weight gain are uncertain\n\nThe company included an assumption that 3\xa0years after stopping semaglutide (with a 2‑year treatment period), the weight advantage with semaglutide would be lost. This means the average weight for people taking semaglutide would be in line with what it would be in the average population in the diet and exercise treatment arm after 5\xa0years. The company also assumed that people whose glucose tolerance became normal on treatment would revert to having non-diabetic hyperglycaemia 3\xa0years after treatment stopped. In response to consultation, the committee noted the suggestion that the SCALE\xa01839 trial showed rapid weight gain in the first 12\xa0weeks after stopping liraglutide. It was also suggested that the SCALE\xa01839 trial showed that weight would return to baseline weight following liraglutide treatment after 6\xa0to 12\xa0months, and that similar would be expected for semaglutide. The NHS England representative also noted evidence from a pharmacokinetic modelling study of liraglutide that showed weight returned to close to baseline by 29\xa0weeks after stopping treatment following 56\xa0weeks of liraglutide. The clinical experts noted that the assumptions around the rate of weight gain after treatment were very uncertain. They suggested that, on average, it would be expected that the weight advantage gained with semaglutide would be lost around 2\xa0to 3\xa0years after stopping treatment. But they explained that some people would maintain clinically relevant weight loss for longer. A committee member with experience of using semaglutide and liraglutide for treating diabetes explained that liraglutide is a less active and less effective treatment. Therefore, less weight would be expected to be lost with liraglutide than semaglutide (see section\xa03.9). Because of the expected greater weight loss with semaglutide the time to regain the weight following semaglutide treatment would be longer than the time to regain the weight following liraglutide treatment. The ERG explained that the STEP\xa04 clinical trial provided some evidence that not all weight lost is regained 1\xa0year after stopping semaglutide. STEP\xa04 was a randomised trial that included a treatment arm including semaglutide treatment for 20\xa0weeks, followed by placebo for 48\xa0weeks for people with overweight or obesity. A 20‑week treatment duration is less than the time in the marketing authorisation specified for reassessment of benefit (see section\xa03.11). Therefore, initial weight loss in STEP\xa04 was expected to be less than that with 2\xa0years of semaglutide treatment in clinical practice. If initial weight loss were lower because of a shorter treatment duration, it would be expected that the time to lose the weight advantage associated with semaglutide would be shorter than if semaglutide was given for 2\xa0years. The ERG agreed that the assumption of the loss of weight advantage over 3\xa0years was reasonable. It also provided a scenario analysis showing a modest effect on the cost-effectiveness results when an assumption of a loss of weight advantage over 2\xa0years was included in the model. The committee concluded that this was an area of uncertainty. It accepted that there is not yet any long-term evidence to show the true average time to lose the weight advantage after semaglutide treatment. However, it noted that including an assumption in the model of loss of weight advantage at the lower end of the clinical expert's estimation (2\xa0years) did not have a major effect on the cost-effectiveness estimate.\n\n## Retreatment might be appropriate for some people meeting the eligibility criteria for a rereferral to a specialist weight management service\n\nThe company's model included the assumption that there would be no retreatment with semaglutide. The clinical experts explained that some people who have regained weight after weight loss with semaglutide may wish to have it again. They also noted that rereferral into specialist weight management services is not usual but does happen occasionally. The committee discussed that the cost effectiveness of retreatment with semaglutide after weight regain was unknown because this was not included in the trial or the model. However, it acknowledged that retreatment might be appropriate for some people who have lost and regained weight and who become eligible for treatment again according to the same starting criteria.\n\n## The model assumes that all people with non-diabetic hyperglycaemia develop type\xa02 diabetes after a cardiovascular event\n\nThe company included a simplifying assumption in the model that all people with non-diabetic hyperglycaemia who have a cardiovascular event develop type\xa02 diabetes within the following year. The clinical experts explained that people with non-diabetic hyperglycaemia are more likely to be diagnosed with type\xa02 diabetes after a cardiovascular event, but that this relationship is not causal. However, they did agree that some people with non-diabetic hyperglycaemia would be diagnosed with type\xa02 diabetes after a cardiovascular event. So, because the model could only include this assumption for none or all of the people in the model, they thought it was reasonable to include it. The committee noted that the ERG's scenario analysis, which removed this assumption, had minimal effect on the ICER. The committee concluded that the true proportion of people who would be diagnosed with type\xa02 diabetes would fall somewhere between none and all people with non-diabetic hyperglycaemia who had a cardiovascular event.\n\n## Risk equations are the only available method for modelling long-term health outcomes\n\nThe company's model used risk equations to estimate the risk of long-term cardiovascular events such as an acute coronary event or stroke, and the risk of developing type\xa02 diabetes. These equations were based on surrogate outcomes from STEP\xa01 including BMI, systolic blood pressure, total cholesterol, high density lipoprotein and HbA1c levels. The NHS England representative explained that the risk equations used had not been validated by any data showing beneficial cardiovascular outcomes with weight loss in people without diabetes. They quoted a real-world, large UK study (with a follow up of up to 6\xa0years) that did not show a reduction in cardiovascular events related to sustained weight loss alone. The clinical experts highlighted that a reduction in cardiovascular events has been shown with GLP‑1 inhibitors (the same class of drug as semaglutide) in people with diabetes. However, they accepted this had not yet been shown in people without diabetes. The committee was also aware that risk equations were based on an assumption of a steady state. They were not designed for estimating long-term risk when using an intervention with a time-limited benefit (such as a 2‑year treatment course; see section\xa03.12). Also, risk equations are not prognostic on an individual basis. The ERG explained that there was no practical alternative to using risk equations in the modelling. In response to consultation comments that disagreed with using risk equations to predict long-term cardiovascular disease outcomes, the ERG conducted scenario analyses excluding the cardiovascular disease benefits alone, or in combination with diabetes outcomes from the model. These showed that excluding cardiovascular disease benefits from the model had a small upward effect on the cost-effectiveness estimate. However, excluding diabetes benefits had a larger effect. The committee accepted that there was no data available on the effect of semaglutide treatment on long-term cardiovascular outcomes. However, it agreed that even a temporary improvement in weight, diabetic status and other risk parameters seen with semaglutide in STEP\xa01 would have some benefit. It noted, though, that this was difficult to quantify. The company explained that there would be further evidence on the long-term cardiovascular outcomes with semaglutide from the SELECT trial. This is a randomised controlled trial comparing semaglutide with placebo for up to 5\xa0years in people with overweight or obesity and cardiovascular disease. The committee noted that the benefits seen in STEP\xa01 for shifting diabetic status from non-diabetic hyperglycaemic to normoglycemic were both striking and important (see section\xa03.8). This suggested that the time spent without diabetes could be increased for people taking semaglutide. The committee agreed that prolonging time without diabetes was an important and highly beneficial outcome, even if this was limited in duration. It noted that removing diabetic benefits from the model had a much greater upward effect on the ICER than removing cardiovascular benefits, which only modestly increased the ICER. Despite the uncertainties associated with using risk equations, the committee concluded that they were the only method available. This was because it had not been presented with an alternative method for estimating long-term health outcomes.\n\n# Cost-effectiveness estimate\n\n## Because of uncertainty, there needs to be a high level of confidence that the ICER is around £20,000 per quality-adjusted life year gained\n\nNICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, decisions about the acceptability of a technology as an effective use of NHS resources will consider the degree of certainty around the ICER. The committee noted the uncertainties in the modelling assumptions, particularly:\n\nthe rebound in weight gain after semaglutide is stopped (see section\xa03.13)\n\nthe calculation of long-term benefits using risk equations based on data about a temporary benefit (see section\xa03.16)\n\nthe possible implications for NHS delivery of services.Based on these uncertainties, the committee agreed that it needed a high level of confidence that the ICER was at the lower end of the range for acceptable cost effectiveness (£20,000 to £30,000 per QALY gained).\n\n## The ERG's and company's assumptions are reasonable\n\nThe company's base-case analysis included:\n\na stopping rule for people who have not lost at least 5% initial body weight at 6\xa0months (see section\xa03.11)\n\na maximum treatment duration of 2\xa0years (see section\xa03.12)\n\na loss of the weight advantage gained with semaglutide, and a return to the original glycaemic state 3\xa0years after stopping treatment (see section\xa03.13)\n\nno retreatment throughout the full time horizon of the model (see section\xa03.14)\n\nthat 100% of people with non-diabetic hyperglycaemia develop type 2\xa0diabetes after a cardiovascular event (see section\xa03.15).The ERG's base case included some of the same assumptions as the company's, with the following differences:\n\npeople with non-diabetic hyperglycaemia do not automatically develop type\xa02 diabetes after a cardiovascular event (see section\xa03.15)\n\nthere is a natural weight increase per year of 0.30\xa0kg (compared with the company's assumption of 0.46\xa0kg)\n\nweight no longer increases after age\xa066 (compared with the company's assumption of age\xa068)\n\nnatural weight decreases by 0.30\xa0kg after age\xa066 (compared with the company's assumption of weight remaining constant)\n\nthe annual cost of sleep apnoea is £274 (compared with the company's assumption of £1,081).The committee concluded that the company's and the ERG's assumptions were reasonable and that, individually, none of those that differed between the analyses had a major effect on the ICER.\n\n## Semaglutide is cost effective compared with liraglutide in both the company's and ERG's base case\n\nFor the population who were eligible for liraglutide (people with a BMI of 35\xa0kg/m2 or more with non-diabetic hyperglycaemia and high cardiovascular risk), the company's base-case ICER was dominant (that is, semaglutide is more effective and costs less than liraglutide). The ERG's base-case ICER was £600 per QALY gained. The committee concluded that semaglutide was cost effective compared with liraglutide.\n\n## A restricted version of the company's original target population is appropriate\n\nThe company presented cost-effectiveness estimates for semaglutide in comparison with diet plus exercise for people with a BMI of 30\xa0kg/m2 or more with at least 1\xa0weight-related comorbidity (company's original target population; see section\xa03.4). For this population, the company's base-case ICER was £14,827 per QALY gained and the ERG's base-case ICER was £16,337 per QALY gained. In STEP\xa01, 60% of people had a BMI of at least 35.0\xa0kg/m2 and 33% had a BMI of 30.0\xa0kg/m2 to 34.9\xa0kg/m2, and the average BMI was 37.9\xa0kg/m2 (see section\xa03.6). The company's original target population made up 75% of the STEP\xa01 trial population (see section\xa03.6). The committee questioned whether this population in the trial represented the population who, in practice, would be eligible for treatment if the company's original target population were to be recommended. This was because, in the general population, the prevalence of a BMI between 30.0\xa0kg/m2 and 34.9\xa0kg/m2 far exceeded that of a BMI of at least 35.0\xa0kg/m2. In the trial and the modelled population, it was a smaller percentage (see section\xa03.2). Scenario analyses done by the ERG showed that, if the mean starting BMI was 32.5\xa0kg/m2, the ICER increased from the base case of £16,337 per QALY gained (including a mean starting BMI of 38.7\xa0kg/m2) to £22,192 per QALY gained. Therefore, expanding the population to include large numbers with a lower BMI would increase the ICER. There was additional underlying uncertainty related to model inputs. This included the time to losing the weight advantage associated with semaglutide (see section\xa03.13), and the percentage of people with type\xa02 diabetes who would have treatment in practice (see section\xa03.7). The ERG's scenario analysis assuming a loss of weight advantage over 2\xa0years rather than 3\xa0years increased the ICER to £21,060 per QALY gained. The company's scenario analysis including people with type\xa02 diabetes in the model increased the ICER to £21,277 per QALY gained. The committee also discussed the concern about the reliability of using risk equations to predict cardiovascular events. It noted that these were predictions alone and not based on clinical evidence (see section\xa03.16). However, although this remained an uncertainty, semaglutide was still cost effective if these benefits were not included in the model. It also discussed that only providing semaglutide for a maximum of 2\xa0years was not ideal for treating a chronic condition (see section\xa03.12). It noted that the ICER increased when treatment duration was increased in the model because of a plateauing of the benefits seen with semaglutide. The committee was aware that referral to specialist weight management services for people with a BMI of less than 35.0\xa0kg/m2 is only made in specific circumstances. Also, according to 1\xa0clinical expert, the population of people with a BMI of less than 35.0\xa0kg/m2 in tier\xa03 services is 1.5% (see section\xa03.2). There would therefore be big implications for NHS service delivery if the population were to be significantly expanded as in the company's original target population. The committee considered that it therefore needed to have a high level of confidence that this was a cost-effective strategy for the NHS. Given the high level of uncertainty, the committee agreed that it was appropriate to consider a population at the highest risk for the adverse effects of obesity and likely to gain the most benefit from semaglutide. This would increase the likelihood of semaglutide being a cost-effective treatment. Therefore, the committee concluded that it was appropriate to consider the company's original target population for treatment with semaglutide. But this was only if they also meet the criteria for treatment in specialist weight management services in line with the criteria in NICE's guideline on obesity.\n\n# Other factors\n\n## There are likely to be uncounted benefits not included in the QALY calculation\n\nThe committee considered whether there were further benefits associated with semaglutide treatment that had not been captured by the QALY calculation. It discussed that, while the long-term benefits of weight loss were modelled, some long-term benefits such as reduced risk of liver disease may not have been captured in the model. It also discussed that weight loss may have other benefits that may not have been captured in the model. Examples could include:\n\na decreased risk of adverse events associated with respiratory infections such as COVID‑19\n\na reduction in social isolation and stigma associated with obesity, and related improvement in career prospects (see section\xa03.1)\n\nimprovement in fertility or success rate for in vitro fertilisation.The committee noted that there was some uncertainty around the assumptions in the model. However, it concluded that it was also important to consider these uncounted benefits, which may positively affect the cost-effectiveness estimates if they were to be modelled.\n\n## There are equality issues related to people from some minority ethnic family backgrounds\n\nThe committee noted that people from some minority ethnic family backgrounds are at an equivalent risk of the consequences of obesity at a lower BMI than people from a White ethnic family background. Also, NICE's guideline on obesity recommends using lower BMI thresholds for South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds when identifying the risk of developing type\xa02 diabetes and providing interventions to prevent it. The committee agreed that a similar adjustment would be suitable when considering treatment with semaglutide.\n\n## Specialist weight management services are not equally accessible throughout England\n\nThe committee noted that specialist weight management services are not equally available throughout the country (see section\xa03.2). It discussed that the uneven distribution of specialist weight management services produces a postcode lottery for access to these services. It also considered comments from consultees that access to specialist weight management services is restricted for some people with severe mental illness. Because of these issues, the committee discussed whether semaglutide should be offered in different settings, such as tier\xa02 or mental health services. However, it considered that specialist weight management services (with a suitable duration of care) are the only appropriate setting for semaglutide treatment. This is because they can provide the necessary multidisciplinary specialist weight management interventions needed to provide semaglutide as a package of care. This is in line with the marketing authorisation for semaglutide, which specifies that it is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management. It is also in line with advice from the clinical experts that semaglutide is not a stand-alone treatment. They explained that semaglutide should only be given alongside a suitably sustained programme of lifestyle interventions with multidisciplinary input, and in line with the trial design (see section\xa03.3). The committee noted a consultation comment that some secondary care mental health services provide advice on and management of physical health. This includes lifestyle advice for weight management alongside treatment for mental health issues. However, the committee agreed that this is not equivalent to the setting in the trial, which included weight-loss orientated multidisciplinary treatment. It also agreed that there was no evidence that semaglutide would be effective outside this setting. The committee noted comments that even intensive diet and lifestyle interventions are ineffective in people with severe mental illness. This means that pharmacological management of obesity might be particularly important in this group. However, the committee understood that semaglutide is licensed only as an adjunct to diet and exercise, and it could not make a recommendation that was not in line with either the marketing authorisation or the evidence base for semaglutide. The committee agreed that specialist weight management services should be accessible to anyone who is eligible and able to engage with the interventions provided, regardless of comorbidities. The committee concluded that the system for obesity management is not ideal. It suggested that this system, including the referral criteria for people with severe mental illness, should be reconsidered. It welcomed any review of NHS services for overweight and obesity, which is not uniform.\n\n# Conclusion\n\n## Semaglutide is recommended for some people living with obesity\n\nThe committee noted that the estimated ICERs for the company's original target population were below what would normally be considered a cost-effective use of NHS resources. However, it discussed the high levels of uncertainty associated with these estimates, and that the population in the model may not have been representative of the company's original target population (see section\xa03.20). It also discussed that semaglutide should be used alongside lifestyle interventions available in specialist weight management services, in line with its marketing authorisation (see section\xa03.3). Therefore, the committee agreed that semaglutide, when used as part of a specialist weight management service for a maximum of 2\xa0years, could be recommended for adults:\n\nwith at least 1\xa0weight-related comorbidity and:\n\n\n\na BMI of at least 35.0\xa0kg/m2, or\n\na BMI of 30.0\xa0kg/m2 to 34.9\xa0kg/m2 and they meet the criteria for referral to specialist weight management services in NICE's guideline on obesity: identification, assessment and management.They noted that lower BMI thresholds (usually reduced by 2.5\xa0kg/m2) should be used for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds. Whether semaglutide should be stopped if less than 5% of the initial weight has been lost after 6\xa0months of treatment should be considered.\n\n"}	https://www.nice.org.uk/guidance/ta875	Evidence-based recommendations on semaglutide (Wegovy) for managing overweight and obesity in adults.
01f778b9bb9e634afe07c22ad578937154f2f34d	nice	Eptinezumab for preventing migraine	Eptinezumab for preventing migraine Evidence-based recommendations on eptinezumab (VYEPTI) for preventing migraine in adults. # Recommendations Eptinezumab is recommended as an option for preventing migraine in adults, only if: they have 4 or more migraine days a month at least 3 preventive drug treatments have failed and the company provides it according to the commercial arrangement. Stop eptinezumab after 12 weeks of treatment if: in episodic migraine (fewer than 15 headache days a month), the frequency does not reduce by at least 50% in chronic migraine (15 headache days a month or more with at least 8 of those having features of migraine), the frequency does not reduce by at least 30%. If people with the condition and their clinicians consider eptinezumab to be 1 of a range of suitable treatments (including erenumab, fremanezumab and galcanezumab), discuss the advantages and disadvantages of the available treatments. After that discussion, if more than 1 treatment is suitable, choose the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements. These recommendations are not intended to affect treatment with eptinezumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why these recommendations were made Treatments for preventing chronic or episodic migraines include erenumab, fremanezumab and galcanezumab when they have not responded to at least 3 oral preventive drug treatments. These treatments are already recommended in NICE's technology appraisal guidance on erenumab, fremanezumab and galcanezumab. They are all administered as injections under the skin. Eptinezumab is another treatment option that works in a similar way but is administered as an infusion into a vein. There are no clinical trials directly comparing eptinezumab with erenumab, fremanezumab or galcanezumab. An indirect comparison suggests that eptinezumab works as well as these treatments. A cost comparison suggests that eptinezumab has similar costs and overall health benefits to erenumab, fremanezumab and galcanezumab. So, eptinezumab is recommended for preventing migraine if it is used in the same population as these treatments.# Information about eptinezumab # Marketing authorisation indication Eptinezumab (VYEPTI, Lundbeck) is indicated for 'the prophylaxis of migraine in adults who have at least 4 migraine days per month'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for eptinezumab. # Price The price of eptinezumab is £1,350 for a 100 mg per ml vial (excluding VAT; BNF online accessed January 2023). The company has a commercial arrangement. This makes eptinezumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Discussion The recommendations were made after consideration of the evidence submitted by Lundbeck, a review of this submission by the external assessment group (EAG) and submissions from stakeholders. See the committee papers for full details of the evidence. # The condition and current treatment Patient and professional organisations, and patient experts described in their submissions how migraine has a significant effect on the quality of life for people with the condition, and their families and carers. They explained how migraine can negatively affect a person's work, family relationships, social life, and mental health and wellbeing. The submissions highlighted the high disease burden, particularly for people with frequent episodes of migraine, chronic migraine or other comorbidities. People with migraine first try a range of oral preventive drug treatments before considering more specialist treatment, such as botulinum toxin type A (for chronic migraine) or erenumab, fremanezumab or galcanezumab (for episodic or chronic migraine). Usual practice in the NHS is that there is an insufficient response to at least 3 oral preventive drug treatments before more specialist treatment is considered. Stakeholders commented that oral preventive drug treatments are often poorly tolerated and ineffective in preventing migraine. They also explained that access to specialist care and treatment can vary depending on where someone lives. It was agreed that there is a need for effective preventive treatments that can improve quality of life for people with migraine. # Comparators Erenumab, fremanezumab and galcanezumab are calcitonin gene-related peptide (CGRP) inhibitors. They are recommended in NICE's technology appraisal guidance on erenumab, fremanezumab and galcanezumab for preventing chronic or episodic migraines after at least 3 oral preventive drug treatments have failed. These treatments are available as subcutaneous injections that can be self-administered at home. Erenumab is administered 4‑weekly, galcanezumab monthly, and fremanezumab monthly or 3‑monthly. Eptinezumab is another CGRP inhibitor that works in a similar way, but it is administered by intravenous infusion every 12 weeks in hospital. Clinical opinion suggests that eptinezumab would therefore be reserved for people with severe migraine attacks or who are unable to use the CGRP inhibitors administered subcutaneously. This may include people who struggle to self-administer the injections, such as those with needle phobia. The EAG noted that the company's positioning of eptinezumab in its submission (people with episodic or chronic migraine who have had at least 3 oral preventive drug treatments) aligned with the positioning of the other CGRP inhibitors recommended by NICE. It was agreed that erenumab, fremanezumab and galcanezumab were all appropriate comparators. # Clinical effectiveness The company did not identify any evidence directly comparing eptinezumab with the relevant comparators (see section 3.2). So, it did a network meta-analysis to indirectly compare eptinezumab with erenumab, fremanezumab and galcanezumab in people whose migraine had not responded to at least 3 preventive drug treatments. The company used data from randomised controlled trials that compared each of the treatments with placebo. The results of the network meta-analysis suggested that eptinezumab has similar clinical effectiveness to erenumab, fremanezumab and galcanezumab in reducing migraine frequency in people with chronic or episodic migraines. Clinical opinion also suggested that the treatments are similar. The EAG noted that there were some limitations associated with the company's network meta-analysis but that these had also been considered in NICE's technology appraisal guidance on erenumab, fremanezumab and galcanezumab. It was agreed that there was sufficient evidence of similar clinical efficacy for eptinezumab compared with erenumab, fremanezumab and galcanezumab. # Cost comparison The company submission stated that 'eptinezumab is only available in a 100 mg vial; a 300 mg vial is not available, and the 300 mg dose is not being commercialised in the UK'. When taking account of administration costs, dosage, price per dose and commercial arrangements for all treatments, the total cost associated with eptinezumab 100 mg every 12 weeks was similar to or lower than that with erenumab (140 mg 4‑weekly), fremanezumab (225 mg monthly or 675 mg 3‑monthly) or galcanezumab (120 mg monthly after a 240 mg initial loading dose). The exact results are confidential and cannot be reported here. It was agreed that, after people with the condition and their clinicians have discussed the advantages and disadvantages of the available treatments, if more than 1 treatment is suitable, it would be appropriate to choose the least expensive option. So, the decision was made to recommend eptinezumab for preventing migraine in line with the previous recommendations for erenumab, fremanezumab and galcanezumab. # Equality issues Stakeholders raised several potential equality issues during the evaluation. This included that migraine is more common in women, particularly in those of childbearing age. But it was agreed that issues relating to differences in prevalence or incidence of a condition cannot be addressed in a technology evaluation. A stakeholder commented that appropriate treatments should be available for everyone including people who cannot self-administer available treatments because of a physical, cognitive or other disability. It was agreed that eptinezumab would likely improve access to specialist treatment for people with difficulty self-injecting the CGRP inhibitors administered subcutaneously. This is because it would be administered in a hospital setting intravenously. A stakeholder commented that there should be equality of access to treatment for people with migraine and that best supportive care should not be the default option because of where someone lives. The decision making took into account any obligations in relation to the Equality Act 2010 and that eptinezumab can only be recommended for use within its marketing authorisation. It was noted that issues about healthcare implementation could not be addressed in the evaluation. It was agreed that there were no equality issues relevant to the recommendations.	{'Recommendations': "Eptinezumab is recommended as an option for preventing migraine in adults, only if:\n\nthey have 4\xa0or more migraine days a month\n\nat least 3\xa0preventive drug treatments have failed and\n\nthe company provides it according to the commercial arrangement.\n\nStop eptinezumab after 12\xa0weeks of treatment if:\n\nin episodic migraine (fewer than 15\xa0headache days a month), the frequency does not reduce by at least 50%\n\nin chronic migraine (15\xa0headache days a month or more with at least 8\xa0of those having features of migraine), the frequency does not reduce by at least 30%.\n\nIf people with the condition and their clinicians consider eptinezumab to be 1\xa0of a range of suitable treatments (including erenumab, fremanezumab and galcanezumab), discuss the advantages and disadvantages of the available treatments. After that discussion, if more than 1\xa0treatment is suitable, choose the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements.\n\nThese recommendations are not intended to affect treatment with eptinezumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy these recommendations were made\n\nTreatments for preventing chronic or episodic migraines include erenumab, fremanezumab and galcanezumab when they have not responded to at least 3\xa0oral preventive drug treatments. These treatments are already recommended in NICE's technology appraisal guidance on erenumab, fremanezumab and galcanezumab. They are all administered as injections under the skin. Eptinezumab is another treatment option that works in a similar way but is administered as an infusion into a vein.\n\nThere are no clinical trials directly comparing eptinezumab with erenumab, fremanezumab or galcanezumab. An indirect comparison suggests that eptinezumab works as well as these treatments.\n\nA cost comparison suggests that eptinezumab has similar costs and overall health benefits to erenumab, fremanezumab and galcanezumab. So, eptinezumab is recommended for preventing migraine if it is used in the same population as these treatments.", 'Information about eptinezumab': "# Marketing authorisation indication\n\nEptinezumab (VYEPTI, Lundbeck) is indicated for 'the prophylaxis of migraine in adults who have at least 4\xa0migraine days per month'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for eptinezumab.\n\n# Price\n\nThe price of eptinezumab is £1,350 for a 100\xa0mg per ml vial (excluding VAT; BNF online accessed January\xa02023).\n\nThe company has a commercial arrangement. This makes eptinezumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Discussion': "The recommendations were made after consideration of the evidence submitted by Lundbeck, a review of this submission by the external assessment group (EAG) and submissions from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition and current treatment\n\nPatient and professional organisations, and patient experts described in their submissions how migraine has a significant effect on the quality of life for people with the condition, and their families and carers. They explained how migraine can negatively affect a person's work, family relationships, social life, and mental health and wellbeing. The submissions highlighted the high disease burden, particularly for people with frequent episodes of migraine, chronic migraine or other comorbidities. People with migraine first try a range of oral preventive drug treatments before considering more specialist treatment, such as botulinum toxin type\xa0A (for chronic migraine) or erenumab, fremanezumab or galcanezumab (for episodic or chronic migraine). Usual practice in the NHS is that there is an insufficient response to at least 3\xa0oral preventive drug treatments before more specialist treatment is considered. Stakeholders commented that oral preventive drug treatments are often poorly tolerated and ineffective in preventing migraine. They also explained that access to specialist care and treatment can vary depending on where someone lives. It was agreed that there is a need for effective preventive treatments that can improve quality of life for people with migraine.\n\n# Comparators\n\nErenumab, fremanezumab and galcanezumab are calcitonin gene-related peptide (CGRP) inhibitors. They are recommended in NICE's technology appraisal guidance on erenumab, fremanezumab and galcanezumab for preventing chronic or episodic migraines after at least 3\xa0oral preventive drug treatments have failed. These treatments are available as subcutaneous injections that can be self-administered at home. Erenumab is administered 4‑weekly, galcanezumab monthly, and fremanezumab monthly or 3‑monthly. Eptinezumab is another CGRP inhibitor that works in a similar way, but it is administered by intravenous infusion every 12\xa0weeks in hospital. Clinical opinion suggests that eptinezumab would therefore be reserved for people with severe migraine attacks or who are unable to use the CGRP inhibitors administered subcutaneously. This may include people who struggle to self-administer the injections, such as those with needle phobia. The EAG noted that the company's positioning of eptinezumab in its submission (people with episodic or chronic migraine who have had at least 3\xa0oral preventive drug treatments) aligned with the positioning of the other CGRP inhibitors recommended by NICE. It was agreed that erenumab, fremanezumab and galcanezumab were all appropriate comparators.\n\n# Clinical effectiveness\n\nThe company did not identify any evidence directly comparing eptinezumab with the relevant comparators (see section\xa03.2). So, it did a network meta-analysis to indirectly compare eptinezumab with erenumab, fremanezumab and galcanezumab in people whose migraine had not responded to at least 3 preventive drug treatments. The company used data from randomised controlled trials that compared each of the treatments with placebo. The results of the network meta-analysis suggested that eptinezumab has similar clinical effectiveness to erenumab, fremanezumab and galcanezumab in reducing migraine frequency in people with chronic or episodic migraines. Clinical opinion also suggested that the treatments are similar. The EAG noted that there were some limitations associated with the company's network meta-analysis but that these had also been considered in NICE's technology appraisal guidance on erenumab, fremanezumab and galcanezumab. It was agreed that there was sufficient evidence of similar clinical efficacy for eptinezumab compared with erenumab, fremanezumab and galcanezumab.\n\n# Cost comparison\n\nThe company submission stated that 'eptinezumab is only available in a 100\xa0mg vial; a 300\xa0mg vial is not available, and the 300\xa0mg dose is not being commercialised in the UK'. When taking account of administration costs, dosage, price per dose and commercial arrangements for all treatments, the total cost associated with eptinezumab 100\xa0mg every 12\xa0weeks was similar to or lower than that with erenumab (140\xa0mg 4‑weekly), fremanezumab (225\xa0mg monthly or 675\xa0mg 3‑monthly) or galcanezumab (120\xa0mg monthly after a 240\xa0mg initial loading dose). The exact results are confidential and cannot be reported here. It was agreed that, after people with the condition and their clinicians have discussed the advantages and disadvantages of the available treatments, if more than 1\xa0treatment is suitable, it would be appropriate to choose the least expensive option. So, the decision was made to recommend eptinezumab for preventing migraine in line with the previous recommendations for erenumab, fremanezumab and galcanezumab.\n\n# Equality issues\n\nStakeholders raised several potential equality issues during the evaluation. This included that migraine is more common in women, particularly in those of childbearing age. But it was agreed that issues relating to differences in prevalence or incidence of a condition cannot be addressed in a technology evaluation. A stakeholder commented that appropriate treatments should be available for everyone including people who cannot self-administer available treatments because of a physical, cognitive or other disability. It was agreed that eptinezumab would likely improve access to specialist treatment for people with difficulty self-injecting the CGRP inhibitors administered subcutaneously. This is because it would be administered in a hospital setting intravenously. A stakeholder commented that there should be equality of access to treatment for people with migraine and that best supportive care should not be the default option because of where someone lives. The decision making took into account any obligations in relation to the Equality Act 2010 and that eptinezumab can only be recommended for use within its marketing authorisation. It was noted that issues about healthcare implementation could not be addressed in the evaluation. It was agreed that there were no equality issues relevant to the recommendations."}	https://www.nice.org.uk/guidance/ta871	Evidence-based recommendations on eptinezumab (VYEPTI) for preventing migraine in adults.
06a61927ebcf207b497477e1288144366df5a3c5	nice	Cannabidiol for treating seizures caused by tuberous sclerosis complex	Cannabidiol for treating seizures caused by tuberous sclerosis complex Evidence-based recommendations on cannabidiol (Epidyolex) for treating seizures caused by tuberous sclerosis complex. # Recommendations Cannabidiol is recommended as an add-on treatment option for seizures caused by tuberous sclerosis complex in people aged 2 years and over, only if: their seizures are not controlled well enough by 2 or more antiseizure medications (either used alone or in combination) or these treatments were not tolerated seizure frequency is checked every 6 months, and cannabidiol is stopped if the frequency has not fallen by at least 30% compared with the 6 months before starting treatment the company provides cannabidiol according to the commercial arrangement. These recommendations are not intended to affect treatment with cannabidiol that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children, this decision should be made jointly by the clinician and the child and/or the child's parents or carers. Why the committee made these recommendations Usual care for seizures caused by tuberous sclerosis complex includes antiseizure medications. Cannabidiol is licensed as an add-on treatment option for people aged 2 years and over. The company has positioned it for use when seizures are not controlled well enough by 2 or more antiseizure medications or when these were not tolerated. Clinical trial evidence shows that cannabidiol plus usual care reduces seizure frequency and increases the number of seizure-free days compared with placebo plus usual care. The cost-effectiveness estimates for cannabidiol are uncertain because some of the assumptions in the company's economic model are uncertain. However, cannabidiol has benefits that are not included in the modelling, such as reducing the severity of seizures and lowering the risk of sudden unexpected death in epilepsy. When taking the uncertainties, uncaptured benefits and severity of the disease into account, cannabidiol is considered an appropriate use of NHS resources. So, it is recommended.# Information about cannabidiol # Marketing authorisation indication Cannabidiol (Epidyolex, GW Pharma) is indicated 'for use as adjunctive therapy of seizures associated with tuberous sclerosis complex (TSC) for patients 2 years of age and older'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for cannabidiol. # Price The list price is £850.29 per 100 ml (100 mg/ml) bottle. The company has a commercial arrangement. This makes cannabidiol available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by GW Pharma, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Disease background ## Tuberous sclerosis complex severely affects the quality of life of patients, carers and their families Tuberous sclerosis complex is a rare genetic disorder characterised by growth of noncancerous tumours (known as tubers). Tubers can form in many parts of the body, but most commonly occur in the brain, eyes, kidneys, heart, lungs and skin. Seizures resulting from tubers that have formed in the brain affect up to 85% of people with the condition. Seizures usually start by the age of 2 years as focal onset seizures (which begin in 1 side of the brain) but may progress to generalised seizures involving both sides of the brain. Clinical experts explained that there is high variability in seizure type, severity and frequency depending on where the tubers are located. Any seizure type is possible (with or without the person retaining consciousness). The patient experts explained that seizures can be traumatic for people with tuberous sclerosis complex and their families. Drop seizures, in which people lose muscle tone or muscles stiffen, are particularly dangerous and are associated with a risk of injury as people crash to the ground. The clinical experts also highlighted that tubers that form in the brain can cause a range of cognitive, behavioural, and psychiatric manifestations (known as tuberous sclerosis complex-associated neuropsychiatric disorders or TAND) in around half of people with seizures caused by tuberous sclerosis complex. Patient experts highlighted the significant quality-of-life impact from TAND for patients and families. Severe learning difficulties occur in around 30% of people with tuberous sclerosis complex and may impede speech. Impaired movement may also limit all aspects of daily living. Poor behaviour including anger, mood swings, aggression and a lack of perception of risk often makes daily activities impossible and people may need round-the-clock care. People with the condition also have disrupted sleep, which can impact on the mental health of the entire family. The committee concluded that seizures caused by tuberous sclerosis complex severely affect the quality of life of patients, families and carers. # Current treatments ## People with tuberous sclerosis complex and their carers would value a new treatment option The clinical experts explained that it is difficult to control seizures associated with tuberous sclerosis complex. They highlighted that the aim of treatment is seizure freedom, but this is rarely achieved in this population. This is because of the complexity and heterogeneity of the underlying disease and variability of tuber locations in the brain. Also, it is harder to control seizures in people with moderate to severe learning difficulties. At the second committee meeting, the patient and clinical experts explained that reducing the frequency of seizures is important in improving quality of life for people with tuberous sclerosis complex, their families and carers. Fewer, less severe and more predictable seizures allow people with severe forms of the disease to leave the house, carry out daily activities and attend mainstream school. Indirectly, fewer seizures can also improve behaviour, reduce anxiety and decrease the risk of sudden unexpected death in epilepsy (SUDEP). Clinical experts explained that the treatment pathway for treating seizures associated with tuberous sclerosis complex is complicated. However, resective surgery should always be considered in people with structural brain lesions. Because there is a long waiting list for surgery, and a limited number of centres providing it, combinations of other treatments are often used. First-line treatment is monotherapy with an antiseizure medication. If seizures remain uncontrolled, a range of antiseizure medications are added. A clinical expert explained that a person's condition would be classed as refractory to treatment if their seizures are inadequately controlled by 2 or more antiseizure medications at a therapeutic dose. For these people, further adjunctive antiseizure medications and non-pharmacological treatments (ketogenic diet and vagus nerve stimulation) are used. Everolimus is also commissioned under an NHS clinical commissioning policy for treating refractory focal onset seizures associated with tuberous sclerosis complex in people aged 2 years and above, when surgery and vagus nerve stimulation has failed or is not considered appropriate. A clinical expert stressed that there is an unmet need for treatments to control seizures and behavioural problems associated with the condition. This is because the range of current antiseizure medications do not control seizures for long and are often associated with side effects. The committee concluded that people with tuberous sclerosis complex and their carers would value a new treatment option. ## The appropriate comparator for cannabidiol is usual care including antiseizure medications, surgery and vagus nerve stimulation The scoped positioning for cannabidiol was as an adjunctive therapy for people whose seizures are inadequately controlled by established clinical management. In its submission, the company updated the population to include people in whom usual care is not tolerated. This was based on the International League Against Epilepsy's definition of refractory epilepsy as ʻfailure of adequate trials of 2 tolerated and appropriately chosen' antiseizure medications to achieve sustained seizure freedom. The committee noted that the company's population was narrower than the marketing authorisation which specified only that cannabidiol should be used adjunctively. The ERG was concerned that usual care may differ for people when antiseizure medications are not tolerated rather than when they are ineffective. This is because antiseizure medications can be continued adjunctively if seizures remain inadequately controlled, but are stopped if not tolerated. The ERG also highlighted the possibility that everolimus may form usual care in the company's updated population. The clinical experts explained that everolimus has a different indication to cannabidiol because of its mode of action. Everolimus treats the underlying cause of tuberous sclerosis complex. It has also been shown to reduce the size of existing tumours and slow the formation of new tuberous sclerosis complex-related tumours including astrocytomas (tumours arising from the glial cells in the brain), kidney and lung lesions, and skin conditions. The committee noted that everolimus requires close monitoring and can only be used in people with focal seizures after consideration of surgery and vagus nerve stimulation. So, the population who would have everolimus at the same point in the pathway as cannabidiol was likely to be very small. The committee agreed that usual care including antiseizure medications with or without surgery or vagus nerve stimulation was the appropriate comparator. # Clinical-effectiveness evidence ## GWPCARE6 is the key trial for cannabidiol and is broadly generalisable to NHS clinical practice Cannabidiol (plus usual care) has been compared with placebo (plus usual care) in the randomised controlled trial, GWPCARE6. In this, 2 maintenance doses of cannabidiol (25 mg/kg/day ; and 50 mg/kg/day ) were compared with placebo (n=76). However, because the marketing authorisation for cannabidiol is granted for a maximum 25 mg/kg/day, the company did not present results from the 50 mg/kg/day dose in its submission. GWPCARE6 had a dose titration period of 4 weeks, followed by 12 weeks at the maintenance dose. It included people aged 1 year to 65 years, 7 of whom were from the UK. A clinical expert stated that the baseline characteristics and usual care treatments in GWPCARE6 were similar to those expected in UK clinical practice. However, the committee noted differences between arms in the amount of people who had vigabatrin and clobazam (2 of the most common antiseizure medications). A clinical expert stated that vigabatrin is unlikely to impact the effectiveness of cannabidiol because it treats infantile spasms as opposed to seizures. However, both patient and clinical experts reported that clobazam increases the effectiveness of cannabidiol when taken adjunctively. So, the GWPCARE6 results may not be generalisable to UK clinical practice if clobazam use differs between the trial and the NHS. The committee noted that cannabidiol's marketing authorisation mandates use with clobazam for Lennox–Gastaut and Dravet syndromes, but not for tuberous sclerosis complex. A clinical expert explained that clobazam is currently used in NHS practice in a similar way to GWPCARE6. Also, its use would not be expected to increase if cannabidiol was recommended. This is because clobazam is associated with side effects so its risks and benefits would be evaluated on an individual basis and dose adjustments of both drugs may be needed. The company also submitted data from the following ongoing studies to support cannabidiol's long-term effect: An open-label extension study to GWPCARE6 in which all patients are having cannabidiol at a starting dose of 25 mg/kg/day with an expected follow-up of 4 years; 3‑year (156‑week) data from an interim analysis was provided at consultation. An expanded access programme in the US in which 34 people are having cannabidiol up to a maximum of 25 mg/kg/day to 50 mg/kg/day (depending on study site). Data is available for up to 4.4 years of follow-up. The committee concluded that the main trial data to support cannabidiol's treatment effect comes from GWPCARE6, the patient population for which is broadly generalisable to NHS clinical practice. ## Cannabidiol reduces seizure frequency and, at least in the short term, increases the number of seizure-free days The primary endpoint for GWPCARE6 was the percentage change in tuberous sclerosis complex-associated seizures during the treatment period (4‑week titration plus 12‑week maintenance periods). For people taking 25 mg/kg/day cannabidiol with usual care, there was a statistically significant reduction in tuberous sclerosis complex-associated seizures compared with placebo with usual care (30% reduction, 95% confidence interval 14% to 43%, p<0.001). There were 5% of people having cannabidiol 25 mg/kg/day who were seizure-free throughout the maintenance period compared with 0% taking placebo. People in the cannabidiol arm also experienced an additional 2.8 seizure-free days compared with placebo. At consultation, the company provided 3‑year follow-up data from the open-label extension study. For people still having treatment at 3 years, seizure reductions of 50% and over, 75% and over and 100% were observed in 78%, 69% and 31% of people, respectively. At least 6% of people taking cannabidiol were seizure-free at any given time during the follow-up period. The committee noted that only people whose disease showed some level of response would continue cannabidiol in clinical practice. Also, the primary outcome of the open-label study was a safety endpoint and data on seizure-free days had not been collected. However, it acknowledged that the 3‑year data from the extension study suggested ongoing seizure control in people who continued treatment. Clinical experts confirmed that, based on their experience of people with refractory epilepsy taking cannabidiol, the treatment effect did not wane over time. The committee recalled that both seizure freedom and reducing the number of seizures are important outcomes to patients and their families (see section 3.2). However, it noted that GWPCARE6 did not show an association between reducing seizure frequency and improving quality of life (as assessed by the Quality of Life in Childhood Epilepsy (QOLCE) and Quality of Life in Epilepsy -31-P questionnaires). However, the clinical experts suggested this was because the 16‑week follow-up period in GWPCARE6 was insufficient to fully capture the benefits of reducing or stopping seizures on daily activities and mental health. They explained that, in their experience, seizure reduction did align with improved quality of life. The committee remained concerned that, by pooling usual care treatments, cannabidiol had not been compared with individual antiseizure medications. However, it concluded cannabidiol plus usual care likely reduces seizure frequency and, at least in the short term, increases the number of seizure-free days compared with usual care alone. # Adverse events ## Cannabidiol is associated with adverse events that are manageable, but monitoring and adjustment of concurrent medications may be needed GWPCARE6 showed that a large proportion of patients having cannabidiol had adverse events. The most common adverse events in this group were diarrhoea, decreased appetite and somnolence (drowsiness). A clinical expert noted that people with tuberous sclerosis complex often experience adverse effects from their medications. They also noted that cannabidiol's adverse effects are mostly, but not always, mild and tolerated. They stated that the choice of treatment depends on the balance of its safety and tolerability, with adverse events representing an important consideration. The committee also recalled that cannabis-based medicines can increase the exposure of other antiseizure medications, so dose modifications for concomitant medications may be needed in clinical practice. It agreed that, while cannabidiol's adverse effects are mostly manageable, they are an important consideration when making decisions about whether to start or continue treatment. The committee concluded that cannabidiol is associated with adverse events that are manageable but monitoring and adjustment of concurrent antiseizure medications may be needed. # Stopping treatment ## It is appropriate to assess response to treatment every 6 months and stop cannabidiol if it is not effective Cannabidiol's marketing authorisation does not specify a stopping rule, that is, stopping treatment if or when it does not work. However, the company proposed that cannabidiol should be stopped if the frequency of seizures caused by tuberous sclerosis complex does not reduce by 30% from baseline. Baseline seizure frequency in the model was taken from the 28‑day baseline period in GWPCARE6, assumed to represent the 6 months before starting treatment which would be used in clinical practice. The company implemented this stopping rule every 6 months in its model. The committee noted that this aligned with the stopping rule in NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome and cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome. However, the company had implemented an additional stopping rate for cannabidiol in tuberous sclerosis complex. This was based on stopping rates in GWPCARE6 in the short term, the open-label extension study in the medium term and NICE's guidance on cannabidiol for Lennox–Gastaut syndrome in the long term. The committee concluded that this was acceptable, and it was appropriate to assess response to treatment every 6 months and stop cannabidiol if it is not effective. # Company's economic model ## The company's model structure is appropriate The company presented a cohort-level model to estimate the cost effectiveness of cannabidiol. It had 3 health states: alive having cannabidiol with usual care, alive having usual care alone, and dead. The alive health states were further divided by the number of seizures per week (seizure-free, 2 and under, over 2 to 7, and over 7) and number of seizures per day (seizure-free, 1 and under, over 1 to 2, over 2 to 4, and over 4). The model used a lifetime horizon and a cycle length of 1 week. The company did not include vagus nerve stimulation, ketogenic diet or surgery as comparators in its model because it stated these would be used equally between arms. So, the comparator was usual care with antiseizure medications. The committee concluded that the company's general model structure was appropriate. ## The company's linear regression model approach for seizure-free days and number of seizures is acceptable for decision making The company derived efficacy data for the sub-health states for number of seizures per week and number of seizures per day from GWPCARE6 at week 16. For the long-term effect on seizures, the company applied 2 linear regression models sequentially. The first predicted the number of seizure-free days per 7‑day cycle in the model using a binomial regression model based on individual patient data from GWPCARE6 at week 16. The second, a negative binomial model, predicted the total seizure frequency on non-seizure-free days per cycle. The company chose this approach to capture correlation between seizure frequency and seizure-free days. It applied the regression coefficients to each patient's baseline seizure frequency to predict outcomes for each 7‑day model cycle. Using this approach, the relative treatment effect was maintained over the modelled time horizon. Results showed a trend for reduced seizure frequency and increased odds of seizure-free days for cannabidiol plus usual care compared with placebo plus usual care. The committee noted that the relative treatment effect was not statistically significant. The company stated this was because the powers of the analyses were low because of use of weekly model cycles and 2 different regression models. The committee noted that the seizure frequency per day predicted by the company's regression model broadly aligned with data from the open-label extension study, but the study did not collect data on seizure-free days. It acknowledged the uncertainty in the company's approach but noted that the ERG had not suggested an alternative method for modelling seizures. Given this, it considered analyses using the company's linear regression models for seizure-free days and seizure frequency were acceptable for decision making. ## Modelling the proportion of people who are seizure-free over 7 days is uncertain but a 6.61-day cut-off is most appropriate for decision making At the first committee meeting, the ERG was concerned that the company had modelled seizure freedom over a 7‑day cycle by using the proportion of people who were seizure-free over 6.5 days. This was because a negative binomial regression model cannot predict discrete outcomes (that is, seizure-free over 0 days or 7 days). Using this approach, 0% of the placebo and 11% of the cannabidiol arm were seizure-free at 10 weeks (the latter reduced as people stopped treatment over time). The ERG highlighted that using a cut-off of 6.5 days would overestimate the number of people having cannabidiol who were seizure-free per cycle. This is because the predicted number of seizure-free days using the linear regression model results was 6.62 for cannabidiol compared with 5.89 for placebo. At technical engagement, the company provided a scenario using a cut-off of 6.61 days to model the number of people per cycle who were seizure-free to better align with the regression model results. The committee also considered a scenario provided by the ERG using a cut-off of 7 days, in which no one was seizure‑free over the course of a week in either arm but still gained a benefit for cannabidiol in other seizure frequency categories. The committee recalled that seizure-free days per week had not been collected as an outcome in GWPCARE6 so could not directly inform the modelling. However, it compared the number of people who were seizure-free over 7 days using different cut-offs in the model with that expected in clinical practice to determine the most clinically plausible approach. It recalled that achieving seizure freedom is challenging in this population (see section 3.2). A clinical expert agreed it was plausible that a small number of people taking cannabidiol may achieve seizure freedom but that this would be unlikely in people only having usual care. This was supported by data from GWPCARE6 in which 5% of people taking cannabidiol and 0% of people taking placebo were seizure-free during the maintenance period. So, the ERG's scenario using a 7‑day cut-off was likely conservative. This also aligned with testimonies from patients who had taken cannabidiol. The committee recognised that the number of seizure-free days is a useful outcome for determining response to treatment. However, it was concerned that measuring this outcome over the course of a week introduced artificial effects into the model that favoured cannabidiol or usual care depending on which cut-off was chosen. It would have preferred the company to use a longer time-period, as in NICE's technology appraisal guidance on fenfluramine for treating seizures associated with Dravet syndrome which modelled the number of seizure-free days in a month. The committee agreed that the proportion of people who are seizure-free over 7 days in the model was uncertain because the company's methodology was problematic. It recalled that a 6.5‑day cut-off likely overestimated the proportion who were seizure-free per week in clinical practice while a 7‑day cut-off underestimated this. So, it concluded that a 6.61‑day cut-off was most appropriate for decision making. # Costs in the model ## An average dose of 15 mg/kg/day for cannabidiol is appropriate for decision making The summary of product characteristics for cannabidiol states that the dose can be increased from a maintenance dose of 10 mg/kg/day to a maximum of 25 mg/kg/day based on response. Yet, the company assumed an average dose of 12 mg/kg/day in its base case. This was based on clinical expert advice to the company and German dispensing data from 118 people with tuberous sclerosis complex, in which the median cannabidiol dose was 12.2 mg/kg/day in children and 7.8 mg/kg/day in adults. The committee noted that the European regulator mandates a maintenance dose of cannabidiol of 10 mg/kg/day for Lennox–Gastaut and Dravet syndromes and there is no evidence that increasing the doses above this results in a different treatment effect. It also noted data from the open-label extension study that suggested a maintenance dose above 15 mg/kg/day did not improve response. The ERG was concerned that a maintenance dose of 12 mg/kg/day was not verified by clinical trial data (because treatment was titrated up to 25 mg/kg/day or 50 mg/kg/day in GWPCARE6 regardless of response) and that the proportion of people needing a higher dose in the open-label extension study was unknown. It presented scenarios varying the average dose of cannabidiol. At the second meeting, clinical experts provided dosing information based on clinical experience of treating people with tuberous sclerosis complex in clinical practice (including people who had concurrent Lennox–Gastaut syndrome) in Scotland and Wales. They stated that most people would have a dose about 12 mg/kg/day in clinical practice. This was normally lower in adults, for whom 1 clinical expert estimated an average dose of 8 mg/kg/day. This was because, although there is potential that higher doses may be more effective, they cause more side effects than lower doses. So, 12 mg/kg/day is likely to be the average dose in clinical practice as a trade-off between efficacy and side effects. The clinical experts acknowledged a dose–response effect for cannabidiol but noted that, in their experience, they had observed similar effectiveness using lower doses to those reported for the trial dose of 25 mg/kg/day. This was because people with refractory epilepsy are taking other antiseizure medications that may increase the effectiveness of cannabidiol when used in combination (see section 3.6). Dose titration would also be much slower in clinical practice, allowing clinicians to establish response at a lower dose than used in the trial. However, the committee remained concerned that the efficacy data in the model came from people having 25 mg/kg/day in GWPCARE6 and it had no credible evidence that efficacy at half that dose would be identical. It also noted that a 15 mg/kg/day average dose for cannabidiol was accepted in NICE's technology appraisal guidance on fenfluramine for treating seizures associated with Dravet syndrome. It therefore considered that, although 12 mg/kg/day was likely the average dose used in clinical practice, some adjustment for loss of benefit compared to GWPCARE6 results should be included in the modelling. So, it preferred an average dose of 15 mg/kg/day for decision making. ## The company's Delphi panel likely overestimates healthcare resource use and a 50% reduction in hospitalisation rates should be modelled Annual healthcare resource use based on seizure frequency for people with tuberous sclerosis complex-associated epilepsy was sourced from a 2‑round Delphi panel of clinical experts. Separate resource use estimates were produced for adults and children. The company validated these estimates using a study by Shepherd et al. (2017). This reported a cost of £44,259 over a period of 3 years for resource use (GP visits, hospitalisation, other drugs and outpatient visits) in UK patients with tuberous sclerosis complex. The committee noted that the costs in the company's model for the same 3‑year period for usual care (£55,578) were significantly higher than those in Shepherd et al. and NICE's technology appraisal guidance on cannabidiol with clobazam for Dravet syndrome and cannabidiol with clobazam for Lennox–Gastaut syndrome. The ERG modelled a scenario applying the resource use costs from these appraisals. The company explained that the discrepancy was because of inflation rates in NHS reference costs (which it updated at consultation to align with inflation). The ERG also highlighted that hospitalisation costs and number of hospital days (both in a general ward and intensive care) were higher in the company's model for tuberous sclerosis complex than in the appraisals for other cannabidiol indications and costs reported in Shepherd et al. In the second committee meeting the company explained that there is a spectrum of severity in tuberous sclerosis complex. Although many people do not need frequent hospitalisation, a small proportion are associated with high resource use from having up to 40 hospitalisations per year. It defended the use of the Delphi panel for sourcing expert opinion, noting the methodology was more robust than the interviews with clinicians in the appraisals for Dravet and Lennox–Gastaut syndromes. Clinical experts explained that although tuberous sclerosis complex is a multi-organ disease, non-epilepsy-related hospital admissions are rare. So, hospitalisation rates are likely comparable to other cannabidiol indications, and may be lower than for Dravet syndrome, which causes very frequent seizures. This was supported by more frequent use of rescue medication by people with Dravet syndrome compared to the other cannabidiol appraisals. The ERG's base case after consultation reduced hospitalisation rates by 50% to better align with the other cannabidiol appraisals (the values from the Dravet and Lennox–Gastaut syndrome appraisals could not be used because seizure frequency categories differed across indications). At the second committee meeting, the committee also considered additional scenarios reducing hospitalisation rates from those in the Delphi panel by 10%, 20%, 30% and 40% provided by the company and by 25% provided by the ERG. It noted that the hospitalisation rates in scenarios were not underpinned by evidence, so the true resource use for people with tuberous sclerosis complex was unknown. However, the committee agreed it was appropriate to use the scenario that best aligned with the hospitalisation rates used in the technology appraisals for Dravet and Lennox–Gastaut syndromes. It concluded that healthcare resource use is likely overestimated in the company's model and a 50% reduction from the Delphi panel hospitalisation rates should be used for decision making. # Utilities in the economic model ## The company's health state utilities are uncertain and differ from utilities in other cannabidiol appraisals The committee recalled that the company had collected data from responses to the QOLCE and QOLIE‑31‑P questionnaires in GWPCARE6, but did not use the data in its model. This was because, during the trial, the company considered that the questions were inappropriate for assessing people with severe learning difficulties. The company also noted that data on quality of life in the literature does not consider health states and substates used in the company's model (that is, number of seizures and seizure-free days). So, the company instead asked members of the general public to estimate the quality of life associated with each health state and substate in the model. Respondents were asked to consider 'vignettes', that is, descriptions of each health state and, using a time trade-off method, give each a value. Values ranged between less than 0 (worse than death), 0 (death) and 1 (perfect health). The company considered the quality-of-life values it used in its model to be confidential. The committee understood why the company had chosen to use a vignette study given the lack of literature utility values. However, it noted a discrepancy in the health state utilities used for tuberous sclerosis complex compared with those for Lennox–Gastaut and Dravet syndromes. This was especially so for the values published in Lo et al. (2021) which used vignettes from the general public (collected after the publication of guidance on cannabidiol for Lennox–Gastaut and Dravet syndromes to align with the committee's preferred assumptions in these appraisals). The company explained that, in part, this might be because of the difference in seizure severity categories and types of seizures in the other appraisals. The vignettes were considered by the general public who may find it hard to quantify the difference between the worst health state for Lennox–Gastaut syndrome (more than 110 drop seizures per month) compared with that for tuberous sclerosis complex (more than 4 seizures per day). A clinical expert stated that, although the epilepsy aspect of the 3 conditions may be similar, it is difficult to compare the severity of the indications. This is because tuberous sclerosis complex is a multi-organ disease associated with complications such as those in the skin, eyes and lungs that affect quality of life and are not present in the other conditions. So, correcting seizures will only partly correct the quality-of-life decrement associated with severe tuberous sclerosis complex. The committee was concerned that this was not captured in the company's model because the utility values for the seizure-free health state for both people with the condition and their carers was relatively high. It also noted that the health state utility values used in NICE's technology appraisal guidance on fenfluramine for treating seizures associated with Dravet syndrome encompassed a much narrower range than those used in the company's modelling of cannabidiol for tuberous sclerosis complex. In the fenfluramine appraisal, values were derived using empirical measurements collected in clinical trials, which had been mapped to EQ‑5D values in a way that matches the NICE reference case. The committee noted that it had not been presented with scenarios that used alternative health state utilities for cannabidiol, so could not determine the impact on the cost-effectiveness estimates. Given the lack of utility values in the literature, it would have liked to see data supporting the plausibility of the vignette values, especially for the seizure-free and most severe health states. However, acknowledging the high level of uncertainty, the committee considered the analyses using the company's utility values in its decision making. It concluded that the company's health state utilities are uncertain and differ from utilities in other cannabidiol appraisals. ## The effect on carers' quality of life should be modelled and it is appropriate to use 1.8 carers in the modelling The committee recalled that caring for someone with tuberous sclerosis complex affects carers' quality of life (see section 3.1), and that capturing this in the model is appropriate. The company included utility decrements in its model for seizure frequency health states (number of seizures per day) based on the vignette study. This was because carer quality of life had not been measured using a preference-based approach in GWPCARE6, so utilities could not be derived directly from the trial. In its base case at the first committee meeting, the company assumed that people with tuberous sclerosis complex would have a cumulative 2 carers (1 primary caregiver plus others such as partners, friends and family). This was based on a paper by Lagae et al. (2019), which reported that people with Dravet syndrome had an average 2.06 carers. The clinical experts explained that there are no significant differences in the burden of care for seizures between cannabidiol indications. However, the total burden of care for people with tuberous sclerosis complex may be higher because of the combined effect of the epilepsy, associated learning disabilities and other comorbidities that occur with the condition. The ERG was concerned that the carer disutilities were applied additively in the company's model. It used 1.8 carers in its base case, which aligned with the committee's preferred assumptions in NICE's technology appraisal guidance for Dravet syndrome and Lennox–Gastaut syndrome. The committee agreed that the company's approach implied that the caring burden increases linearly the more carers a patient has. However, for a patient with multiple carers, it expected there to be less effect on the quality of life of each carer because they would 'share' some of the burden. At consultation, the patient organisations highlighted that care given by 2 carers does not reduce burden of care. The company supported this, stating that each carer will have worry and psychological distress from caring for a patient at risk from injury and death because of seizures. However, it updated its modelling to align with the committee's preference at the first meeting of 1.8 carers. This was because, while the total burden for 2 carers may be greater than the burden for a sole carer, the committee agreed that it would likely not be 2 times greater. It recalled that people with tuberous sclerosis complex may need help with every aspect of daily life (see section 3.1). However, given the multifactorial nature of the disease and associated care needs of people living with it, reducing seizure frequency would only go some way towards relieving carer burden. The committee recalled that carer health state utility values could not be derived directly from the clinical trial and that the values from the company's vignette were uncertain (see section 3.13). Given this uncertainty, it agreed that the model should use 1.8 carers to align with assumptions used in previous appraisals of cannabidiol. ## The seizure-free health state utility for carers is uncertain but a value of 0.881 is acceptable for decision making The vignette calculated the impact of worsening seizure frequencies on carers as an incremental decrease from the carer utility for the seizure-free health state. After technical engagement, the company updated its base case to use a utility value for the seizure-free health state for carers equal to that of an average 45‑year‑old. This was because in the vignettes, members of the general public were asked to adopt the perspective of the primary caregiver of a 13‑year‑old child and the average parent of a child this age was 45 years (Office for National Statistics data). However, the ERG was concerned that the company's value overestimated the impact of seizure freedom on carers. This was because it had not adjusted for carers ageing and that the burden of care for non-seizure-related aspects of tuberous sclerosis complex may not be captured in the company's estimate. At consultation, the ERG also highlighted that carer utility was unlikely to adjust the moment a patient becomes seizure-free. It provided scenarios with lower utility values for the seizure-free health state for carers. The committee considered these scenarios in its decision making. However, it noted that the absolute utility decrement was unchanged regardless of the value used for seizure freedom. Also, the ERG had maintained the value of 0.881 in its preferred assumption after consultation. It concluded that the seizure-free health state utility for carers is uncertain but the utility value in the company and ERG's base cases is appropriate for decision making. ## It is appropriate to include a reduction in carer utility associated with institutionalisation and the ERG's approach is preferable Based on the consensus in the Delphi panel, the company assumed that 31% of people with tuberous sclerosis complex-associated epilepsy were institutionalised at an average age of 27 years. However, in its base case it did not model any impact on carer utility during this period. The company stated that carers for people who were institutionalised would still have: concerns about the risk of injury from seizures or worsening of seizures in a new environment everyday life centred around visiting patients and accompanying them to healthcare visitsThe ERG assumed a 50% reduction in carer disutility for 31% of adults in its base-case model. The company also provided scenarios that increased caregiver utility by 50% for the same proportion of people. A clinical expert stated that institutionalisation was expected to be associated with an increase in quality of life for carers. The patient expert agreed that although carers had more free time if a person with tuberous sclerosis complex was institutionalised, concerns and guilt would remain, especially about exposure to abuse. The committee recalled that tuberous sclerosis complex significantly impacts sleep for the whole family, which would improve when a patient was institutionalised (see section 3.1). It noted that the ERG's method was conservative in that it resulted in lower utility values for the less severe health states. However, the committee considered that the increase in carer quality of life in the company and ERG's analyses were not supported by data and other scenarios would be equally plausible. At consultation, the company updated its base case to adjust for institutionalisation using the ERG's approach, after correction of an error in the modelling. The committee concluded that it is appropriate to include a reduction in carer disutility associated with institutionalisation. Given the lack of evidence to support the size of this reduction, it considered the ERG's approach preferable. # Accounting for TAND aspects in the model ## It is appropriate to model cannabidiol's effect on TAND aspects accepting that this adds uncertainty The company included a cost in the model associated with managing TAND aspects. It also assumed a benefit on TAND aspects for people whose condition responds to cannabidiol, which it modelled as a utility benefit and a reduced cost. The utility benefit for delaying TAND was estimated by weighting utility increments for common TAND aspects from various literature sources by their prevalence using data from the tuberous sclerosis registry to increase disease awareness (TOSCA; de Vries et al. 2015). 'Responders' to cannabidiol were defined as the proportion of people with a reduction in tuberous sclerosis complex-associated seizures of 50% or more from baseline over 6 months. Based on the Delphi panel consensus that treatment with cannabidiol is likely to be most beneficial at an early age, only people aged 2 years to 6 years accrued costs and benefits associated with TAND aspects. The ERG had the following concerns about the company's assumption for TAND: Prevalence rates, costs and utility benefits were not based on data collected in the clinical trials. The Delphi panel did not reach a full consensus on the level of response to cannabidiol needed to delay TAND aspects. The proportion of responders was based on the full trial population but applied only to 2- to 6-year-olds.The committee noted that the vignettes used to elicit health state utilities may already have captured some of the aspects of TAND, so there was potential for double counting. However, the company explained that it had updated its base case at technical engagement to use conservative estimates (using the lowest utility benefit from the literature and applying TAND aspects to ages 2 years to 6 years only). A clinical expert explained that evidence supports an improvement in long-term TAND aspects with a reduction in seizure frequency at an early age. However, it is unclear whether this is the case for adults. The committee acknowledged the uncertainty around the company's modelling but recalled that TAND has a significant effect on the quality of life of people with tuberous sclerosis complex and their carers (see section 3.1). It agreed that costs and utility benefits for TAND should be included in the modelling using the company's estimates provided at technical engagement. # Cost-effectiveness estimates ## Cost-effectiveness analyses include plausible ICERs outside the range normally considered a cost-effective use of NHS resources NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life-year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of confidential commercial arrangements for cannabidiol and comparators, none of the cost-effectiveness results are reported here. The committee noted the differences between the ERG's and company's base case after consultation in that the ERG used a 15 mg/kg/day dose instead of 12 mg/kg/day and reduced hospitalisation rates by 50% compared with those from the Delphi panel. The company base case was under £20,000 per QALY gained compared with usual care. However, the ERG base case was over £30,000 per QALY gained compared with usual care. This was when considering confidential discounts. The committee agreed that its preferred assumptions to compare cannabidiol with usual care aligned with the ERG base case, that is, they included: using a 6.61‑day cut-off for the proportion of people who are seizure-free over 7 days (see section 3.10) using an average dose of 15 mg/kg/day (see section 3.11) considering a lower number of hospital admissions, that is, reduced by 50% (see section 3.12) using the health state utilities from the company's vignette while acknowledging the high uncertainty surrounding the estimates (see section 3.13) assuming a cumulative 1.8 carers (see section 3.14) using a utility value of 0.881 for the seizure-free health state for carers (see section 3.15) adjusting for institutionalisation using the ERG's approach corrected for errors (see section 3.16) including cost and benefits for TAND aspects for people aged 2 years to 6 years, using the utility benefit from the company's base case (see section 3.17).The committee noted there were several uncertainties in the company's modelling. It acknowledged that changing the average dose of cannabidiol significantly increased the cost-effectiveness estimates. It also recalled that healthcare resource use was likely overestimated in the company's model. It noted that including a 50% reduction in hospitalisation rates also increased the cost-effectiveness estimates. The committee considered a range of cost-effectiveness analyses including plausible ICERs outside the range normally considered to be a cost-effective use of NHS resources. # Other factors ## Uncaptured benefits of cannabidiol and severity of the disease should be considered in decision making The committee noted NICE's principles for the development of NICE guidance. This emphasises the importance of considering the distribution of health resources fairly within society as a whole, and factors other than relative costs and benefits alone. It recalled that tuberous sclerosis complex is a severe and multisystemic disease that significantly affects the quality of life of patients, carers and families (see section 3.1). It agreed that the severity of disease should be considered in the decision making. At the second committee meeting, the committee also noted that the following benefits of cannabidiol were not captured in the company's model: a quality-of-life benefit for people with the condition from reducing severity of seizures including to a point at which they no longer impact usual activities a reduction in hospitalisation rates from reducing the severity of seizures the physical and mental benefit on the wider family, including siblings, because of the improved behaviour and reduction in healthcare visits associated with seizure control a mortality benefit from reducing SUDEP related to tuberous sclerosis complex.The committee considered these factors important for improving quality of life. It concluded that it would take these benefits into account in its decision making. ## Cannabidiol does not meet the criteria for an innovative treatment The clinical experts stated that they would welcome an additional treatment option for tuberous sclerosis complex. However, they considered that cannabidiol represents only a modest change when managing tuberous sclerosis complex because few people became seizure‑free (see section 3.10). The committee concluded that cannabidiol did not meet the criteria for an innovative treatment. ## Equalities The committee noted that the population for which cannabidiol is indicated includes children and young people. It discussed the need to balance the importance of improving the lives of children and their families with fairness to people of all ages. The committee also noted that half of people with tuberous sclerosis complex have associated learning difficulties, which is a protected characteristic under the Equality Act 2010. At the second committee meeting, the clinical experts highlighted that access to care for people with learning difficulties may be harder. Also, tuberous sclerosis complex is a hereditary disease, so one or more parents might also have the condition, increasing the challenge in accessing appropriate healthcare. The committee acknowledged and considered the nature of the population as part of its decision making. # Conclusion ## Cannabidiol is recommended for treating seizures caused by tuberous sclerosis complex The committee recalled its conclusion to consider factors other than relative costs and benefits of cannabidiol alone (see section 3.19). It acknowledged that the cost-effectiveness estimates were uncertain for cannabidiol because of some of the assumptions in the company's model (see section 3.18). However, the committee concluded that, despite these uncertainties and considering the uncaptured benefits and severity of the disease, cannabidiol is an effective treatment and a good use of NHS resources. It therefore recommended cannabidiol for treating seizures caused by tuberous sclerosis complex. It agreed that seizure frequency should be checked every 6 months and that, if the frequency has not fallen by at least 30% compared with the 6 months before starting treatment, cannabidiol should be stopped (see section 3.7).	{'Recommendations': "Cannabidiol is recommended as an add-on treatment option for seizures caused by tuberous sclerosis complex in people aged 2\xa0years and over, only if:\n\ntheir seizures are not controlled well enough by 2 or more antiseizure medications (either used alone or in combination) or these treatments were not tolerated\n\nseizure frequency is checked every 6\xa0months, and cannabidiol is stopped if the frequency has not fallen by at least 30% compared with the 6\xa0months before starting treatment\n\nthe company provides cannabidiol according to the commercial arrangement.\n\nThese recommendations are not intended to affect treatment with cannabidiol that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For children, this decision should be made jointly by the clinician and the child and/or the child's parents or carers.\n\nWhy the committee made these recommendations\n\nUsual care for seizures caused by tuberous sclerosis complex includes antiseizure medications. Cannabidiol is licensed as an add-on treatment option for people aged 2\xa0years and over. The company has positioned it for use when seizures are not controlled well enough by 2 or more antiseizure medications or when these were not tolerated.\n\nClinical trial evidence shows that cannabidiol plus usual care reduces seizure frequency and increases the number of seizure-free days compared with placebo plus usual care.\n\nThe cost-effectiveness estimates for cannabidiol are uncertain because some of the assumptions in the company's economic model are uncertain. However, cannabidiol has benefits that are not included in the modelling, such as reducing the severity of seizures and lowering the risk of sudden unexpected death in epilepsy. When taking the uncertainties, uncaptured benefits and severity of the disease into account, cannabidiol is considered an appropriate use of NHS resources. So, it is recommended.", 'Information about cannabidiol': "# Marketing authorisation indication\n\nCannabidiol (Epidyolex, GW Pharma) is indicated 'for use as adjunctive therapy of seizures associated with tuberous sclerosis complex (TSC) for patients 2 years of age and older'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for cannabidiol.\n\n# Price\n\nThe list price is £850.29 per 100\xa0ml (100\xa0mg/ml) bottle. The company has a commercial arrangement. This makes cannabidiol available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by GW Pharma, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Disease background\n\n## Tuberous sclerosis complex severely affects the quality of life of patients, carers and their families\n\nTuberous sclerosis complex is a rare genetic disorder characterised by growth of noncancerous tumours (known as tubers). Tubers can form in many parts of the body, but most commonly occur in the brain, eyes, kidneys, heart, lungs and skin. Seizures resulting from tubers that have formed in the brain affect up to 85% of people with the condition. Seizures usually start by the age of 2\xa0years as focal onset seizures (which begin in 1\xa0side of the brain) but may progress to generalised seizures involving both sides of the brain. Clinical experts explained that there is high variability in seizure type, severity and frequency depending on where the tubers are located. Any seizure type is possible (with or without the person retaining consciousness). The patient experts explained that seizures can be traumatic for people with tuberous sclerosis complex and their families. Drop seizures, in which people lose muscle tone or muscles stiffen, are particularly dangerous and are associated with a risk of injury as people crash to the ground. The clinical experts also highlighted that tubers that form in the brain can cause a range of cognitive, behavioural, and psychiatric manifestations (known as tuberous sclerosis complex-associated neuropsychiatric disorders or TAND) in around half of people with seizures caused by tuberous sclerosis complex. Patient experts highlighted the significant quality-of-life impact from TAND for patients and families. Severe learning difficulties occur in around 30% of people with tuberous sclerosis complex and may impede speech. Impaired movement may also limit all aspects of daily living. Poor behaviour including anger, mood swings, aggression and a lack of perception of risk often makes daily activities impossible and people may need round-the-clock care. People with the condition also have disrupted sleep, which can impact on the mental health of the entire family. The committee concluded that seizures caused by tuberous sclerosis complex severely affect the quality of life of patients, families and carers.\n\n# Current treatments\n\n## People with tuberous sclerosis complex and their carers would value a new treatment option\n\nThe clinical experts explained that it is difficult to control seizures associated with tuberous sclerosis complex. They highlighted that the aim of treatment is seizure freedom, but this is rarely achieved in this population. This is because of the complexity and heterogeneity of the underlying disease and variability of tuber locations in the brain. Also, it is harder to control seizures in people with moderate to severe learning difficulties. At the second committee meeting, the patient and clinical experts explained that reducing the frequency of seizures is important in improving quality of life for people with tuberous sclerosis complex, their families and carers. Fewer, less severe and more predictable seizures allow people with severe forms of the disease to leave the house, carry out daily activities and attend mainstream school. Indirectly, fewer seizures can also improve behaviour, reduce anxiety and decrease the risk of sudden unexpected death in epilepsy (SUDEP). Clinical experts explained that the treatment pathway for treating seizures associated with tuberous sclerosis complex is complicated. However, resective surgery should always be considered in people with structural brain lesions. Because there is a long waiting list for surgery, and a limited number of centres providing it, combinations of other treatments are often used. First-line treatment is monotherapy with an antiseizure medication. If seizures remain uncontrolled, a range of antiseizure medications are added. A clinical expert explained that a person's condition would be classed as refractory to treatment if their seizures are inadequately controlled by 2 or more antiseizure medications at a therapeutic dose. For these people, further adjunctive antiseizure medications and non-pharmacological treatments (ketogenic diet and vagus nerve stimulation) are used. Everolimus is also commissioned under an NHS clinical commissioning policy for treating refractory focal onset seizures associated with tuberous sclerosis complex in people aged 2 years and above, when surgery and vagus nerve stimulation has failed or is not considered appropriate. A clinical expert stressed that there is an unmet need for treatments to control seizures and behavioural problems associated with the condition. This is because the range of current antiseizure medications do not control seizures for long and are often associated with side effects. The committee concluded that people with tuberous sclerosis complex and their carers would value a new treatment option.\n\n## The appropriate comparator for cannabidiol is usual care including antiseizure medications, surgery and vagus nerve stimulation\n\nThe scoped positioning for cannabidiol was as an adjunctive therapy for people whose seizures are inadequately controlled by established clinical management. In its submission, the company updated the population to include people in whom usual care is not tolerated. This was based on the International League Against Epilepsy's definition of refractory epilepsy as ʻfailure of adequate trials of 2 tolerated and appropriately chosen' antiseizure medications to achieve sustained seizure freedom. The committee noted that the company's population was narrower than the marketing authorisation which specified only that cannabidiol should be used adjunctively. The ERG was concerned that usual care may differ for people when antiseizure medications are not tolerated rather than when they are ineffective. This is because antiseizure medications can be continued adjunctively if seizures remain inadequately controlled, but are stopped if not tolerated. The ERG also highlighted the possibility that everolimus may form usual care in the company's updated population. The clinical experts explained that everolimus has a different indication to cannabidiol because of its mode of action. Everolimus treats the underlying cause of tuberous sclerosis complex. It has also been shown to reduce the size of existing tumours and slow the formation of new tuberous sclerosis complex-related tumours including astrocytomas (tumours arising from the glial cells in the brain), kidney and lung lesions, and skin conditions. The committee noted that everolimus requires close monitoring and can only be used in people with focal seizures after consideration of surgery and vagus nerve stimulation. So, the population who would have everolimus at the same point in the pathway as cannabidiol was likely to be very small. The committee agreed that usual care including antiseizure medications with or without surgery or vagus nerve stimulation was the appropriate comparator.\n\n# Clinical-effectiveness evidence\n\n## GWPCARE6 is the key trial for cannabidiol and is broadly generalisable to NHS clinical practice\n\nCannabidiol (plus usual care) has been compared with placebo (plus usual care) in the randomised controlled trial, GWPCARE6. In this, 2\xa0maintenance doses of cannabidiol (25\xa0mg/kg/day [n=75]; and 50\xa0mg/kg/day [n=73]) were compared with placebo (n=76). However, because the marketing authorisation for cannabidiol is granted for a maximum 25\xa0mg/kg/day, the company did not present results from the 50\xa0mg/kg/day dose in its submission. GWPCARE6 had a dose titration period of 4\xa0weeks, followed by 12\xa0weeks at the maintenance dose. It included people aged 1\xa0year to 65\xa0years, 7 of whom were from the UK. A clinical expert stated that the baseline characteristics and usual care treatments in GWPCARE6 were similar to those expected in UK clinical practice. However, the committee noted differences between arms in the amount of people who had vigabatrin and clobazam (2 of the most common antiseizure medications). A clinical expert stated that vigabatrin is unlikely to impact the effectiveness of cannabidiol because it treats infantile spasms as opposed to seizures. However, both patient and clinical experts reported that clobazam increases the effectiveness of cannabidiol when taken adjunctively. So, the GWPCARE6 results may not be generalisable to UK clinical practice if clobazam use differs between the trial and the NHS. The committee noted that cannabidiol's marketing authorisation mandates use with clobazam for Lennox–Gastaut and Dravet syndromes, but not for tuberous sclerosis complex. A clinical expert explained that clobazam is currently used in NHS practice in a similar way to GWPCARE6. Also, its use would not be expected to increase if cannabidiol was recommended. This is because clobazam is associated with side effects so its risks and benefits would be evaluated on an individual basis and dose adjustments of both drugs may be needed. The company also submitted data from the following ongoing studies to support cannabidiol's long-term effect:\n\nAn open-label extension study to GWPCARE6 in which all patients are having cannabidiol at a starting dose of 25\xa0mg/kg/day with an expected follow-up of 4\xa0years; 3‑year (156‑week) data from an interim analysis was provided at consultation.\n\nAn expanded access programme in the US in which 34\xa0people are having cannabidiol up to a maximum of 25\xa0mg/kg/day to 50\xa0mg/kg/day (depending on study site). Data is available for up to 4.4\xa0years of follow-up. The committee concluded that the main trial data to support cannabidiol's treatment effect comes from GWPCARE6, the patient population for which is broadly generalisable to NHS clinical practice.\n\n## Cannabidiol reduces seizure frequency and, at least in the short term, increases the number of seizure-free days\n\nThe primary endpoint for GWPCARE6 was the percentage change in tuberous sclerosis complex-associated seizures during the treatment period (4‑week titration plus 12‑week maintenance periods). For people taking 25\xa0mg/kg/day cannabidiol with usual care, there was a statistically significant reduction in tuberous sclerosis complex-associated seizures compared with placebo with usual care (30% reduction, 95% confidence interval 14% to 43%, p<0.001). There were 5% of people having cannabidiol 25\xa0mg/kg/day who were seizure-free throughout the maintenance period compared with 0% taking placebo. People in the cannabidiol arm also experienced an additional 2.8\xa0seizure-free days compared with placebo. At consultation, the company provided 3‑year follow-up data from the open-label extension study. For people still having treatment at 3\xa0years, seizure reductions of 50% and over, 75% and over and 100% were observed in 78%, 69% and 31% of people, respectively. At least 6% of people taking cannabidiol were seizure-free at any given time during the follow-up period. The committee noted that only people whose disease showed some level of response would continue cannabidiol in clinical practice. Also, the primary outcome of the open-label study was a safety endpoint and data on seizure-free days had not been collected. However, it acknowledged that the 3‑year data from the extension study suggested ongoing seizure control in people who continued treatment. Clinical experts confirmed that, based on their experience of people with refractory epilepsy taking cannabidiol, the treatment effect did not wane over time. The committee recalled that both seizure freedom and reducing the number of seizures are important outcomes to patients and their families (see section\xa03.2). However, it noted that GWPCARE6 did not show an association between reducing seizure frequency and improving quality of life (as assessed by the Quality of Life in Childhood Epilepsy (QOLCE) and Quality of Life in Epilepsy [QOLIE]-31-P questionnaires). However, the clinical experts suggested this was because the 16‑week follow-up period in GWPCARE6 was insufficient to fully capture the benefits of reducing or stopping seizures on daily activities and mental health. They explained that, in their experience, seizure reduction did align with improved quality of life. The committee remained concerned that, by pooling usual care treatments, cannabidiol had not been compared with individual antiseizure medications. However, it concluded cannabidiol plus usual care likely reduces seizure frequency and, at least in the short term, increases the number of seizure-free days compared with usual care alone.\n\n# Adverse events\n\n## Cannabidiol is associated with adverse events that are manageable, but monitoring and adjustment of concurrent medications may be needed\n\nGWPCARE6 showed that a large proportion of patients having cannabidiol had adverse events. The most common adverse events in this group were diarrhoea, decreased appetite and somnolence (drowsiness). A clinical expert noted that people with tuberous sclerosis complex often experience adverse effects from their medications. They also noted that cannabidiol's adverse effects are mostly, but not always, mild and tolerated. They stated that the choice of treatment depends on the balance of its safety and tolerability, with adverse events representing an important consideration. The committee also recalled that cannabis-based medicines can increase the exposure of other antiseizure medications, so dose modifications for concomitant medications may be needed in clinical practice. It agreed that, while cannabidiol's adverse effects are mostly manageable, they are an important consideration when making decisions about whether to start or continue treatment. The committee concluded that cannabidiol is associated with adverse events that are manageable but monitoring and adjustment of concurrent antiseizure medications may be needed.\n\n# Stopping treatment\n\n## It is appropriate to assess response to treatment every 6 months and stop cannabidiol if it is not effective\n\nCannabidiol's marketing authorisation does not specify a stopping rule, that is, stopping treatment if or when it does not work. However, the company proposed that cannabidiol should be stopped if the frequency of seizures caused by tuberous sclerosis complex does not reduce by 30% from baseline. Baseline seizure frequency in the model was taken from the 28‑day baseline period in GWPCARE6, assumed to represent the 6\xa0months before starting treatment which would be used in clinical practice. The company implemented this stopping rule every 6\xa0months in its model. The committee noted that this aligned with the stopping rule in NICE's technology appraisal guidance on cannabidiol with clobazam for treating seizures associated with Dravet syndrome and cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome. However, the company had implemented an additional stopping rate for cannabidiol in tuberous sclerosis complex. This was based on stopping rates in GWPCARE6 in the short term, the open-label extension study in the medium term and NICE's guidance on cannabidiol for Lennox–Gastaut syndrome in the long term. The committee concluded that this was acceptable, and it was appropriate to assess response to treatment every 6\xa0months and stop cannabidiol if it is not effective.\n\n# Company's economic model\n\n## The company's model structure is appropriate\n\nThe company presented a cohort-level model to estimate the cost effectiveness of cannabidiol. It had 3\xa0health states: alive having cannabidiol with usual care, alive having usual care alone, and dead. The alive health states were further divided by the number of seizures per week (seizure-free, 2 and under, over 2 to 7, and over 7) and number of seizures per day (seizure-free, 1 and under, over 1 to 2, over 2 to 4, and over 4). The model used a lifetime horizon and a cycle length of 1\xa0week. The company did not include vagus nerve stimulation, ketogenic diet or surgery as comparators in its model because it stated these would be used equally between arms. So, the comparator was usual care with antiseizure medications. The committee concluded that the company's general model structure was appropriate.\n\n## The company's linear regression model approach for seizure-free days and number of seizures is acceptable for decision making\n\nThe company derived efficacy data for the sub-health states for number of seizures per week and number of seizures per day from GWPCARE6 at week\xa016. For the long-term effect on seizures, the company applied 2 linear regression models sequentially. The first predicted the number of seizure-free days per 7‑day cycle in the model using a binomial regression model based on individual patient data from GWPCARE6 at week\xa016. The second, a negative binomial model, predicted the total seizure frequency on non-seizure-free days per cycle. The company chose this approach to capture correlation between seizure frequency and seizure-free days. It applied the regression coefficients to each patient's baseline seizure frequency to predict outcomes for each 7‑day model cycle. Using this approach, the relative treatment effect was maintained over the modelled time horizon. Results showed a trend for reduced seizure frequency and increased odds of seizure-free days for cannabidiol plus usual care compared with placebo plus usual care. The committee noted that the relative treatment effect was not statistically significant. The company stated this was because the powers of the analyses were low because of use of weekly model cycles and 2 different regression models. The committee noted that the seizure frequency per day predicted by the company's regression model broadly aligned with data from the open-label extension study, but the study did not collect data on seizure-free days. It acknowledged the uncertainty in the company's approach but noted that the ERG had not suggested an alternative method for modelling seizures. Given this, it considered analyses using the company's linear regression models for seizure-free days and seizure frequency were acceptable for decision making.\n\n## Modelling the proportion of people who are seizure-free over 7\xa0days is uncertain but a 6.61-day cut-off is most appropriate for decision making\n\nAt the first committee meeting, the ERG was concerned that the company had modelled seizure freedom over a 7‑day cycle by using the proportion of people who were seizure-free over 6.5\xa0days. This was because a negative binomial regression model cannot predict discrete outcomes (that is, seizure-free over 0\xa0days or 7\xa0days). Using this approach, 0% of the placebo and 11% of the cannabidiol arm were seizure-free at 10\xa0weeks (the latter reduced as people stopped treatment over time). The ERG highlighted that using a cut-off of 6.5\xa0days would overestimate the number of people having cannabidiol who were seizure-free per cycle. This is because the predicted number of seizure-free days using the linear regression model results was 6.62 for cannabidiol compared with 5.89 for placebo. At technical engagement, the company provided a scenario using a cut-off of 6.61\xa0days to model the number of people per cycle who were seizure-free to better align with the regression model results. The committee also considered a scenario provided by the ERG using a cut-off of 7\xa0days, in which no one was seizure‑free over the course of a week in either arm but still gained a benefit for cannabidiol in other seizure frequency categories. The committee recalled that seizure-free days per week had not been collected as an outcome in GWPCARE6 so could not directly inform the modelling. However, it compared the number of people who were seizure-free over 7\xa0days using different cut-offs in the model with that expected in clinical practice to determine the most clinically plausible approach. It recalled that achieving seizure freedom is challenging in this population (see section\xa03.2). A clinical expert agreed it was plausible that a small number of people taking cannabidiol may achieve seizure freedom but that this would be unlikely in people only having usual care. This was supported by data from GWPCARE6 in which 5% of people taking cannabidiol and 0% of people taking placebo were seizure-free during the maintenance period. So, the ERG's scenario using a 7‑day cut-off was likely conservative. This also aligned with testimonies from patients who had taken cannabidiol. The committee recognised that the number of seizure-free days is a useful outcome for determining response to treatment. However, it was concerned that measuring this outcome over the course of a week introduced artificial effects into the model that favoured cannabidiol or usual care depending on which cut-off was chosen. It would have preferred the company to use a longer time-period, as in NICE's technology appraisal guidance on fenfluramine for treating seizures associated with Dravet syndrome which modelled the number of seizure-free days in a month. The committee agreed that the proportion of people who are seizure-free over 7\xa0days in the model was uncertain because the company's methodology was problematic. It recalled that a 6.5‑day cut-off likely overestimated the proportion who were seizure-free per week in clinical practice while a 7‑day cut-off underestimated this. So, it concluded that a 6.61‑day cut-off was most appropriate for decision making.\n\n# Costs in the model\n\n## An average dose of 15\xa0mg/kg/day for cannabidiol is appropriate for decision making\n\nThe summary of product characteristics for cannabidiol states that the dose can be increased from a maintenance dose of 10\xa0mg/kg/day to a maximum of 25\xa0mg/kg/day based on response. Yet, the company assumed an average dose of 12\xa0mg/kg/day in its base case. This was based on clinical expert advice to the company and German dispensing data from 118\xa0people with tuberous sclerosis complex, in which the median cannabidiol dose was 12.2\xa0mg/kg/day in children and 7.8\xa0mg/kg/day in adults. The committee noted that the European regulator mandates a maintenance dose of cannabidiol of 10\xa0mg/kg/day for Lennox–Gastaut and Dravet syndromes and there is no evidence that increasing the doses above this results in a different treatment effect. It also noted data from the open-label extension study that suggested a maintenance dose above 15\xa0mg/kg/day did not improve response. The ERG was concerned that a maintenance dose of 12\xa0mg/kg/day was not verified by clinical trial data (because treatment was titrated up to 25\xa0mg/kg/day or 50\xa0mg/kg/day in GWPCARE6 regardless of response) and that the proportion of people needing a higher dose in the open-label extension study was unknown. It presented scenarios varying the average dose of cannabidiol. At the second meeting, clinical experts provided dosing information based on clinical experience of treating people with tuberous sclerosis complex in clinical practice (including people who had concurrent Lennox–Gastaut syndrome) in Scotland and Wales. They stated that most people would have a dose about 12\xa0mg/kg/day in clinical practice. This was normally lower in adults, for whom 1 clinical expert estimated an average dose of 8\xa0mg/kg/day. This was because, although there is potential that higher doses may be more effective, they cause more side effects than lower doses. So, 12\xa0mg/kg/day is likely to be the average dose in clinical practice as a trade-off between efficacy and side effects. The clinical experts acknowledged a dose–response effect for cannabidiol but noted that, in their experience, they had observed similar effectiveness using lower doses to those reported for the trial dose of 25\xa0mg/kg/day. This was because people with refractory epilepsy are taking other antiseizure medications that may increase the effectiveness of cannabidiol when used in combination (see section\xa03.6). Dose titration would also be much slower in clinical practice, allowing clinicians to establish response at a lower dose than used in the trial. However, the committee remained concerned that the efficacy data in the model came from people having 25\xa0mg/kg/day in GWPCARE6 and it had no credible evidence that efficacy at half that dose would be identical. It also noted that a 15\xa0mg/kg/day average dose for cannabidiol was accepted in NICE's technology appraisal guidance on fenfluramine for treating seizures associated with Dravet syndrome. It therefore considered that, although 12\xa0mg/kg/day was likely the average dose used in clinical practice, some adjustment for loss of benefit compared to GWPCARE6 results should be included in the modelling. So, it preferred an average dose of 15\xa0mg/kg/day for decision making.\n\n## The company's Delphi panel likely overestimates healthcare resource use and a 50% reduction in hospitalisation rates should be modelled\n\nAnnual healthcare resource use based on seizure frequency for people with tuberous sclerosis complex-associated epilepsy was sourced from a 2‑round Delphi panel of clinical experts. Separate resource use estimates were produced for adults and children. The company validated these estimates using a study by Shepherd et al. (2017). This reported a cost of £44,259 over a period of 3\xa0years for resource use (GP visits, hospitalisation, other drugs and outpatient visits) in UK patients with tuberous sclerosis complex. The committee noted that the costs in the company's model for the same 3‑year period for usual care (£55,578) were significantly higher than those in Shepherd et al. and NICE's technology appraisal guidance on cannabidiol with clobazam for Dravet syndrome and cannabidiol with clobazam for Lennox–Gastaut syndrome. The ERG modelled a scenario applying the resource use costs from these appraisals. The company explained that the discrepancy was because of inflation rates in NHS reference costs (which it updated at consultation to align with inflation). The ERG also highlighted that hospitalisation costs and number of hospital days (both in a general ward and intensive care) were higher in the company's model for tuberous sclerosis complex than in the appraisals for other cannabidiol indications and costs reported in Shepherd et al. In the second committee meeting the company explained that there is a spectrum of severity in tuberous sclerosis complex. Although many people do not need frequent hospitalisation, a small proportion are associated with high resource use from having up to 40 hospitalisations per year. It defended the use of the Delphi panel for sourcing expert opinion, noting the methodology was more robust than the interviews with clinicians in the appraisals for Dravet and Lennox–Gastaut syndromes. Clinical experts explained that although tuberous sclerosis complex is a multi-organ disease, non-epilepsy-related hospital admissions are rare. So, hospitalisation rates are likely comparable to other cannabidiol indications, and may be lower than for Dravet syndrome, which causes very frequent seizures. This was supported by more frequent use of rescue medication by people with Dravet syndrome compared to the other cannabidiol appraisals. The ERG's base case after consultation reduced hospitalisation rates by 50% to better align with the other cannabidiol appraisals (the values from the Dravet and Lennox–Gastaut syndrome appraisals could not be used because seizure frequency categories differed across indications). At the second committee meeting, the committee also considered additional scenarios reducing hospitalisation rates from those in the Delphi panel by 10%, 20%, 30% and 40% provided by the company and by 25% provided by the ERG. It noted that the hospitalisation rates in scenarios were not underpinned by evidence, so the true resource use for people with tuberous sclerosis complex was unknown. However, the committee agreed it was appropriate to use the scenario that best aligned with the hospitalisation rates used in the technology appraisals for Dravet and Lennox–Gastaut syndromes. It concluded that healthcare resource use is likely overestimated in the company's model and a 50% reduction from the Delphi panel hospitalisation rates should be used for decision making.\n\n# Utilities in the economic model\n\n## The company's health state utilities are uncertain and differ from utilities in other cannabidiol appraisals\n\nThe committee recalled that the company had collected data from responses to the QOLCE and QOLIE‑31‑P questionnaires in GWPCARE6, but did not use the data in its model. This was because, during the trial, the company considered that the questions were inappropriate for assessing people with severe learning difficulties. The company also noted that data on quality of life in the literature does not consider health states and substates used in the company's model (that is, number of seizures and seizure-free days). So, the company instead asked members of the general public to estimate the quality of life associated with each health state and substate in the model. Respondents were asked to consider 'vignettes', that is, descriptions of each health state and, using a time trade-off method, give each a value. Values ranged between less than 0 (worse than death), 0 (death) and 1 (perfect health). The company considered the quality-of-life values it used in its model to be confidential. The committee understood why the company had chosen to use a vignette study given the lack of literature utility values. However, it noted a discrepancy in the health state utilities used for tuberous sclerosis complex compared with those for Lennox–Gastaut and Dravet syndromes. This was especially so for the values published in Lo et al. (2021) which used vignettes from the general public (collected after the publication of guidance on cannabidiol for Lennox–Gastaut and Dravet syndromes to align with the committee's preferred assumptions in these appraisals). The company explained that, in part, this might be because of the difference in seizure severity categories and types of seizures in the other appraisals. The vignettes were considered by the general public who may find it hard to quantify the difference between the worst health state for Lennox–Gastaut syndrome (more than 110 drop seizures per month) compared with that for tuberous sclerosis complex (more than 4 seizures per day). A clinical expert stated that, although the epilepsy aspect of the 3\xa0conditions may be similar, it is difficult to compare the severity of the indications. This is because tuberous sclerosis complex is a multi-organ disease associated with complications such as those in the skin, eyes and lungs that affect quality of life and are not present in the other conditions. So, correcting seizures will only partly correct the quality-of-life decrement associated with severe tuberous sclerosis complex. The committee was concerned that this was not captured in the company's model because the utility values for the seizure-free health state for both people with the condition and their carers was relatively high. It also noted that the health state utility values used in NICE's technology appraisal guidance on fenfluramine for treating seizures associated with Dravet syndrome encompassed a much narrower range than those used in the company's modelling of cannabidiol for tuberous sclerosis complex. In the fenfluramine appraisal, values were derived using empirical measurements collected in clinical trials, which had been mapped to EQ‑5D values in a way that matches the NICE reference case. The committee noted that it had not been presented with scenarios that used alternative health state utilities for cannabidiol, so could not determine the impact on the cost-effectiveness estimates. Given the lack of utility values in the literature, it would have liked to see data supporting the plausibility of the vignette values, especially for the seizure-free and most severe health states. However, acknowledging the high level of uncertainty, the committee considered the analyses using the company's utility values in its decision making. It concluded that the company's health state utilities are uncertain and differ from utilities in other cannabidiol appraisals.\n\n## The effect on carers' quality of life should be modelled and it is appropriate to use 1.8 carers in the modelling\n\nThe committee recalled that caring for someone with tuberous sclerosis complex affects carers' quality of life (see section\xa03.1), and that capturing this in the model is appropriate. The company included utility decrements in its model for seizure frequency health states (number of seizures per day) based on the vignette study. This was because carer quality of life had not been measured using a preference-based approach in GWPCARE6, so utilities could not be derived directly from the trial. In its base case at the first committee meeting, the company assumed that people with tuberous sclerosis complex would have a cumulative 2\xa0carers (1 primary caregiver plus others such as partners, friends and family). This was based on a paper by Lagae et al. (2019), which reported that people with Dravet syndrome had an average 2.06\xa0carers. The clinical experts explained that there are no significant differences in the burden of care for seizures between cannabidiol indications. However, the total burden of care for people with tuberous sclerosis complex may be higher because of the combined effect of the epilepsy, associated learning disabilities and other comorbidities that occur with the condition. The ERG was concerned that the carer disutilities were applied additively in the company's model. It used 1.8\xa0carers in its base case, which aligned with the committee's preferred assumptions in NICE's technology appraisal guidance for Dravet syndrome and Lennox–Gastaut syndrome. The committee agreed that the company's approach implied that the caring burden increases linearly the more carers a patient has. However, for a patient with multiple carers, it expected there to be less effect on the quality of life of each carer because they would 'share' some of the burden. At consultation, the patient organisations highlighted that care given by 2\xa0carers does not reduce burden of care. The company supported this, stating that each carer will have worry and psychological distress from caring for a patient at risk from injury and death because of seizures. However, it updated its modelling to align with the committee's preference at the first meeting of 1.8\xa0carers. This was because, while the total burden for 2\xa0carers may be greater than the burden for a sole carer, the committee agreed that it would likely not be 2\xa0times greater. It recalled that people with tuberous sclerosis complex may need help with every aspect of daily life (see section\xa03.1). However, given the multifactorial nature of the disease and associated care needs of people living with it, reducing seizure frequency would only go some way towards relieving carer burden. The committee recalled that carer health state utility values could not be derived directly from the clinical trial and that the values from the company's vignette were uncertain (see section\xa03.13). Given this uncertainty, it agreed that the model should use 1.8\xa0carers to align with assumptions used in previous appraisals of cannabidiol.\n\n## The seizure-free health state utility for carers is uncertain but a value of 0.881 is acceptable for decision making\n\nThe vignette calculated the impact of worsening seizure frequencies on carers as an incremental decrease from the carer utility for the seizure-free health state. After technical engagement, the company updated its base case to use a utility value for the seizure-free health state for carers equal to that of an average 45‑year‑old. This was because in the vignettes, members of the general public were asked to adopt the perspective of the primary caregiver of a 13‑year‑old child and the average parent of a child this age was 45\xa0years (Office for National Statistics data). However, the ERG was concerned that the company's value overestimated the impact of seizure freedom on carers. This was because it had not adjusted for carers ageing and that the burden of care for non-seizure-related aspects of tuberous sclerosis complex may not be captured in the company's estimate. At consultation, the ERG also highlighted that carer utility was unlikely to adjust the moment a patient becomes seizure-free. It provided scenarios with lower utility values for the seizure-free health state for carers. The committee considered these scenarios in its decision making. However, it noted that the absolute utility decrement was unchanged regardless of the value used for seizure freedom. Also, the ERG had maintained the value of 0.881 in its preferred assumption after consultation. It concluded that the seizure-free health state utility for carers is uncertain but the utility value in the company and ERG's base cases is appropriate for decision making.\n\n## It is appropriate to include a reduction in carer utility associated with institutionalisation and the ERG's approach is preferable\n\nBased on the consensus in the Delphi panel, the company assumed that 31% of people with tuberous sclerosis complex-associated epilepsy were institutionalised at an average age of 27\xa0years. However, in its base case it did not model any impact on carer utility during this period. The company stated that carers for people who were institutionalised would still have:\n\nconcerns about the risk of injury from seizures or worsening of seizures in a new environment\n\neveryday life centred around visiting patients and accompanying them to healthcare visitsThe ERG assumed a 50% reduction in carer disutility for 31% of adults in its base-case model. The company also provided scenarios that increased caregiver utility by 50% for the same proportion of people. A clinical expert stated that institutionalisation was expected to be associated with an increase in quality of life for carers. The patient expert agreed that although carers had more free time if a person with tuberous sclerosis complex was institutionalised, concerns and guilt would remain, especially about exposure to abuse. The committee recalled that tuberous sclerosis complex significantly impacts sleep for the whole family, which would improve when a patient was institutionalised (see section\xa03.1). It noted that the ERG's method was conservative in that it resulted in lower utility values for the less severe health states. However, the committee considered that the increase in carer quality of life in the company and ERG's analyses were not supported by data and other scenarios would be equally plausible. At consultation, the company updated its base case to adjust for institutionalisation using the ERG's approach, after correction of an error in the modelling. The committee concluded that it is appropriate to include a reduction in carer disutility associated with institutionalisation. Given the lack of evidence to support the size of this reduction, it considered the ERG's approach preferable.\n\n# Accounting for TAND aspects in the model\n\n## It is appropriate to model cannabidiol's effect on TAND aspects accepting that this adds uncertainty\n\nThe company included a cost in the model associated with managing TAND aspects. It also assumed a benefit on TAND aspects for people whose condition responds to cannabidiol, which it modelled as a utility benefit and a reduced cost. The utility benefit for delaying TAND was estimated by weighting utility increments for common TAND aspects from various literature sources by their prevalence using data from the tuberous sclerosis registry to increase disease awareness (TOSCA; de Vries et al. 2015). 'Responders' to cannabidiol were defined as the proportion of people with a reduction in tuberous sclerosis complex-associated seizures of 50% or more from baseline over 6\xa0months. Based on the Delphi panel consensus that treatment with cannabidiol is likely to be most beneficial at an early age, only people aged 2\xa0years to 6\xa0years accrued costs and benefits associated with TAND aspects. The ERG had the following concerns about the company's assumption for TAND:\n\nPrevalence rates, costs and utility benefits were not based on data collected in the clinical trials.\n\nThe Delphi panel did not reach a full consensus on the level of response to cannabidiol needed to delay TAND aspects.\n\nThe proportion of responders was based on the full trial population but applied only to 2- to 6-year-olds.The committee noted that the vignettes used to elicit health state utilities may already have captured some of the aspects of TAND, so there was potential for double counting. However, the company explained that it had updated its base case at technical engagement to use conservative estimates (using the lowest utility benefit from the literature and applying TAND aspects to ages 2\xa0years to 6\xa0years only). A clinical expert explained that evidence supports an improvement in long-term TAND aspects with a reduction in seizure frequency at an early age. However, it is unclear whether this is the case for adults. The committee acknowledged the uncertainty around the company's modelling but recalled that TAND has a significant effect on the quality of life of people with tuberous sclerosis complex and their carers (see section\xa03.1). It agreed that costs and utility benefits for TAND should be included in the modelling using the company's estimates provided at technical engagement.\n\n# Cost-effectiveness estimates\n\n## Cost-effectiveness analyses include plausible ICERs outside the range normally considered a cost-effective use of NHS resources\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life-year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of confidential commercial arrangements for cannabidiol and comparators, none of the cost-effectiveness results are reported here. The committee noted the differences between the ERG's and company's base case after consultation in that the ERG used a 15\xa0mg/kg/day dose instead of 12\xa0mg/kg/day and reduced hospitalisation rates by 50% compared with those from the Delphi panel. The company base case was under £20,000 per QALY gained compared with usual care. However, the ERG base case was over £30,000 per QALY gained compared with usual care. This was when considering confidential discounts. The committee agreed that its preferred assumptions to compare cannabidiol with usual care aligned with the ERG base case, that is, they included:\n\nusing a 6.61‑day cut-off for the proportion of people who are seizure-free over 7\xa0days (see section\xa03.10)\n\nusing an average dose of 15\xa0mg/kg/day (see section\xa03.11)\n\nconsidering a lower number of hospital admissions, that is, reduced by 50% (see section\xa03.12)\n\nusing the health state utilities from the company's vignette while acknowledging the high uncertainty surrounding the estimates (see section\xa03.13)\n\nassuming a cumulative 1.8\xa0carers (see section\xa03.14)\n\nusing a utility value of 0.881 for the seizure-free health state for carers (see section\xa03.15)\n\nadjusting for institutionalisation using the ERG's approach corrected for errors (see section\xa03.16)\n\nincluding cost and benefits for TAND aspects for people aged 2\xa0years to 6\xa0years, using the utility benefit from the company's base case (see section\xa03.17).The committee noted there were several uncertainties in the company's modelling. It acknowledged that changing the average dose of cannabidiol significantly increased the cost-effectiveness estimates. It also recalled that healthcare resource use was likely overestimated in the company's model. It noted that including a 50% reduction in hospitalisation rates also increased the cost-effectiveness estimates. The committee considered a range of cost-effectiveness analyses including plausible ICERs outside the range normally considered to be a cost-effective use of NHS resources.\n\n# Other factors\n\n## Uncaptured benefits of cannabidiol and severity of the disease should be considered in decision making\n\nThe committee noted NICE's principles for the development of NICE guidance. This emphasises the importance of considering the distribution of health resources fairly within society as a whole, and factors other than relative costs and benefits alone. It recalled that tuberous sclerosis complex is a severe and multisystemic disease that significantly affects the quality of life of patients, carers and families (see section\xa03.1). It agreed that the severity of disease should be considered in the decision making. At the second committee meeting, the committee also noted that the following benefits of cannabidiol were not captured in the company's model:\n\na quality-of-life benefit for people with the condition from reducing severity of seizures including to a point at which they no longer impact usual activities\n\na reduction in hospitalisation rates from reducing the severity of seizures\n\nthe physical and mental benefit on the wider family, including siblings, because of the improved behaviour and reduction in healthcare visits associated with seizure control\n\na mortality benefit from reducing SUDEP related to tuberous sclerosis complex.The committee considered these factors important for improving quality of life. It concluded that it would take these benefits into account in its decision making.\n\n## Cannabidiol does not meet the criteria for an innovative treatment\n\nThe clinical experts stated that they would welcome an additional treatment option for tuberous sclerosis complex. However, they considered that cannabidiol represents only a modest change when managing tuberous sclerosis complex because few people became seizure‑free (see section\xa03.10). The committee concluded that cannabidiol did not meet the criteria for an innovative treatment.\n\n## Equalities\n\nThe committee noted that the population for which cannabidiol is indicated includes children and young people. It discussed the need to balance the importance of improving the lives of children and their families with fairness to people of all ages. The committee also noted that half of people with tuberous sclerosis complex have associated learning difficulties, which is a protected characteristic under the Equality Act 2010. At the second committee meeting, the clinical experts highlighted that access to care for people with learning difficulties may be harder. Also, tuberous sclerosis complex is a hereditary disease, so one or more parents might also have the condition, increasing the challenge in accessing appropriate healthcare. The committee acknowledged and considered the nature of the population as part of its decision making.\n\n# Conclusion\n\n## Cannabidiol is recommended for treating seizures caused by tuberous sclerosis complex\n\nThe committee recalled its conclusion to consider factors other than relative costs and benefits of cannabidiol alone (see section\xa03.19). It acknowledged that the cost-effectiveness estimates were uncertain for cannabidiol because of some of the assumptions in the company's model (see section\xa03.18). However, the committee concluded that, despite these uncertainties and considering the uncaptured benefits and severity of the disease, cannabidiol is an effective treatment and a good use of NHS resources. It therefore recommended cannabidiol for treating seizures caused by tuberous sclerosis complex. It agreed that seizure frequency should be checked every 6\xa0months and that, if the frequency has not fallen by at least 30% compared with the 6 months before starting treatment, cannabidiol should be stopped (see section\xa03.7)."}	https://www.nice.org.uk/guidance/ta873	Evidence-based recommendations on cannabidiol (Epidyolex) for treating seizures caused by tuberous sclerosis complex.
6ff25c79583e6dffd81a0c99a7764d3ee8e60d70	nice	Polatuzumab vedotin in combination for untreated diffuse large B-cell lymphoma	Polatuzumab vedotin in combination for untreated diffuse large B-cell lymphoma Evidence-based recommendations on polatuzumab vedotin (Polivy) with rituximab, cyclophosphamide, doxorubicin and prednisolone for untreated diffuse large B-cell lymphoma in adults. # Recommendations Polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisolone (R‑CHP) is recommended for untreated diffuse large B-cell lymphoma (DLBCL) in adults, only if they have an International Prognostic Index (IPI) score of 2 to 5 the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with polatuzumab vedotin with R-CHP that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard treatment for untreated DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP). The company only provided evidence for polatuzumab vedotin with R-CHP for people with an IPI score of 2 to 5. This is narrower than polatuzumab vedotin's marketing authorisation, but clinical experts advised this is how it would be used in clinical practice. Clinical evidence suggests that people with an IPI score of 2 to 5 having polatuzumab vedotin with R‑CHP have more time before their cancer gets worse than people having R‑CHOP alone. It is not clear if polatuzumab vedotin with R‑CHP increases how long people live compared with R‑CHOP. The cost-effectiveness estimates for polatuzumab vedotin with R‑CHP are likely to be within what NICE considers an acceptable use of NHS resources. So, polatuzumab vedotin with R-CHP is recommended for people with an IPI score of 2 to 5.# Information about polatuzumab vedotin # Marketing authorisation indication Polatuzumab vedotin (Polivy, Roche) in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone is indicated for 'the treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL)'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for polatuzumab vedotin. # Price Polatuzumab vedotin costs £2,370 per 30 mg vial or £11,060 per 140 mg vial (excluding VAT, BNF online accessed December 2022). The company has a commercial arrangement. This makes polatuzumab vedotin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need and treatment pathway ## There is a high unmet need for a first-line treatment that stops diffuse large B-cell lymphoma progressing Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease. Symptoms usually develop rapidly and progress quickly. The disease is treated with the aim of cure, but it is refractory to treatment or relapses after initial treatment in up to 50% of people. The clinical experts explained that current treatment for untreated DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP). They noted that first-line treatment has the best chance of cure. They explained there is an unmet need to stop the disease from progressing. This is because treatment options for relapsed or refractory disease are associated with significant burden and toxicity. The clinical experts explained that relapsed or refractory disease has poor survival rates. A patient expert submission to NICE explained that DLBCL is difficult to live with because of the symptoms of both the disease and treatment. Common symptoms include painless swellings at single or multiple sites (lymph node and non-lymph node), excessive night sweating, unexplained fever and weight loss. The patient expert submission also highlighted the psychological effects of relapsed or refractory disease for both patients and carers. People may have insomnia, anxiety and a constant fear of relapse and death. The committee agreed that DLBCL is an aggressive form of lymphoma that needs intensive treatment. It concluded that there is a high unmet need for first-line treatments that prevent disease progression. # Clinical evidence ## It is appropriate to exclude DLBCL with an IPI score of 0 to 1 from this appraisal in line with the evidence available The International Prognostic Index (IPI) risk group is usually used to predict DLBCL prognosis. IPI risk group is categorised based on independent predictors for outcomes like overall survival and progression-free survival. IPI risk group is determined by the number of predictors met: 0 or 1 is low risk, 2 is low-intermediate risk, 3 is high-intermediate risk, and 4 or 5 is high risk. The company positioned polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisolone (R‑CHP) for DLBCL with an IPI score of 2 to 5. This is because the clinical trial excluded those with an IPI score of 0 to 1. However, the committee recalled that the marketing authorisation is 'adult patients with previously untreated DLBCL' and does not restrict by IPI risk group. The clinical experts explained that the outcomes for IPI 0 to 1 were usually very good and only a small proportion of people with DLBCL have an IPI score of 0 to 1. They noted that it was appropriate to exclude DLBCL with an IPI score of 0 to 1. The committee concluded that it was appropriate to exclude DLBCL with an IPI score of 0 to 1 for this appraisal, in line with the evidence available. ## The appropriate population for decision making is people with DLBCL with an IPI score of 2 to 5 The main clinical evidence was from the POLARIX trial. This was a multicentre phase 3, double-blind, placebo-controlled study in adults with previously untreated DLBCL with an IPI score of 2 to 5. POLARIX compared polatuzumab vedotin plus R‑CHP with R‑CHOP. The primary end point was progression-free survival. People who had polatuzumab vedotin with R‑CHP had a 24-month progression-free survival rate of 76.7 (95% confidence interval 72.7 to 80.8) compared with 70.2 (95% CI 65.8 to 74.6) for people who had R‑CHOP. The hazard ratio for disease progression or death was 0.73 (95% CI 0.57 to 0.95, p=0.02). The company did pre-specified exploratory subgroup analyses, dividing by IPI risk group, among other things. For the IPI 3 to 5 subgroup the hazard ratio for disease progression or death was 0.7 (95% CI 0.5 to 0.9). The committee noted that for some subgroups, such as IPI 2, age 60 or below, presence of bulky disease, and women, the 95% CIs for disease progression or death crossed 1. It noted that in the IPI 2 subgroup, which was 38% of the trial population, the hazard ratio for disease progression or death was 1.0 and 95% CIs ranged from 0.6 to 1.6, suggesting a lack of progression-free survival benefit in this group. The company noted in its submission that the subgroup analyses in the trial were exploratory and not confirmatory, and that POLARIX was not designed or powered to compare subgroups. It also explained that because IPI 2 disease is lower risk and progression or death occurs less often in this population the effect may not be picked up in the trial. The ERG explained that noise in the data could be a reason for the lack of effect shown in some of the subgroups. The clinical experts agreed with the company that IPI 2 disease is a lower risk group and that it is difficult to draw conclusions from the subgroup analysis when it is exploratory. In response to the appraisal consultation document, the company provided a scenario analysis for the IPI 3 to 5 subgroup. The committee noted that there was biological plausibility that people with IPI 3 to 5 disease would benefit more from treatment with polatuzumab vedotin plus R-CHP than people with IPI 2 to 5 disease. It noted that this is because they have more risk factors associated with poorer prognosis, which was supported by the exploratory subgroup analyses. However, the committee noted that the trial was designed to investigate the IPI 2 to 5 population and that the company had previously stated that the IPI 3 to 5 subgroup was only exploratory. The committee also noted that the company had not presented estimates of long-term survival for the IPI 3 to 5 population. Also, it did not have enough information on how the subgroup data had been used by the company to include it in its decision making. The committee concluded that people with an IPI score of 2 to 5 was the appropriate population for decision making. ## An overall survival benefit for polatuzumab vedotin with R-CHP compared with R-CHOP cannot be determined using current data People who had polatuzumab vedotin with R‑CHP had a 24‑month overall survival rate of 88.7% (95% CI 85.7 to 91.7) compared with 88.6% (95% CI 85.6 to 91.6) for R-CHOP. The hazard ratio for death was 0.94 (95% CI 0.65 to 1.37). The company explained that the overall survival results are immature and follow up is not long enough to capture the effect of polatuzumab vedotin with R‑CHP on survival. The ERG explained that the POLARIX overall survival analysis did not show a statistically significant difference between polatuzumab vedotin with R‑CHP and R‑CHOP because the confidence interval crossed 1. The committee concluded that it was uncertain if there was an overall survival benefit of polatuzumab vedotin with R‑CHP compared with R‑CHOP. # Survival modelling ## Progression-free and overall survival are extrapolated using a mixture-cure model The company and ERG both used a mixture-cure model to extrapolate progression-free survival and overall survival. The mixture-cure model assumed the population consisted of 2 groups: a 'cured' population and a population whose disease would progress. The 'cured' population is assumed to have the same risk of death as the age- and sex-matched general population after 2 years. The committee concluded that a mixture-cure model was a reasonable approach. ## The overall survival extrapolations are highly uncertain The company explained that it was not possible to estimate long-term survival from the overall survival data in POLARIX because the overall survival data was immature (see section 3.4). Because of this, the overall survival mixture-cure model was informed by the progression-free survival cure fraction. The ERG explained that the approach seemed logical given the immaturity of the overall survival data in POLARIX. However, it noted that the company's overall survival extrapolations were highly uncertain. After consultation, the ERG presented a scenario showing how assuming no overall survival benefit with polatuzumab vedotin with R‑CHP compared with R‑CHOP affects the cost-effectiveness results. It explained that this was in line with the evidence from POLARIX which had not shown any difference in overall survival at 24‑month follow up (see section 3.4). The committee noted that the overall survival extrapolations were highly uncertain. But, based on the benefits in progression-free survival seen in POLARIX (see section 3.3), it was plausible that there would be an overall survival benefit with polatuzumab with R‑CHP, meaning the ERG's scenario analysis was conservative. The company noted that more overall survival data will be available in the future from data cuts in August 2022 and 2024. The committee noted that given the overall survival event rate seen in the POLARIX trial, it is unlikely that a meaningful number of overall survival events will have occurred at these data cuts to meaningfully address the overall survival uncertainty. The committee concluded that the ERG's scenario assuming no overall survival benefit with polatuzumab vedotin with R‑CHP was likely an underestimate of overall survival. It further concluded that the company's overall survival extrapolation was broadly appropriate but highly uncertain, and that forthcoming clinical trial data is unlikely to meaningfully address the uncertainty. ## It is not appropriate to include treatment effect waning POLARIX showed no statistically significant survival benefit for polatuzumab vedotin with R‑CHP compared with R‑CHOP (hazard ratio 0.94; 95% CI 0.65 to 1.37). However, the company's extrapolation (based on the mixture-cure model, see section 3.5) assumed a continued survival benefit for polatuzumab vedotin with R‑CHP over R‑CHOP. The company explained that because DLBCL is curable in first line, a waning effect should not be applied. The company considered that because overall survival estimated in the model is informed by progression-free survival from POLARIX, the long-term efficacy of polatuzumab vedotin with R‑CHP is likely to be underestimated. The ERG explained that there is uncertainty in the overall survival benefit from POLARIX (see section 3.4 and section 3.6) and other subsequent treatments would affect long-term survival. So the ERG applied a waning effect to overall survival to try to account for some of the uncertainty. After consultation, the ERG updated its approach to treatment waning by assuming equal overall survival in each treatment arm after 60 months. The company also presented evidence from first-line and relapsed and refractory DLBCL trials to support a continued survival benefit. The ERG noted that the additional trial evidence provided by the company supported a continued overall survival benefit in DLBCL. But it explained that these trials had different treatment regimens, patient characteristics and study lengths, which limited how applicable this evidence was to polatuzumab vedotin with R‑CHP. The ERG highlighted that the waning effect is in the context of a mixture-cure model. This means waning is applied to the whole population, even those whose disease is cured, which is a more conservative approach than the company's. The clinical experts explained that most death and relapse would occur within 2 years and that subsequent treatments are associated with significant toxicity. The committee noted that applying treatment waning to the whole population in the context of the mixture-cure model, meant that there is a 'cured' population initially, whose disease is then considered 'uncured' later. It noted that the company's approach favoured polatuzumab vedotin with R‑CHP and was associated with uncertainty. But it considered the company's approach to be more clinically plausible than the ERG's. Because of this, the committee concluded that treatment effect waning should not be included, but took account of uncertainty about the modelled overall survival estimates in its decision making. ## It is unclear if the company's correction to the progression-free survival modelling is appropriate In response to the appraisal consultation document, the company highlighted a technical error in the model. It corrected the model at consultation so that at the point progression-free survival extrapolation estimates meet and exceed overall survival extrapolation estimates, they are capped in line with the overall survival extrapolation. The ERG suggested that the company's correction provides counter-intuitive results when changes are made to overall survival. It explained that this is because the mixture-cure model is inflexible to changes such as the correction the company had made. The ERG also explained that based on the information provided by the company, it had been unable to scrutinise this issue adequately. After requests for clarification by the committee at the second appraisal committee meeting, the nature of the error and the appropriateness of the correction was still uncertain. After the second committee meeting, the company provided further explanation on the correction. But the ERG noted that without further scrutiny it remained unclear if the correction was valid. The committee concluded that it was unclear if the company's correction to the progression-free survival modelling was appropriate. # Economic modelling ## The company's model structure is suitable for decision making The company used a 3‑state partitioned survival model to estimate the cost effectiveness of polatuzumab vedotin with R‑CHP compared with R‑CHOP. It had 3 health states: progression-free, progressed disease and death. The committee considered that the partitioned survival model is a standard approach to estimating the cost effectiveness of cancer drugs and concluded that it was appropriate in this instance. ## Patient weight from the Western European, US, Canadian and Australian population in POLARIX is appropriate to use in the model The model used patient weight distributions from the full population in the POLARIX trial. The committee noted that the mean patient weight from POLARIX was 75.92 kg, which is lower than calculated in the 2019 NHS Health Survey for England on overweight and obesity in adults and children (78.75 kg for adults). So the committee questioned if the weight distribution used in the model represented NHS clinical practice. It noted that this could affect the number of vials needed for each person, which would in turn influence costs. It was also aware that no vial sharing was assumed in the model, which may be a conservative approach. In response to the appraisal consultation document, the company explained that the mean patient weight from the subgroup of people in Western Europe, US, Canada and Australia (referred to from now as the Western subgroup) in POLARIX was 80.1 kg. It presented a scenario analysis using the height and weight distribution from the Western subgroup which increased the incremental cost-effectiveness ratio (ICER) by 11%. The committee noted that the average weight in the Western subgroup of POLARIX was more generalisable to the UK population than the weight in the full trial population. The company also presented evidence from a US study (O'Brian et al. 2015) predominantly in men (97%) who received a DLBCL diagnosis between 1998 and 2008. The company explained that this evidence showed that on average, people with DLBCL have 5% weight loss in the year leading up to diagnosis. It explained that the average weight in the general population with 5% weight loss applied (74.8 kg) is generalisable to the weight in the full POLARIX population. The ERG explained that O'Brian et al. was done in a population that may not be generalisable to people who are having treatment for DLBCL in the NHS. The committee noted that the company's assumption that people with DLBCL would have 5% weight loss before diagnosis was based on 1 study in a population that is likely to have a different weight distribution to the population with DLBCL in the NHS. The committee concluded that it was appropriate to use the weight distribution of the Western subgroup in the model because this was most likely to be generalisable to the weight of people with DLBCL in the NHS. ## The company's progressed disease supportive care costs are likely to be overestimated Supportive care costs are applied to people in every weekly cycle in the model for the duration of the time the person is in the health state. For progressed disease, this is every year until the disease is cured or death occurs. In its original submission, the company used resource use data for progressed disease based on NICE's technology appraisal guidance on polatuzumab vedotin (TA649) which used progressed disease resource data from NICE's technology appraisal guidance on pixantrone monotherapy (TA306). In its original base case, the ERG preferred to estimate resource use based on NICE's technology appraisal guidance on rituximab (TA243). The committee concluded at the first appraisal committee meeting that neither the company nor ERG base cases represented supportive care resource use for DLBCL in the NHS. It further concluded that end of life costs, included in the company's progressed disease resource use, should be removed. In response to the appraisal consultation document, the company removed end of life costs from the progressed disease supportive care costs. Also in response to the appraisal consultation document, the company updated its approach to estimating progressed disease resource use and costs. The ERG highlighted that the company's approach assumed supportive care costs for progressed disease would apply indefinitely. However, many people would have response to subsequent treatments and no longer incur these costs. Or, they may have end of life care only. The company explained that the same progressed disease costs were applied in every weekly cycle even though there are periods of high intensity treatment and lower intensity follow up. It explained that this meant that on average, the weekly costs included for progressed disease were appropriate. To inform its updated approach, the company did a survey with 3 clinicians to estimate resource use associated with second-line treatment for DLBCL. Based on this survey, it applied updated costs for the progressed disease state to its model. The company explained that the survey asked clinicians what the resource use was for people with DLBCL having second-line treatment only and did not ask about the off-treatment costs. People in the progressed disease state spend all their time after first progression in this state. So, the committee noted that the survey should have accounted for second-line treatment and all subsequent lines of therapy. The committee considered that this survey may have produced biased results, which reflected the costs of being on second-line treatment, but not the costs of being off treatment or on subsequent treatments. Further bias was possible because it was an opinion-based survey and not based on quantitative data. The committee noted that time off treatment should be considered when estimating the supportive care costs in progressed disease. It was not persuaded that this had been accounted for in the company's model. The committee concluded that the company's progressed disease costs are likely to be overestimated. ## Reduction in the company's progressed disease supportive care costs by between 25% to 50% is appropriate The ERG explained that to accurately estimate costs for the progressed disease state, on and off treatment costs should be included in the model, but the model was not structured to allow for this. The ERG estimated the time spent incurring costs in the progressed disease state in the model. It based its estimate on the number of subsequent treatments in POLARIX and an estimate of average time to progression on subsequent treatments for relapsed or refractory DLBCL, based on a study by Ohmachi et al. (2013). Based on this, it estimated that a 50% reduction in the company's progressed disease costs (see section 3.11) was appropriate, accounting for minimal costs when off treatment. The committee noted that the ERG's estimate of a 50% reduction in the company's progressed disease costs was uncertain and based on an estimate of time to progression in relapsed and refractory DLBCL from a single study. It was also uncertain what costs were estimated for people who were off treatment in the ERG's analysis and considered that these may be too low. So, it agreed that a reduction in the company's estimate of progressed disease costs was appropriate, but the ERG's estimate of a 50% reduction in costs was likely too large. It noted that the ERG had also provided a scenario analysis including a 25% reduction in the company's progressed disease costs. But it was uncertain if this scenario analysis was appropriate because it may not reduce the costs enough. It concluded that the appropriate supportive care costs for progressed disease were likely to be somewhere between the ERG's scenario analysis reducing the company's costs by 25% and the ERG's preferred assumption of reducing the company's costs by 50%. ## Utility for progressed disease may not have been fully accounted for The company used utility values from the GOYA trial because it had a longer follow up than POLARIX. GOYA was a phase 3, open-label study of obinutuzumab plus CHOP compared with R‑CHOP in adults with previously untreated CD20-positive DLBCL with an IPI score of 2 to 5. The company explained that 11 clinicians had confirmed that the GOYA utility values were more representative of DLBCL than the POLARIX utility values. The company presented several reasons why the POLARIX utilities were not representative of people with relapsed or refractory DLBCL seen in the NHS. Some people whose disease progressed did not report health-related quality of life (the exact number is considered confidential by the company and cannot be reported here) and those who did report had better health outcomes than those who did not. The company also explained that the timing of collection of the health-related quality of life data affected its applicability. The company considered the timing to be confidential so it cannot be reported here. The ERG noted that the GOYA utility values were similar to those used in NICE's technology appraisal guidance on polatuzumab vedotin (TA649) so agreed to use the GOYA utility values in the base case. The ERG also age adjusted the progressed disease utility values using UK general population utility values from Ara and Brazier (2010). The committee queried the timing of the health-related quality of life data collection in the GOYA trial, which the company explained was before second-line treatment. The committee questioned whether the valuation of health-related quality of life data was overestimated because the GOYA data was collected before later line treatments were started. Clinical experts explained that the toxicity of later line treatments is significant and that they would expect this to contribute to quality of life. The committee noted it would have preferred to have seen GOYA utilities after second-line treatment was started. However, it concluded that the company's approach was acceptable for decision making but uncertain. ## CAR-T therapies should not be included as subsequent treatments In its initial submission, the company included 2 chimeric antigen receptor T‑cell (CAR‑T) therapies as subsequent treatments in the model. These CAR‑T therapies are currently in the Cancer Drugs Fund; see NICE's technology appraisal guidance on axicabtagene ciloleucel (TA559) and NICE's technology appraisal guidance on tisagenlecleucel (TA567). NICE's position statement is that technologies with Cancer Drugs Fund recommendations cannot be considered as part of the treatment sequence in relevant appraisals because they cannot be considered established practice. The committee acknowledged the relevance of TA559 to this appraisal, and noted that it is currently being reviewed. At technical engagement, the company explained that CAR‑T therapies have high costs, which may make polatuzumab vedotin with R‑CHP more cost effective in the long term. But it agreed to remove CAR‑T therapies as subsequent treatments from the model. The committee concluded that CAR‑T therapies should not be included as subsequent treatments because they are not routinely commissioned. ## Redistributing CAR-T therapy use to other subsequent treatments is acceptable After technical engagement, in the model the company redistributed people having CAR‑T therapies to have other subsequent treatments. The ERG explained this meant the total use of subsequent treatments was more than 100%, which is implausible. Instead, the ERG did not adjust the proportion of people having each subsequent treatment when CAR‑T therapies were removed at technical engagement. This made total subsequent treatment use 97%. The committee noted that use of subsequent treatments in the model was more than 100% before the redistribution of CAR‑T therapies. The company explained that this was because chemotherapy and stem cell transplants were considered separately in the model (that is, if someone had chemotherapy and a stem cell transplant, this would be counted as 2 subsequent treatments, meaning the percentage would be higher than 100%). The committee concluded at the first appraisal committee meeting that people would have other treatments if CAR‑T therapy was not available. After consultation, the ERG updated its base case to include redistribution of CAR‑T therapies to other subsequent treatments. The committee concluded that the company's and updated ERG assumption about CAR‑T therapy redistribution was appropriate. # End of life ## End of life criteria are not met for polatuzumab vedotin with R-CHP The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal 2013. The committee was aware that the mean life expectancy for people with untreated DLBCL who had R‑CHOP was more than 24 months. So, it concluded that polatuzumab vedotin with R‑CHP did not meet the end of life criteria. # Innovation ## Polatuzumab vedotin with R-CHP is innovative Clinical experts explained that POLARIX is the first international double-blind randomised controlled trial in over 20 years to show meaningful improvement in the benefit-risk profile of another treatment over R‑CHOP. The committee concluded that polatuzumab vedotin with R‑CHP is innovative. # Cost-effectiveness estimates ## An acceptable ICER is between £20,000 and £30,000 per QALY gained NICE's guide to the methods of technology appraisal 2013 notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered polatuzumab vedotin with R‑CHP innovative but noted that the long-term overall survival estimates were highly uncertain (see section 3.6). It also took into account the likelihood of decision error and its consequences. So, it agreed that an acceptable ICER would be between £20,000 and £30,000 per QALY gained. ## Polatuzumab vedotin with R-CHP is likely to be cost effective The committee noted that its preferences were not fully reflected in either the company's or the ERG's base case at the second committee meeting. The committee's preferred assumptions included: considering the full POLARIX population (see section 3.3) the company's overall survival extrapolation approach (although noting this was highly uncertain; see section 3.6) no treatment effect waning (see section 3.7) the patient weight distribution from the POLARIX Western population subgroup (see section 3.10) excluding CAR‑T therapies (see section 3.14) redistributing CAR‑T therapy use to other subsequent treatments (see section 3.15).The committee noted that the company provided a scenario analysis for the IPI 3 to 5 subgroup (see section 3.3). However, it was unclear how the subgroup data had been incorporated into the company's economic model in the scenario analysis. So the committee preferred to consider the full POLARIX population in its decision making. The committee noted that the utility values for progressed disease were uncertain but that the approach used in the company's and ERG's base case was acceptable for decision making (see section 3.13). It also noted that the company included a correction to the progression-free survival modelling after consultation. But it noted that it was unclear if this correction was appropriate and that including it lowered the ICER (see section 3.8). The committee also noted that the company's progressed disease supportive care costs were likely overestimated (see section 3.11). But it considered that the ERG's assumption of a 50% reduction in the company's costs was likely an underestimate and that reducing the company's progressed disease costs by between 25% to 50% is appropriate (see section 3.12). After the second appraisal committee meeting, the company provided an updated base case, including all of the committee's preferred assumptions, as well as: removal of the progression-free survival curve correction a reduction in the progressed disease costs by 30% an updated commercial arrangement for polatuzumab vedotin.The committee agreed that the company's updated base case ICER was appropriate for decision making. Because of confidential commercial arrangements for cyclophosphamide, doxorubicin, prednisolone and rituximab, the exact ICERs are confidential and cannot be reported here. Taking into account all the confidential discounts, the company's updated base case ICER was at the lower end of the range of what NICE considers a cost-effective use of NHS resources. So, the committee concluded that polatuzumab vedotin with R-CHP is likely to be cost effective. # Conclusion ## Polatuzumab vedotin with R-CHP is recommended for untreated DLBCL The committee noted that when taking into account all its preferred assumptions and the commercial arrangement offered by the company, polatuzumab vedotin is likely to be a cost-effective use of NHS resources. So, it recommended polatuzumab vedotin with R-CHP for untreated DLBCL with an IPI score of 2 to 5, only if the company provides it according to the commercial arrangement.	{'Recommendations': "Polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisolone (R‑CHP) is recommended for untreated diffuse large B-cell lymphoma (DLBCL) in adults, only if\n\nthey have an International Prognostic Index (IPI) score of 2 to 5\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with polatuzumab vedotin with R-CHP that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard treatment for untreated DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP). The company only provided evidence for polatuzumab vedotin with R-CHP for people with an IPI score of 2 to 5. This is narrower than polatuzumab vedotin's marketing authorisation, but clinical experts advised this is how it would be used in clinical practice.\n\nClinical evidence suggests that people with an IPI score of 2 to 5 having polatuzumab vedotin with R‑CHP have more time before their cancer gets worse than people having R‑CHOP alone. It is not clear if polatuzumab vedotin with R‑CHP increases how long people live compared with R‑CHOP.\n\nThe cost-effectiveness estimates for polatuzumab vedotin with R‑CHP are likely to be within what NICE considers an acceptable use of NHS resources. So, polatuzumab vedotin with R-CHP is recommended for people with an IPI score of 2 to 5.", 'Information about polatuzumab vedotin': "# Marketing authorisation indication\n\nPolatuzumab vedotin (Polivy, Roche) in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone is indicated for 'the treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for polatuzumab vedotin.\n\n# Price\n\nPolatuzumab vedotin costs £2,370 per 30\xa0mg vial or £11,060 per 140\xa0mg vial (excluding VAT, BNF online accessed December 2022).\n\nThe company has a commercial arrangement. This makes polatuzumab vedotin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## There is a high unmet need for a first-line treatment that stops diffuse large B-cell lymphoma progressing\n\nDiffuse large B-cell lymphoma (DLBCL) is an aggressive disease. Symptoms usually develop rapidly and progress quickly. The disease is treated with the aim of cure, but it is refractory to treatment or relapses after initial treatment in up to 50% of people. The clinical experts explained that current treatment for untreated DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP). They noted that first-line treatment has the best chance of cure. They explained there is an unmet need to stop the disease from progressing. This is because treatment options for relapsed or refractory disease are associated with significant burden and toxicity. The clinical experts explained that relapsed or refractory disease has poor survival rates. A patient expert submission to NICE explained that DLBCL is difficult to live with because of the symptoms of both the disease and treatment. Common symptoms include painless swellings at single or multiple sites (lymph node and non-lymph node), excessive night sweating, unexplained fever and weight loss. The patient expert submission also highlighted the psychological effects of relapsed or refractory disease for both patients and carers. People may have insomnia, anxiety and a constant fear of relapse and death. The committee agreed that DLBCL is an aggressive form of lymphoma that needs intensive treatment. It concluded that there is a high unmet need for first-line treatments that prevent disease progression.\n\n# Clinical evidence\n\n## It is appropriate to exclude DLBCL with an IPI score of 0 to 1 from this appraisal in line with the evidence available\n\nThe International Prognostic Index (IPI) risk group is usually used to predict DLBCL prognosis. IPI risk group is categorised based on independent predictors for outcomes like overall survival and progression-free survival. IPI risk group is determined by the number of predictors met: 0 or 1 is low risk, 2 is low-intermediate risk, 3 is high-intermediate risk, and 4 or 5 is high risk. The company positioned polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisolone (R‑CHP) for DLBCL with an IPI score of 2 to 5. This is because the clinical trial excluded those with an IPI score of 0 to 1. However, the committee recalled that the marketing authorisation is 'adult patients with previously untreated DLBCL' and does not restrict by IPI risk group. The clinical experts explained that the outcomes for IPI 0 to 1 were usually very good and only a small proportion of people with DLBCL have an IPI score of 0 to 1. They noted that it was appropriate to exclude DLBCL with an IPI score of 0 to 1. The committee concluded that it was appropriate to exclude DLBCL with an IPI score of 0 to 1 for this appraisal, in line with the evidence available.\n\n## The appropriate population for decision making is people with DLBCL with an IPI score of 2 to 5\n\nThe main clinical evidence was from the POLARIX trial. This was a multicentre phase 3, double-blind, placebo-controlled study in adults with previously untreated DLBCL with an IPI score of 2 to 5. POLARIX compared polatuzumab vedotin plus R‑CHP with R‑CHOP. The primary end point was progression-free survival. People who had polatuzumab vedotin with R‑CHP had a 24-month progression-free survival rate of 76.7 (95% confidence interval [CI] 72.7 to 80.8) compared with 70.2 (95%\xa0CI 65.8 to 74.6) for people who had R‑CHOP. The hazard ratio for disease progression or death was 0.73 (95% CI 0.57 to 0.95, p=0.02). The company did pre-specified exploratory subgroup analyses, dividing by IPI risk group, among other things. For the IPI 3 to 5 subgroup the hazard ratio for disease progression or death was 0.7 (95% CI 0.5 to 0.9). The committee noted that for some subgroups, such as IPI 2, age 60 or below, presence of bulky disease, and women, the 95% CIs for disease progression or death crossed 1. It noted that in the IPI 2 subgroup, which was 38% of the trial population, the hazard ratio for disease progression or death was 1.0 and 95% CIs ranged from 0.6 to 1.6, suggesting a lack of progression-free survival benefit in this group. The company noted in its submission that the subgroup analyses in the trial were exploratory and not confirmatory, and that POLARIX was not designed or powered to compare subgroups. It also explained that because IPI 2 disease is lower risk and progression or death occurs less often in this population the effect may not be picked up in the trial. The ERG explained that noise in the data could be a reason for the lack of effect shown in some of the subgroups. The clinical experts agreed with the company that IPI 2 disease is a lower risk group and that it is difficult to draw conclusions from the subgroup analysis when it is exploratory. In response to the appraisal consultation document, the company provided a scenario analysis for the IPI 3 to 5 subgroup. The committee noted that there was biological plausibility that people with IPI 3 to 5 disease would benefit more from treatment with polatuzumab vedotin plus R-CHP than people with IPI 2 to 5 disease. It noted that this is because they have more risk factors associated with poorer prognosis, which was supported by the exploratory subgroup analyses. However, the committee noted that the trial was designed to investigate the IPI 2 to 5 population and that the company had previously stated that the IPI 3 to 5 subgroup was only exploratory. The committee also noted that the company had not presented estimates of long-term survival for the IPI 3 to 5 population. Also, it did not have enough information on how the subgroup data had been used by the company to include it in its decision making. The committee concluded that people with an IPI score of 2 to 5 was the appropriate population for decision making.\n\n## An overall survival benefit for polatuzumab vedotin with R-CHP compared with R-CHOP cannot be determined using current data\n\nPeople who had polatuzumab vedotin with R‑CHP had a 24‑month overall survival rate of 88.7% (95% CI 85.7 to 91.7) compared with 88.6% (95% CI 85.6 to 91.6) for R-CHOP. The hazard ratio for death was 0.94 (95% CI 0.65 to 1.37). The company explained that the overall survival results are immature and follow up is not long enough to capture the effect of polatuzumab vedotin with R‑CHP on survival. The ERG explained that the POLARIX overall survival analysis did not show a statistically significant difference between polatuzumab vedotin with R‑CHP and R‑CHOP because the confidence interval crossed 1. The committee concluded that it was uncertain if there was an overall survival benefit of polatuzumab vedotin with R‑CHP compared with R‑CHOP.\n\n# Survival modelling\n\n## Progression-free and overall survival are extrapolated using a mixture-cure model\n\nThe company and ERG both used a mixture-cure model to extrapolate progression-free survival and overall survival. The mixture-cure model assumed the population consisted of 2 groups: a 'cured' population and a population whose disease would progress. The 'cured' population is assumed to have the same risk of death as the age- and sex-matched general population after 2\xa0years. The committee concluded that a mixture-cure model was a reasonable approach.\n\n## The overall survival extrapolations are highly uncertain\n\nThe company explained that it was not possible to estimate long-term survival from the overall survival data in POLARIX because the overall survival data was immature (see section 3.4). Because of this, the overall survival mixture-cure model was informed by the progression-free survival cure fraction. The ERG explained that the approach seemed logical given the immaturity of the overall survival data in POLARIX. However, it noted that the company's overall survival extrapolations were highly uncertain. After consultation, the ERG presented a scenario showing how assuming no overall survival benefit with polatuzumab vedotin with R‑CHP compared with R‑CHOP affects the cost-effectiveness results. It explained that this was in line with the evidence from POLARIX which had not shown any difference in overall survival at 24‑month follow up (see section 3.4). The committee noted that the overall survival extrapolations were highly uncertain. But, based on the benefits in progression-free survival seen in POLARIX (see section 3.3), it was plausible that there would be an overall survival benefit with polatuzumab with R‑CHP, meaning the ERG's scenario analysis was conservative. The company noted that more overall survival data will be available in the future from data cuts in August 2022 and 2024. The committee noted that given the overall survival event rate seen in the POLARIX trial, it is unlikely that a meaningful number of overall survival events will have occurred at these data cuts to meaningfully address the overall survival uncertainty. The committee concluded that the ERG's scenario assuming no overall survival benefit with polatuzumab vedotin with R‑CHP was likely an underestimate of overall survival. It further concluded that the company's overall survival extrapolation was broadly appropriate but highly uncertain, and that forthcoming clinical trial data is unlikely to meaningfully address the uncertainty.\n\n## It is not appropriate to include treatment effect waning\n\nPOLARIX showed no statistically significant survival benefit for polatuzumab vedotin with R‑CHP compared with R‑CHOP (hazard ratio 0.94; 95% CI 0.65 to 1.37). However, the company's extrapolation (based on the mixture-cure model, see section 3.5) assumed a continued survival benefit for polatuzumab vedotin with R‑CHP over R‑CHOP. The company explained that because DLBCL is curable in first line, a waning effect should not be applied. The company considered that because overall survival estimated in the model is informed by progression-free survival from POLARIX, the long-term efficacy of polatuzumab vedotin with R‑CHP is likely to be underestimated. The ERG explained that there is uncertainty in the overall survival benefit from POLARIX (see section 3.4 and section\xa03.6) and other subsequent treatments would affect long-term survival. So the ERG applied a waning effect to overall survival to try to account for some of the uncertainty. After consultation, the ERG updated its approach to treatment waning by assuming equal overall survival in each treatment arm after 60\xa0months. The company also presented evidence from first-line and relapsed and refractory DLBCL trials to support a continued survival benefit. The ERG noted that the additional trial evidence provided by the company supported a continued overall survival benefit in DLBCL. But it explained that these trials had different treatment regimens, patient characteristics and study lengths, which limited how applicable this evidence was to polatuzumab vedotin with R‑CHP. The ERG highlighted that the waning effect is in the context of a mixture-cure model. This means waning is applied to the whole population, even those whose disease is cured, which is a more conservative approach than the company's. The clinical experts explained that most death and relapse would occur within 2\xa0years and that subsequent treatments are associated with significant toxicity. The committee noted that applying treatment waning to the whole population in the context of the mixture-cure model, meant that there is a 'cured' population initially, whose disease is then considered 'uncured' later. It noted that the company's approach favoured polatuzumab vedotin with R‑CHP and was associated with uncertainty. But it considered the company's approach to be more clinically plausible than the ERG's. Because of this, the committee concluded that treatment effect waning should not be included, but took account of uncertainty about the modelled overall survival estimates in its decision making.\n\n## It is unclear if the company's correction to the progression-free survival modelling is appropriate\n\nIn response to the appraisal consultation document, the company highlighted a technical error in the model. It corrected the model at consultation so that at the point progression-free survival extrapolation estimates meet and exceed overall survival extrapolation estimates, they are capped in line with the overall survival extrapolation. The ERG suggested that the company's correction provides counter-intuitive results when changes are made to overall survival. It explained that this is because the mixture-cure model is inflexible to changes such as the correction the company had made. The ERG also explained that based on the information provided by the company, it had been unable to scrutinise this issue adequately. After requests for clarification by the committee at the second appraisal committee meeting, the nature of the error and the appropriateness of the correction was still uncertain. After the second committee meeting, the company provided further explanation on the correction. But the ERG noted that without further scrutiny it remained unclear if the correction was valid. The committee concluded that it was unclear if the company's correction to the progression-free survival modelling was appropriate.\n\n# Economic modelling\n\n## The company's model structure is suitable for decision making\n\nThe company used a 3‑state partitioned survival model to estimate the cost effectiveness of polatuzumab vedotin with R‑CHP compared with R‑CHOP. It had 3 health states: progression-free, progressed disease and death. The committee considered that the partitioned survival model is a standard approach to estimating the cost effectiveness of cancer drugs and concluded that it was appropriate in this instance.\n\n## Patient weight from the Western European, US, Canadian and Australian population in POLARIX is appropriate to use in the model\n\nThe model used patient weight distributions from the full population in the POLARIX trial. The committee noted that the mean patient weight from POLARIX was 75.92\xa0kg, which is lower than calculated in the 2019 NHS Health Survey for England on overweight and obesity in adults and children (78.75\xa0kg for adults). So the committee questioned if the weight distribution used in the model represented NHS clinical practice. It noted that this could affect the number of vials needed for each person, which would in turn influence costs. It was also aware that no vial sharing was assumed in the model, which may be a conservative approach. In response to the appraisal consultation document, the company explained that the mean patient weight from the subgroup of people in Western Europe, US, Canada and Australia (referred to from now as the Western subgroup) in POLARIX was 80.1\xa0kg. It presented a scenario analysis using the height and weight distribution from the Western subgroup which increased the incremental cost-effectiveness ratio (ICER) by 11%. The committee noted that the average weight in the Western subgroup of POLARIX was more generalisable to the UK population than the weight in the full trial population. The company also presented evidence from a US study (O'Brian et al. 2015) predominantly in men (97%) who received a DLBCL diagnosis between 1998 and 2008. The company explained that this evidence showed that on average, people with DLBCL have 5% weight loss in the year leading up to diagnosis. It explained that the average weight in the general population with 5% weight loss applied (74.8\xa0kg) is generalisable to the weight in the full POLARIX population. The ERG explained that O'Brian et al. was done in a population that may not be generalisable to people who are having treatment for DLBCL in the NHS. The committee noted that the company's assumption that people with DLBCL would have 5% weight loss before diagnosis was based on 1\xa0study in a population that is likely to have a different weight distribution to the population with DLBCL in the NHS. The committee concluded that it was appropriate to use the weight distribution of the Western subgroup in the model because this was most likely to be generalisable to the weight of people with DLBCL in the NHS.\n\n## The company's progressed disease supportive care costs are likely to be overestimated\n\nSupportive care costs are applied to people in every weekly cycle in the model for the duration of the time the person is in the health state. For progressed disease, this is every year until the disease is cured or death occurs. In its original submission, the company used resource use data for progressed disease based on NICE's technology appraisal guidance on polatuzumab vedotin (TA649) which used progressed disease resource data from NICE's technology appraisal guidance on pixantrone monotherapy (TA306). In its original base case, the ERG preferred to estimate resource use based on NICE's technology appraisal guidance on rituximab (TA243). The committee concluded at the first appraisal committee meeting that neither the company nor ERG base cases represented supportive care resource use for DLBCL in the NHS. It further concluded that end of life costs, included in the company's progressed disease resource use, should be removed. In response to the appraisal consultation document, the company removed end of life costs from the progressed disease supportive care costs. Also in response to the appraisal consultation document, the company updated its approach to estimating progressed disease resource use and costs. The ERG highlighted that the company's approach assumed supportive care costs for progressed disease would apply indefinitely. However, many people would have response to subsequent treatments and no longer incur these costs. Or, they may have end of life care only. The company explained that the same progressed disease costs were applied in every weekly cycle even though there are periods of high intensity treatment and lower intensity follow up. It explained that this meant that on average, the weekly costs included for progressed disease were appropriate. To inform its updated approach, the company did a survey with 3\xa0clinicians to estimate resource use associated with second-line treatment for DLBCL. Based on this survey, it applied updated costs for the progressed disease state to its model. The company explained that the survey asked clinicians what the resource use was for people with DLBCL having second-line treatment only and did not ask about the off-treatment costs. People in the progressed disease state spend all their time after first progression in this state. So, the committee noted that the survey should have accounted for second-line treatment and all subsequent lines of therapy. The committee considered that this survey may have produced biased results, which reflected the costs of being on second-line treatment, but not the costs of being off treatment or on subsequent treatments. Further bias was possible because it was an opinion-based survey and not based on quantitative data. The committee noted that time off treatment should be considered when estimating the supportive care costs in progressed disease. It was not persuaded that this had been accounted for in the company's model. The committee concluded that the company's progressed disease costs are likely to be overestimated.\n\n## Reduction in the company's progressed disease supportive care costs by between 25% to 50% is appropriate\n\nThe ERG explained that to accurately estimate costs for the progressed disease state, on and off treatment costs should be included in the model, but the model was not structured to allow for this. The ERG estimated the time spent incurring costs in the progressed disease state in the model. It based its estimate on the number of subsequent treatments in POLARIX and an estimate of average time to progression on subsequent treatments for relapsed or refractory DLBCL, based on a study by Ohmachi et al. (2013). Based on this, it estimated that a 50% reduction in the company's progressed disease costs (see section 3.11) was appropriate, accounting for minimal costs when off treatment. The committee noted that the ERG's estimate of a 50% reduction in the company's progressed disease costs was uncertain and based on an estimate of time to progression in relapsed and refractory DLBCL from a single study. It was also uncertain what costs were estimated for people who were off treatment in the ERG's analysis and considered that these may be too low. So, it agreed that a reduction in the company's estimate of progressed disease costs was appropriate, but the ERG's estimate of a 50% reduction in costs was likely too large. It noted that the ERG had also provided a scenario analysis including a 25% reduction in the company's progressed disease costs. But it was uncertain if this scenario analysis was appropriate because it may not reduce the costs enough. It concluded that the appropriate supportive care costs for progressed disease were likely to be somewhere between the ERG's scenario analysis reducing the company's costs by 25% and the ERG's preferred assumption of reducing the company's costs by 50%.\n\n## Utility for progressed disease may not have been fully accounted for\n\nThe company used utility values from the GOYA trial because it had a longer follow up than POLARIX. GOYA was a phase 3, open-label study of obinutuzumab plus CHOP compared with R‑CHOP in adults with previously untreated CD20-positive DLBCL with an IPI score of 2 to 5. The company explained that 11 clinicians had confirmed that the GOYA utility values were more representative of DLBCL than the POLARIX utility values. The company presented several reasons why the POLARIX utilities were not representative of people with relapsed or refractory DLBCL seen in the NHS. Some people whose disease progressed did not report health-related quality of life (the exact number is considered confidential by the company and cannot be reported here) and those who did report had better health outcomes than those who did not. The company also explained that the timing of collection of the health-related quality of life data affected its applicability. The company considered the timing to be confidential so it cannot be reported here. The ERG noted that the GOYA utility values were similar to those used in NICE's technology appraisal guidance on polatuzumab vedotin (TA649) so agreed to use the GOYA utility values in the base case. The ERG also age adjusted the progressed disease utility values using UK general population utility values from Ara and Brazier (2010). The committee queried the timing of the health-related quality of life data collection in the GOYA trial, which the company explained was before second-line treatment. The committee questioned whether the valuation of health-related quality of life data was overestimated because the GOYA data was collected before later line treatments were started. Clinical experts explained that the toxicity of later line treatments is significant and that they would expect this to contribute to quality of life. The committee noted it would have preferred to have seen GOYA utilities after second-line treatment was started. However, it concluded that the company's approach was acceptable for decision making but uncertain.\n\n## CAR-T therapies should not be included as subsequent treatments\n\nIn its initial submission, the company included 2 chimeric antigen receptor T‑cell (CAR‑T) therapies as subsequent treatments in the model. These CAR‑T therapies are currently in the Cancer Drugs Fund; see NICE's technology appraisal guidance on axicabtagene ciloleucel (TA559) and NICE's technology appraisal guidance on tisagenlecleucel (TA567). NICE's position statement is that technologies with Cancer Drugs Fund recommendations cannot be considered as part of the treatment sequence in relevant appraisals because they cannot be considered established practice. The committee acknowledged the relevance of TA559 to this appraisal, and noted that it is currently being reviewed. At technical engagement, the company explained that CAR‑T therapies have high costs, which may make polatuzumab vedotin with R‑CHP more cost effective in the long term. But it agreed to remove CAR‑T therapies as subsequent treatments from the model. The committee concluded that CAR‑T therapies should not be included as subsequent treatments because they are not routinely commissioned.\n\n## Redistributing CAR-T therapy use to other subsequent treatments is acceptable\n\nAfter technical engagement, in the model the company redistributed people having CAR‑T therapies to have other subsequent treatments. The ERG explained this meant the total use of subsequent treatments was more than 100%, which is implausible. Instead, the ERG did not adjust the proportion of people having each subsequent treatment when CAR‑T therapies were removed at technical engagement. This made total subsequent treatment use 97%. The committee noted that use of subsequent treatments in the model was more than 100% before the redistribution of CAR‑T therapies. The company explained that this was because chemotherapy and stem cell transplants were considered separately in the model (that is, if someone had chemotherapy and a stem cell transplant, this would be counted as 2 subsequent treatments, meaning the percentage would be higher than 100%). The committee concluded at the first appraisal committee meeting that people would have other treatments if CAR‑T therapy was not available. After consultation, the ERG updated its base case to include redistribution of CAR‑T therapies to other subsequent treatments. The committee concluded that the company's and updated ERG assumption about CAR‑T therapy redistribution was appropriate.\n\n# End of life\n\n## End of life criteria are not met for polatuzumab vedotin with R-CHP\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal 2013. The committee was aware that the mean life expectancy for people with untreated DLBCL who had R‑CHOP was more than 24\xa0months. So, it concluded that polatuzumab vedotin with R‑CHP did not meet the end of life criteria.\n\n# Innovation\n\n## Polatuzumab vedotin with R-CHP is innovative\n\nClinical experts explained that POLARIX is the first international double-blind randomised controlled trial in over 20\xa0years to show meaningful improvement in the benefit-risk profile of another treatment over R‑CHOP. The committee concluded that polatuzumab vedotin with R‑CHP is innovative.\n\n# Cost-effectiveness estimates\n\n## An acceptable ICER is between £20,000 and £30,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal 2013 notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered polatuzumab vedotin with R‑CHP innovative but noted that the long-term overall survival estimates were highly uncertain (see section 3.6). It also took into account the likelihood of decision error and its consequences. So, it agreed that an acceptable ICER would be between £20,000 and £30,000 per QALY gained.\n\n## Polatuzumab vedotin with R-CHP is likely to be cost effective\n\nThe committee noted that its preferences were not fully reflected in either the company's or the ERG's base case at the second committee meeting. The committee's preferred assumptions included:\n\nconsidering the full POLARIX population (see section 3.3)\n\nthe company's overall survival extrapolation approach (although noting this was highly uncertain; see section 3.6)\n\nno treatment effect waning (see section 3.7)\n\nthe patient weight distribution from the POLARIX Western population subgroup (see section 3.10)\n\nexcluding CAR‑T therapies (see section 3.14)\n\nredistributing CAR‑T therapy use to other subsequent treatments (see section 3.15).The committee noted that the company provided a scenario analysis for the IPI 3 to 5 subgroup (see section 3.3). However, it was unclear how the subgroup data had been incorporated into the company's economic model in the scenario analysis. So the committee preferred to consider the full POLARIX population in its decision making. The committee noted that the utility values for progressed disease were uncertain but that the approach used in the company's and ERG's base case was acceptable for decision making (see section 3.13). It also noted that the company included a correction to the progression-free survival modelling after consultation. But it noted that it was unclear if this correction was appropriate and that including it lowered the ICER (see section 3.8). The committee also noted that the company's progressed disease supportive care costs were likely overestimated (see section 3.11). But it considered that the ERG's assumption of a 50% reduction in the company's costs was likely an underestimate and that reducing the company's progressed disease costs by between 25% to 50% is appropriate (see section 3.12). After the second appraisal committee meeting, the company provided an updated base case, including all of the committee's preferred assumptions, as well as:\n\nremoval of the progression-free survival curve correction\n\na reduction in the progressed disease costs by 30%\n\nan updated commercial arrangement for polatuzumab vedotin.The committee agreed that the company's updated base case ICER was appropriate for decision making. Because of confidential commercial arrangements for cyclophosphamide, doxorubicin, prednisolone and rituximab, the exact ICERs are confidential and cannot be reported here. Taking into account all the confidential discounts, the company's updated base case ICER was at the lower end of the range of what NICE considers a cost-effective use of NHS resources. So, the committee concluded that polatuzumab vedotin with R-CHP is likely to be cost effective.\n\n# Conclusion\n\n## Polatuzumab vedotin with R-CHP is recommended for untreated DLBCL\n\nThe committee noted that when taking into account all its preferred assumptions and the commercial arrangement offered by the company, polatuzumab vedotin is likely to be a cost-effective use of NHS resources. So, it recommended polatuzumab vedotin with R-CHP for untreated DLBCL with an IPI score of 2 to 5, only if the company provides it according to the commercial arrangement."}	https://www.nice.org.uk/guidance/ta874	Evidence-based recommendations on polatuzumab vedotin (Polivy) with rituximab, cyclophosphamide, doxorubicin and prednisolone for untreated diffuse large B-cell lymphoma in adults.
08fadcebb1caef0e33a1d3702056cd087c2d9095	nice	Endoluminal gastroplication for gastro-oesophageal reflux disease	Endoluminal gastroplication for gastro-oesophageal reflux disease Evidence-based recommendations on endoluminal gastroplication for gastro-oesophageal reflux disease. This involves an endoscopic fastening device being inserted through the mouth and into the stomach, along with an endoscope for constant visualisation. The device is used to attach the fundus to the anterior and left lateral wall of the distal oesophagus slightly above the oesophagogastric junction. # Recommendations Evidence on the safety of endoluminal gastroplication for gastro-oesophageal reflux disease is adequate. However, evidence on its efficacy is inadequate in quality, particularly in terms of patient selection and long-term outcomes. Therefore, this procedure should be used only in research. Find out what only in research means on the NICE interventional procedures guidance page. Further research should include suitably powered randomised controlled trials with details of patient selection, physiological measurements, and long-term outcomes.# The condition, current treatments and procedure # The condition Gastro-oesophageal reflux disease (GORD) is a common condition caused by failure of the sphincter mechanism at the lower end of the oesophagus. Symptoms of GORD can be broadly grouped into those directly related to reflux episodes, such as heartburn, regurgitation, chest pain and nausea, and those symptoms caused by complications of reflux disease, including problems swallowing (dysphagia) and respiratory symptoms. Repeat episodes of GORD can damage the lining of the oesophagus and lead to oesophageal ulceration, oesophageal stricture, and Barrett's oesophagus. # Current treatments NICE's guideline on the investigation and management of gastro-oesophageal reflux disease and dyspepsia in adults makes recommendations for treatment. The standard treatments for symptomatic GORD are lifestyle modification and drug therapy. Drug therapy includes acid-lowering agents such as H2 receptor antagonists and proton pump inhibitors (PPIs). People with reflux symptoms that do not respond to medical treatment or who develop intolerance to medication may have anti-reflux surgery. Surgical or laparoscopic fundoplication may be used, and minimally invasive treatments such as endoscopic radiofrequency ablation or endoscopic injection of bulking agents are available. # The procedure Different devices have been used for this procedure and exact details of the technique vary. The procedure is usually done with the patient under general anaesthesia. An endoscopic fastening device is inserted through the mouth and into the stomach, along with an endoscope for constant visualisation. The device is used to attach the fundus to the anterior and left lateral wall of the distal oesophagus slightly above the oesophagogastric junction. With 1 of the devices, polypropylene fasteners are delivered through apposed layers of oesophageal and fundus tissue to anchor the repair. About 20 fasteners are implanted during the procedure to create a full thickness, partial circumference, gastro-oesophageal fundoplication. The aim is to recreate a valve and form a barrier to reflux. Endoluminal gastroplication for gastro-oesophageal reflux disease aims to reduce the morbidity associated with open or laparoscopic fundoplication.	{'Recommendations': 'Evidence on the safety of endoluminal gastroplication for gastro-oesophageal reflux disease is adequate. However, evidence on its efficacy is inadequate in quality, particularly in terms of patient selection and long-term outcomes. Therefore, this procedure should be used only in research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should include suitably powered randomised controlled trials with details of patient selection, physiological measurements, and long-term outcomes.', 'The condition, current treatments and procedure': "# The condition\n\nGastro-oesophageal reflux disease (GORD) is a common condition caused by failure of the sphincter mechanism at the lower end of the oesophagus. Symptoms of GORD can be broadly grouped into those directly related to reflux episodes, such as heartburn, regurgitation, chest pain and nausea, and those symptoms caused by complications of reflux disease, including problems swallowing (dysphagia) and respiratory symptoms. Repeat episodes of GORD can damage the lining of the oesophagus and lead to oesophageal ulceration, oesophageal stricture, and Barrett's oesophagus.\n\n# Current treatments\n\nNICE's guideline on the investigation and management of gastro-oesophageal reflux disease and dyspepsia in adults makes recommendations for treatment. The standard treatments for symptomatic GORD are lifestyle modification and drug therapy. Drug therapy includes acid-lowering agents such as H2 receptor antagonists and proton pump inhibitors (PPIs). People with reflux symptoms that do not respond to medical treatment or who develop intolerance to medication may have anti-reflux surgery.\n\nSurgical or laparoscopic fundoplication may be used, and minimally invasive treatments such as endoscopic radiofrequency ablation or endoscopic injection of bulking agents are available.\n\n# The procedure\n\nDifferent devices have been used for this procedure and exact details of the technique vary. The procedure is usually done with the patient under general anaesthesia. An endoscopic fastening device is inserted through the mouth and into the stomach, along with an endoscope for constant visualisation. The device is used to attach the fundus to the anterior and left lateral wall of the distal oesophagus slightly above the oesophagogastric junction.\n\nWith 1 of the devices, polypropylene fasteners are delivered through apposed layers of oesophageal and fundus tissue to anchor the repair. About 20\xa0fasteners are implanted during the procedure to create a full thickness, partial circumference, gastro-oesophageal fundoplication. The aim is to recreate a valve and form a barrier to reflux. Endoluminal gastroplication for gastro-oesophageal reflux disease aims to reduce the morbidity associated with open or laparoscopic fundoplication."}	https://www.nice.org.uk/guidance/ipg753	Evidence-based recommendations on endoluminal gastroplication for gastro-oesophageal reflux disease. This involves an endoscopic fastening device being inserted through the mouth and into the stomach, along with an endoscope for constant visualisation. The device is used to attach the fundus to the anterior and left lateral wall of the distal oesophagus slightly above the oesophagogastric junction.
9b78305f0ba9d1a63ba399443876ebce02f93fb9	nice	Percutaneous transluminal renal sympathetic denervation for resistant hypertension	Percutaneous transluminal renal sympathetic denervation for resistant hypertension Evidence-based recommendations on percutaneous transluminal renal sympathetic denervation for resistant hypertension. This involves inserting a device through the skin (percutaneous) into an artery in the thigh and then into the renal arteries (transluminal). It sends radio or sound waves to destroy the nerves in the renal arteries (sympathetic denervation). The aim is to lower blood pressure. # Recommendations Percutaneous transluminal renal sympathetic denervation for resistant hypertension should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do percutaneous transluminal renal sympathetic denervation for resistant hypertension should: Inform the clinical governance leads in their healthcare organisation. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Take account of NICE's guidance on shared decision making, and NICE's information for the public. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Further research should include randomised controlled trials or analysis of registry data. It should report details of patient selection, technique used and long-term outcomes. Patient selection should be done by a multidisciplinary team including experts in managing hypertension and potential complications, and clinicians with specific training in this procedure. Why the committee made these recommendations Evidence from a Cochrane review, a meta-analysis and clinical trials, supplemented by observational studies (registries) was reviewed by the committee. The evidence suggests that there are no major safety concerns in the short term, and complications are well recognised such as renal artery damage. The evidence shows that it reduces blood pressure in the short and medium term. Overall, there are uncertainties about how well it works in the long term and whether there are long-term complications. So, it should only be used with special arrangements. Hypertension can be a lifelong condition, so further evidence generation to establish the long-term outcomes of this procedure is particularly important.# The condition, current treatments and procedure # The condition Hypertension is a major risk factor for cardiovascular disease and chronic kidney disease. Hypertension can be primary or secondary. Primary hypertension does not have a single known cause, whereas secondary hypertension develops because of an underlying medical condition or disease. Hypertension is considered resistant if it is not controlled after treatment with at least 3 antihypertensive medications from different classes. # Current treatments NICE's guideline on hypertension in adults describes diagnosing and managing hypertension, including resistant hypertension. Current treatments for hypertension include lifestyle modifications and antihypertensive medications. Blood pressure and treatment are regularly monitored, and treatment is adjusted as needed. For resistant hypertension, additional medications and device-based antihypertensive therapies (for example renal denervation and carotid baroreceptor stimulation) can be considered. # The procedure This procedure is usually done using local anaesthesia, with sedation and anticoagulation. A catheter is introduced through the femoral artery and advanced into each renal artery under fluoroscopic guidance. The catheter is connected to a generator which delivers radiofrequency or ultrasound energy (depending on the type of system used) from the distal to proximal end of each renal artery. This ablates the renal nerves leading to the kidney, with the aim of disrupting neurogenic reflexes involved in blood pressure control. There are different systems with different technologies in use for renal sympathetic denervation.	{'Recommendations': "Percutaneous transluminal renal sympathetic denervation for resistant hypertension should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do percutaneous transluminal renal sympathetic denervation for resistant hypertension should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nTake account of NICE's guidance on shared decision making, and NICE's information for the public.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nFurther research should include randomised controlled trials or analysis of registry data. It should report details of patient selection, technique used and long-term outcomes.\n\nPatient selection should be done by a multidisciplinary team including experts in managing hypertension and potential complications, and clinicians with specific training in this procedure.\n\nWhy the committee made these recommendations\n\nEvidence from a Cochrane review, a meta-analysis and clinical trials, supplemented by observational studies (registries) was reviewed by the committee.\n\nThe evidence suggests that there are no major safety concerns in the short term, and complications are well recognised such as renal artery damage. The evidence shows that it reduces blood pressure in the short and medium term. Overall, there are uncertainties about how well it works in the long term and whether there are long-term complications. So, it should only be used with special arrangements.\n\nHypertension can be a lifelong condition, so further evidence generation to establish the long-term outcomes of this procedure is particularly important.", 'The condition, current treatments and procedure': "# The condition\n\nHypertension is a major risk factor for cardiovascular disease and chronic kidney disease. Hypertension can be primary or secondary. Primary hypertension does not have a single known cause, whereas secondary hypertension develops because of an underlying medical condition or disease. Hypertension is considered resistant if it is not controlled after treatment with at least 3\xa0antihypertensive medications from different classes.\n\n# Current treatments\n\nNICE's guideline on hypertension in adults describes diagnosing and managing hypertension, including resistant hypertension. Current treatments for hypertension include lifestyle modifications and antihypertensive medications. Blood pressure and treatment are regularly monitored, and treatment is adjusted as needed. For resistant hypertension, additional medications and device-based antihypertensive therapies (for example renal denervation and carotid baroreceptor stimulation) can be considered.\n\n# The procedure\n\nThis procedure is usually done using local anaesthesia, with sedation and anticoagulation. A catheter is introduced through the femoral artery and advanced into each renal artery under fluoroscopic guidance. The catheter is connected to a generator which delivers radiofrequency or ultrasound energy (depending on the type of system used) from the distal to proximal end of each renal artery. This ablates the renal nerves leading to the kidney, with the aim of disrupting neurogenic reflexes involved in blood pressure control. There are different systems with different technologies in use for renal sympathetic denervation."}	https://www.nice.org.uk/guidance/ipg754	Evidence-based recommendations on percutaneous transluminal renal sympathetic denervation for resistant hypertension. This involves inserting a device through the skin (percutaneous) into an artery in the thigh and then into the renal arteries (transluminal). It sends radio or sound waves to destroy the nerves in the renal arteries (sympathetic denervation). The aim is to lower blood pressure.
e3045686fd45f4e81523b8a61167eda4b851944c	nice	Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies	Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies Evidence-based recommendations on axicabtagene ciloleucel (Yescarta) for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma in adults after 2 or more systemic therapies. # Recommendation Axicabtagene ciloleucel is recommended, within its marketing authorisation, as an option for treating relapsed or refractory diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma in adults after 2 or more systemic therapies. It is recommended only if the company provides axicabtagene ciloleucel according to the commercial arrangement. Why the committee made this recommendation This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma in adults after 2 or more systemic therapies (NICE technology appraisal guidance 559). There is no standard treatment for relapsed or refractory diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma after 2 or more systemic therapies. Best supportive care is used and usually includes salvage chemotherapy. Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T‑cell therapy (also called CAR‑T therapy). It uses the patient's own immune cells that have been modified to attach to and kill cancer cells. The new evidence includes data from a clinical trial and from people having axicabtagene ciloleucel in the NHS while it was available in the Cancer Drugs Fund. It suggests that people having axicabtagene ciloleucel live longer than people having salvage chemotherapy and have longer before their condition gets worse. Axicabtagene ciloleucel meets NICE's criteria to be considered a life-extending treatment at the end of life. Taking this into account, the cost-effectiveness estimates for axicabtagene ciloleucel are within what NICE considers an acceptable use of NHS resources. So, axicabtagene ciloleucel is recommended for routine use in the NHS.# Information about axicabtagene ciloleucel # Marketing authorisation indication Axicabtagene ciloleucel (Yescarta, Kite) is 'indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) after 2 or more lines of systemic therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for axicabtagene ciloleucel. # Price The list price for axicabtagene ciloleucel is £280,451 per single infusion bag (approximately 68 ml, company submission). The company has a commercial arrangement. This makes axicabtagene ciloleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Kite, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund's managed access arrangement, the company was required to collect updated efficacy data from the ZUMA‑1 trial. Data was also collected on the use of axicabtagene ciloleucel in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset. # Clinical need ## Value of treatment Diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma are aggressive subtypes of non-Hodgkin lymphoma. The condition does not respond well to chemotherapy, and outcomes for people with refractory or relapsed disease are poor and survival is limited. Axicabtagene ciloleucel is part of a group of advanced cancer treatments called chimeric antigen receptor (CAR) T‑cell therapies. CAR T‑cell therapies are personalised cancer immunotherapies which involve collecting and modifying people's own immune cells to treat their cancer. Axicabtagene ciloleucel is indicated for the treatment of relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more lines of systemic therapy in adults. Clinical and patient experts explained that without CAR T‑cell therapy there is a lack of treatment options if the condition relapses after 2 therapies. The patient expert explained that chemotherapy treatments are intense, frequent and extremely difficult to tolerate. They described that chemotherapy treatments have challenging side effects and a large impact on quality of life for little clinical success. The patient and clinical experts explained that the introduction of axicabtagene ciloleucel into the treatment pathway has revolutionised treatment and provided hope of a cure for this aggressive condition. The committee concluded that axicabtagene ciloleucel is a valuable treatment option. ## Treatment pathway In the original appraisal, the company proposed that axicabtagene ciloleucel can be used in 4 possible positions in the treatment pathway, specifically for people whose disease: was refractory after 1 systemic therapy, or has relapsed after 1 systemic therapy, but who cannot have an autologous stem cell transplant, or has relapsed after 1 systemic therapy, and who have had chemotherapy and an autologous stem cell transplant but whose disease has then relapsed again, or has relapsed after 1 systemic therapy, and who would have been able to have an autologous stem cell transplant as part of a second treatment, but whose disease does not respond to salvage chemotherapy. The committee considered the company's proposed positions in the pathway. During the original appraisal, the committee concluded that it could not consider axicabtagene ciloleucel for people whose disease has not responded to 1 systemic therapy but who are unable to have an autologous stem cell transplant. It considered this position was not in line with the anticipated marketing authorisation of axicabtagene ciloleucel (that is, after 2 or more systemic therapies). Axicabtagene ciloleucel would also not be used as an alternative to autologous stem cell transplant, because this would be part of the second systemic treatment. So, the committee concluded that axicabtagene ciloleucel would be positioned as a treatment option for people whose disease: did not respond after 2 systemic therapies, or has relapsed after 1 systemic therapy, and who have had chemotherapy and an autologous stem cell transplant but whose disease has then relapsed again, or has relapsed after 1 systemic therapy, and who would have been able to have an autologous stem cell transplant as part of a second treatment, but whose disease does not respond to salvage chemotherapy. Clinical experts explained that all 3 populations have had axicabtagene ciloleucel in NHS clinical practice, and they would expect this to continue. Without axicabtagene ciloleucel, the only available treatment option for people who have had 2 previous systemic therapies is salvage chemotherapy. Salvage chemotherapy is only expected to provide short-term benefits, but axicabtagene ciloleucel has the potential to be curative. The committee concluded that considering axicabtagene ciloleucel in 3 positions of the treatment pathway is appropriate. # Clinical evidence ## ZUMA-1 data The clinical-effectiveness evidence for axicabtagene ciloleucel was from ZUMA‑1, an ongoing, phase 1/2, multicentre, open-label, single-arm trial. ZUMA‑1 investigated axicabtagene ciloleucel for aggressive relapsed or refractory B-cell non-Hodgkin lymphoma (including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma and transformed follicular lymphoma) in adults that was refractory to treatment or had relapsed within 12 months of autologous stem cell transplant. The company presented updated overall survival results collected in ZUMA‑1 which included a minimum follow-up of 5 years. The updated ZUMA‑1 results showed that 64 patients (59%) had died at database lock (11 August 2021). Updated median overall survival was 23.5 months with an observed plateau of 45% at around 26.0 months. Updated median progression-free survival was 5.8 months with an observed plateau in progression-free survival of 40% at 9.0 months. The committee heard that ZUMA‑1 progression-free survival was only updated to 2 years, because there was no protocol mandate to collect data after 2 years. The company stated that any progression-free survival data collected after 2 years would not be consistent with progression-free survival data collected before 2 years. The committee would have preferred to see more mature progression-free survival data but accepted that additional overall survival data had reduced uncertainty. The committee concluded that additional axicabtagene ciloleucel data supported the predictions in the original submission of long survival times for a substantial proportion of patients. ## SACT data Further clinical evidence was collected from the SACT dataset while axicabtagene ciloleucel was available in the Cancer Drugs Fund. The SACT dataset contains UK real-world clinical-effectiveness data from the Cancer Drugs Fund population between December 2018 and October 2021. The median age of people having axicabtagene ciloleucel was 59.5 years, similar to ZUMA‑1. Overall survival rates in the Cancer Drugs Fund population were comparable to ZUMA‑1 over the 36 months of data collection. Median overall survival of people having axicabtagene ciloleucel was 28.5 months and 45% of people were alive after 3 years. The ERG highlighted that Eastern Cooperative Oncology Group (ECOG) performance status was not collected for a proportion of people in the SACT dataset, which made comparisons with ZUMA‑1 more difficult. Clinical experts explained that they expect axicabtagene ciloleucel to perform similarly in routine NHS clinical practice to ZUMA‑1 and the SACT dataset. The committee concluded that outcomes from the SACT dataset were comparable to those from ZUMA‑1 and supported the use of axicabtagene ciloleucel in routine NHS clinical practice. ## Salvage chemotherapy efficacy Because ZUMA-1 is a single-arm trial, the primary evidence source for the comparator was the SCHOLAR‑1 study. SCHOLAR‑1 was a retrospective study of pooled data from 4 datasets. These datasets included adults with diffuse large B-cell lymphoma (n=552), primary mediastinal large B-cell lymphoma (n=14), transformed follicular lymphoma (n=27) and 'other' (n=43). Treatment options included salvage chemotherapy, rituximab maintenance therapy and observation after autologous stem cell transplant. The company did a targeted literature review of studies on diffuse large B-cell lymphoma after 2 or more lines of systemic therapy. This was to respond to the Cancer Drugs Fund review terms of engagement's request for additional data to address uncertainties in comparator data. The company identified 3 studies, with only 1 study from the UK. Radford et al. (2019) investigated treatment patterns and outcomes for people with relapsed or refractory diffuse large B-cell lymphoma from a single UK centre. The company argued that SCHOLAR‑1 is still the most appropriate source of data for salvage chemotherapy and stressed the approach maintained consistency with the original submission. The company also outlined that SCHOLAR‑1 outcomes were similar to the third-line population in the Radford study, validating their SCHOLAR‑1 approach. Clinical experts highlighted issues with SCHOLAR‑1. They argued that the populations in SCHOLAR‑1 were not comparable to ZUMA-1. They also noted that there are large datasets that could have been used to validate SCHOLAR‑1. The ERG explained that the company's targeted literature review used only 1 database, and highlighted that important sources of comparator data may have been missed. The ERG explained that both ZUMA‑1 and SCHOLAR‑1 were not done in the UK, so the company's argument for not selecting other studies on this basis was flawed. The ERG explained that running alternative survival extrapolation scenarios with the SCHOLAR‑1 data showed that results are sensitive to changes in survival estimates for salvage chemotherapy. The committee noted that it would have liked the company to have explored further sources of comparator data. It noted the limitations with SCHOLAR‑1 but concluded that the dataset was appropriate for decision making. ## Indirect comparison The same approach used in the original appraisal to model salvage chemotherapy was applied. SCHOLAR‑1 data was adjusted to address imbalances in baseline characteristics and ensure comparability between ZUMA‑1 and SCHOLAR‑1. People with an ECOG performance status of 2 to 4, an unknown ECOG status or primary refractory disease were excluded from the SCHOLAR-1 dataset. Separate survival curves were used to generate a weighted survival estimate dependent on whether people had a stem cell transplant or not. The ERG highlighted that these adjustments substantially reduced the sample size of the study, from 562 people to 133 people, increasing uncertainty. The ERG also highlighted that this reduced sample size was similar to those in the alternative comparator studies (Radford , n=89; Fuji , n=189; Nakaya , n=131). The committee asked why the company didn't apply more formal adjustment methods involving matching. The company explained that it did not update the analysis because the adjustment approaches were accepted by the committee in the original appraisal. The committee would have preferred to see matching adjustments applied in the indirect comparison. Comparing ZUMA‑1 and SCHOLAR‑1 data, axicabtagene ciloleucel is associated with longer overall survival than salvage chemotherapy and sustained progression-free survival. The committee concluded that axicabtagene ciloleucel showed clinical benefit compared with salvage chemotherapy, however limitations in the comparator data mean that the exact size of the benefit was unknown. # Cost effectiveness ## Company economic model The company's economic model used the same approach as in the original appraisal. The model included 3 health states: pre-progression survival, post-progression survival, and death. The company used a partitioned survival modelling approach in which progression-free and overall survival estimates were modelled independently. The proportion of people whose disease progressed at each cycle was calculated as the difference between the overall survival and progression-free survival curves. The company modelled axicabtagene ciloleucel using updated data from ZUMA‑1, and salvage chemotherapy using data from SCHOLAR‑1. The company analysis was largely consistent with the original appraisal. The model time horizon was 44 years with a monthly cycle length. The company updated inputs for intravenous immunoglobulin (IVIg). In the original appraisal, the proportion of people who had IVIg was informed by ZUMA‑1 data and was assumed to be for 12 months. During technical engagement, the company and ERG agreed to use available SACT data to inform IVIg inputs, that is, 16% of people had IVIg treatment for 6.5 months. Health state utility values were applied using data from ZUMA‑1. The committee questioned the assumption that people in remission returned to general population utility. The committee thought it would be more clinically valid for people in remission to have a utility decrement applied to account for the impact of having had diffuse large B‑cell lymphoma or primary mediastinal large B-cell lymphoma and intensive treatments. The company explained that it kept the analysis consistent with the original appraisal. The committee would have preferred scenarios investigating the impact of health state utility, but concluded that, as in the original appraisal, the economic model was appropriate for decision making. ## Modelling overall survival Since the original appraisal, the company collected additional 60‑month axicabtagene ciloleucel overall survival data in ZUMA‑1. The company used a mixture cure modelling approach containing a proportion of people whose disease responds to axicabtagene ciloleucel and a proportion whose does not. People whose disease responds were assumed to have a mortality rate identical to that of the general population. Survival of people whose disease does not respond to axicabtagene ciloleucel was modelled using a standard parametric survival model. The combined survival curves made up the overall population of people with diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies. The company indicated that all mixture cure models fit well to ZUMA‑1 overall survival data and selected a log-logistic model based on statistical fit. The ERG generally agreed with the company approach and explained that the updated 60‑month ZUMA‑1 data reduced uncertainty in the estimated cure fraction. However, the ERG highlighted that all extrapolations using mixture cure and spline models were higher than ZUMA‑1 Kaplan–Meier data from 50 months onwards. It argued that this was potentially overestimating long-term survival. Clinical experts thought the company extrapolations fitted well with their experience of how CAR T‑cell therapies perform in clinical practice. They explained that CAR T‑cell therapies are expected to provide a durable response in a minority of people, and the plateau present in the extrapolations seemed reasonable. The committee concluded that the company's overall survival extrapolation modelling approach was appropriate. ## Modelling progression-free survival The company extrapolated progression-free survival using a standard Gompertz distribution. The company noted that this was the distribution used in the original appraisal and was based on the updated progression-free survival results at 2 years. The committee heard that the ERG had requested progression‑free survival data beyond 2 years, but the company explained this was not collected (see section 3.3). The company further explained that, because overall survival data was mature and stable, further progression-free survival data was not likely to impact cost-effectiveness estimates. The NICE technical team and ERG outlined that, because of the heavy censoring in the progression-free survival curve and low numbers at risk in the tail of the curve, any plateau in progression-free survival is still uncertain. The technical team highlighted that there were overall survival events between 2 years and 4 years and these events may well feature in the progression-free survival curve. These would cause the progression-free survival curve to drop. Clinical experts explained that people whose condition had not progressed by 2 years would likely remain progression-free. Clinical experts thought the company's axicabtagene ciloleucel progression-free survival extrapolation was plausible and stated they would be surprised to see many people progressing after 2 years. The committee noted that other plausible extrapolations increased the incremental cost-effectiveness ratio (ICER). The committee also asked why the company hadn't used mixture cure models for progression-free survival as it had for overall survival. The committee would have preferred longer-term progression data, as outlined in the terms of engagement, and flexible models considered in the base-case analysis. The committee concluded that the company analysis was acceptable but associated with uncertainty. ## Modelling salvage chemotherapy The company used SCHOLAR-1 data to extrapolate long-term overall and progression-free survival data for the comparator (salvage chemotherapy). For overall survival, the company used a standard generalised gamma parametric model fit to adjusted SCHOLAR-1 data in the base case. To extrapolate progression-free survival the company generated an estimate by applying the ratio between axicabtagene ciloleucel overall survival and progression-free survival to salvage chemotherapy overall survival. These were consistent with the methods used in the original appraisal. Overall and progression-free survival extrapolation curves showed a steep drop over the first 24 months before levelling off. Clinical experts explained that these extrapolations were clinically plausible for people who had the available treatment at the time. They added that the proportion of people alive in the extrapolation using SCHOLAR-1 data and people who remain progression-free using the company's methods were broadly consistent with other studies. The committee would have preferred to see consistent methods across outcomes for the 2 treatments but acknowledged limitations of available data. The committee concluded that the company's approach to modelling long-term survival for people having salvage chemotherapy was appropriate. ## CAR T-cell therapy delivery costs The company used a 'bottom-up' costing approach to calculate the cost of delivering axicabtagene ciloleucel in the NHS. The company included the costs of: hospital administration leukapheresis conditioning chemotherapy retreatment training stem cell transplants treating adverse events.The company considered each cost category individually and combined them to give an estimate for the cost of delivering axicabtagene ciloleucel in the NHS. The committee understood that NHS England had established a single tariff to capture these costs. The tariff was developed after NICE recommended the first CAR T‑cell therapy, tisagenlecleucel, for use through the Cancer Drugs Fund in December 2018. NHS England explained that the tariff includes all costs of care from the decision for the person to have CAR T‑cell therapy to 100 days after infusion. NHS England explained that there is not currently a healthcare resource group code that adequately captures the administration of CAR T‑cell therapies. It also commented that a key difference between its tariff and the company's costs is the time and number of staff required to look after people who have had CAR T‑cell therapy. The company commented that is it not appropriate to use the tariff in the modelling. This is because it is a mechanism for NHS England to fund hospitals to provide CAR T‑cell therapy and is not designed for health technology evaluation. It was concerned that the evidence underlying the tariff has not been transparently shared and that it may include costs that are not relevant. The ERG was also concerned about the methods used by NHS England to derive the tariff. It was unclear how individual trusts estimated expenditure and how this corresponded to quantities of resource use. However, the ERG also commented that the company's approach likely underestimated the true cost of delivering CAR T‑cell therapy. After the first appraisal committee meeting the company submitted a further analysis using a CAR T‑cell therapy delivery cost of £41,101, informed by an ERG scenario analysis in the ongoing NICE technology appraisal of axicabtagene ciloleucel for treating diffuse large B-cell lymphoma after 1 systemic therapy. This accounted for the impact of increased staffing requirements associated with providing CAR T‑cell therapy. The updated company analysis consisted of a one-off cost of £41,101 for the first 100 days plus the costs of conditioning chemotherapy drugs, stem cell transplantation and IVIg. These 3 costs are reimbursed separately by NHS England. NHS England considered that, although the company's cost differs from the tariff for CAR T‑cell therapy, it was an acceptable cost to use in the cost-effectiveness analysis. This is because while the current tariff represents the high hospital costs of establishing the infrastructure of a CAR T‑cell therapy service and delivering a relatively new type of treatment, economies of scale may be expected over time. This is particularly expected with clinical developments in care that reduce toxicity and the need for more intense monitoring and treatment. The committee noted NHS England's comments and was satisfied that the company's costs adequately captured a reasonable projection of the cost to the NHS of delivering CAR T‑cell therapy. # Cost-effectiveness estimates ## Most plausible ICER The company's base-case analysis was updated after technical engagement and aligned with the ERG's preferred analysis. Because there are confidential discounts for treatments included in best supportive care, the exact ICERs cannot be reported here. The committee concluded that the most plausible probabilistic ICER, using the £41,101 CAR T‑cell therapy delivery cost, was below £50,000 per quality-adjusted life year gained. # End of life ## End of life criteria are met The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal the committee concluded that axicabtagene ciloleucel met both criteria for end of life. The company updated ZUMA‑1 survival data for axicabtagene ciloleucel for this review, but salvage chemotherapy data was not updated. The committee concluded that axicabtagene ciloleucel offers more than 3 months' extension to life for a population that has a life expectancy of less than 24 months. The committee concluded that axicabtagene ciloleucel continues to meet the end of life criteria. # Other factors No equality or social value judgement issues were identified. # Conclusion ## Axicabtagene ciloleucel is recommended for routine use New evidence was considered from the ZUMA‑1 trial and the Cancer Drugs Fund SACT data (see section 3.3 and section 3.4). The committee recognised that there was some uncertainty in the company's, progression-free survival extrapolation and limited available data on the comparator (see section 3.5 and section 3.6). The committee also acknowledged uncertainty in the true cost of providing CAR T-cell therapies in the NHS (see section 3.11). However, the cost-effectiveness estimates for axicabtagene ciloleucel compared with salvage chemotherapy were below what NICE considers a cost-effective use of NHS resources. This is in the context of the end of life criteria being met. Axicabtagene ciloleucel is therefore recommended as an option in routine commissioning for treating diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma after 2 or more systemic therapies.	{'Recommendation': "Axicabtagene ciloleucel is recommended, within its marketing authorisation, as an option for treating relapsed or refractory diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma in adults after 2 or more systemic therapies. It is recommended only if the company provides axicabtagene ciloleucel according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma in adults after 2 or more systemic therapies (NICE technology appraisal guidance 559).\n\nThere is no standard treatment for relapsed or refractory diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma after 2 or more systemic therapies. Best supportive care is used and usually includes salvage chemotherapy. Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T‑cell therapy (also called CAR‑T therapy). It uses the patient's own immune cells that have been modified to attach to and kill cancer cells.\n\nThe new evidence includes data from a clinical trial and from people having axicabtagene ciloleucel in the NHS while it was available in the Cancer Drugs Fund. It suggests that people having axicabtagene ciloleucel live longer than people having salvage chemotherapy and have longer before their condition gets worse.\n\nAxicabtagene ciloleucel meets NICE's criteria to be considered a life-extending treatment at the end of life. Taking this into account, the cost-effectiveness estimates for axicabtagene ciloleucel are within what NICE considers an acceptable use of NHS resources. So, axicabtagene ciloleucel is recommended for routine use in the NHS.", 'Information about axicabtagene ciloleucel': "# Marketing authorisation indication\n\nAxicabtagene ciloleucel (Yescarta, Kite) is 'indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) after 2 or more lines of systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for axicabtagene ciloleucel.\n\n# Price\n\nThe list price for axicabtagene ciloleucel is £280,451 per single infusion bag (approximately 68\xa0ml, company submission).\n\nThe company has a commercial arrangement. This makes axicabtagene ciloleucel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Kite, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund's managed access arrangement, the company was required to collect updated efficacy data from the ZUMA‑1 trial. Data was also collected on the use of axicabtagene ciloleucel in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\n# Clinical need\n\n## Value of treatment\n\nDiffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma are aggressive subtypes of non-Hodgkin lymphoma. The condition does not respond well to chemotherapy, and outcomes for people with refractory or relapsed disease are poor and survival is limited. Axicabtagene ciloleucel is part of a group of advanced cancer treatments called chimeric antigen receptor (CAR) T‑cell therapies. CAR\xa0T‑cell therapies are personalised cancer immunotherapies which involve collecting and modifying people's own immune cells to treat their cancer. Axicabtagene ciloleucel is indicated for the treatment of relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more lines of systemic therapy in adults. Clinical and patient experts explained that without CAR\xa0T‑cell therapy there is a lack of treatment options if the condition relapses after 2\xa0therapies. The patient expert explained that chemotherapy treatments are intense, frequent and extremely difficult to tolerate. They described that chemotherapy treatments have challenging side effects and a large impact on quality of life for little clinical success. The patient and clinical experts explained that the introduction of axicabtagene ciloleucel into the treatment pathway has revolutionised treatment and provided hope of a cure for this aggressive condition. The committee concluded that axicabtagene ciloleucel is a valuable treatment option.\n\n## Treatment pathway\n\nIn the original appraisal, the company proposed that axicabtagene ciloleucel can be used in 4\xa0possible positions in the treatment pathway, specifically for people whose disease:\n\nwas refractory after 1 systemic therapy, or\n\nhas relapsed after 1 systemic therapy, but who cannot have an autologous stem cell transplant, or\n\nhas relapsed after 1 systemic therapy, and who have had chemotherapy and an autologous stem cell transplant but whose disease has then relapsed again, or\n\nhas relapsed after 1 systemic therapy, and who would have been able to have an autologous stem cell transplant as part of a second treatment, but whose disease does not respond to salvage chemotherapy. The committee considered the company's proposed positions in the pathway. During the original appraisal, the committee concluded that it could not consider axicabtagene ciloleucel for people whose disease has not responded to 1 systemic therapy but who are unable to have an autologous stem cell transplant. It considered this position was not in line with the anticipated marketing authorisation of axicabtagene ciloleucel (that is, after 2 or more systemic therapies). Axicabtagene ciloleucel would also not be used as an alternative to autologous stem cell transplant, because this would be part of the second systemic treatment. So, the committee concluded that axicabtagene ciloleucel would be positioned as a treatment option for people whose disease:\n\ndid not respond after 2 systemic therapies, or\n\nhas relapsed after 1 systemic therapy, and who have had chemotherapy and an autologous stem cell transplant but whose disease has then relapsed again, or\n\nhas relapsed after 1 systemic therapy, and who would have been able to have an autologous stem cell transplant as part of a second treatment, but whose disease does not respond to salvage chemotherapy. Clinical experts explained that all 3 populations have had axicabtagene ciloleucel in NHS clinical practice, and they would expect this to continue. Without axicabtagene ciloleucel, the only available treatment option for people who have had 2 previous systemic therapies is salvage chemotherapy. Salvage chemotherapy is only expected to provide short-term benefits, but axicabtagene ciloleucel has the potential to be curative. The committee concluded that considering axicabtagene ciloleucel in 3\xa0positions of the treatment pathway is appropriate.\n\n# Clinical evidence\n\n## ZUMA-1 data\n\nThe clinical-effectiveness evidence for axicabtagene ciloleucel was from ZUMA‑1, an ongoing, phase 1/2, multicentre, open-label, single-arm trial. ZUMA‑1 investigated axicabtagene ciloleucel for aggressive relapsed or refractory B-cell non-Hodgkin lymphoma (including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma and transformed follicular lymphoma) in adults that was refractory to treatment or had relapsed within 12\xa0months of autologous stem cell transplant. The company presented updated overall survival results collected in ZUMA‑1 which included a minimum follow-up of 5\xa0years. The updated ZUMA‑1 results showed that 64\xa0patients (59%) had died at database lock (11\xa0August\xa02021). Updated median overall survival was 23.5\xa0months with an observed plateau of 45% at around 26.0\xa0months. Updated median progression-free survival was 5.8\xa0months with an observed plateau in progression-free survival of 40% at 9.0\xa0months. The committee heard that ZUMA‑1 progression-free survival was only updated to 2\xa0years, because there was no protocol mandate to collect data after 2\xa0years. The company stated that any progression-free survival data collected after 2\xa0years would not be consistent with progression-free survival data collected before 2\xa0years. The committee would have preferred to see more mature progression-free survival data but accepted that additional overall survival data had reduced uncertainty. The committee concluded that additional axicabtagene ciloleucel data supported the predictions in the original submission of long survival times for a substantial proportion of patients.\n\n## SACT data\n\nFurther clinical evidence was collected from the SACT dataset while axicabtagene ciloleucel was available in the Cancer Drugs Fund. The SACT dataset contains UK real-world clinical-effectiveness data from the Cancer Drugs Fund population between December 2018 and October 2021. The median age of people having axicabtagene ciloleucel was 59.5\xa0years, similar to ZUMA‑1. Overall survival rates in the Cancer Drugs Fund population were comparable to ZUMA‑1 over the 36\xa0months of data collection. Median overall survival of people having axicabtagene ciloleucel was 28.5\xa0months and 45% of people were alive after 3\xa0years. The ERG highlighted that Eastern Cooperative Oncology Group (ECOG) performance status was not collected for a proportion of people in the SACT dataset, which made comparisons with ZUMA‑1 more difficult. Clinical experts explained that they expect axicabtagene ciloleucel to perform similarly in routine NHS clinical practice to ZUMA‑1 and the SACT dataset. The committee concluded that outcomes from the SACT dataset were comparable to those from ZUMA‑1 and supported the use of axicabtagene ciloleucel in routine NHS clinical practice.\n\n## Salvage chemotherapy efficacy\n\nBecause ZUMA-1 is a single-arm trial, the primary evidence source for the comparator was the SCHOLAR‑1 study. SCHOLAR‑1 was a retrospective study of pooled data from 4\xa0datasets. These datasets included adults with diffuse large B-cell lymphoma (n=552), primary mediastinal large B-cell lymphoma (n=14), transformed follicular lymphoma (n=27) and 'other' (n=43). Treatment options included salvage chemotherapy, rituximab maintenance therapy and observation after autologous stem cell transplant. The company did a targeted literature review of studies on diffuse large B-cell lymphoma after 2 or more lines of systemic therapy. This was to respond to the Cancer Drugs Fund review terms of engagement's request for additional data to address uncertainties in comparator data. The company identified 3\xa0studies, with only 1\xa0study from the UK. Radford et al. (2019) investigated treatment patterns and outcomes for people with relapsed or refractory diffuse large B-cell lymphoma from a single UK centre. The company argued that SCHOLAR‑1 is still the most appropriate source of data for salvage chemotherapy and stressed the approach maintained consistency with the original submission. The company also outlined that SCHOLAR‑1 outcomes were similar to the third-line population in the Radford study, validating their SCHOLAR‑1 approach. Clinical experts highlighted issues with SCHOLAR‑1. They argued that the populations in SCHOLAR‑1 were not comparable to ZUMA-1. They also noted that there are large datasets that could have been used to validate SCHOLAR‑1. The ERG explained that the company's targeted literature review used only 1\xa0database, and highlighted that important sources of comparator data may have been missed. The ERG explained that both ZUMA‑1 and SCHOLAR‑1 were not done in the UK, so the company's argument for not selecting other studies on this basis was flawed. The ERG explained that running alternative survival extrapolation scenarios with the SCHOLAR‑1 data showed that results are sensitive to changes in survival estimates for salvage chemotherapy. The committee noted that it would have liked the company to have explored further sources of comparator data. It noted the limitations with SCHOLAR‑1 but concluded that the dataset was appropriate for decision making.\n\n## Indirect comparison\n\nThe same approach used in the original appraisal to model salvage chemotherapy was applied. SCHOLAR‑1 data was adjusted to address imbalances in baseline characteristics and ensure comparability between ZUMA‑1 and SCHOLAR‑1. People with an ECOG performance status of 2 to 4, an unknown ECOG status or primary refractory disease were excluded from the SCHOLAR-1 dataset. Separate survival curves were used to generate a weighted survival estimate dependent on whether people had a stem cell transplant or not. The ERG highlighted that these adjustments substantially reduced the sample size of the study, from 562\xa0people to 133\xa0people, increasing uncertainty. The ERG also highlighted that this reduced sample size was similar to those in the alternative comparator studies (Radford [UK], n=89; Fuji [Japan], n=189; Nakaya [Japan], n=131). The committee asked why the company didn't apply more formal adjustment methods involving matching. The company explained that it did not update the analysis because the adjustment approaches were accepted by the committee in the original appraisal. The committee would have preferred to see matching adjustments applied in the indirect comparison. Comparing ZUMA‑1 and SCHOLAR‑1 data, axicabtagene ciloleucel is associated with longer overall survival than salvage chemotherapy and sustained progression-free survival. The committee concluded that axicabtagene ciloleucel showed clinical benefit compared with salvage chemotherapy, however limitations in the comparator data mean that the exact size of the benefit was unknown.\n\n# Cost effectiveness\n\n## Company economic model\n\nThe company's economic model used the same approach as in the original appraisal. The model included 3\xa0health states: pre-progression survival, post-progression survival, and death. The company used a partitioned survival modelling approach in which progression-free and overall survival estimates were modelled independently. The proportion of people whose disease progressed at each cycle was calculated as the difference between the overall survival and progression-free survival curves. The company modelled axicabtagene ciloleucel using updated data from ZUMA‑1, and salvage chemotherapy using data from SCHOLAR‑1. The company analysis was largely consistent with the original appraisal. The model time horizon was 44\xa0years with a monthly cycle length. The company updated inputs for intravenous immunoglobulin (IVIg). In the original appraisal, the proportion of people who had IVIg was informed by ZUMA‑1 data and was assumed to be for 12\xa0months. During technical engagement, the company and ERG agreed to use available SACT data to inform IVIg inputs, that is, 16% of people had IVIg treatment for 6.5\xa0months. Health state utility values were applied using data from ZUMA‑1. The committee questioned the assumption that people in remission returned to general population utility. The committee thought it would be more clinically valid for people in remission to have a utility decrement applied to account for the impact of having had diffuse large B‑cell lymphoma or primary mediastinal large B-cell lymphoma and intensive treatments. The company explained that it kept the analysis consistent with the original appraisal. The committee would have preferred scenarios investigating the impact of health state utility, but concluded that, as in the original appraisal, the economic model was appropriate for decision making.\n\n## Modelling overall survival\n\nSince the original appraisal, the company collected additional 60‑month axicabtagene ciloleucel overall survival data in ZUMA‑1. The company used a mixture cure modelling approach containing a proportion of people whose disease responds to axicabtagene ciloleucel and a proportion whose does not. People whose disease responds were assumed to have a mortality rate identical to that of the general population. Survival of people whose disease does not respond to axicabtagene ciloleucel was modelled using a standard parametric survival model. The combined survival curves made up the overall population of people with diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies. The company indicated that all mixture cure models fit well to ZUMA‑1 overall survival data and selected a log-logistic model based on statistical fit. The ERG generally agreed with the company approach and explained that the updated 60‑month ZUMA‑1 data reduced uncertainty in the estimated cure fraction. However, the ERG highlighted that all extrapolations using mixture cure and spline models were higher than ZUMA‑1 Kaplan–Meier data from 50\xa0months onwards. It argued that this was potentially overestimating long-term survival. Clinical experts thought the company extrapolations fitted well with their experience of how CAR\xa0T‑cell therapies perform in clinical practice. They explained that CAR\xa0T‑cell therapies are expected to provide a durable response in a minority of people, and the plateau present in the extrapolations seemed reasonable. The committee concluded that the company's overall survival extrapolation modelling approach was appropriate.\n\n## Modelling progression-free survival\n\nThe company extrapolated progression-free survival using a standard Gompertz distribution. The company noted that this was the distribution used in the original appraisal and was based on the updated progression-free survival results at 2\xa0years. The committee heard that the ERG had requested progression‑free survival data beyond 2\xa0years, but the company explained this was not collected (see section\xa03.3). The company further explained that, because overall survival data was mature and stable, further progression-free survival data was not likely to impact cost-effectiveness estimates. The NICE technical team and ERG outlined that, because of the heavy censoring in the progression-free survival curve and low numbers at risk in the tail of the curve, any plateau in progression-free survival is still uncertain. The technical team highlighted that there were overall survival events between 2\xa0years and 4\xa0years and these events may well feature in the progression-free survival curve. These would cause the progression-free survival curve to drop. Clinical experts explained that people whose condition had not progressed by 2\xa0years would likely remain progression-free. Clinical experts thought the company's axicabtagene ciloleucel progression-free survival extrapolation was plausible and stated they would be surprised to see many people progressing after 2\xa0years. The committee noted that other plausible extrapolations increased the incremental cost-effectiveness ratio (ICER). The committee also asked why the company hadn't used mixture cure models for progression-free survival as it had for overall survival. The committee would have preferred longer-term progression data, as outlined in the terms of engagement, and flexible models considered in the base-case analysis. The committee concluded that the company analysis was acceptable but associated with uncertainty.\n\n## Modelling salvage chemotherapy\n\nThe company used SCHOLAR-1 data to extrapolate long-term overall and progression-free survival data for the comparator (salvage chemotherapy). For overall survival, the company used a standard generalised gamma parametric model fit to adjusted SCHOLAR-1 data in the base case. To extrapolate progression-free survival the company generated an estimate by applying the ratio between axicabtagene ciloleucel overall survival and progression-free survival to salvage chemotherapy overall survival. These were consistent with the methods used in the original appraisal. Overall and progression-free survival extrapolation curves showed a steep drop over the first 24\xa0months before levelling off. Clinical experts explained that these extrapolations were clinically plausible for people who had the available treatment at the time. They added that the proportion of people alive in the extrapolation using SCHOLAR-1 data and people who remain progression-free using the company's methods were broadly consistent with other studies. The committee would have preferred to see consistent methods across outcomes for the 2\xa0treatments but acknowledged limitations of available data. The committee concluded that the company's approach to modelling long-term survival for people having salvage chemotherapy was appropriate.\n\n## CAR T-cell therapy delivery costs\n\nThe company used a 'bottom-up' costing approach to calculate the cost of delivering axicabtagene ciloleucel in the NHS. The company included the costs of:\n\nhospital administration\n\nleukapheresis\n\nconditioning chemotherapy\n\nretreatment\n\ntraining\n\nstem cell transplants\n\ntreating adverse events.The company considered each cost category individually and combined them to give an estimate for the cost of delivering axicabtagene ciloleucel in the NHS. The committee understood that NHS England had established a single tariff to capture these costs. The tariff was developed after NICE recommended the first CAR\xa0T‑cell therapy, tisagenlecleucel, for use through the Cancer Drugs Fund in December 2018. NHS England explained that the tariff includes all costs of care from the decision for the person to have CAR\xa0T‑cell therapy to 100\xa0days after infusion. NHS England explained that there is not currently a healthcare resource group code that adequately captures the administration of CAR\xa0T‑cell therapies. It also commented that a key difference between its tariff and the company's costs is the time and number of staff required to look after people who have had CAR\xa0T‑cell therapy. The company commented that is it not appropriate to use the tariff in the modelling. This is because it is a mechanism for NHS England to fund hospitals to provide CAR\xa0T‑cell therapy and is not designed for health technology evaluation. It was concerned that the evidence underlying the tariff has not been transparently shared and that it may include costs that are not relevant. The ERG was also concerned about the methods used by NHS England to derive the tariff. It was unclear how individual trusts estimated expenditure and how this corresponded to quantities of resource use. However, the ERG also commented that the company's approach likely underestimated the true cost of delivering CAR\xa0T‑cell therapy. After the first appraisal committee meeting the company submitted a further analysis using a CAR\xa0T‑cell therapy delivery cost of £41,101, informed by an ERG scenario analysis in the ongoing NICE technology appraisal of axicabtagene ciloleucel for treating diffuse large B-cell lymphoma after 1\xa0systemic therapy. This accounted for the impact of increased staffing requirements associated with providing CAR\xa0T‑cell therapy. The updated company analysis consisted of a one-off cost of £41,101 for the first 100\xa0days plus the costs of conditioning chemotherapy drugs, stem cell transplantation and IVIg. These 3 costs are reimbursed separately by NHS England. NHS England considered that, although the company's cost differs from the tariff for CAR\xa0T‑cell therapy, it was an acceptable cost to use in the cost-effectiveness analysis. This is because while the current tariff represents the high hospital costs of establishing the infrastructure of a CAR\xa0T‑cell therapy service and delivering a relatively new type of treatment, economies of scale may be expected over time. This is particularly expected with clinical developments in care that reduce toxicity and the need for more intense monitoring and treatment. The committee noted NHS England's comments and was satisfied that the company's costs adequately captured a reasonable projection of the cost to the NHS of delivering CAR\xa0T‑cell therapy.\n\n# Cost-effectiveness estimates\n\n## Most plausible ICER\n\nThe company's base-case analysis was updated after technical engagement and aligned with the ERG's preferred analysis. Because there are confidential discounts for treatments included in best supportive care, the exact ICERs cannot be reported here. The committee concluded that the most plausible probabilistic ICER, using the £41,101 CAR\xa0T‑cell therapy delivery cost, was below £50,000 per quality-adjusted life year gained.\n\n# End of life\n\n## End of life criteria are met\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal the committee concluded that axicabtagene ciloleucel met both criteria for end of life. The company updated ZUMA‑1 survival data for axicabtagene ciloleucel for this review, but salvage chemotherapy data was not updated. The committee concluded that axicabtagene ciloleucel offers more than 3\xa0months' extension to life for a population that has a life expectancy of less than 24\xa0months. The committee concluded that axicabtagene ciloleucel continues to meet the end of life criteria.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Axicabtagene ciloleucel is recommended for routine use\n\nNew evidence was considered from the ZUMA‑1 trial and the Cancer Drugs Fund SACT data (see section\xa03.3 and section\xa03.4). The committee recognised that there was some uncertainty in the company's, progression-free survival extrapolation and limited available data on the comparator (see section\xa03.5 and section\xa03.6). The committee also acknowledged uncertainty in the true cost of providing CAR\xa0T-cell therapies in the NHS (see section\xa03.11). However, the cost-effectiveness estimates for axicabtagene ciloleucel compared with salvage chemotherapy were below what NICE considers a cost-effective use of NHS resources. This is in the context of the end of life criteria being met. Axicabtagene ciloleucel is therefore recommended as an option in routine commissioning for treating diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma after 2 or more systemic therapies."}	https://www.nice.org.uk/guidance/ta872	Evidence-based recommendations on axicabtagene ciloleucel (Yescarta) for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma in adults after 2 or more systemic therapies.
0d94a4ead190055657fd5266144eb686882d75ed	nice	Ixazomib with lenalidomide and dexamethasone for treating relapsed or refractory multiple myeloma	Ixazomib with lenalidomide and dexamethasone for treating relapsed or refractory multiple myeloma Evidence-based recommendations on Ixazomib (Ninlaro) with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma. # Recommendations Ixazomib, with lenalidomide and dexamethasone, is recommended as an option for treating multiple myeloma in adults, only if: they have had 2 or 3 lines of therapy and the company provides ixazomib according to the commercial arrangement. This recommendation is not intended to affect treatment with ixazomib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for ixazomib with lenalidomide and dexamethasone (ixazomib combination) for treating relapsed or refractory multiple myeloma (NICE technology appraisal guidance 505). The original appraisal recommended ixazomib combination in people who have already had 2 or 3 lines of treatment. The usual treatment for these people is lenalidomide and dexamethasone. The new evidence includes data from a clinical trial and from people having ixazomib combination in the NHS while it was available in the Cancer Drugs Fund. The evidence suggests that people with multiple myeloma who have ixazomib combination live longer compared with people who have lenalidomide and dexamethasone. The cost-effectiveness estimates for ixazomib combination are likely to be within what NICE considers an acceptable use of NHS resources, so it is recommended.# Information about ixazomib # Marketing authorisation indication Ixazomib citrate (Ninlaro, Takeda), in combination with lenalidomide and dexamethasone, is indicated for 'the treatment of adult patients with multiple myeloma who have had at least 1 previous therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for ixazomib. # Price The list price is £6,336 per pack of 3 capsules (excluding VAT; BNF online, accessed November 2022). The company has a commercial arrangement. This makes ixazomib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know the details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect efficacy data from the TOURMALINE-MM1 (TMM1) study. Data was also collected using the Systemic Anti-Cancer Therapy (SACT) dataset. The committee was aware that there were remaining areas of uncertainty associated with the analyses presented (see ERG report page 9) and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage: the company's Weibull models for overall survival appeared almost indistinguishable from the generalised gamma models uncertainty regarding the post-progression life-year gains in the adjusted overall-survival modelling the sustained effect of treatment when people have stopped taking the study treatments. # The condition and clinical management ## Ixazomib combination is a valuable treatment option for people with relapsed or refractory multiple myeloma Multiple myeloma is typically incurable and is a progressive disease that affects survival and quality of life. The patient experts explained that multiple myeloma causes debilitating symptoms including bone pain and bone fractures, tiredness, infections, hypercalcaemia (too much calcium in the blood) and kidney problems. The clinical experts noted that treating the disease becomes more and more challenging with each relapse. Treatment side effects and frequent hospital visits have an impact on people with multiple myeloma and their carers. The patient expert explained that ixazomib with lenalidomide and dexamethasone (ixazomib combination) has allowed them a long period of progression-free survival and an improved quality of life with minimal side effects. The patient expert noted that they valued the oral administration of ixazomib combination. The committee considered the evidence from patient experts who have experience taking ixazomib combination and concluded that it is a valuable treatment option for people with relapsed or refractory multiple myeloma. ## The population relevant to this appraisal is people who have had 2 or 3 previous therapies Treatment options for multiple myeloma depend on a person's treatment history, their response to the treatments and their preferences. After 2 previous lines of treatment, options include lenalidomide plus dexamethasone, or panobinostat plus bortezomib and dexamethasone. After 3 previous lines of treatment, options include pomalidomide plus dexamethasone, or panobinostat plus bortezomib and dexamethasone. Daratumumab alone, and isatuximab with pomalidomide and dexamethasone are also available in the Cancer Drugs Fund. Ixazomib combination can be used after at least 1 previous therapy. The committee in the original appraisal (NICE technology appraisal guidance 505, from now referred to as TA505) understood that ixazomib combination would be used in the same place in the pathway that lenalidomide and dexamethasone is currently used; that is, for people who have had 2 or 3 previous therapies. The committee concluded that the population relevant to this review was people who have had 2 or 3 previous therapies. ## Without ixazomib combination, there would be an unmet need for an oral triplet therapy for people who have had 2 or 3 previous therapies The clinical experts explained that oral treatment regimens, which reduce pressure on hospital outpatient units and chemotherapy day units compared with intravenous options, are very important to people with multiple myeloma. They explained that oral treatment regimens reduce the risk of acquiring infections and that many people with multiple myeloma are particularly concerned about contracting COVID-19 from hospitals. The clinical lead for the Cancer Drugs Fund explained that triple therapy is now standard at first and second line for people with multiple myeloma and that a fourth-line triplet therapy is available in the Cancer Drugs Fund. The patient expert explained that the benefits of ixazomib combination were not limited to the oral administration of the treatment, but also that it is a triplet therapy. The clinical lead for the Cancer Drugs Fund added that ixazomib combination has met the need for this preferred treatment option at third line. The committee concluded that, without ixazomib combination, there would be an unmet need for an oral triplet therapy for people who have had 2 or 3 previous therapies. ## Lenalidomide plus dexamethasone remains the only relevant comparator In TA505 the committee agreed that lenalidomide with dexamethasone was the relevant comparator. This was because, although the scope included bortezomib for people who have had at least 1 therapy, the committee for TA505 recalled that ixazomib combination was not expected to be widely used in people who have had 1 previous therapy. So, the committee in TA505 agreed bortezomib was not a relevant comparator. NICE guidance recommends both panobinostat plus bortezomib and dexamethasone, and lenalidomide plus dexamethasone after 2 previous lines of treatment. But the clinical experts in TA505 stated that they would always prefer to use lenalidomide before panobinostat, and therefore panobinostat is not used unless people have had 3 therapies or more. No changes to the scope are permitted in a Cancer Drugs Fund review and treatments in the Cancer Drugs Fund cannot be considered comparators or included in the treatment sequence. So, the committee concluded that after 2 or 3 lines of treatment, lenalidomide plus dexamethasone remained the most relevant comparator. # Clinical-effectiveness evidence ## Ixazomib combination improves progression-free survival after 2 or 3 lines of therapy In TA505 the clinical-effectiveness evidence for ixazomib combination came from a second interim analysis data cut of TMM1, a phase 3 randomised controlled trial. The primary endpoint of the trial was progression-free survival. The median progression-free survival for ixazomib combination after 2 or 3 previous lines of treatment was 22 months compared with 13 months for lenalidomide and dexamethasone. The stratified hazard ratio was 0.62 (95% confidence interval 0.45 to 0.86, p=0.0033). This showed that ixazomib combination was associated with a statistically significant improvement in progression-free survival compared with lenalidomide and dexamethasone. The progression-free survival observations were not collected beyond the second interim analysis of TMM1 because this data was mature. So, the progression-free survival data was the same as the original appraisal. In TA505 the committee noted that the second interim analysis showed a reduced progression-free survival difference between arms compared with the first analysis, which was no longer statistically significant for the intention-to-treat population. However, it did remain significant for people who had had 2 or 3 previous therapies. The committee concluded that ixazomib combination improved progression-free survival in people who have had 2 or 3 lines of therapy. ## The evidence from TMM1 is appropriate for decision making but has limitations The committee in TA505 was concerned that the clinical benefit of ixazomib combination was uncertain because the overall-survival data was too immature to be considered robust. To address the committee's concerns from the original appraisal, the company provided the clinical-effectiveness for ixazomib combination from the final data cut of TMM1. The trial included 722 people with relapsed or refractory multiple myeloma. A subgroup of 297 people, which included people who had had 2 or 3 previous lines of treatment, was relevant to this appraisal. The unadjusted median overall survival was 53 months for ixazomib combination and 43 months for lenalidomide and dexamethasone. The stratified hazard ratio was 0.85 (95% CI 0.64 to 1.11, p=0.232), showing ixazomib combination was not associated with a statistically significant improvement in overall survival compared with lenalidomide and dexamethasone. However, the clinical experts explained that overall survival is highly dependent on the choice of post-progression treatments. They further explained that the TMM1 trial had no UK centres, and the post-progression treatments would have varied depending on location and so were unlikely to be representative of UK practice. The company considered it was not appropriate to use the unadjusted overall-survival estimates from TMM1. The company explained that it had adjusted the data to remove the effect of subsequent therapies. This was because the treatment pathway in the trial did not reflect UK clinical practice and the distribution of subsequent treatments was not balanced between treatment arms (see section 3.8). The clinical experts noted that ixazomib is a proteasome inhibitor. They explained that because TMM1 was a blinded trial, some people whose disease progressed with ixazomib combination may have been given another proteasome inhibitor as a subsequent therapy. These people were likely to have been refractory to proteasome inhibitors at progression, so were given a potentially less effective treatment sequence than people in the lenalidomide and dexamethasone arm. The company did not adjust for this potential confounding, so, the committee heard that the overall-survival results were likely to be biased against ixazomib combination. The committee concluded that although the effect of ixazomib commination on overall survival in TMM1 was likely confounded by subsequent treatments, the data was acceptable for decision making. ## Ixazomib likely improves overall survival Treatments recommended in the Cancer Drugs Fund cannot be considered comparators or subsequent treatments in NICE appraisals. NICE's guide to the methods of technology appraisal 2013 also advises that treatments not embedded in clinical practice in the NHS should not be considered as comparators or subsequent treatments. So, the company used the 2-stage method with recensoring to remove the effect of subsequent treatments from TMM1 not routinely used in the NHS, including those available via the Cancer Drugs Fund. The company assumed that the treatments removed in the 2-stage adjustment were effective and improved survival. The adjusted median overall survival was 51.4 months for ixazomib combination and 41.5 months for lenalidomide and dexamethasone. The stratified hazard ratio was 0.71 (95% CI 0.54 to 0.95, p=0.0216), showing ixazomib combination was associated with a statistically significant improvement in overall survival compared with lenalidomide and dexamethasone. The ERG explored additional analyses of the intention-to-treat population, including all 722 people, from TMM1. The ERG stated that in this population, which included people who had only had 1 previous line of treatment, the confidence intervals of overall survival crossed 1. The company highlighted that analysing this population was outside the scope of this review and it included people from a different treatment line who would have had different treatments and disease prognoses. The company also noted that a regional study of TMM1, in China, which did not face challenges of adjusting data for subsequent treatment therapies, showed a survival benefit with ixazomib combination. The committee concluded that an overall-survival benefit of ixazomib combination is likely. ## Adjusting overall survival to remove the effect of subsequent treatments is appropriate After adjustment for subsequent treatments, modelled post-progression life expectancy reduced to a greater extent in the lenalidomide and dexamethasone arm (a reduction of 0.3 life years) compared with the ixazomib combination arm (a reduction of 0.03 life years). The ERG noted that there were only small differences in the proportion of treatments not routinely used in the NHS or within the Cancer Drugs Fund in both treatment arms. Therefore, it was unclear why the reduction in life years was larger in the lenalidomide plus dexamethasone arm. The company explained that more people had treatments that extend survival in the lenalidomide and dexamethasone arm. The ERG also noted that modelled post-progression life-year gain, after adjustment, was 30.5% of the total life-year gain. Whereas, modelled post-progression life-year gain before adjustment was 7.4% of total life-year gain. The ERG stated that the change in life years gained departed from clinical plausibility. The company highlighted that there was a minimal difference between the cost-effectiveness estimates for the 2-stage method with recensoring and the unadjusted analysis. The committee noted these areas of uncertainty associated with the company's overall-survival adjustment, but was aware that using the adjusted analysis with recensoring versus unadjusted overall-survival data in the model made very little difference to the cost-effectiveness results. The committee concluded that although there was uncertainty about the adjustment to overall survival for subsequent treatments, the company's approach was appropriate. ## Recensoring data in the 2-stage adjustment lowers the cost-effectiveness estimates The committee noted that the company recensored the overall-survival data following its 2-stage adjustment, and that recensoring can overestimate the treatment effect. The committee considered that uncensored data should have been considered and that the cost-effectiveness estimates were lower than they would have been if the company had not recensored the data. The company highlighted that the NICE Decision Support Unit technical support document 16 states that recensoring is required to avoid bias, particularly in cases where treatment switching is likely to be associated with prognosis, which was the case in TMM1. The committee concluded that the bias from recensoring the data was likely less than the bias from not censoring the data, but that the true cost-effectiveness estimates could be higher than the ones presented by the company. ## There are differences between the population in TMM1 and the people eligible to have ixazomib combination in the NHS NHS England also provided data from the SACT dataset. It was collected from 2,460 people who had ixazomib combination through the Cancer Drugs Fund between December 2017 and June 2020. The clinical experts explained that the clinical experience with ixazomib combination was positive. The clinical experts added that the SACT dataset shows that disease control and disease response with ixazomib combination was encouraging. The committee noted that the adjusted median overall survival in the trial was longer (51.4 months) than in the SACT dataset (30 months). Both the clinical experts and the clinical lead for the Cancer Drugs Fund explained that people included in the SACT dataset were older and had a poorer prognosis than people in TMM1. This may have contributed to the differences in the median survival estimates. The clinical experts added that the median follow up for overall survival was also shorter than the follow up in TMM1 and so not all benefits from ixazomib combination would have been captured. The committee recalled that the SACT dataset did not provide comparative evidence versus lenalidomide and dexamethasone and so a relative treatment effect from the use of ixazomib combination in the NHS could not be estimated. The committee agreed that the evidence from TMM1 was robust and the most appropriate for decision making. The committee concluded that population differences likely contributed to the differences in treatment effects between TMM1 and the SACT dataset. # The company's economic model ## The estimates of overall survival from each approach to modelling are similar The company used data from the subgroup of people from TMM1 with relapsed and refractory multiple myeloma who had 2 or 3 previous lines of treatment. It used the generalised gamma model to estimate overall survival with ixazomib combination and lenalidomide and dexamethasone. It explained that it chose this model because its clinicians stated that the generalised gamma provided a reasonable estimation of long-term outcomes. The ERG proposed that the Weibull model was as valid on the grounds of clinical plausibility as the generalised gamma curve and was statistically better fitting than the generalised gamma model for both ixazomib combination and lenalidomide and dexamethasone. The clinical experts acknowledged that both the generalised gamma and Weibull curves estimated similar overall-survival outcomes. The clinical experts noted that survival seen in real-world practice in the NHS was much lower than the survival estimated by the parametric models. The company highlighted that there was a difference between clinical trial data and real-world data; in TMM1 around 35% of people were still alive after 8 years. The company added that people in clinical trials are often younger, have fewer comorbidities and have a better prognosis compared with people not in clinical trials. The committee concluded that although the generalised gamma curve was acceptable to extrapolate overall survival for ixazomib combination and lenalidomide and dexamethasone, the Weibull curve should also be considered. ## The treatment waning effect is almost completely included in the trial follow up In TA505 the company assumed that ixazomib combination's relative survival benefit in the clinical trial, compared with lenalidomide and dexamethasone, was maintained for the rest of a person's life after treatment stopped. The committee concluded in TA505 that, although it was biologically plausible for the relative treatment benefit to continue after stopping treatment, that level might not be maintained for the rest of a person's life. For this review, the company did not include a treatment waning effect in its base case. The company explained that the discontinuation of treatment had been almost completely captured within the 8-year observation time of TMM1. The company added that the hazard ratio or treatment effect in the ixazomib combination arm was a composite measure reflecting a pathway of treatments. The ERG agreed that the discontinuation and waning of treatment had been almost completely captured within the observed time of the trial, but noted that this was separate to the waning of the treatment effect. The ERG noted that over 90% of people were only observed for around 2 years following discontinuation of ixazomib combination. The ERG thought this was an insufficient time to capture any waning of treatment effect and conducted scenarios to explore the potential impact of treatment waning. The ERG did not include these scenarios in its base case. The ERG applied weighted hazards produced at each model cycle to generate an adjusted overall-survival estimate for people having ixazomib combination. Introducing a treatment waning effect increased the cost-effectiveness estimates of ixazomib combination. The committee recalled the long follow up of TMM1 and concluded that it largely captured the treatment waning and no other adjustments to treatment waning were needed. ## The utility values used in the model are appropriate In TA505 the committee recognised that the utility for progressed disease was higher than the UK population norms, and higher than in previous multiple myeloma appraisals. In this review the company used updated EQ-5D data from TMM1. The ERG agreed that the utilities estimated from the final analysis of TMM1 better aligned with the literature and reflected the health-related quality of life of people with relapsed or refractory multiple myeloma. The committee concluded that the utility values used in the model were acceptable. # End of life ## Ixazomib combination does not meet the end of life criteria The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In TA505 the committee considered that although ixazomib combination has the potential to improve overall survival, it did not meet the criterion for extension to life. The committee concluded that ixazomib combination could not be considered as an end of life therapy. The committee in this review concluded that its view from TA505 had not changed. # Cost effectiveness ## The most likely cost-effectiveness estimates is below £30,000 per QALY gained The committee preferred an analysis that included: either the generalised gamma or Weibull curve to extrapolate overall survival for ixazomib combination and lenalidomide and dexamethasone adjusted overall-survival modelling no additional treatment waning.Using these preferred assumptions, the committee considered that the most plausible incremental cost-effectiveness ratio (ICER) for ixazomib combination compared with lenalidomide and dexamethasone was below £30,000 per quality-adjusted life-year (QALY) gained. Because of confidential commercial arrangements for the treatments and comparators, the exact cost-effectiveness results cannot be reported here. The committee noted the level of uncertainty associated with the clinical- and cost-effectiveness results, specifically the adjusted and unadjusted estimates of overall survival and choice of model for extrapolating overall survival. But, it acknowledged that TMM1 was a robust study with a long follow up and mature data, and that this is rare in multiple myeloma. The committee commended the company on its efforts to present robust data. The committee also recognised the company's challenge to achieve cost-effectiveness for an add-on treatment to a combination therapy. The committee noted that the assumptions in the company and ERG base cases were very similar. It also recalled that there was a high level of unmet need for people with relapsed or refractory multiple myeloma at this line of treatment. The committee noted that people would welcome a new oral triplet therapy option for multiple myeloma at the third- and fourth-line treatment setting. The committee also noted the clinical need of this population, recalling the absence of an all-oral triple therapy at this point in the myeloma treatment pathway (see section 3.3). Taking these additional factors into consideration, the committee concluded that it was appropriate to recommend ixazomib combination for treating multiple myeloma after 2 or 3 therapies. # Equality issues ## The recommendations apply equally to all people with relapsed or refractory multiple myeloma Clinical experts noted that myeloma is twice as common in people of African-Caribbean family background. The committee considered that its recommendation applies equally, regardless of family background. It concluded that this difference in prevalence did not itself represent an equality issue in this appraisal. # Other factors The clinical lead for the Cancer Drugs Fund highlighted that since December 2017, around 100 people per month who had previously had 2 or 3 lines of treatment have been able to have ixazomib combination through the Cancer Drugs Fund. The clinical experts explained that both clinicians and patients think ixazomib combination is a valuable treatment, as evidenced by the number of people having it. The patient experts noted that some of the treatments used to manage multiple myeloma involve injections and infusions and people would welcome another oral treatment option. The committee acknowledged that the oral administration of ixazomib combination is a benefit, particularly for people who are older or frail, who find it difficult to travel to hospital for treatment. But the committee recalled that the main comparator, lenalidomide plus dexamethasone, is also an all-oral regimen. The clinical experts highlighted that ixazomib combination is the only oral triplet therapy for third-line treatments. The committee heard that this was an important treatment at this line of therapy, because triplet regiments are standard for people with multiple myeloma at first, second and fourth line. The patient expert described that people with multiple myeloma are often anxious about the COVID-19 pandemic, particularly because people with multiple myeloma are more at risk of severe infection and death. The clinical lead for the Cancer Drugs Fund added that because ixazomib combination is associated with longer progression-free survival compared with lenalidomide and dexamethasone, it delays the need for people to go into hospital. This reduces anxiety about hospital associated infections and the COVID-19 pandemic. The patient experts also noted that longer progression-free survival can be seen as a bridge to other future treatments that may be more effective. The committee concluded that ixazomib combination provides clinical benefit, in a population that has an unmet need for effective treatments, and that not all of the relevant benefits of ixazomib combination were captured in the modelling. The committee considered these benefits qualitatively in determining an acceptable ICER (see section 3.15).	{'Recommendations': 'Ixazomib, with lenalidomide and dexamethasone, is recommended as an option for treating multiple myeloma in adults, only if:\n\nthey have had 2 or 3 lines of therapy and\n\nthe company provides ixazomib according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with ixazomib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for ixazomib with lenalidomide and dexamethasone (ixazomib combination) for treating relapsed or refractory multiple myeloma (NICE technology appraisal guidance 505). The original appraisal recommended ixazomib combination in people who have already had 2 or 3 lines of treatment. The usual treatment for these people is lenalidomide and dexamethasone.\n\nThe new evidence includes data from a clinical trial and from people having ixazomib combination in the NHS while it was available in the Cancer Drugs Fund. The evidence suggests that people with multiple myeloma who have ixazomib combination live longer compared with people who have lenalidomide and dexamethasone.\n\nThe cost-effectiveness estimates for ixazomib combination are likely to be within what NICE considers an acceptable use of NHS resources, so it is recommended.', 'Information about ixazomib': "# Marketing authorisation indication\n\nIxazomib citrate (Ninlaro, Takeda), in combination with lenalidomide and dexamethasone, is indicated for 'the treatment of adult patients with multiple myeloma who have had at least 1 previous therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for ixazomib.\n\n# Price\n\nThe list price is £6,336 per pack of 3 capsules (excluding VAT; BNF online, accessed November 2022).\n\nThe company has a commercial arrangement. This makes ixazomib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know the details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect efficacy data from the TOURMALINE-MM1 (TMM1) study. Data was also collected using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\nThe committee was aware that there were remaining areas of uncertainty associated with the analyses presented (see ERG report page 9) and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:\n\nthe company's Weibull models for overall survival appeared almost indistinguishable from the generalised gamma models\n\nuncertainty regarding the post-progression life-year gains in the adjusted overall-survival modelling\n\nthe sustained effect of treatment when people have stopped taking the study treatments.\n\n# The condition and clinical management\n\n## Ixazomib combination is a valuable treatment option for people with relapsed or refractory multiple myeloma\n\nMultiple myeloma is typically incurable and is a progressive disease that affects survival and quality of life. The patient experts explained that multiple myeloma causes debilitating symptoms including bone pain and bone fractures, tiredness, infections, hypercalcaemia (too much calcium in the blood) and kidney problems. The clinical experts noted that treating the disease becomes more and more challenging with each relapse. Treatment side effects and frequent hospital visits have an impact on people with multiple myeloma and their carers. The patient expert explained that ixazomib with lenalidomide and dexamethasone (ixazomib combination) has allowed them a long period of progression-free survival and an improved quality of life with minimal side effects. The patient expert noted that they valued the oral administration of ixazomib combination. The committee considered the evidence from patient experts who have experience taking ixazomib combination and concluded that it is a valuable treatment option for people with relapsed or refractory multiple myeloma.\n\n## The population relevant to this appraisal is people who have had 2\xa0or 3\xa0previous therapies\n\nTreatment options for multiple myeloma depend on a person's treatment history, their response to the treatments and their preferences. After 2\xa0previous lines of treatment, options include lenalidomide plus dexamethasone, or panobinostat plus bortezomib and dexamethasone. After 3\xa0previous lines of treatment, options include pomalidomide plus dexamethasone, or panobinostat plus bortezomib and dexamethasone. Daratumumab alone, and isatuximab with pomalidomide and dexamethasone are also available in the Cancer Drugs Fund. Ixazomib combination can be used after at least 1\xa0previous therapy. The committee in the original appraisal (NICE technology appraisal guidance 505, from now referred to as TA505) understood that ixazomib combination would be used in the same place in the pathway that lenalidomide and dexamethasone is currently used; that is, for people who have had 2\xa0or 3\xa0previous therapies. The committee concluded that the population relevant to this review was people who have had 2\xa0or 3\xa0previous therapies.\n\n## Without ixazomib combination, there would be an unmet need for an oral triplet therapy for people who have had 2\xa0or 3\xa0previous therapies\n\nThe clinical experts explained that oral treatment regimens, which reduce pressure on hospital outpatient units and chemotherapy day units compared with intravenous options, are very important to people with multiple myeloma. They explained that oral treatment regimens reduce the risk of acquiring infections and that many people with multiple myeloma are particularly concerned about contracting COVID-19 from hospitals. The clinical lead for the Cancer Drugs Fund explained that triple therapy is now standard at first and second line for people with multiple myeloma and that a fourth-line triplet therapy is available in the Cancer Drugs Fund. The patient expert explained that the benefits of ixazomib combination were not limited to the oral administration of the treatment, but also that it is a triplet therapy. The clinical lead for the Cancer Drugs Fund added that ixazomib combination has met the need for this preferred treatment option at third line. The committee concluded that, without ixazomib combination, there would be an unmet need for an oral triplet therapy for people who have had 2\xa0or 3\xa0previous therapies.\n\n## Lenalidomide plus dexamethasone remains the only relevant comparator\n\nIn TA505 the committee agreed that lenalidomide with dexamethasone was the relevant comparator. This was because, although the scope included bortezomib for people who have had at least 1\xa0therapy, the committee for TA505 recalled that ixazomib combination was not expected to be widely used in people who have had 1\xa0previous therapy. So, the committee in TA505 agreed bortezomib was not a relevant comparator. NICE guidance recommends both panobinostat plus bortezomib and dexamethasone, and lenalidomide plus dexamethasone after 2\xa0previous lines of treatment. But the clinical experts in TA505 stated that they would always prefer to use lenalidomide before panobinostat, and therefore panobinostat is not used unless people have had 3 therapies or more. No changes to the scope are permitted in a Cancer Drugs Fund review and treatments in the Cancer Drugs Fund cannot be considered comparators or included in the treatment sequence. So, the committee concluded that after 2\xa0or 3\xa0lines of treatment, lenalidomide plus dexamethasone remained the most relevant comparator.\n\n# Clinical-effectiveness evidence\n\n## Ixazomib combination improves progression-free survival after 2\xa0or 3\xa0lines of therapy\n\nIn TA505 the clinical-effectiveness evidence for ixazomib combination came from a second interim analysis data cut of TMM1, a phase\xa03 randomised controlled trial. The primary endpoint of the trial was progression-free survival. The median progression-free survival for ixazomib combination after 2\xa0or 3\xa0previous lines of treatment was 22\xa0months compared with 13\xa0months for lenalidomide and dexamethasone. The stratified hazard ratio was 0.62 (95% confidence interval [CI] 0.45 to 0.86, p=0.0033). This showed that ixazomib combination was associated with a statistically significant improvement in progression-free survival compared with lenalidomide and dexamethasone. The progression-free survival observations were not collected beyond the second interim analysis of TMM1 because this data was mature. So, the progression-free survival data was the same as the original appraisal. In TA505 the committee noted that the second interim analysis showed a reduced progression-free survival difference between arms compared with the first analysis, which was no longer statistically significant for the intention-to-treat population. However, it did remain significant for people who had had 2\xa0or 3\xa0previous therapies. The committee concluded that ixazomib combination improved progression-free survival in people who have had 2\xa0or 3\xa0lines of therapy.\n\n## The evidence from TMM1 is appropriate for decision making but has limitations\n\nThe committee in TA505 was concerned that the clinical benefit of ixazomib combination was uncertain because the overall-survival data was too immature to be considered robust. To address the committee's concerns from the original appraisal, the company provided the clinical-effectiveness for ixazomib combination from the final data cut of TMM1. The trial included 722\xa0people with relapsed or refractory multiple myeloma. A subgroup of 297\xa0people, which included people who had had 2\xa0or 3\xa0previous lines of treatment, was relevant to this appraisal. The unadjusted median overall survival was 53\xa0months for ixazomib combination and 43\xa0months for lenalidomide and dexamethasone. The stratified hazard ratio was 0.85 (95% CI 0.64 to 1.11, p=0.232), showing ixazomib combination was not associated with a statistically significant improvement in overall survival compared with lenalidomide and dexamethasone. However, the clinical experts explained that overall survival is highly dependent on the choice of post-progression treatments. They further explained that the TMM1 trial had no UK centres, and the post-progression treatments would have varied depending on location and so were unlikely to be representative of UK practice. The company considered it was not appropriate to use the unadjusted overall-survival estimates from TMM1. The company explained that it had adjusted the data to remove the effect of subsequent therapies. This was because the treatment pathway in the trial did not reflect UK clinical practice and the distribution of subsequent treatments was not balanced between treatment arms (see section 3.8). The clinical experts noted that ixazomib is a proteasome inhibitor. They explained that because TMM1 was a blinded trial, some people whose disease progressed with ixazomib combination may have been given another proteasome inhibitor as a subsequent therapy. These people were likely to have been refractory to proteasome inhibitors at progression, so were given a potentially less effective treatment sequence than people in the lenalidomide and dexamethasone arm. The company did not adjust for this potential confounding, so, the committee heard that the overall-survival results were likely to be biased against ixazomib combination. The committee concluded that although the effect of ixazomib commination on overall survival in TMM1 was likely confounded by subsequent treatments, the data was acceptable for decision making.\n\n## Ixazomib likely improves overall survival\n\nTreatments recommended in the Cancer Drugs Fund cannot be considered comparators or subsequent treatments in NICE appraisals. NICE's guide to the methods of technology appraisal 2013 also advises that treatments not embedded in clinical practice in the NHS should not be considered as comparators or subsequent treatments. So, the company used the 2-stage method with recensoring to remove the effect of subsequent treatments from TMM1 not routinely used in the NHS, including those available via the Cancer Drugs Fund. The company assumed that the treatments removed in the 2-stage adjustment were effective and improved survival. The adjusted median overall survival was 51.4\xa0months for ixazomib combination and 41.5\xa0months for lenalidomide and dexamethasone. The stratified hazard ratio was 0.71 (95% CI 0.54 to 0.95, p=0.0216), showing ixazomib combination was associated with a statistically significant improvement in overall survival compared with lenalidomide and dexamethasone. The ERG explored additional analyses of the intention-to-treat population, including all 722\xa0people, from TMM1. The ERG stated that in this population, which included people who had only had 1\xa0previous line of treatment, the confidence intervals of overall survival crossed\xa01. The company highlighted that analysing this population was outside the scope of this review and it included people from a different treatment line who would have had different treatments and disease prognoses. The company also noted that a regional study of TMM1, in China, which did not face challenges of adjusting data for subsequent treatment therapies, showed a survival benefit with ixazomib combination. The committee concluded that an overall-survival benefit of ixazomib combination is likely.\n\n## Adjusting overall survival to remove the effect of subsequent treatments is appropriate\n\nAfter adjustment for subsequent treatments, modelled post-progression life expectancy reduced to a greater extent in the lenalidomide and dexamethasone arm (a reduction of 0.3\xa0life years) compared with the ixazomib combination arm (a reduction of 0.03\xa0life years). The ERG noted that there were only small differences in the proportion of treatments not routinely used in the NHS or within the Cancer Drugs Fund in both treatment arms. Therefore, it was unclear why the reduction in life years was larger in the lenalidomide plus dexamethasone arm. The company explained that more people had treatments that extend survival in the lenalidomide and dexamethasone arm. The ERG also noted that modelled post-progression life-year gain, after adjustment, was 30.5% of the total life-year gain. Whereas, modelled post-progression life-year gain before adjustment was 7.4% of total life-year gain. The ERG stated that the change in life years gained departed from clinical plausibility. The company highlighted that there was a minimal difference between the cost-effectiveness estimates for the 2-stage method with recensoring and the unadjusted analysis. The committee noted these areas of uncertainty associated with the company's overall-survival adjustment, but was aware that using the adjusted analysis with recensoring versus unadjusted overall-survival data in the model made very little difference to the cost-effectiveness results. The committee concluded that although there was uncertainty about the adjustment to overall survival for subsequent treatments, the company's approach was appropriate.\n\n## Recensoring data in the 2-stage adjustment lowers the cost-effectiveness estimates\n\nThe committee noted that the company recensored the overall-survival data following its 2-stage adjustment, and that recensoring can overestimate the treatment effect. The committee considered that uncensored data should have been considered and that the cost-effectiveness estimates were lower than they would have been if the company had not recensored the data. The company highlighted that the NICE Decision Support Unit technical support document 16 states that recensoring is required to avoid bias, particularly in cases where treatment switching is likely to be associated with prognosis, which was the case in TMM1. The committee concluded that the bias from recensoring the data was likely less than the bias from not censoring the data, but that the true cost-effectiveness estimates could be higher than the ones presented by the company.\n\n## There are differences between the population in TMM1 and the people eligible to have ixazomib combination in the NHS\n\nNHS England also provided data from the SACT dataset. It was collected from 2,460 people who had ixazomib combination through the Cancer Drugs Fund between December 2017 and June 2020. The clinical experts explained that the clinical experience with ixazomib combination was positive. The clinical experts added that the SACT dataset shows that disease control and disease response with ixazomib combination was encouraging. The committee noted that the adjusted median overall survival in the trial was longer (51.4\xa0months) than in the SACT dataset (30\xa0months). Both the clinical experts and the clinical lead for the Cancer Drugs Fund explained that people included in the SACT dataset were older and had a poorer prognosis than people in TMM1. This may have contributed to the differences in the median survival estimates. The clinical experts added that the median follow\xa0up for overall survival was also shorter than the follow\xa0up in TMM1 and so not all benefits from ixazomib combination would have been captured. The committee recalled that the SACT dataset did not provide comparative evidence versus lenalidomide and dexamethasone and so a relative treatment effect from the use of ixazomib combination in the NHS could not be estimated. The committee agreed that the evidence from TMM1 was robust and the most appropriate for decision making. The committee concluded that population differences likely contributed to the differences in treatment effects between TMM1 and the SACT dataset.\n\n# The company's economic model\n\n## The estimates of overall survival from each approach to modelling are similar\n\nThe company used data from the subgroup of people from TMM1 with relapsed and refractory multiple myeloma who had 2\xa0or 3\xa0previous lines of treatment. It used the generalised gamma model to estimate overall survival with ixazomib combination and lenalidomide and dexamethasone. It explained that it chose this model because its clinicians stated that the generalised gamma provided a reasonable estimation of long-term outcomes. The ERG proposed that the Weibull model was as valid on the grounds of clinical plausibility as the generalised gamma curve and was statistically better fitting than the generalised gamma model for both ixazomib combination and lenalidomide and dexamethasone. The clinical experts acknowledged that both the generalised gamma and Weibull curves estimated similar overall-survival outcomes. The clinical experts noted that survival seen in real-world practice in the NHS was much lower than the survival estimated by the parametric models. The company highlighted that there was a difference between clinical trial data and real-world data; in TMM1 around 35% of people were still alive after 8\xa0years. The company added that people in clinical trials are often younger, have fewer comorbidities and have a better prognosis compared with people not in clinical trials. The committee concluded that although the generalised gamma curve was acceptable to extrapolate overall survival for ixazomib combination and lenalidomide and dexamethasone, the Weibull curve should also be considered.\n\n## The treatment waning effect is almost completely included in the trial follow\xa0up\n\nIn TA505 the company assumed that ixazomib combination's relative survival benefit in the clinical trial, compared with lenalidomide and dexamethasone, was maintained for the rest of a person's life after treatment stopped. The committee concluded in TA505 that, although it was biologically plausible for the relative treatment benefit to continue after stopping treatment, that level might not be maintained for the rest of a person's life. For this review, the company did not include a treatment waning effect in its base case. The company explained that the discontinuation of treatment had been almost completely captured within the 8-year observation time of TMM1. The company added that the hazard ratio or treatment effect in the ixazomib combination arm was a composite measure reflecting a pathway of treatments. The ERG agreed that the discontinuation and waning of treatment had been almost completely captured within the observed time of the trial, but noted that this was separate to the waning of the treatment effect. The ERG noted that over 90% of people were only observed for around 2\xa0years following discontinuation of ixazomib combination. The ERG thought this was an insufficient time to capture any waning of treatment effect and conducted scenarios to explore the potential impact of treatment waning. The ERG did not include these scenarios in its base case. The ERG applied weighted hazards produced at each model cycle to generate an adjusted overall-survival estimate for people having ixazomib combination. Introducing a treatment waning effect increased the cost-effectiveness estimates of ixazomib combination. The committee recalled the long follow\xa0up of TMM1 and concluded that it largely captured the treatment waning and no other adjustments to treatment waning were needed.\n\n## The utility values used in the model are appropriate\n\nIn TA505 the committee recognised that the utility for progressed disease was higher than the UK population norms, and higher than in previous multiple myeloma appraisals. In this review the company used updated EQ-5D data from TMM1. The ERG agreed that the utilities estimated from the final analysis of TMM1 better aligned with the literature and reflected the health-related quality of life of people with relapsed or refractory multiple myeloma. The committee concluded that the utility values used in the model were acceptable.\n\n# End of life\n\n## Ixazomib combination does not meet the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In TA505 the committee considered that although ixazomib combination has the potential to improve overall survival, it did not meet the criterion for extension to life. The committee concluded that ixazomib combination could not be considered as an end of life therapy. The committee in this review concluded that its view from TA505 had not changed.\n\n# Cost effectiveness\n\n## The most likely cost-effectiveness estimates is below £30,000 per QALY gained\n\nThe committee preferred an analysis that included:\n\neither the generalised gamma or Weibull curve to extrapolate overall survival for ixazomib combination and lenalidomide and dexamethasone\n\nadjusted overall-survival modelling\n\nno additional treatment waning.Using these preferred assumptions, the committee considered that the most plausible incremental cost-effectiveness ratio (ICER) for ixazomib combination compared with lenalidomide and dexamethasone was below £30,000 per quality-adjusted life-year (QALY) gained. Because of confidential commercial arrangements for the treatments and comparators, the exact cost-effectiveness results cannot be reported here. The committee noted the level of uncertainty associated with the clinical- and cost-effectiveness results, specifically the adjusted and unadjusted estimates of overall survival and choice of model for extrapolating overall survival. But, it acknowledged that TMM1 was a robust study with a long follow up and mature data, and that this is rare in multiple myeloma. The committee commended the company on its efforts to present robust data. The committee also recognised the company's challenge to achieve cost-effectiveness for an add-on treatment to a combination therapy. The committee noted that the assumptions in the company and ERG base cases were very similar. It also recalled that there was a high level of unmet need for people with relapsed or refractory multiple myeloma at this line of treatment. The committee noted that people would welcome a new oral triplet therapy option for multiple myeloma at the third- and fourth-line treatment setting. The committee also noted the clinical need of this population, recalling the absence of an all-oral triple therapy at this point in the myeloma treatment pathway (see section\xa03.3). Taking these additional factors into consideration, the committee concluded that it was appropriate to recommend ixazomib combination for treating multiple myeloma after 2 or 3 therapies.\n\n# Equality issues\n\n## The recommendations apply equally to all people with relapsed or refractory multiple myeloma\n\nClinical experts noted that myeloma is twice as common in people of African-Caribbean family background. The committee considered that its recommendation applies equally, regardless of family background. It concluded that this difference in prevalence did not itself represent an equality issue in this appraisal.\n\n# Other factors\n\nThe clinical lead for the Cancer Drugs Fund highlighted that since December 2017, around 100 people per month who had previously had 2\xa0or 3\xa0lines of treatment have been able to have ixazomib combination through the Cancer Drugs Fund. The clinical experts explained that both clinicians and patients think ixazomib combination is a valuable treatment, as evidenced by the number of people having it. The patient experts noted that some of the treatments used to manage multiple myeloma involve injections and infusions and people would welcome another oral treatment option. The committee acknowledged that the oral administration of ixazomib combination is a benefit, particularly for people who are older or frail, who find it difficult to travel to hospital for treatment. But the committee recalled that the main comparator, lenalidomide plus dexamethasone, is also an all-oral regimen. The clinical experts highlighted that ixazomib combination is the only oral triplet therapy for third-line treatments. The committee heard that this was an important treatment at this line of therapy, because triplet regiments are standard for people with multiple myeloma at first, second and fourth line. The patient expert described that people with multiple myeloma are often anxious about the COVID-19 pandemic, particularly because people with multiple myeloma are more at risk of severe infection and death. The clinical lead for the Cancer Drugs Fund added that because ixazomib combination is associated with longer progression-free survival compared with lenalidomide and dexamethasone, it delays the need for people to go into hospital. This reduces anxiety about hospital associated infections and the COVID-19 pandemic. The patient experts also noted that longer progression-free survival can be seen as a bridge to other future treatments that may be more effective. The committee concluded that ixazomib combination provides clinical benefit, in a population that has an unmet need for effective treatments, and that not all of the relevant benefits of ixazomib combination were captured in the modelling. The committee considered these benefits qualitatively in determining an acceptable ICER (see section 3.15)."}	https://www.nice.org.uk/guidance/ta870	Evidence-based recommendations on Ixazomib (Ninlaro) with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma.
dc459cba6b3283115fcf94be70ba3f0882fe44f8	nice	Vutrisiran for treating hereditary transthyretin-related amyloidosis	Vutrisiran for treating hereditary transthyretin-related amyloidosis Evidence-based recommendations on vutrisiran (Amvuttra) for treating hereditary transthyretin-related amyloidosis in adults. # Recommendations Vutrisiran is recommended, within its marketing authorisation, as an option for treating hereditary transthyretin-related amyloidosis in adults with stage 1 or stage 2 polyneuropathy. It is only recommended if the company provides vutrisiran according to the commercial arrangement. If people with the condition and their clinicians consider vutrisiran to be 1 of a range of suitable treatments, discuss the advantages and disadvantages of the available treatments. After that discussion, if more than 1 treatment is suitable, choose the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements. Why these recommendations were made Hereditary transthyretin-related amyloidosis is usually treated with patisiran, which is already recommended in NICE's highly specialised technologies guidance on patisiran. Vutrisiran works in a similar way, but it is given as an injection under the skin instead of into a vein. Evidence from a clinical trial and an indirect comparison shows that vutrisiran works as well as patisiran. In the economic model, the company estimated costs for patisiran using pharmacy data showing the number of vials used per person. It provided a scenario using clinical trial evidence. The clinical experts suggested that more vials of patisiran would be used in clinical practice than in the clinical trial. If more vials of patisiran are used, vutrisiran is more likely to be cost saving. The cost savings for vutrisiran also depend on how long it takes to administer patisiran and which type of healthcare professional administers it. The clinical experts agreed with the company's estimate of administration time. In the model, when the administration cost for patisiran increases, vutrisiran is more cost saving. Taking the number of vials used per person in the pharmacy data and administration costs into account, a cost comparison suggests vutrisiran is cost saving compared with patisiran. So vutrisiran is recommended. For all evidence see the committee papers. To see what NICE did for patisiran, see the committee discussion in NICE's highly specialised technologies guidance on patisiran.# Information about vutrisiran # Marketing authorisation indication Vutrisiran (Amvuttra, Alnylam) is indicated for the 'treatment of hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for vutrisiran. # Price £95,862.36 per 0.5 ml solution for injection containing 25 mg of vutrisiran (excluding VAT; company submission). At the recommended dose of 25 mg administered subcutaneously every 3 months, the estimated annual cost per patient is £383,449.44. The company has a commercial arrangement. This makes vutrisiran available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.	{'Recommendations': "Vutrisiran is recommended, within its marketing authorisation, as an option for treating hereditary transthyretin-related amyloidosis in adults with stage 1 or stage 2\xa0polyneuropathy. It is only recommended if the company provides vutrisiran according to the commercial arrangement.\n\nIf people with the condition and their clinicians consider vutrisiran to be 1\xa0of a range of suitable treatments, discuss the advantages and disadvantages of the available treatments. After that discussion, if more than 1\xa0treatment is suitable, choose the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements.\n\nWhy these recommendations were made\n\nHereditary transthyretin-related amyloidosis is usually treated with patisiran, which is already recommended in NICE's highly specialised technologies guidance on patisiran. Vutrisiran works in a similar way, but it is given as an injection under the skin instead of into a vein.\n\nEvidence from a clinical trial and an indirect comparison shows that vutrisiran works as well as patisiran.\n\nIn the economic model, the company estimated costs for patisiran using pharmacy data showing the number of vials used per person. It provided a scenario using clinical trial evidence. The clinical experts suggested that more vials of patisiran would be used in clinical practice than in the clinical trial. If more vials of patisiran are used, vutrisiran is more likely to be cost saving.\n\nThe cost savings for vutrisiran also depend on how long it takes to administer patisiran and which type of healthcare professional administers it. The clinical experts agreed with the company's estimate of administration time. In the model, when the administration cost for patisiran increases, vutrisiran is more cost saving.\n\nTaking the number of vials used per person in the pharmacy data and administration costs into account, a cost comparison suggests vutrisiran is cost saving compared with patisiran. So vutrisiran is recommended.\n\nFor all evidence see the committee papers. To see what NICE did for patisiran, see the committee discussion in NICE's highly specialised technologies guidance on patisiran.", 'Information about vutrisiran': "# Marketing authorisation indication\n\nVutrisiran (Amvuttra, Alnylam) is indicated for the 'treatment of hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for vutrisiran.\n\n# Price\n\n£95,862.36 per 0.5\xa0ml solution for injection containing 25\xa0mg of vutrisiran (excluding VAT; company submission). At the recommended dose of 25\xa0mg administered subcutaneously every 3\xa0months, the estimated annual cost per patient is £383,449.44.\n\nThe company has a commercial arrangement. This makes vutrisiran available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount."}	https://www.nice.org.uk/guidance/ta868	Evidence-based recommendations on vutrisiran (Amvuttra) for treating hereditary transthyretin-related amyloidosis in adults.
fe8684e237db9854d532fa061a1a6d62de2be5d4	nice	Nivolumab with fluoropyrimidine- and platinum-based chemotherapy for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma	Nivolumab with fluoropyrimidine- and platinum-based chemotherapy for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma Evidence-based recommendations on nivolumab (Opdivo) with fluoropyrimidine- and platinum-based chemotherapy for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma in adults. # Recommendations Nivolumab with fluoropyrimidine-based and platinum-based combination chemotherapy is recommended as an option for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma in adults whose tumours express PD‑L1 at a level of 1% or more. It is recommended only if: pembrolizumab plus chemotherapy is not suitable the company provides nivolumab according to the commercial arrangement. This recommendation is not intended to affect treatment with nivolumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard care for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma is fluoropyrimidine-based and platinum-based chemotherapy (chemotherapy). Some people may have pembrolizumab plus chemotherapy if their tumours express PD‑L1 with a combined positive score (CPS) of 10 or more. Clinical trial evidence shows that for people whose tumours express PD‑L1 at a level of 1% or more, nivolumab plus chemotherapy increases how long they live compared with chemotherapy alone. It also increases the time before their cancer gets worse. Nivolumab plus chemotherapy has only been indirectly compared with pembrolizumab plus chemotherapy. Uncertainty in this comparison means it is difficult to determine which combination is more effective. The cost-effectiveness estimates for nivolumab compared with pembrolizumab are also uncertain, but nivolumab is unlikely to be cost effective compared with pembrolizumab. When compared with chemotherapy alone, nivolumab plus chemotherapy meets NICE's criteria to be a life-extending treatment at the end of life. Taking this into account, the cost-effectiveness estimates are likely within what NICE considers an acceptable use of NHS resources for this group. Therefore, nivolumab plus chemotherapy is recommended when pembrolizumab plus chemotherapy is unsuitable. Tests for suitability of nivolumab (tumours express PD‑L1 at 1% or more) or pembrolizumab (tumours express PD‑L1 with CPS of 10 or more) should be done at the same time. This is to minimise any unnecessary delays in accessing treatment.# Information about nivolumab # Marketing authorisation indication Nivolumab (Opdivo, Bristol Myers Squibb) 'in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD‑L1 expression ≥ 1%'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for nivolumab. # Price The list price is £1,097 for a 100-mg vial (excluding VAT; BNF online accessed September 2022). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Oesophageal cancer is often diagnosed late and has a large impact on quality of life and a poor prognosis The patient experts explained that there are no screening tools to identify oesophageal squamous cell carcinoma and often the condition is diagnosed at an advanced stage. They explained that people with the condition can struggle to maintain their fitness and manage their condition. The patient experts described that the condition and treatment side effects massively affect patients' quality of life, social experience and relationships with family and carers. They highlighted that advanced oesophageal squamous cell carcinoma is less survivable than other cancers. # Treatment pathway ## People would welcome a new treatment option for oesophageal squamous cell carcinoma NICE's technology appraisal guidance recommends pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy for untreated advanced oesophageal and gastro-oesophageal junction cancer (TA737) in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more. The clinical experts explained that pembrolizumab plus chemotherapy is widely used when it is suitable. However, patient experts were aware that some people do not have pembrolizumab plus chemotherapy despite its suitability. The clinical and patient experts agreed there is an unmet need in people for whom treatment with pembrolizumab plus chemotherapy is not suitable. The clinical experts explained that clinicians would value an additional treatment option because there may be circumstances in which nivolumab is preferred over pembrolizumab. The committee concluded that patients and clinicians would welcome a new treatment for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma. ## Testing for suitability of nivolumab or pembrolizumab should be done concurrently in NHS practice Suitability of nivolumab and pembrolizumab is assessed by measuring PD‑L1 status. The way that PD‑L1 positivity was measured and defined differed in the marketing authorisations for nivolumab and pembrolizumab. In the CheckMate-648 trial around half of participants in the intention-to-treat (ITT) population had tumour cell PD‑L1 expression with a level of 1% or more in line with nivolumab's marketing authorisation (measure of PD‑L1 expression on tumour cells as a ratio percentage). Pembrolizumab was also a suitable option for more than half of these participants because their tumours expressed PD‑L1 with a CPS of 10 or more, in line with its marketing authorisation (measure of PD‑L1 expression on tumour cells and immune cells as a ratio score). This means that both nivolumab and pembrolizumab were suitable for some people. In the pembrolizumab clinical trial (KEYNOTE-590), 51% of people had tumours that expressed PD‑L1 with a CPS of 10 or more. PD‑L1 status defined by tumour cell expression was not reported. The clinical experts highlighted that there is no clear clinical justification for attributing each specific test to either nivolumab or pembrolizumab. The committee acknowledged the overlap and differences between the 2 tests and the complexity it introduces. The company explained that, in clinical practice, treatment decisions for oesophageal squamous cell carcinoma might vary at different hospitals. It also explained they will not be based on tumour cell expression and CPS collectively because the 2 tests for assessing PD‑L1 are independent of each other. The committee was aware that testing is time and resource intensive. The clinical experts explained that it was preferrable that the 2 tests (tumour cell expression and CPS) would be done concurrently, rather than sequentially, to determine whether nivolumab or pembrolizumab is suitable and permissible. However, they highlighted that treatment decisions are often guided by local health service protocols which may use different approaches. The clinical experts did not agree on whether sequential testing would occur in practice. Clinical experts noted that testing tumour cell PD‑L1 expression may be more accessible to clinicians than testing PD‑L1 expression through CPS. This is because most hospitals can do the tumour cell test but few hospitals have facilities to do the CPS test. This means CPS test results can take 2 weeks or more when external testing is needed. Clinical experts suggested that because tumour cell testing is more accessible than CPS testing, clinicians are more likely to request it first when testing sequentially. The clinical and patient experts were concerned that the waiting time for CPS results and requirement for concurrent testing for nivolumab and pembrolizumab suitability could delay starting a suitable immunotherapy. They highlighted that a delay could disadvantage people, because it is better to start treatment as soon as possible so that the immune response associated with immunotherapies is generated as early as possible. There was uncertainty on whether both tests would be done sequentially or concurrently. The committee heard that in clinical practice there were implementation issues for pembrolizumab (TA737; see section 3.4). However, the committee's remit is to compare the clinical and cost effectiveness of new interventions with currently available treatments for the same indication. This is to ensure patients and the NHS access the most effective, best value treatments. So, the committee's evaluation of nivolumab should include a NICE-recommended cost-effective comparator treatment which was available and used in NHS practice such as pembrolizumab. However, the committee noted the implementation issues for pembrolizumab and strongly concluded that tests for pembrolizumab and nivolumab suitability should be done concurrently. This is to minimise unnecessary delays in accessing treatment. ## Chemotherapy and pembrolizumab plus chemotherapy are relevant comparators, subject to the suitability of pembrolizumab The company maintained that pembrolizumab plus chemotherapy was recommended too recently to be considered standard of care. It considered chemotherapy to be the main comparator for nivolumab plus chemotherapy. The clinical experts mentioned that in their centres they had observed slower uptake of pembrolizumab than anticipated. They attributed this to testing capacity issues associated with the COVID‑19 pandemic and differences in how diagnostic services do CPS tests. The Cancer Drugs Fund (CDF) lead stated that use of pembrolizumab plus chemotherapy had been increasing slowly, which is not unusual when there is a test needed for treatment. Despite differing opinions on the uptake of pembrolizumab, the clinical experts and CDF lead agreed that pembrolizumab should be considered as a comparator in this appraisal. The committee concluded that: chemotherapy alone is a relevant comparator when only nivolumab is suitable (tumour cell PD‑L1 expression at a level of 1% or more and a CPS of less than 10) pembrolizumab plus chemotherapy is a relevant comparator when both nivolumab and pembrolizumab are suitable options (PD‑L1 positivity with tumour cell expression at a level of 1% or more and a CPS of 10 or more). # Clinical evidence ## CheckMate 648 data for the subgroup of people whose tumour cells express PD-L1 at 1% or more is appropriate for decision making CheckMate 648 is a randomised, three-arm, open-label, placebo-controlled trial (n=970). It compared cisplatin and fluorouracil, with or without nivolumab, and nivolumab plus ipilimumab, as first-line treatment for unresectable advanced, recurrent or metastatic oesophageal cancer. The nivolumab plus ipilimumab and chemotherapy trial arm was not included in the decision problem. The primary outcomes were progression-free survival and overall survival in the ITT population (n=645 for the nivolumab plus chemotherapy and chemotherapy trial arms). Progression-free survival and overall survival were reported for people with squamous cell oesophageal carcinoma whose tumour cells expressed PD‑L1 at 1% or more (n=315). The committee concluded that the data from this subgroup is appropriate for decision making when only nivolumab is suitable (see section 3.4). ## Nivolumab improves progression-free survival and overall survival compared with chemotherapy alone Data on progression-free survival and overall survival outcomes from the CheckMate 648 subgroup (see section 3.5) are academic in confidence and cannot be presented here. The committee concluded that nivolumab plus chemotherapy improves both progression-free survival and overall survival compared with chemotherapy alone. # Indirect comparison with pembrolizumab ## There is uncertainty around the comparability of the trials included in the indirect treatment comparison Nivolumab plus chemotherapy was indirectly compared with pembrolizumab plus chemotherapy in the absence of a direct trial comparison. Data for pembrolizumab came from the KEYNOTE‑590 trial. There was no efficacy data from the KEYNOTE‑590 population in whom nivolumab plus chemotherapy was suitable (tumour cell PD‑L1 expression of 1% or more). The indirect treatment comparison (ITC) used outcomes from the population for whom pembrolizumab plus chemotherapy was suitable (PD‑L1 expression with a CPS of 10 or more). Progression-free survival and overall survival outcome data from CheckMate 648 and KEYNOTE‑590 were indirectly compared. In KEYNOTE‑590, progression-free survival data was restricted to oesophageal cancer with squamous cell carcinoma or adenocarcinoma histologies, and overall survival data was restricted to squamous cell histology. A comparability assessment between the 2 trials showed that CheckMate 648 included more people with an Asian family background and fewer people had metastatic disease. The company compared some baseline characteristics from people in both trials whose tumours had PD‑L1 expression with a CPS of 10 or more. The ERG agreed that this subgroup appeared comparable to the ITT populations in the trials. However, it was noted that conclusions around trial comparability are limited because the only characteristics presented were age, Asian family background, Eastern Cooperative Oncology Group status and metastatic disease. Also, these characteristics were only available as an average of both trial arms in KEYNOTE‑590 (pembrolizumab plus chemotherapy and chemotherapy alone). One clinical expert highlighted that people in the 2 trials are likely to be comparable, based on the overall survival that was observed in the control arms of both trials. They also said there is little clinical understanding of how outcomes may differ by how PD‑L1 expression was measured (tumour cell expression or CPS). Furthermore, they stated there is also uncertainty in how outcomes may differ in the broader oesophageal cancer population and in tumours which express PD‑L1. Another clinical expert commented that while CheckMate 648 included only people with oesophageal squamous cell carcinoma, KEYNOTE‑590 included people with squamous cell carcinoma and adenocarcinoma, located in either the oesophagus or the gastroesophageal junction. This made it difficult to reach any conclusions about trial comparability. The committee noted there was uncertainty about the comparability of the 2 trials used in the ITC. ## The indirect comparison does not give clear evidence of superiority of one treatment over the other The company explored various ITC analyses to estimate the relative treatment effect of nivolumab plus chemotherapy versus pembrolizumab plus chemotherapy in terms of progression-free survival and overall survival. The company's analyses included people from CheckMate 648 for whom both nivolumab and pembrolizumab were suitable (see section 3.4). This generated time-varying progression-free survival hazard ratios (HRs) which favoured pembrolizumab plus chemotherapy from 3 months. The overall survival HRs favoured nivolumab plus chemotherapy after 6 months. The ERG's base-case analyses included people from CheckMate 648 for whom pembrolizumab was suitable (see section 3.4). These generated time-varying progression-free survival and overall survival HRs which favoured pembrolizumab plus chemotherapy over all time points. The ERG favoured including people for whom pembrolizumab was suitable, to maintain maximum trial comparability because the information on suitability of nivolumab in KEYNOTE‑590 was not available (see section 3.3 and section 3.7). The company and ERG base-case analyses also differed in the distributions used to extrapolate survival and which treatments were used as the baseline to scale pembrolizumab survival estimates. In both analyses, the HR credible intervals were wide and crossed 1. The ERG commented that the methodologies used in the ITC were robust and there were some arguments for using the company's base-case analysis. However, the ERG concluded that it was difficult to determine whether 1 treatment extended progression-free survival or overall survival more than the other.The clinical experts maintained that the effectiveness of nivolumab and pembrolizumab (in terms of response or survival) is almost the same in other cancers, highlighting an immunotherapy 'class effect'. They expect this effect to be consistent in treating oesophageal squamous cell carcinoma tumours. They further explained that comparing nivolumab and pembrolizumab across different definitions of PD‑L1 positivity and trial datasets was 'risky' in terms of validity. The CDF lead explained that pembrolizumab is administered less frequently than nivolumab, which may provide added benefit to people and also reduce the burden on NHS cancer services because fewer hospital visits would be needed.The committee acknowledged the complexity of calculating a reliable relative treatment effect in the comparison of nivolumab and pembrolizumab. The clinical experts, company, ERG and committee all agreed that no definitive evidence of superiority of one treatment over the other had been presented. # The company's economic model ## The company's economic model is appropriate for decision making The company presented a 3‑state partitioned survival model to estimate the cost effectiveness of nivolumab plus chemotherapy compared with chemotherapy and pembrolizumab plus chemotherapy. The 3 health states were progression-free survival, progressive disease, and death. The ERG agreed that the company's model structure captured all relevant health states and that partitioned survival models are widely used in cancer modelling. The ERG's concerns on the model structure related to the modelling of effectiveness associated with subsequent therapy. The company included a 2‑year stopping rule for nivolumab. Although this is not included in the marketing authorisation, it reflects the use in the trial and expected use in clinical practice, in line with nivolumab use in other cancers. The committee concluded that the company's model structure was acceptable for decision making. # Assumptions for the comparison with chemotherapy ## It is unclear which model for estimating overall survival is more appropriate The company used Kaplan–Meier data from CheckMate 648 to model overall survival in both treatment arms, with a log-normal extrapolation from 6.9 months. The company justified the semi-parametric approach stating it better reflects the changing hazard observed after 20 months in both trial arms and noted a clear inflection point for the chemotherapy arm smoothed hazard plot at around 6 months. The ERG did not agree with the company's approach and used a parametric log-logistic extrapolation in their base case. It justified the parametric extrapolation by noting no clear inflection point for the nivolumab plus chemotherapy smoothed hazard plot. It also found a reasonable correspondence of the landmark overall survival observed in CheckMate 648 with the parametric overall survival analysis. The committee heard that a semi-parametric extrapolation of overall survival was broadly accepted by the committee in TA737. The committee acknowledged there was uncertainty in the long-term overall survival and there were arguments for each approach. ## In-trial switching may have had an impact on overall survival, but its effect is uncertain There was evidence of treatment switching in CheckMate 648, with a proportion of both arms who had subsequent systemic and anti-PD‑L1 therapies (including nivolumab and pembrolizumab). The company considered that a decreasing hazard rate (mortality rate) observed in the chemotherapy arm of CheckMate 648 was implausible. The ERG argued that it might be partly because of in-trial switching to an anti-PD‑L1 therapy. The ERG also noted that, although only a fraction of people in the trial switched to an anti-PD‑L1 therapy, the company assumed in its economic model that all people who had subsequent treatment in clinical practice would have an anti-PD‑L1 therapy. The ERG suggested that this might lead to a bias where the effectiveness of chemotherapy had been underestimated in the economic model. To overcome the bias in results, it preferred an adjustment of overall survival in the model using methods outlined in NICE's Decision Support Unit technical support document 16. The company elected against including a switching adjustment in their base-case modelling of overall survival, commenting that few people switched to an anti-PD‑L1 therapy in the trial. It also explained that the switching adjustment methods in the technical support document place large demands on limited data which can create more uncertainty. The company presented 2 switching adjustment scenario analyses: a rank-preserving structural failure time model and a model-based approach. As the incremental cost-effectiveness ratio (ICER) of nivolumab plus chemotherapy versus chemotherapy increased markedly in these scenarios, the ERG maintained that the ICER is underestimated without a switching adjustment. The committee heard that switching was not included in TA737. While the ERG acknowledged this, it again referred to the clinical evidence that it said demonstrated switching and the difference between the proportion switching in the trial and that which would occur in clinical practice. A clinical expert explained that switching to an anti-PD‑L1 therapy may introduce some bias, but it was not expected to be impactful on overall survival. The committee concluded that the switching may have an impact on the overall survival in both trial arms, but that its overall impact was uncertain. ## It is reasonable to expect some treatment waning after treatment is stopped, but the impact on overall survival is uncertain In its base case, the company assumed there was no waning of treatment effect after stopping nivolumab. It commented that there was evidence of a robust and durable treatment effect lasting beyond discontinuation for immunotherapies. It stated that if any treatment waning was to occur it would be 5 years after starting therapy. It referenced NICE's technology appraisal of nivolumab for untreated HER2-negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in which the committee considered a 5‑year assumption of treatment waning to be plausible. The ERG disagreed with this assumption and included the waning of treatment effect on overall survival for nivolumab from 2.5 years to 4.0 years after starting therapy and 6 months after stopping therapy. The ERG justified the assumptions, explaining that for some overall survival parametric functions the nivolumab plus chemotherapy treatment effect versus chemotherapy alone increased over time, which was considered implausible. Additionally, the ERG highlighted that treatment waning assumptions were not disregarded by the committee in TA737. However, it noted that no conclusions about the appropriateness of waning were made by the committee. The company commented that there was no clear justification for the 2.5 years to 4.0 years treatment waning assumptions preferred by the ERG.The clinical experts commented that some treatment waning is possible and it is more likely when nivolumab plus chemotherapy is discontinued early. The committee considered that based on the maturity of the data in CheckMate 648, the treatment effect may be captured within the observed results making an adjustment of the extrapolation of overall survival for treatment waning unnecessary.The committee acknowledged that the treatment waning effect of pembrolizumab was discussed in TA737 and that no conclusions on the appropriateness of waning were stated in the final guidance. It concluded that assuming a lifelong treatment effect of nivolumab may be over optimistic and some treatment waning might be expected. However, there was not enough evidence to be precise about when this would occur. The committee concluded that it would consider scenarios with and without treatment waning in its decision making, only if they impact the final decision on cost effectiveness. ## Modelling risk of death is uncertain, but has minimal impact on the cost-effectiveness estimates The reduction in the risk of death in CheckMate 648 was similar to that of background mortality. The company and the ERG agreed that mortality should not be any lower than background (all-cause) mortality. To enforce a plausible minimum rate of mortality, a background mortality rate was included in the model, additional to the predicted overall survival. The company maintained that the approach resulted in very little difference in the overall survival. However, the ERG considered this approach to double-count mortality in the model and preferred the use of alternative methods which prevent implausibly low mortality hazard with any overall survival extrapolation. The committee acknowledged the justifications for each modelling approach but did not conclude which was preferable because each assumption had a minimal impact on the cost-effectiveness estimates. ## Treatment-specific health-related quality of life estimates are not considered appropriate Utility values in the model were calculated using EQ‑5D data from CheckMate 648. The company attributed utilities to the progression-based health states in its base case, using the average utility reported in the 2 trial arms. The ERG explained that because the EQ‑5D scores reported were consistently higher for chemotherapy compared with nivolumab plus chemotherapy, treatment-specific utilities were more appropriate. The clinical experts suggested toxicity associated with nivolumab therapy may explain lower utility values compared with chemotherapy alone. The clinical experts stated that they would expect the opposite in practice, with people who had nivolumab plus chemotherapy likely to have higher utility because of better disease control. The CDF lead and clinical experts did not agree with using the treatment-specific utilities. This is based on their experience that health-related quality of life disutilities associated with anti-PD‑(L)‑1 immunotherapies toxicity would be outweighed by the health benefit derived from response to therapy. Because treatment-specific utilities are clinically plausible, the committee concluded that treatment-specific utilities were not appropriate. ## There is uncertainty in the calculation of treatment costs weighted by delayed or missed doses A proportion of people in CheckMate 648 delayed or missed doses of their trial treatment. In its base-case analysis, the company adjusted treatment costs based on the mean relative dose intensity observed in the trial. These treatment costs were then weighted by the time each patient spent on treatment. The ERG explained that time on therapy was not relevant for capturing the relative dose intensity and omitted this from its base case. The company stated that the treatment discontinuation biased the treatment cost calculations. The committee noted uncertainty in both approaches taken. # End of life ## Nivolumab plus chemotherapy meets end of life criteria compared with chemotherapy, but not with pembrolizumab plus chemotherapy The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered whether nivolumab plus chemotherapy met the end of life criteria compared with chemotherapy for people in whom pembrolizumab is unsuitable. The company and ERG both agreed that data suggests that life expectancy in this population is less than 24 months. The observed median overall survival benefit with nivolumab plus chemotherapy in CheckMate 648 was larger than the additional 3‑month extension to life needed by the criteria (data are academic in confidence and cannot be presented here). The committee considered whether nivolumab plus chemotherapy met the end of life criteria compared with pembrolizumab plus chemotherapy for people in whom pembrolizumab is suitable. The company and ERG both agreed, based on the KEYNOTE‑590 analyses, that life expectancy in this population is less than 24 months. Based on the ITC analyses (see section 3.8), the median overall survival benefit of nivolumab plus chemotherapy compared with pembrolizumab plus chemotherapy did not exceed the additional 3‑month extension to life needed by the criteria (the data cannot be reported here because the company submitted it as academic in confidence). The committee concluded that nivolumab met the end of life criteria compared with chemotherapy but that criteria were not met compared with pembrolizumab plus chemotherapy. # Cost-effectiveness estimate ## Nivolumab is unlikely to be cost effective when compared with pembrolizumab The company's base-case comparison of nivolumab with pembrolizumab included the following assumptions: semi-parametric extrapolation of progression-free and overall survival data from CheckMate 648 for nivolumab (see section 3.10) excluding any adjustments to overall survival for subsequent therapy (see section 3.11) excluding nivolumab treatment waning (see section 3.12) including all-cause mortality, additional to the predicted overall survival mortality (see section 3.13) using progression-based utilities, independent of the treatment received (see section 3.14) adjusting treatment costs by the relative dose intensity, weighted by the time on treatment (see section 3.15).Differences in the company's and ERG's base case are in the methodology used for the ITC. The company base case used the following ITC analyses assumptions (see section 3.8): including outcome data from people in CheckMate 648 for whom both nivolumab and pembrolizumab was suitable and people from KEYNOTE‑590 for whom pembrolizumab was suitable (see section 3.4) scaling nivolumab and pembrolizumab survival using chemotherapy as the baseline using log-normal distribution to extrapolate overall survival.The ERG's base-case analyses differed from the company's because it included people from CheckMate 648 for whom only pembrolizumab was suitable. The company and ERG base-case analyses also differed in the distribution used to extrapolate survival and which treatment was used as the baseline to scale pembrolizumab survival estimates.The ICERs cannot be reported here because of confidential commercial arrangements for nivolumab and pembrolizumab. The company's and ERG's base-case cost-effectiveness estimates were similar, both showing nivolumab plus chemotherapy to be dominated by pembrolizumab plus chemotherapy. The committee concluded that it was unlikely that nivolumab plus chemotherapy would be a cost-effective use of NHS resources when pembrolizumab is a suitable option. ## Nivolumab plus chemotherapy is cost effective when compared with chemotherapy alone when pembrolizumab is unsuitable The company's comparison of nivolumab plus chemotherapy with chemotherapy for people in whom pembrolizumab is not suitable used the same assumptions as for the comparison with pembrolizumab plus chemotherapy (see section 3.17). The ERG's base case included the same assumptions as the company in its exclusion of an adjustment on survival for switching (see section 3.11). The ERG's assumptions differed from the company in the approach to modelling progression-free survival and overall survival, and parametric extrapolation was modelled with a waning of nivolumab treatment effect between 2.5 years and 4 years (see section 3.12). Additionally, treatment-specific progression utilities were included in the model (see section 3.14), and the relative dose intensity was not weighted by time on treatment (see section 3.15). The ICERs cannot be reported here because of confidential commercial arrangements for nivolumab and subsequent treatments. Including the ERG's assumptions increased the ICER compared with the company's base case, however the company's cost-effectiveness estimates are below the end of life threshold of £50,000 per quality-adjusted life year (QALY) gained. While the ERG's cost-effectiveness estimates are above £50,000 per QALY gained, the committee did not agree with the assumption of treatment-specific utilities. Removing this assumption provided cost-effectiveness estimates which were below £50,000 per QALY gained. Because end of life criteria have been met (see section 3.16), the committee concluded that nivolumab plus chemotherapy is likely a cost-effective use of NHS resources when pembrolizumab is unsuitable. # Equalities ## There are no equality issues relevant to the recommendations Patient experts explained that people living in the most deprived areas are more likely to be diagnosed with oesophageal squamous cell carcinoma later than others. The committee noted that the issues surrounding the delays in diagnosis are unable to be addressed in technology appraisal guidance. # Innovation The company and patient experts stated that nivolumab plus chemotherapy has a number of benefits including improved efficacy outcomes compared with chemotherapy, maintenance of quality of life, an acceptable safety profile and providing an additional treatment option for people with high unmet need. They also stated that PD‑L1 test results for suitability of nivolumab are available quicker than PD‑L1 test results for suitability of pembrolizumab. This is because the CPS test is more complex than the tumour cell test and often needs to be requested from an external diagnostic centre. The committee concluded that it had not been presented with any evidence for benefits not captured in the model. # Conclusion ## Nivolumab is recommended for routine use only when pembrolizumab is unsuitable The committee noted that the company's and ERG's base-case conclusions aligned in that nivolumab plus chemotherapy was dominated by pembrolizumab plus chemotherapy, that is higher cost and lower efficacy. The committee acknowledged the uncertainty around relative treatment effects for the 2 treatments, but concluded that nivolumab plus chemotherapy was unlikely to be cost effective compared with pembrolizumab plus chemotherapy.The committee noted that the company's base case suggested that nivolumab plus chemotherapy is likely to be cost effective compared with chemotherapy, for people for whom pembrolizumab is not suitable. This is when considering nivolumab as a life-extending treatment for people with short life expectancy (see section 3.17). The committee also noted that the ERG's base case suggested that it was unlikely to be cost effective compared with chemotherapy alone, even in the context of a life-extending treatment for people with a short life expectancy (see section 3.16). However, nivolumab was cost effective when treatment-specific utilities, which the committee deemed as inappropriate, were removed from the ERG's analyses and when considering end of life criteria (see section 3.17).Despite the remaining areas of uncertainty, it was agreed that the cost-effectiveness estimates for nivolumab when pembrolizumab is not suitable are likely to be within the range usually considered a cost-effective use of NHS resources. This is for a life-extending treatment for people with short life expectancy. Therefore, nivolumab with platinum- and fluoropyrimidine-based chemotherapy is recommended for use in the NHS as an option for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma, in adults whose tumour cells express PD‑L1 at 1% or more. It is recommended only if pembrolizumab plus chemotherapy is unsuitable. The committee recalled the current implementation issues for testing (see section 3.3). It therefore also concluded that testing for suitability of nivolumab and pembrolizumab should be done at the same time.	{'Recommendations': "Nivolumab with fluoropyrimidine-based and platinum-based combination chemotherapy is recommended as an option for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma in adults whose tumours express PD‑L1 at a level of 1% or more. It is recommended only if:\n\npembrolizumab plus chemotherapy is not suitable\n\nthe company provides nivolumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with nivolumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma is fluoropyrimidine-based and platinum-based chemotherapy (chemotherapy). Some people may have pembrolizumab plus chemotherapy if their tumours express PD‑L1 with a combined positive score (CPS) of 10 or more.\n\nClinical trial evidence shows that for people whose tumours express PD‑L1 at a level of 1% or more, nivolumab plus chemotherapy increases how long they live compared with chemotherapy alone. It also increases the time before their cancer gets worse. Nivolumab plus chemotherapy has only been indirectly compared with pembrolizumab plus chemotherapy. Uncertainty in this comparison means it is difficult to determine which combination is more effective. The cost-effectiveness estimates for nivolumab compared with pembrolizumab are also uncertain, but nivolumab is unlikely to be cost effective compared with pembrolizumab.\n\nWhen compared with chemotherapy alone, nivolumab plus chemotherapy meets NICE's criteria to be a life-extending treatment at the end of life. Taking this into account, the cost-effectiveness estimates are likely within what NICE considers an acceptable use of NHS resources for this group. Therefore, nivolumab plus chemotherapy is recommended when pembrolizumab plus chemotherapy is unsuitable.\n\nTests for suitability of nivolumab (tumours express PD‑L1 at 1% or more) or pembrolizumab (tumours express PD‑L1 with CPS of 10 or more) should be done at the same time. This is to minimise any unnecessary delays in accessing treatment.", 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol Myers Squibb) 'in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD‑L1 expression ≥ 1%'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for nivolumab.\n\n# Price\n\nThe list price is £1,097 for a 100-mg vial (excluding VAT; BNF online accessed September\xa02022). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Oesophageal cancer is often diagnosed late and has a large impact on quality of life and a poor prognosis\n\nThe patient experts explained that there are no screening tools to identify oesophageal squamous cell carcinoma and often the condition is diagnosed at an advanced stage. They explained that people with the condition can struggle to maintain their fitness and manage their condition. The patient experts described that the condition and treatment side effects massively affect patients' quality of life, social experience and relationships with family and carers. They highlighted that advanced oesophageal squamous cell carcinoma is less survivable than other cancers.\n\n# Treatment pathway\n\n## People would welcome a new treatment option for oesophageal squamous cell carcinoma\n\nNICE's technology appraisal guidance recommends pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy for untreated advanced oesophageal and gastro-oesophageal junction cancer (TA737) in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more. The clinical experts explained that pembrolizumab plus chemotherapy is widely used when it is suitable. However, patient experts were aware that some people do not have pembrolizumab plus chemotherapy despite its suitability. The clinical and patient experts agreed there is an unmet need in people for whom treatment with pembrolizumab plus chemotherapy is not suitable. The clinical experts explained that clinicians would value an additional treatment option because there may be circumstances in which nivolumab is preferred over pembrolizumab. The committee concluded that patients and clinicians would welcome a new treatment for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma.\n\n## Testing for suitability of nivolumab or pembrolizumab should be done concurrently in NHS practice\n\nSuitability of nivolumab and pembrolizumab is assessed by measuring PD‑L1 status. The way that PD‑L1 positivity was measured and defined differed in the marketing authorisations for nivolumab and pembrolizumab. In the CheckMate-648 trial around half of participants in the intention-to-treat (ITT) population had tumour cell PD‑L1 expression with a level of 1% or more in line with nivolumab's marketing authorisation (measure of PD‑L1 expression on tumour cells as a ratio percentage). Pembrolizumab was also a suitable option for more than half of these participants because their tumours expressed PD‑L1 with a CPS of 10 or more, in line with its marketing authorisation (measure of PD‑L1 expression on tumour cells and immune cells as a ratio score). This means that both nivolumab and pembrolizumab were suitable for some people. In the pembrolizumab clinical trial (KEYNOTE-590), 51% of people had tumours that expressed PD‑L1 with a CPS of 10 or more. PD‑L1 status defined by tumour cell expression was not reported. The clinical experts highlighted that there is no clear clinical justification for attributing each specific test to either nivolumab or pembrolizumab. The committee acknowledged the overlap and differences between the 2\xa0tests and the complexity it introduces. The company explained that, in clinical practice, treatment decisions for oesophageal squamous cell carcinoma might vary at different hospitals. It also explained they will not be based on tumour cell expression and CPS collectively because the 2\xa0tests for assessing PD‑L1 are independent of each other. The committee was aware that testing is time and resource intensive. The clinical experts explained that it was preferrable that the 2\xa0tests (tumour cell expression and CPS) would be done concurrently, rather than sequentially, to determine whether nivolumab or pembrolizumab is suitable and permissible. However, they highlighted that treatment decisions are often guided by local health service protocols which may use different approaches. The clinical experts did not agree on whether sequential testing would occur in practice. Clinical experts noted that testing tumour cell PD‑L1 expression may be more accessible to clinicians than testing PD‑L1 expression through CPS. This is because most hospitals can do the tumour cell test but few hospitals have facilities to do the CPS test. This means CPS test results can take 2\xa0weeks or more when external testing is needed. Clinical experts suggested that because tumour cell testing is more accessible than CPS testing, clinicians are more likely to request it first when testing sequentially. The clinical and patient experts were concerned that the waiting time for CPS results and requirement for concurrent testing for nivolumab and pembrolizumab suitability could delay starting a suitable immunotherapy. They highlighted that a delay could disadvantage people, because it is better to start treatment as soon as possible so that the immune response associated with immunotherapies is generated as early as possible. There was uncertainty on whether both tests would be done sequentially or concurrently. The committee heard that in clinical practice there were implementation issues for pembrolizumab (TA737; see section\xa03.4). However, the committee's remit is to compare the clinical and cost effectiveness of new interventions with currently available treatments for the same indication. This is to ensure patients and the NHS access the most effective, best value treatments. So, the committee's evaluation of nivolumab should include a NICE-recommended cost-effective comparator treatment which was available and used in NHS practice such as pembrolizumab. However, the committee noted the implementation issues for pembrolizumab and strongly concluded that tests for pembrolizumab and nivolumab suitability should be done concurrently. This is to minimise unnecessary delays in accessing treatment.\n\n## Chemotherapy and pembrolizumab plus chemotherapy are relevant comparators, subject to the suitability of pembrolizumab\n\nThe company maintained that pembrolizumab plus chemotherapy was recommended too recently to be considered standard of care. It considered chemotherapy to be the main comparator for nivolumab plus chemotherapy. The clinical experts mentioned that in their centres they had observed slower uptake of pembrolizumab than anticipated. They attributed this to testing capacity issues associated with the COVID‑19 pandemic and differences in how diagnostic services do CPS tests. The Cancer Drugs Fund (CDF) lead stated that use of pembrolizumab plus chemotherapy had been increasing slowly, which is not unusual when there is a test needed for treatment. Despite differing opinions on the uptake of pembrolizumab, the clinical experts and CDF lead agreed that pembrolizumab should be considered as a comparator in this appraisal. The committee concluded that:\n\nchemotherapy alone is a relevant comparator when only nivolumab is suitable (tumour cell PD‑L1 expression at a level of 1% or more and a CPS of less than 10)\n\npembrolizumab plus chemotherapy is a relevant comparator when both nivolumab and pembrolizumab are suitable options (PD‑L1 positivity with tumour cell expression at a level of 1% or more and a CPS of 10 or more).\n\n# Clinical evidence\n\n## CheckMate\xa0648 data for the subgroup of people whose tumour cells express PD-L1 at 1% or more is appropriate for decision making\n\nCheckMate\xa0648 is a randomised, three-arm, open-label, placebo-controlled trial (n=970). It compared cisplatin and fluorouracil, with or without nivolumab, and nivolumab plus ipilimumab, as first-line treatment for unresectable advanced, recurrent or metastatic oesophageal cancer. The nivolumab plus ipilimumab and chemotherapy trial arm was not included in the decision problem. The primary outcomes were progression-free survival and overall survival in the ITT population (n=645 for the nivolumab plus chemotherapy and chemotherapy trial arms). Progression-free survival and overall survival were reported for people with squamous cell oesophageal carcinoma whose tumour cells expressed PD‑L1 at 1% or more (n=315). The committee concluded that the data from this subgroup is appropriate for decision making when only nivolumab is suitable (see section\xa03.4).\n\n## Nivolumab improves progression-free survival and overall survival compared with chemotherapy alone\n\nData on progression-free survival and overall survival outcomes from the CheckMate\xa0648 subgroup (see section\xa03.5) are academic in confidence and cannot be presented here. The committee concluded that nivolumab plus chemotherapy improves both progression-free survival and overall survival compared with chemotherapy alone.\n\n# Indirect comparison with pembrolizumab\n\n## There is uncertainty around the comparability of the trials included in the indirect treatment comparison\n\nNivolumab plus chemotherapy was indirectly compared with pembrolizumab plus chemotherapy in the absence of a direct trial comparison. Data for pembrolizumab came from the KEYNOTE‑590 trial. There was no efficacy data from the KEYNOTE‑590 population in whom nivolumab plus chemotherapy was suitable (tumour cell PD‑L1 expression of 1% or more). The indirect treatment comparison (ITC) used outcomes from the population for whom pembrolizumab plus chemotherapy was suitable (PD‑L1 expression with a CPS of 10 or more). Progression-free survival and overall survival outcome data from CheckMate\xa0648 and KEYNOTE‑590 were indirectly compared. In KEYNOTE‑590, progression-free survival data was restricted to oesophageal cancer with squamous cell carcinoma or adenocarcinoma histologies, and overall survival data was restricted to squamous cell histology. A comparability assessment between the 2\xa0trials showed that CheckMate\xa0648 included more people with an Asian family background and fewer people had metastatic disease. The company compared some baseline characteristics from people in both trials whose tumours had PD‑L1 expression with a CPS of 10 or more. The ERG agreed that this subgroup appeared comparable to the ITT populations in the trials. However, it was noted that conclusions around trial comparability are limited because the only characteristics presented were age, Asian family background, Eastern Cooperative Oncology Group status and metastatic disease. Also, these characteristics were only available as an average of both trial arms in KEYNOTE‑590 (pembrolizumab plus chemotherapy and chemotherapy alone). One clinical expert highlighted that people in the 2\xa0trials are likely to be comparable, based on the overall survival that was observed in the control arms of both trials. They also said there is little clinical understanding of how outcomes may differ by how PD‑L1 expression was measured (tumour cell expression or CPS). Furthermore, they stated there is also uncertainty in how outcomes may differ in the broader oesophageal cancer population and in tumours which express PD‑L1. Another clinical expert commented that while CheckMate\xa0648 included only people with oesophageal squamous cell carcinoma, KEYNOTE‑590 included people with squamous cell carcinoma and adenocarcinoma, located in either the oesophagus or the gastroesophageal junction. This made it difficult to reach any conclusions about trial comparability. The committee noted there was uncertainty about the comparability of the 2\xa0trials used in the ITC.\n\n## The indirect comparison does not give clear evidence of superiority of one treatment over the other\n\nThe company explored various ITC analyses to estimate the relative treatment effect of nivolumab plus chemotherapy versus pembrolizumab plus chemotherapy in terms of progression-free survival and overall survival. The company's analyses included people from CheckMate\xa0648 for whom both nivolumab and pembrolizumab were suitable (see section\xa03.4). This generated time-varying progression-free survival hazard ratios (HRs) which favoured pembrolizumab plus chemotherapy from 3\xa0months. The overall survival HRs favoured nivolumab plus chemotherapy after 6\xa0months. The ERG's base-case analyses included people from CheckMate\xa0648 for whom pembrolizumab was suitable (see section\xa03.4). These generated time-varying progression-free survival and overall survival HRs which favoured pembrolizumab plus chemotherapy over all time points. The ERG favoured including people for whom pembrolizumab was suitable, to maintain maximum trial comparability because the information on suitability of nivolumab in KEYNOTE‑590 was not available (see section\xa03.3 and section\xa03.7). The company and ERG base-case analyses also differed in the distributions used to extrapolate survival and which treatments were used as the baseline to scale pembrolizumab survival estimates. In both analyses, the HR credible intervals were wide and crossed 1. The ERG commented that the methodologies used in the ITC were robust and there were some arguments for using the company's base-case analysis. However, the ERG concluded that it was difficult to determine whether 1 treatment extended progression-free survival or overall survival more than the other.The clinical experts maintained that the effectiveness of nivolumab and pembrolizumab (in terms of response or survival) is almost the same in other cancers, highlighting an immunotherapy 'class effect'. They expect this effect to be consistent in treating oesophageal squamous cell carcinoma tumours. They further explained that comparing nivolumab and pembrolizumab across different definitions of PD‑L1 positivity and trial datasets was 'risky' in terms of validity. The CDF lead explained that pembrolizumab is administered less frequently than nivolumab, which may provide added benefit to people and also reduce the burden on NHS cancer services because fewer hospital visits would be needed.The committee acknowledged the complexity of calculating a reliable relative treatment effect in the comparison of nivolumab and pembrolizumab. The clinical experts, company, ERG and committee all agreed that no definitive evidence of superiority of one treatment over the other had been presented.\n\n# The company's economic model\n\n## The company's economic model is appropriate for decision making\n\nThe company presented a 3‑state partitioned survival model to estimate the cost effectiveness of nivolumab plus chemotherapy compared with chemotherapy and pembrolizumab plus chemotherapy. The 3\xa0health states were progression-free survival, progressive disease, and death. The ERG agreed that the company's model structure captured all relevant health states and that partitioned survival models are widely used in cancer modelling. The ERG's concerns on the model structure related to the modelling of effectiveness associated with subsequent therapy. The company included a 2‑year stopping rule for nivolumab. Although this is not included in the marketing authorisation, it reflects the use in the trial and expected use in clinical practice, in line with nivolumab use in other cancers. The committee concluded that the company's model structure was acceptable for decision making.\n\n# Assumptions for the comparison with chemotherapy\n\n## It is unclear which model for estimating overall survival is more appropriate\n\nThe company used Kaplan–Meier data from CheckMate\xa0648 to model overall survival in both treatment arms, with a log-normal extrapolation from 6.9\xa0months. The company justified the semi-parametric approach stating it better reflects the changing hazard observed after 20\xa0months in both trial arms and noted a clear inflection point for the chemotherapy arm smoothed hazard plot at around 6\xa0months. The ERG did not agree with the company's approach and used a parametric log-logistic extrapolation in their base case. It justified the parametric extrapolation by noting no clear inflection point for the nivolumab plus chemotherapy smoothed hazard plot. It also found a reasonable correspondence of the landmark overall survival observed in CheckMate\xa0648 with the parametric overall survival analysis. The committee heard that a semi-parametric extrapolation of overall survival was broadly accepted by the committee in TA737. The committee acknowledged there was uncertainty in the long-term overall survival and there were arguments for each approach.\n\n## In-trial switching may have had an impact on overall survival, but its effect is uncertain\n\nThere was evidence of treatment switching in CheckMate\xa0648, with a proportion of both arms who had subsequent systemic and anti-PD‑L1 therapies (including nivolumab and pembrolizumab). The company considered that a decreasing hazard rate (mortality rate) observed in the chemotherapy arm of CheckMate\xa0648 was implausible. The ERG argued that it might be partly because of in-trial switching to an anti-PD‑L1 therapy. The ERG also noted that, although only a fraction of people in the trial switched to an anti-PD‑L1 therapy, the company assumed in its economic model that all people who had subsequent treatment in clinical practice would have an anti-PD‑L1 therapy. The ERG suggested that this might lead to a bias where the effectiveness of chemotherapy had been underestimated in the economic model. To overcome the bias in results, it preferred an adjustment of overall survival in the model using methods outlined in NICE's Decision Support Unit technical support document 16. The company elected against including a switching adjustment in their base-case modelling of overall survival, commenting that few people switched to an anti-PD‑L1 therapy in the trial. It also explained that the switching adjustment methods in the technical support document place large demands on limited data which can create more uncertainty. The company presented 2 switching adjustment scenario analyses: a rank-preserving structural failure time model and a model-based approach. As the incremental cost-effectiveness ratio (ICER) of nivolumab plus chemotherapy versus chemotherapy increased markedly in these scenarios, the ERG maintained that the ICER is underestimated without a switching adjustment. The committee heard that switching was not included in TA737. While the ERG acknowledged this, it again referred to the clinical evidence that it said demonstrated switching and the difference between the proportion switching in the trial and that which would occur in clinical practice. A clinical expert explained that switching to an anti-PD‑L1 therapy may introduce some bias, but it was not expected to be impactful on overall survival. The committee concluded that the switching may have an impact on the overall survival in both trial arms, but that its overall impact was uncertain.\n\n## It is reasonable to expect some treatment waning after treatment is stopped, but the impact on overall survival is uncertain\n\nIn its base case, the company assumed there was no waning of treatment effect after stopping nivolumab. It commented that there was evidence of a robust and durable treatment effect lasting beyond discontinuation for immunotherapies. It stated that if any treatment waning was to occur it would be 5\xa0years after starting therapy. It referenced NICE's technology appraisal of nivolumab for untreated HER2-negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in which the committee considered a 5‑year assumption of treatment waning to be plausible. The ERG disagreed with this assumption and included the waning of treatment effect on overall survival for nivolumab from 2.5\xa0years to 4.0\xa0years after starting therapy and 6\xa0months after stopping therapy. The ERG justified the assumptions, explaining that for some overall survival parametric functions the nivolumab plus chemotherapy treatment effect versus chemotherapy alone increased over time, which was considered implausible. Additionally, the ERG highlighted that treatment waning assumptions were not disregarded by the committee in TA737. However, it noted that no conclusions about the appropriateness of waning were made by the committee. The company commented that there was no clear justification for the 2.5\xa0years to 4.0\xa0years treatment waning assumptions preferred by the ERG.The clinical experts commented that some treatment waning is possible and it is more likely when nivolumab plus chemotherapy is discontinued early. The committee considered that based on the maturity of the data in CheckMate\xa0648, the treatment effect may be captured within the observed results making an adjustment of the extrapolation of overall survival for treatment waning unnecessary.The committee acknowledged that the treatment waning effect of pembrolizumab was discussed in TA737 and that no conclusions on the appropriateness of waning were stated in the final guidance. It concluded that assuming a lifelong treatment effect of nivolumab may be over optimistic and some treatment waning might be expected. However, there was not enough evidence to be precise about when this would occur. The committee concluded that it would consider scenarios with and without treatment waning in its decision making, only if they impact the final decision on cost effectiveness.\n\n## Modelling risk of death is uncertain, but has minimal impact on the cost-effectiveness estimates\n\nThe reduction in the risk of death in CheckMate\xa0648 was similar to that of background mortality. The company and the ERG agreed that mortality should not be any lower than background (all-cause) mortality. To enforce a plausible minimum rate of mortality, a background mortality rate was included in the model, additional to the predicted overall survival. The company maintained that the approach resulted in very little difference in the overall survival. However, the ERG considered this approach to double-count mortality in the model and preferred the use of alternative methods which prevent implausibly low mortality hazard with any overall survival extrapolation. The committee acknowledged the justifications for each modelling approach but did not conclude which was preferable because each assumption had a minimal impact on the cost-effectiveness estimates.\n\n## Treatment-specific health-related quality of life estimates are not considered appropriate\n\nUtility values in the model were calculated using EQ‑5D data from CheckMate\xa0648. The company attributed utilities to the progression-based health states in its base case, using the average utility reported in the 2\xa0trial arms. The ERG explained that because the EQ‑5D scores reported were consistently higher for chemotherapy compared with nivolumab plus chemotherapy, treatment-specific utilities were more appropriate. The clinical experts suggested toxicity associated with nivolumab therapy may explain lower utility values compared with chemotherapy alone. The clinical experts stated that they would expect the opposite in practice, with people who had nivolumab plus chemotherapy likely to have higher utility because of better disease control. The CDF lead and clinical experts did not agree with using the treatment-specific utilities. This is based on their experience that health-related quality of life disutilities associated with anti-PD‑(L)‑1 immunotherapies toxicity would be outweighed by the health benefit derived from response to therapy. Because treatment-specific utilities are clinically plausible, the committee concluded that treatment-specific utilities were not appropriate.\n\n## There is uncertainty in the calculation of treatment costs weighted by delayed or missed doses\n\nA proportion of people in CheckMate\xa0648 delayed or missed doses of their trial treatment. In its base-case analysis, the company adjusted treatment costs based on the mean relative dose intensity observed in the trial. These treatment costs were then weighted by the time each patient spent on treatment. The ERG explained that time on therapy was not relevant for capturing the relative dose intensity and omitted this from its base case. The company stated that the treatment discontinuation biased the treatment cost calculations. The committee noted uncertainty in both approaches taken.\n\n# End of life\n\n## Nivolumab plus chemotherapy meets end of life criteria compared with chemotherapy, but not with pembrolizumab plus chemotherapy\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered whether nivolumab plus chemotherapy met the end of life criteria compared with chemotherapy for people in whom pembrolizumab is unsuitable. The company and ERG both agreed that data suggests that life expectancy in this population is less than 24\xa0months. The observed median overall survival benefit with nivolumab plus chemotherapy in CheckMate\xa0648 was larger than the additional 3‑month extension to life needed by the criteria (data are academic in confidence and cannot be presented here). The committee considered whether nivolumab plus chemotherapy met the end of life criteria compared with pembrolizumab plus chemotherapy for people in whom pembrolizumab is suitable. The company and ERG both agreed, based on the KEYNOTE‑590 analyses, that life expectancy in this population is less than 24\xa0months. Based on the ITC analyses (see section\xa03.8), the median overall survival benefit of nivolumab plus chemotherapy compared with pembrolizumab plus chemotherapy did not exceed the additional 3‑month extension to life needed by the criteria (the data cannot be reported here because the company submitted it as academic in confidence). The committee concluded that nivolumab met the end of life criteria compared with chemotherapy but that criteria were not met compared with pembrolizumab plus chemotherapy.\n\n# Cost-effectiveness estimate\n\n## Nivolumab is unlikely to be cost effective when compared with pembrolizumab\n\nThe company's base-case comparison of nivolumab with pembrolizumab included the following assumptions:\n\nsemi-parametric extrapolation of progression-free and overall survival data from CheckMate\xa0648 for nivolumab (see section\xa03.10)\n\nexcluding any adjustments to overall survival for subsequent therapy (see section\xa03.11)\n\nexcluding nivolumab treatment waning (see section\xa03.12)\n\nincluding all-cause mortality, additional to the predicted overall survival mortality (see section\xa03.13)\n\nusing progression-based utilities, independent of the treatment received (see section\xa03.14)\n\nadjusting treatment costs by the relative dose intensity, weighted by the time on treatment (see section\xa03.15).Differences in the company's and ERG's base case are in the methodology used for the ITC. The company base case used the following ITC analyses assumptions (see section\xa03.8):\n\nincluding outcome data from people in CheckMate\xa0648 for whom both nivolumab and pembrolizumab was suitable and people from KEYNOTE‑590 for whom pembrolizumab was suitable (see section\xa03.4)\n\nscaling nivolumab and pembrolizumab survival using chemotherapy as the baseline\n\nusing log-normal distribution to extrapolate overall survival.The ERG's base-case analyses differed from the company's because it included people from CheckMate\xa0648 for whom only pembrolizumab was suitable. The company and ERG base-case analyses also differed in the distribution used to extrapolate survival and which treatment was used as the baseline to scale pembrolizumab survival estimates.The ICERs cannot be reported here because of confidential commercial arrangements for nivolumab and pembrolizumab. The company's and ERG's base-case cost-effectiveness estimates were similar, both showing nivolumab plus chemotherapy to be dominated by pembrolizumab plus chemotherapy. The committee concluded that it was unlikely that nivolumab plus chemotherapy would be a cost-effective use of NHS resources when pembrolizumab is a suitable option.\n\n## Nivolumab plus chemotherapy is cost effective when compared with chemotherapy alone when pembrolizumab is unsuitable\n\nThe company's comparison of nivolumab plus chemotherapy with chemotherapy for people in whom pembrolizumab is not suitable used the same assumptions as for the comparison with pembrolizumab plus chemotherapy (see section\xa03.17). The ERG's base case included the same assumptions as the company in its exclusion of an adjustment on survival for switching (see section\xa03.11). The ERG's assumptions differed from the company in the approach to modelling progression-free survival and overall survival, and parametric extrapolation was modelled with a waning of nivolumab treatment effect between 2.5\xa0years and 4\xa0years (see section\xa03.12). Additionally, treatment-specific progression utilities were included in the model (see section\xa03.14), and the relative dose intensity was not weighted by time on treatment (see section\xa03.15). The ICERs cannot be reported here because of confidential commercial arrangements for nivolumab and subsequent treatments. Including the ERG's assumptions increased the ICER compared with the company's base case, however the company's cost-effectiveness estimates are below the end of life threshold of £50,000 per quality-adjusted life year (QALY) gained. While the ERG's cost-effectiveness estimates are above £50,000 per QALY gained, the committee did not agree with the assumption of treatment-specific utilities. Removing this assumption provided cost-effectiveness estimates which were below £50,000 per QALY gained. Because end of life criteria have been met (see section\xa03.16), the committee concluded that nivolumab plus chemotherapy is likely a cost-effective use of NHS resources when pembrolizumab is unsuitable.\n\n# Equalities\n\n## There are no equality issues relevant to the recommendations\n\nPatient experts explained that people living in the most deprived areas are more likely to be diagnosed with oesophageal squamous cell carcinoma later than others. The committee noted that the issues surrounding the delays in diagnosis are unable to be addressed in technology appraisal guidance.\n\n# Innovation\n\nThe company and patient experts stated that nivolumab plus chemotherapy has a number of benefits including improved efficacy outcomes compared with chemotherapy, maintenance of quality of life, an acceptable safety profile and providing an additional treatment option for people with high unmet need. They also stated that PD‑L1 test results for suitability of nivolumab are available quicker than PD‑L1 test results for suitability of pembrolizumab. This is because the CPS test is more complex than the tumour cell test and often needs to be requested from an external diagnostic centre. The committee concluded that it had not been presented with any evidence for benefits not captured in the model.\n\n# Conclusion\n\n## Nivolumab is recommended for routine use only when pembrolizumab is unsuitable\n\nThe committee noted that the company's and ERG's base-case conclusions aligned in that nivolumab plus chemotherapy was dominated by pembrolizumab plus chemotherapy, that is higher cost and lower efficacy. The committee acknowledged the uncertainty around relative treatment effects for the 2\xa0treatments, but concluded that nivolumab plus chemotherapy was unlikely to be cost effective compared with pembrolizumab plus chemotherapy.The committee noted that the company's base case suggested that nivolumab plus chemotherapy is likely to be cost effective compared with chemotherapy, for people for whom pembrolizumab is not suitable. This is when considering nivolumab as a life-extending treatment for people with short life expectancy (see section\xa03.17). The committee also noted that the ERG's base case suggested that it was unlikely to be cost effective compared with chemotherapy alone, even in the context of a life-extending treatment for people with a short life expectancy (see section\xa03.16). However, nivolumab was cost effective when treatment-specific utilities, which the committee deemed as inappropriate, were removed from the ERG's analyses and when considering end of life criteria (see section\xa03.17).Despite the remaining areas of uncertainty, it was agreed that the cost-effectiveness estimates for nivolumab when pembrolizumab is not suitable are likely to be within the range usually considered a cost-effective use of NHS resources. This is for a life-extending treatment for people with short life expectancy. Therefore, nivolumab with platinum- and fluoropyrimidine-based chemotherapy is recommended for use in the NHS as an option for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma, in adults whose tumour cells express PD‑L1 at 1% or more. It is recommended only if pembrolizumab plus chemotherapy is unsuitable. The committee recalled the current implementation issues for testing (see section\xa03.3). It therefore also concluded that testing for suitability of nivolumab and pembrolizumab should be done at the same time."}	https://www.nice.org.uk/guidance/ta865	Evidence-based recommendations on nivolumab (Opdivo) with fluoropyrimidine- and platinum-based chemotherapy for untreated unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma in adults.
6ef7efe39ab9d3f8f0815503a8ab40107580bc05	nice	Regorafenib for previously treated metastatic colorectal cancer	Regorafenib for previously treated metastatic colorectal cancer Evidence-based recommendations on regorafenib (Stivarga) for previously treated metastatic colorectal cancer in adults. # Recommendations Regorafenib is recommended, within its marketing authorisation, as an option for metastatic colorectal cancer in adults who have had previous treatment (including fluoropyrimidine-based chemotherapy, anti‑VEGF therapy and anti‑EGFR therapy) or when these treatments are unsuitable. Regorafenib is only recommended if the company provides it according to the commercial arrangement. Why the committee made these recommendations The only treatment for metastatic colorectal cancer (mCRC) that has progressed after fluoropyrimidine-based chemotherapy, anti-vascular endothelial growth factor (anti-VEGF) therapy or anti-epidermal growth factor receptor (anti-EGFR) therapy, or when these are unsuitable, is trifluridine–tipiracil. When the cancer has progressed on trifluridine–tipiracil or it is not suitable, the only option is best supportive care. Regorafenib is another possible treatment option. Clinical trial results show that regorafenib increases how long people live compared with best supportive care. There is no clinical trial evidence directly comparing regorafenib with trifluridine–tipiracil. An indirect treatment comparison suggests that regorafenib and trifluridine–tipiracil are likely to have similar clinical effectiveness. The cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So, regorafenib is recommended.# Information about regorafenib # Marketing authorisation indication Regorafenib (Stivarga, Bayer) is indicated for 'the treatment of adult patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for regorafenib. # Price The list price of regorafenib 40 mg is £3,744 per 84 tablets (excluding VAT; BNF online accessed November 2022). The company has a commercial arrangement. This makes regorafenib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Bayer, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Details of condition Colorectal cancer is a malignant tumour arising from the lining of the large intestine (colon and rectum). Metastatic colorectal cancer (mCRC) refers to cancer that has spread beyond the large intestine and nearby lymph nodes to other parts of the body, such as the lungs and liver. ## Unmet need and impact on quality of life The patient expert explained that mCRC can have a significant impact on quality of life, especially for those diagnosed at later stages, when survival rates are poor (fewer than 10% of those diagnosed at stage 4 survive beyond 5 years). They noted that there are limited effective treatment options available, so treatments which give small improvements in quality of life and extensions to length of life are important. Both the patient and clinical experts highlighted that as with some current treatments, regorafenib is administered orally (by mouth), meaning people may be able to take the medicine at home rather than in a hospital. The committee agreed that people with mCRC who have had previous treatments, have an unmet clinical need, and would welcome new treatment options. # Clinical management ## Treatment options The aim of treatment for mCRC is to prolong survival and improve quality of life. The treatment options for mCRC include: Nivolumab with ipilimumab (see NICE's technology appraisal guidance on nivolumab with ipilimumab for previously treated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency) Pembrolizumab (see NICE's technology appraisal guidance on pembrolizumab for untreated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency) Encorafenib with cetuximab (see NICE's technology appraisal guidance on encorafenib plus cetuximab for previously treated BRAF V600E mutation-positive metastatic colorectal cancer) Cetuximab for epidermal growth factor receptor (EGFR)-expressing, RAS wild-type mCRC (see NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer) Panitumumab for RAS wild-type mCRC (see NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer) Trifluridine–tipiracil for mCRC after available therapies (see NICE's technology appraisal guidance on trifluridine–tipiracil for previously treated metastatic colorectal cancer) Other chemotherapy for mCRC listed in NICE's guideline on colorectal cancer.Clinical experts explained that initial treatment choice depends on the presence or absence of 3 molecular markers: BRAF 600, RAS wild-type, and microsatellite instability/mismatch repair deficiency (MSI/MMR). When these molecular markers are present, specific biological treatments and chemotherapy are usually offered as first- and second-line treatment. In the absence of these molecular markers, the committee understood that first-line treatment for mCRC is FOLFOX (folinic acid plus fluorouracil plus oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Second-line treatments include irinotecan (only after FOLFOX) or FOLFIRI (folinic acid plus fluorouracil plus irinotecan). Raltitrexed is an option when fluorouracil and folinic acid are unsuitable. Trifluridine–tipiracil is recommended by NICE as a treatment option for mCRC (with or without molecular markers) 'in adults who have had previous treatment with available therapies including fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapies, anti-vascular endothelial growth factor (anti-VEGF) treatments and anti-epidermal growth factor receptor (anti-EGFR) treatments, or when these therapies are not suitable'. Clinical experts explained that trifluridine–tipiracil is used in clinical practice at third and subsequent lines, when there are no further active treatment options for people well enough to use active treatment. ## Comparators The company's proposed decision problem was narrower than regorafenib's marketing authorisation, proposing that the committee should consider regorafenib specifically as an alternative treatment option to trifluridine–tipiracil. The committee was aware that the marketing authorisation for regorafenib is very similar to that of trifluridine–tipiracil, that is, that it should be used after 'available therapies'. Clinical experts noted that trifluridine–tipiracil and regorafenib would be used at the same position in the treatment pathway. There would be shared decision making between patients and clinicians, based on previous response to therapies, tolerance and patient choice. The committee concluded that regorafenib will be used in the treatment pathway as an alternative treatment option to trifluridine–tipiracil. Clinical experts noted that the number of people who are well enough to have treatment reduces after each line of therapy. But they suggested that around 30% of people would be well enough to have active treatment after trifluridine–tipiracil. Currently, the only option for these people is best supportive care or treatment through a clinical trial. The clinical experts explained that trifluridine–tipiracil and regorafenib could be used in sequence because they have different mechanisms of action, and that this had been done in several observational studies. The committee agreed that, in principle, it was appropriate to consider that regorafenib could be used in sequence. When used after trifluridine–tipiracil, regorafenib would be used instead of best supportive care. So, the committee concluded that best supportive care was also an appropriate comparator. # Clinical effectiveness ## Data sources and results The company submitted clinical evidence from 2 randomised, double-blind, phase 3 clinical trials (CORRECT and CONCUR). These compared regorafenib with placebo in adults with metastatic colorectal cancer whose cancer had progressed within 3 months on approved standard treatment. Standard treatment included: fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, cetuximab, and panitumumab. The primary completion years for CORRECT and CONCUR were 2011 and 2013, respectively. Overall survival was the primary outcome for both trials. Clinical experts explained that the trials included different populations and these differences could confound the results. CORRECT was a global study that included people from 15 countries. These people had heavier pre-treatment with targeted biological therapies and were more likely to have a KRAS mutation and an Eastern Cooperative Oncology Group (ECOG) score of 0. CONCUR only included people in Asia (China, Hong Kong, South Korea, Taiwan and Vietnam), and included more people who had metastatic disease for a shorter time than CORRECT. In CORRECT, the median overall survival was 6.4 months for people having regorafenib and 5 months for people having placebo (hazard ratio 0.77, 95% confidence interval 0.64 to 0.94). For CONCUR, 8.8 months was the median overall survival for people in the regorafenib arm. In the placebo arm this was 6.3 months (hazard ratio 0.55, 95% confidence interval 0.40 to 0.77). The company pooled both datasets to get an overall survival hazard ratio of 0.68 (95% confidence interval 0.59 to 0.79), which it used for its clinical-effectiveness analyses. The committee acknowledged that there were differences in the trial populations and agreed to consider both trials and their pooled results in its decision making. ## Generalisability of the regorafenib clinical trials The committee explored whether the differences in populations between regorafenib trials were likely to have an impact on the efficacy results. That is, if any of the differences could be effect modifiers, and if so, what their impact may be on the efficacy results. The clinical experts noted that it is difficult to fully differentiate between people with an ECOG status of 0 and 1, so the impact of ECOG status on the clinical trial results may be unclear. One of the clinical experts explained that in the UK there is no evidence of differences in treatment effect in people with mCRC by ethnicity, so they would not expect ethnicity to be an effect modifier for regorafenib. But using anti‑VEGF treatment may influence the clinical effectiveness of regorafenib. Bevacizumab (an anti‑VEGF) is not recommended by NICE for treating mCRC, but was used by everyone in CORRECT and by about 60% of people in CONCUR, before entering the clinical trials. Clinical experts explained that because of their similar mechanism of action, regorafenib may be less effective in people who have had previous treatment with bevacizumab. The committee understood that the differences in baseline characteristics are complex, which increases uncertainty in the results across both trials. The committee considered the subgroup analyses presented by the company and whether any of these better represented people in UK clinical practice, but were aware that the trials were not adequately powered to detect differences in these populations. The committee acknowledged the differences in the baseline characteristics of people in the 2 regorafenib trials, and noted the uncertainty associated with these. But in the absence of further data, it concluded that the pooled results were likely to be generalisable and reflective of NHS clinical practice. ## Indirect treatment comparison There are no head-to-head randomised controlled trials comparing regorafenib with trifluridine–tipiracil. So, the company did an indirect treatment comparison to estimate the relative efficacy of the 2 treatments. It included the regorafenib trials (CORRECT and CONCUR), as well as 3 randomised controlled trials comparing trifluridine–tipiracil with best supportive care: RECOURSE, TERRA, and Yoshino (2012). The company reported similar efficacy for regorafenib and trifluridine–tipiracil using a fixed effect network meta-analysis model (overall survival hazard ratio 0.99, 95% confidence interval 0.84 to 1.17). It also reported similar results for an anchored matching-adjusted indirect comparison (MAIC) in which potential efficacy modifiers (sex, age, and previous use of biological treatment) were weighted based on the baseline characteristics of people in the relevant regorafenib and trifluridine–tipiracil trials. The EAG raised concerns about the differences in the clinical trials included in the indirect treatment comparison. It noted that there was a statistically significant difference in the progression-free survival estimates in studies that include only people in Asia (CONCUR, TERRA and Yoshino ). It recalled that, as with the regorafenib trials (see section 3.6), many (45% to 99%) of the people in the trifluridine–tipiracil trials had had previous anti‑VEGF treatment. The EAG also highlighted the uncertainty around the number of previous treatments, noting that fewer people in the regorafenib trials than in the trifluridine–tipiracil trials had more than 3 previous lines of treatment for mCRC. The committee acknowledged the concerns raised by the EAG and noted that in the absence of adequate subgroup power to detect the impact of the differences in the clinical trials, the uncertainties remain. The committee recalled its conclusion about the generalisability of the regorafenib trials (see section 3.6). It understood that all the trials had similar designs, and that in all the trials the disease characteristics at baseline varied. But because of the different mechanisms of action, the clinical experts explained that effect modifiers may differ between treatments. They noted that there was no biological reason for the effect of trifluridine–tipiracil to differ in people who did or did not have biological treatments. But they advised that evidence from studies in Japan suggests there may be increased efficacy for people with an East Asian family background having fluorouracil (a chemotherapy), because of pharmacokinetic differences in this population. The clinical experts agreed that this may impact the efficacy of treatments and, because of the similar mechanism of action, explained that there may also be additional benefit when using trifluridine–tipiracil in this population. The committee concluded that the indirect treatment comparison was associated with uncertainty because of the heterogeneity between trial populations. It concluded that regorafenib is likely to provide similar benefits in terms of progression-free and overall survival compared to trifluridine–tipiracil. ## Observational evidence Because there were no head-to-head randomised controlled trials, the company and the EAG considered observational studies that directly compared regorafenib with trifluridine–tipiracil. Four of the 5 studies considered relevant supported the company's position of equal efficacy between regorafenib and trifluridine–tipiracil. But the study with the best balance in baseline characteristics (Nakashima 2020) did not. The study reported higher overall survival for people who had treatment with trifluridine–tipiracil compared with regorafenib (10.2 months compared with 6.4 months). The company noted that observational studies have a high risk of bias. The clinical expert also highlighted that the full details of the observational studies were not reported and the impact of this on the clinical effectiveness is uncertain. The committee agreed that the observational study had a high risk of bias. The committee was aware that the Nakashima (2020) study compared 4 groups. These were people who had: regorafenib only, trifluridine–tipiracil only, regorafenib then trifluridine–tipiracil, and trifluridine–tipiracil then regorafenib. The EAG reported results for people who only received regorafenib or trifluridine–tipiracil. The committee noted that this was likely to represent people with the poorest outcomes. In addition, clinical-effectiveness estimates for people who had both treatments would be prone to immortal time bias, because only people who lived long enough had both treatments. The committee concluded that given the difference in baseline characteristics inherent within the regorafenib and trifluridine–tipiracil trials, the observational study likely compounds the risk of bias. It preferred clinical-effectiveness estimates using the indirect treatment comparison. # Economic model ## Company's modelling approach The company submitted a 3‑state (progression-free, progressed disease and death) partitioned survival model to estimate the cost effectiveness of regorafenib. The model took the perspective of the NHS and Personal Social Services. It had a time horizon of 10 years, a cycle length of 1 week, and discounted costs and quality adjusted life-years (QALYs) at a rate of 3.5% per year. The committee concluded that the model structure was appropriate for decision making. ## Modelling assumptions For modelling overall survival, the company fit fully parametric survival models to pooled CORRECT and CONCUR data. For time-on-treatment and progression-free survival estimates for regorafenib and best supportive care, it used Kaplan–Meier data then applied parametric models from the point at which Kaplan–Meier data was unavailable. The company noted the maturity of its data and explained that this approach reflected clinical practice because assessment for disease progression occurred every 8 weeks in the clinical trial, and in clinical practice. The EAG highlighted that the stepped nature of Kaplan–Meier curves could result in overfitting, so it preferred fully parametric models for the base case, which aligns with NICE's Decision Support Unit technical support document 14. The committee noted that both the Kaplan–Meier data and the fully parametric model appeared reasonable for extrapolating short-term survival. But it also noted that for modelling overall survival, the company and EAG had only fit parametric curves to the trial data, whereas safety data provided by the company in response to clarification request showed extended survival data for up to 5 years. The committee preferred to use the long-term data. It concluded that generalised gamma was the best visual fit to the company's long-term overall survival data for regorafenib and best supportive care, and this should be used for the cost-effectiveness estimates. # Utility values ## Source of utility values Utility values used in the company's model were obtained from pooling EQ‑5D‑3L results collected in CORRECT and CONCUR. In general, there was no difference in quality-of-life results between regorafenib and best supportive care. But the EAG had some concerns about the plausibility of pooled end-of-treatment results being used to derive the post-progression health state. The clinical trials considered for trifluridine–tipiracil did not report quality-of-life results. So, the company assumed pre-progression (0.72) and post-progression (0.59) utility values to be equal for trifluridine–tipiracil and regorafenib. The committee noted the large difference in pre- and post-progression utility. Clinical experts explained that management of disease progression on best supportive care was difficult and could have a severe effect on quality of life. The committee was aware that the utility values from CORRECT were applied for the NICE technology appraisal guidance on trifluridine–tipiracil and concluded that it was appropriate to use pooled estimates from the clinical trials. ## Adverse events The company explained that regorafenib has an alternate adverse event profile to trifluridine–tipiracil. Myelosuppression, which can cause dose delays, dose reductions or stopping of treatment, is less common with regorafenib, but diarrhoea and fatigue is more common. A network meta-analysis showed both treatments had a similar likelihood of stopping treatment because of adverse events (odds ratio 1.10, 95% confidence interval 0.53 to 2.24) and similar grade 3 and 4 (severe and life-threatening) adverse events (odds ratio 0.90, 95% confidence interval 0.55 to 1.47). But regorafenib showed a higher likelihood of all treatment-emergent adverse events (odds ratio 1.94, 95% confidence interval 1.20 to 3.17), that is, including grade 1 and 2 (mild and moderate) adverse events. Only grade 3 and 4 adverse events, seen in over 2% of people in the trial, were captured in the company's economic model. Adverse event results from the network meta-analysis were not captured. The company noted that this was in line with previous modelling experience. The clinical experts explained grade 2 adverse events, by definition, have an impact on activities of daily living. But less severe adverse events can typically be managed in the short term. They explained that adverse events may not happen independently, and some may not be symptomatic for patients. This means that although a single grade 3 event may be counted as severe, multiple grade 1 and 2 events may have a greater impact on their quality of life. The company presented a scenario analysis which included grade 1 and 2 adverse events, applying a fixed cost of £5 per adverse event and a disutility of 0.01, but this had negligible impact on the cost-effectiveness estimates. The committee concluded that grade 1 and 2 adverse events should be included in the economic model. # Costs ## Relative dose intensity The company modelled relative dose intensity (RDI) differently for regorafenib than for trifluridine–tipiracil. RDI for regorafenib was based on the mean dose used in CORRECT and CONCUR. For trifluridine–tipiracil, data from NICE's technology appraisal on trifluridine–tipiracil was used to model cycle delay and dose reduction separately. The company noted that this approach is similar to how adverse events would be managed in clinical practice, that is, regorafenib would tend to be managed by dose reduction whereas trifluridine–tipiracil would be managed by dose delay. The clinical experts noted that both dose delay and dose reduction are used to manage adverse events in clinical practice. One clinical expert explained that in their NHS trust, granulocyte colony-stimulating factor (GCSF) can be used pre-emptively to manage adverse events. This can prevent dose delay or dose reduction for those on trifluridine–tipiracil. But the NHS England Cancer Drugs Fund lead explained that not all patients have equal access to GCSF. The committee agreed and noted that there would be cost implications associated with GCSF, if it were used. The EAG highlighted that the mean dose from CORRECT and CONCUR includes both dose delay and dose reduction. It also noted that real-world evidence (Nakashima 2020) directly comparing regorafenib and trifluridine–tipiracil suggests a similar dose reduction for both treatments (54% and 48%, respectively). Based on this, the EAG's preference was to apply equal RDI for both treatments. The committee concluded that both dose delay and dose reduction should be used for estimating the RDI, and preferred the EAG's approach of applying equal RDI to trifluridine–tipiracil and regorafenib. ## Post-progression treatment costs Post-progression treatment costs were not included in the company's base case. The company stated that advice from clinical experts suggests fewer than 10% of people having regorafenib or trifluridine–tipiracil would have post-progression treatment. But 26% of people who had regorafenib in CORRECT, and 31% in CONCUR, had post-progression treatment. The committee recalled that around 30% of people would be offered post-progression treatment after regorafenib or trifluridine–tipiracil has failed (see section 3.4). The company did a scenario analysis in which the post-progression treatment cost reported in NICE's technology appraisal on trifluridine–tipiracil was inflated to 2021 values (£1,633.18) and applied as a single cost to people having either regorafenib or trifluridine–tipiracil. The committee heard that the scenario analysis showed post-progression treatment was not a key driver of the cost-effectiveness estimates. But the committee concluded that subsequent treatment should be included in the economic model. It recalled that both trifluridine–tipiracil and regorafenib could be used in sequence (that is, trifluridine–tipiracil after regorafenib has been used, and vice versa). But it heard from the clinical experts that no difference in efficacy would be expected if either trifluridine–tipiracil or regorafenib were used at fourth line. This is because of the different mechanisms of action of the 2 technologies, and that those well enough to benefit from subsequent therapy are similar to the populations in the indirect treatment comparison. Clinical experts noted that maintained efficacy at later lines is also supported by observational data. The committee concluded that subsequent treatments should be included in the cost-effectiveness modelling, to reflect the clinical trials and clinical expert opinion. In the absence of additional evidence, it concluded that there is likely to be no difference in cost effectiveness if trifluridine–tipiracil is used as a further active treatment (that is, at fourth line) instead of best supportive care. This would likely reflect the evidence already considered in the NICE technology appraisal guidance on trifluridine–tipiracil. # Severity ## General population QALYs NICE's health technology evaluations manual notes that when considering overall benefits, the committee can consider decision-making modifiers. In its submission, the company provided evidence that mCRC that has been previously treated (including with fluoropyrimidine-based chemotherapy, anti‑VEGF, and anti‑EGFR treatments) or which is not suitable for treatment with the listed treatment options, is a severe condition. The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company provided absolute and proportional QALY shortfall estimates in line with NICE's health technology evaluations manual. The company calculated the QALYs of people without the condition over their remaining lifetime. It used general population life expectancy estimates based on 2017 to 2019 national life tables, and utility estimates from Health Survey for England 2017 and 2018 data. These were matched to the same age and sex distribution as those with the condition, based on the baseline characteristics of people in the randomised controlled trials. The company and EAG agreed that the population in the trial had a mean age of 60, and 56% were women. The committee agreed that the methods used by the company and the EAG to estimate the remaining lifetime QALYs for the general population and for people living with the condition were appropriate. ## Estimating QALY shortfall QALY shortfall is calculated by estimating the difference between the number of QALYs generated for an individual in the general population and an individual who has metastatic colorectal cancer that has progressed after first-line chemotherapy or biological treatments, and who is well enough for further active treatment. The committee recalled that both trifluridine–tipiracil and best supportive care are potential comparators for regorafenib (see section 3.4), so the QALY shortfall when using both treatments would need to be considered. The company used its economic model to estimate the expected remaining lifetime QALYs for both comparators. This meant pooled CONCUR and CORRECT data was used. To estimate survival and progression through the model for people who had trifluridine–tipiracil, a hazard ratio from the indirect treatment comparison was applied to the survival curves of regorafenib. The committee noted that the QALY shortfall estimates for trifluridine–tipiracil and best supportive care were similar and felt this similarity might lack face validity (that is, the results are unexpected). The trials underpinning the model had their primary completion between 2011 and 2013 (see section 3.5). The clinical experts advised that there had been advancements in the management and treatment of advanced colorectal cancer in the decade since these trials took place. Clinical experts also explained that the COVID‑19 pandemic had impacted outcomes because of delays in diagnosis. They noted that there was likely to be real-world evidence available for people who have active cancer treatments in the NHS from the national cancer registry or Systemic Anti-Cancer Therapy (SACT) dataset, which would better reflect clinical practice. The committee agreed that using real-world evidence as a reference group would have more accurately reflected the QALY estimates. The committee would have preferred using a real-world dataset to derive the absolute event estimates for trifluridine–tipiracil. It would also have preferred using the hazard ratio from the network meta-analysis to estimate the relative effect for survival for those who had best supportive care. ## QALY weighting The committee considered 2 measures of QALY shortfall: absolute QALY shortfall and proportional QALY shortfall. Absolute QALY shortfall is the total health lost because of the condition. That is, the difference between the expected future health of people living without the condition and the future health which is lost by people living with a condition over their remaining lifetimes. Proportional QALY shortfall represents the fraction of health lost because of the condition. That is, the proportion of future health which is lost by people living with the condition compared with the expected future health of people living without the condition. Both the company's and EAG's estimates for proportional shortfall were above 0.95 for trifluridine–tipiracil and best supportive care, so the company considered that the 1.7 QALY weight should apply. The exact QALYs, and the absolute and proportional QALY shortfalls are confidential so cannot be reported here. The committee considered that there was uncertainty around the data used to estimate the QALYs for people living with the condition who had trifluridine–tipiracil. It would have preferred to see estimates using real-world data. The committee noted that the modifier for disease severity was not convincingly met for this population, and without additional data the committee would not be able to apply the 1.7 weighting. The committee then considered the estimates for people who would have best supportive care. Although it would have preferred to see QALY shortfall based on real-world data, it understood that people who had best supportive care in clinical practice would likely be less well, and have a worse prognosis, suggesting the estimates had greater face validity. The committee noted that all sensitivity analyses included estimates for a proportional shortfall above 0.95. The committee concluded that the modifier for disease severity for those who would have best supportive care was met and a weighting of 1.7 should be applied to the health benefits for regorafenib compared with best supportive care. # Cost-effectiveness estimates ## Company and EAG cost-effectiveness estimates The company's probabilistic incremental cost-effectiveness ratio (ICER) for regorafenib compared with trifluridine–tipiracil (including the commercial discount for regorafenib) is within what NICE normally considers an acceptable use of NHS resources, regardless of what severity weighting is applied. The committee recalled that a 1.7 weighting should be applied to health gains in the comparison with best supportive care. When the high severity weighting was applied, the company's cost-effectiveness estimates of regorafenib compared with best supportive care were also within the range NICE considers a cost-effective use of NHS resources. But the company's base case did not reflect the committee's preferred assumptions, which were: fully parametric survival models for overall survival estimates for regorafenib and best supportive care (generalised gamma) fully parametric survival models for progression-free survival estimates for regorafenib and best supportive care (log-logistic) a fully parametric model for regorafenib time-on-treatment estimates (log-logistic) an equal RDI for regorafenib and trifluridine–tipiracil inclusion of grade 1 and 2 adverse events including subsequent treatments. The committee concluded that applying all its preferred assumptions impacted the cost-effectiveness estimates for regorafenib compared with best supportive care but had negligible impact on the estimates for regorafenib compared with trifluridine–tipiracil. # Other factors ## Equality issues The committee heard that no equalities concerns were raised by the stakeholders and did not consider any equality issues to have an impact on its decision making about treatment of mCRC with regorafenib. # Conclusion ## Recommendation The committee concluded that regorafenib was likely to be cost effective compared with both trifluridine–tipiracil and best supportive care. But there remain some uncertainties in the cost-effectiveness estimates of regorafenib compared with best supportive care. The committee considered input from clinical experts, which suggested that treatment sequencing (that is, which treatment to use first, either regorafenib or trifluridine–tipiracil) would be based on individual preference and potential for response. It noted that clinicians would also consider toxicities from previous lines of treatment as well as previous treatment response and patient choice. So, the committee concluded that having regorafenib as an additional treatment option is appropriate, because this allows clinicians to make the most appropriate decision for each patient. So, regorafenib is recommended for previously treated metastatic colorectal cancer.	{'Recommendations': 'Regorafenib is recommended, within its marketing authorisation, as an option for metastatic colorectal cancer in adults who have had previous treatment (including fluoropyrimidine-based chemotherapy, anti‑VEGF therapy and anti‑EGFR therapy) or when these treatments are unsuitable. Regorafenib is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThe only treatment for metastatic colorectal cancer (mCRC) that has progressed after fluoropyrimidine-based chemotherapy, anti-vascular endothelial growth factor (anti-VEGF) therapy or anti-epidermal growth factor receptor (anti-EGFR) therapy, or when these are unsuitable, is trifluridine–tipiracil. When the cancer has progressed on trifluridine–tipiracil or it is not suitable, the only option is best supportive care. Regorafenib is another possible treatment option.\n\nClinical trial results show that regorafenib increases how long people live compared with best supportive care. There is no clinical trial evidence directly comparing regorafenib with trifluridine–tipiracil. An indirect treatment comparison suggests that regorafenib and trifluridine–tipiracil are likely to have similar clinical effectiveness.\n\nThe cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So, regorafenib is recommended.', 'Information about regorafenib': "# Marketing authorisation indication\n\nRegorafenib (Stivarga, Bayer) is indicated for 'the treatment of adult patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for regorafenib.\n\n# Price\n\nThe list price of regorafenib 40\xa0mg is £3,744 per 84\xa0tablets (excluding VAT; BNF online accessed November 2022).\n\nThe company has a commercial arrangement. This makes regorafenib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Bayer, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Details of condition\n\nColorectal cancer is a malignant tumour arising from the lining of the large intestine (colon and rectum). Metastatic colorectal cancer (mCRC) refers to cancer that has spread beyond the large intestine and nearby lymph nodes to other parts of the body, such as the lungs and liver.\n\n## Unmet need and impact on quality of life\n\nThe patient expert explained that mCRC can have a significant impact on quality of life, especially for those diagnosed at later stages, when survival rates are poor (fewer than 10% of those diagnosed at stage\xa04 survive beyond 5\xa0years). They noted that there are limited effective treatment options available, so treatments which give small improvements in quality of life and extensions to length of life are important. Both the patient and clinical experts highlighted that as with some current treatments, regorafenib is administered orally (by mouth), meaning people may be able to take the medicine at home rather than in a hospital. The committee agreed that people with mCRC who have had previous treatments, have an unmet clinical need, and would welcome new treatment options.\n\n# Clinical management\n\n## Treatment options\n\nThe aim of treatment for mCRC is to prolong survival and improve quality of life. The treatment options for mCRC include:\n\nNivolumab with ipilimumab (see NICE's technology appraisal guidance on nivolumab with ipilimumab for previously treated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency)\n\nPembrolizumab (see NICE's technology appraisal guidance on pembrolizumab for untreated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency)\n\nEncorafenib with cetuximab (see NICE's technology appraisal guidance on encorafenib plus cetuximab for previously treated BRAF V600E mutation-positive metastatic colorectal cancer)\n\nCetuximab for epidermal growth factor receptor (EGFR)-expressing, RAS wild-type mCRC (see NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer)\n\nPanitumumab for RAS wild-type mCRC (see NICE's technology appraisal guidance on cetuximab and panitumumab for previously untreated metastatic colorectal cancer)\n\nTrifluridine–tipiracil for mCRC after available therapies (see NICE's technology appraisal guidance on trifluridine–tipiracil for previously treated metastatic colorectal cancer)\n\nOther chemotherapy for mCRC listed in NICE's guideline on colorectal cancer.Clinical experts explained that initial treatment choice depends on the presence or absence of 3 molecular markers: BRAF\xa0600, RAS wild-type, and microsatellite instability/mismatch repair deficiency (MSI/MMR). When these molecular markers are present, specific biological treatments and chemotherapy are usually offered as first- and second-line treatment. In the absence of these molecular markers, the committee understood that first-line treatment for mCRC is FOLFOX (folinic acid plus fluorouracil plus oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Second-line treatments include irinotecan (only after FOLFOX) or FOLFIRI (folinic acid plus fluorouracil plus irinotecan). Raltitrexed is an option when fluorouracil and folinic acid are unsuitable. Trifluridine–tipiracil is recommended by NICE as a treatment option for mCRC (with or without molecular markers) 'in adults who have had previous treatment with available therapies including fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapies, anti-vascular endothelial growth factor (anti-VEGF) treatments and anti-epidermal growth factor receptor (anti-EGFR) treatments, or when these therapies are not suitable'. Clinical experts explained that trifluridine–tipiracil is used in clinical practice at third and subsequent lines, when there are no further active treatment options for people well enough to use active treatment.\n\n## Comparators\n\nThe company's proposed decision problem was narrower than regorafenib's marketing authorisation, proposing that the committee should consider regorafenib specifically as an alternative treatment option to trifluridine–tipiracil. The committee was aware that the marketing authorisation for regorafenib is very similar to that of trifluridine–tipiracil, that is, that it should be used after 'available therapies'. Clinical experts noted that trifluridine–tipiracil and regorafenib would be used at the same position in the treatment pathway. There would be shared decision making between patients and clinicians, based on previous response to therapies, tolerance and patient choice. The committee concluded that regorafenib will be used in the treatment pathway as an alternative treatment option to trifluridine–tipiracil. Clinical experts noted that the number of people who are well enough to have treatment reduces after each line of therapy. But they suggested that around 30% of people would be well enough to have active treatment after trifluridine–tipiracil. Currently, the only option for these people is best supportive care or treatment through a clinical trial. The clinical experts explained that trifluridine–tipiracil and regorafenib could be used in sequence because they have different mechanisms of action, and that this had been done in several observational studies. The committee agreed that, in principle, it was appropriate to consider that regorafenib could be used in sequence. When used after trifluridine–tipiracil, regorafenib would be used instead of best supportive care. So, the committee concluded that best supportive care was also an appropriate comparator.\n\n# Clinical effectiveness\n\n## Data sources and results\n\nThe company submitted clinical evidence from 2 randomised, double-blind, phase\xa03 clinical trials (CORRECT and CONCUR). These compared regorafenib with placebo in adults with metastatic colorectal cancer whose cancer had progressed within 3\xa0months on approved standard treatment. Standard treatment included: fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, cetuximab, and panitumumab. The primary completion years for CORRECT and CONCUR were 2011 and 2013, respectively. Overall survival was the primary outcome for both trials. Clinical experts explained that the trials included different populations and these differences could confound the results. CORRECT was a global study that included people from 15 countries. These people had heavier pre-treatment with targeted biological therapies and were more likely to have a KRAS mutation and an Eastern Cooperative Oncology Group (ECOG) score of 0. CONCUR only included people in Asia (China, Hong Kong, South Korea, Taiwan and Vietnam), and included more people who had metastatic disease for a shorter time than CORRECT. In CORRECT, the median overall survival was 6.4\xa0months for people having regorafenib and 5\xa0months for people having placebo (hazard ratio 0.77, 95% confidence interval 0.64 to 0.94). For CONCUR, 8.8\xa0months was the median overall survival for people in the regorafenib arm. In the placebo arm this was 6.3\xa0months (hazard ratio 0.55, 95% confidence interval 0.40 to 0.77). The company pooled both datasets to get an overall survival hazard ratio of 0.68 (95% confidence interval 0.59 to 0.79), which it used for its clinical-effectiveness analyses. The committee acknowledged that there were differences in the trial populations and agreed to consider both trials and their pooled results in its decision making.\n\n## Generalisability of the regorafenib clinical trials\n\nThe committee explored whether the differences in populations between regorafenib trials were likely to have an impact on the efficacy results. That is, if any of the differences could be effect modifiers, and if so, what their impact may be on the efficacy results. The clinical experts noted that it is difficult to fully differentiate between people with an ECOG status of 0 and 1, so the impact of ECOG status on the clinical trial results may be unclear. One of the clinical experts explained that in the UK there is no evidence of differences in treatment effect in people with mCRC by ethnicity, so they would not expect ethnicity to be an effect modifier for regorafenib. But using anti‑VEGF treatment may influence the clinical effectiveness of regorafenib. Bevacizumab (an anti‑VEGF) is not recommended by NICE for treating mCRC, but was used by everyone in CORRECT and by about 60% of people in CONCUR, before entering the clinical trials. Clinical experts explained that because of their similar mechanism of action, regorafenib may be less effective in people who have had previous treatment with bevacizumab. The committee understood that the differences in baseline characteristics are complex, which increases uncertainty in the results across both trials. The committee considered the subgroup analyses presented by the company and whether any of these better represented people in UK clinical practice, but were aware that the trials were not adequately powered to detect differences in these populations. The committee acknowledged the differences in the baseline characteristics of people in the 2 regorafenib trials, and noted the uncertainty associated with these. But in the absence of further data, it concluded that the pooled results were likely to be generalisable and reflective of NHS clinical practice.\n\n## Indirect treatment comparison\n\nThere are no head-to-head randomised controlled trials comparing regorafenib with trifluridine–tipiracil. So, the company did an indirect treatment comparison to estimate the relative efficacy of the 2 treatments. It included the regorafenib trials (CORRECT and CONCUR), as well as 3 randomised controlled trials comparing trifluridine–tipiracil with best supportive care: RECOURSE, TERRA, and Yoshino (2012). The company reported similar efficacy for regorafenib and trifluridine–tipiracil using a fixed effect network meta-analysis model (overall survival hazard ratio 0.99, 95% confidence interval 0.84 to 1.17). It also reported similar results for an anchored matching-adjusted indirect comparison (MAIC) in which potential efficacy modifiers (sex, age, and previous use of biological treatment) were weighted based on the baseline characteristics of people in the relevant regorafenib and trifluridine–tipiracil trials. The EAG raised concerns about the differences in the clinical trials included in the indirect treatment comparison. It noted that there was a statistically significant difference in the progression-free survival estimates in studies that include only people in Asia (CONCUR, TERRA and Yoshino ). It recalled that, as with the regorafenib trials (see section\xa03.6), many (45% to 99%) of the people in the trifluridine–tipiracil trials had had previous anti‑VEGF treatment. The EAG also highlighted the uncertainty around the number of previous treatments, noting that fewer people in the regorafenib trials than in the trifluridine–tipiracil trials had more than 3 previous lines of treatment for mCRC. The committee acknowledged the concerns raised by the EAG and noted that in the absence of adequate subgroup power to detect the impact of the differences in the clinical trials, the uncertainties remain. The committee recalled its conclusion about the generalisability of the regorafenib trials (see section\xa03.6). It understood that all the trials had similar designs, and that in all the trials the disease characteristics at baseline varied. But because of the different mechanisms of action, the clinical experts explained that effect modifiers may differ between treatments. They noted that there was no biological reason for the effect of trifluridine–tipiracil to differ in people who did or did not have biological treatments. But they advised that evidence from studies in Japan suggests there may be increased efficacy for people with an East Asian family background having fluorouracil (a chemotherapy), because of pharmacokinetic differences in this population. The clinical experts agreed that this may impact the efficacy of treatments and, because of the similar mechanism of action, explained that there may also be additional benefit when using trifluridine–tipiracil in this population. The committee concluded that the indirect treatment comparison was associated with uncertainty because of the heterogeneity between trial populations. It concluded that regorafenib is likely to provide similar benefits in terms of progression-free and overall survival compared to trifluridine–tipiracil.\n\n## Observational evidence\n\nBecause there were no head-to-head randomised controlled trials, the company and the EAG considered observational studies that directly compared regorafenib with trifluridine–tipiracil. Four of the 5 studies considered relevant supported the company's position of equal efficacy between regorafenib and trifluridine–tipiracil. But the study with the best balance in baseline characteristics (Nakashima 2020) did not. The study reported higher overall survival for people who had treatment with trifluridine–tipiracil compared with regorafenib (10.2\xa0months compared with 6.4\xa0months). The company noted that observational studies have a high risk of bias. The clinical expert also highlighted that the full details of the observational studies were not reported and the impact of this on the clinical effectiveness is uncertain. The committee agreed that the observational study had a high risk of bias. The committee was aware that the Nakashima (2020) study compared 4 groups. These were people who had: regorafenib only, trifluridine–tipiracil only, regorafenib then trifluridine–tipiracil, and trifluridine–tipiracil then regorafenib. The EAG reported results for people who only received regorafenib or trifluridine–tipiracil. The committee noted that this was likely to represent people with the poorest outcomes. In addition, clinical-effectiveness estimates for people who had both treatments would be prone to immortal time bias, because only people who lived long enough had both treatments. The committee concluded that given the difference in baseline characteristics inherent within the regorafenib and trifluridine–tipiracil trials, the observational study likely compounds the risk of bias. It preferred clinical-effectiveness estimates using the indirect treatment comparison.\n\n# Economic model\n\n## Company's modelling approach\n\nThe company submitted a 3‑state (progression-free, progressed disease and death) partitioned survival model to estimate the cost effectiveness of regorafenib. The model took the perspective of the NHS and Personal Social Services. It had a time horizon of 10\xa0years, a cycle length of 1\xa0week, and discounted costs and quality adjusted life-years (QALYs) at a rate of 3.5% per year. The committee concluded that the model structure was appropriate for decision making.\n\n## Modelling assumptions\n\nFor modelling overall survival, the company fit fully parametric survival models to pooled CORRECT and CONCUR data. For time-on-treatment and progression-free survival estimates for regorafenib and best supportive care, it used Kaplan–Meier data then applied parametric models from the point at which Kaplan–Meier data was unavailable. The company noted the maturity of its data and explained that this approach reflected clinical practice because assessment for disease progression occurred every 8\xa0weeks in the clinical trial, and in clinical practice. The EAG highlighted that the stepped nature of Kaplan–Meier curves could result in overfitting, so it preferred fully parametric models for the base case, which aligns with NICE's Decision Support Unit technical support document\xa014. The committee noted that both the Kaplan–Meier data and the fully parametric model appeared reasonable for extrapolating short-term survival. But it also noted that for modelling overall survival, the company and EAG had only fit parametric curves to the trial data, whereas safety data provided by the company in response to clarification request showed extended survival data for up to 5\xa0years. The committee preferred to use the long-term data. It concluded that generalised gamma was the best visual fit to the company's long-term overall survival data for regorafenib and best supportive care, and this should be used for the cost-effectiveness estimates.\n\n# Utility values\n\n## Source of utility values\n\nUtility values used in the company's model were obtained from pooling EQ‑5D‑3L results collected in CORRECT and CONCUR. In general, there was no difference in quality-of-life results between regorafenib and best supportive care. But the EAG had some concerns about the plausibility of pooled end-of-treatment results being used to derive the post-progression health state. The clinical trials considered for trifluridine–tipiracil did not report quality-of-life results. So, the company assumed pre-progression (0.72) and post-progression (0.59) utility values to be equal for trifluridine–tipiracil and regorafenib. The committee noted the large difference in pre- and post-progression utility. Clinical experts explained that management of disease progression on best supportive care was difficult and could have a severe effect on quality of life. The committee was aware that the utility values from CORRECT were applied for the NICE technology appraisal guidance on trifluridine–tipiracil and concluded that it was appropriate to use pooled estimates from the clinical trials.\n\n## Adverse events\n\nThe company explained that regorafenib has an alternate adverse event profile to trifluridine–tipiracil. Myelosuppression, which can cause dose delays, dose reductions or stopping of treatment, is less common with regorafenib, but diarrhoea and fatigue is more common. A network meta-analysis showed both treatments had a similar likelihood of stopping treatment because of adverse events (odds ratio 1.10, 95% confidence interval 0.53 to 2.24) and similar grade\xa03 and\xa04 (severe and life-threatening) adverse events (odds ratio 0.90, 95% confidence interval 0.55 to 1.47). But regorafenib showed a higher likelihood of all treatment-emergent adverse events (odds ratio 1.94, 95% confidence interval 1.20 to 3.17), that is, including grade\xa01 and\xa02 (mild and moderate) adverse events. Only grade\xa03 and\xa04 adverse events, seen in over 2% of people in the trial, were captured in the company's economic model. Adverse event results from the network meta-analysis were not captured. The company noted that this was in line with previous modelling experience. The clinical experts explained grade\xa02 adverse events, by definition, have an impact on activities of daily living. But less severe adverse events can typically be managed in the short term. They explained that adverse events may not happen independently, and some may not be symptomatic for patients. This means that although a single grade\xa03 event may be counted as severe, multiple grade\xa01 and\xa02 events may have a greater impact on their quality of life. The company presented a scenario analysis which included grade\xa01 and\xa02 adverse events, applying a fixed cost of £5 per adverse event and a disutility of 0.01, but this had negligible impact on the cost-effectiveness estimates. The committee concluded that grade\xa01 and\xa02 adverse events should be included in the economic model.\n\n# Costs\n\n## Relative dose intensity\n\nThe company modelled relative dose intensity (RDI) differently for regorafenib than for trifluridine–tipiracil. RDI for regorafenib was based on the mean dose used in CORRECT and CONCUR. For trifluridine–tipiracil, data from NICE's technology appraisal on trifluridine–tipiracil was used to model cycle delay and dose reduction separately. The company noted that this approach is similar to how adverse events would be managed in clinical practice, that is, regorafenib would tend to be managed by dose reduction whereas trifluridine–tipiracil would be managed by dose delay. The clinical experts noted that both dose delay and dose reduction are used to manage adverse events in clinical practice. One clinical expert explained that in their NHS trust, granulocyte colony-stimulating factor (GCSF) can be used pre-emptively to manage adverse events. This can prevent dose delay or dose reduction for those on trifluridine–tipiracil. But the NHS England Cancer Drugs Fund lead explained that not all patients have equal access to GCSF. The committee agreed and noted that there would be cost implications associated with GCSF, if it were used. The EAG highlighted that the mean dose from CORRECT and CONCUR includes both dose delay and dose reduction. It also noted that real-world evidence (Nakashima 2020) directly comparing regorafenib and trifluridine–tipiracil suggests a similar dose reduction for both treatments (54% and 48%, respectively). Based on this, the EAG's preference was to apply equal RDI for both treatments. The committee concluded that both dose delay and dose reduction should be used for estimating the RDI, and preferred the EAG's approach of applying equal RDI to trifluridine–tipiracil and regorafenib.\n\n## Post-progression treatment costs\n\nPost-progression treatment costs were not included in the company's base case. The company stated that advice from clinical experts suggests fewer than 10% of people having regorafenib or trifluridine–tipiracil would have post-progression treatment. But 26% of people who had regorafenib in CORRECT, and 31% in CONCUR, had post-progression treatment. The committee recalled that around 30% of people would be offered post-progression treatment after regorafenib or trifluridine–tipiracil has failed (see section\xa03.4). The company did a scenario analysis in which the post-progression treatment cost reported in NICE's technology appraisal on trifluridine–tipiracil was inflated to 2021 values (£1,633.18) and applied as a single cost to people having either regorafenib or trifluridine–tipiracil. The committee heard that the scenario analysis showed post-progression treatment was not a key driver of the cost-effectiveness estimates. But the committee concluded that subsequent treatment should be included in the economic model. It recalled that both trifluridine–tipiracil and regorafenib could be used in sequence (that is, trifluridine–tipiracil after regorafenib has been used, and vice versa). But it heard from the clinical experts that no difference in efficacy would be expected if either trifluridine–tipiracil or regorafenib were used at fourth line. This is because of the different mechanisms of action of the 2 technologies, and that those well enough to benefit from subsequent therapy are similar to the populations in the indirect treatment comparison. Clinical experts noted that maintained efficacy at later lines is also supported by observational data. The committee concluded that subsequent treatments should be included in the cost-effectiveness modelling, to reflect the clinical trials and clinical expert opinion. In the absence of additional evidence, it concluded that there is likely to be no difference in cost effectiveness if trifluridine–tipiracil is used as a further active treatment (that is, at fourth line) instead of best supportive care. This would likely reflect the evidence already considered in the NICE technology appraisal guidance on trifluridine–tipiracil.\n\n# Severity\n\n## General population QALYs\n\nNICE's health technology evaluations manual notes that when considering overall benefits, the committee can consider decision-making modifiers. In its submission, the company provided evidence that mCRC that has been previously treated (including with fluoropyrimidine-based chemotherapy, anti‑VEGF, and anti‑EGFR treatments) or which is not suitable for treatment with the listed treatment options, is a severe condition. The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company provided absolute and proportional QALY shortfall estimates in line with NICE's health technology evaluations manual. The company calculated the QALYs of people without the condition over their remaining lifetime. It used general population life expectancy estimates based on 2017 to 2019 national life tables, and utility estimates from Health Survey for England 2017 and 2018 data. These were matched to the same age and sex distribution as those with the condition, based on the baseline characteristics of people in the randomised controlled trials. The company and EAG agreed that the population in the trial had a mean age of 60, and 56% were women. The committee agreed that the methods used by the company and the EAG to estimate the remaining lifetime QALYs for the general population and for people living with the condition were appropriate.\n\n## Estimating QALY shortfall\n\nQALY shortfall is calculated by estimating the difference between the number of QALYs generated for an individual in the general population and an individual who has metastatic colorectal cancer that has progressed after first-line chemotherapy or biological treatments, and who is well enough for further active treatment. The committee recalled that both trifluridine–tipiracil and best supportive care are potential comparators for regorafenib (see section\xa03.4), so the QALY shortfall when using both treatments would need to be considered. The company used its economic model to estimate the expected remaining lifetime QALYs for both comparators. This meant pooled CONCUR and CORRECT data was used. To estimate survival and progression through the model for people who had trifluridine–tipiracil, a hazard ratio from the indirect treatment comparison was applied to the survival curves of regorafenib. The committee noted that the QALY shortfall estimates for trifluridine–tipiracil and best supportive care were similar and felt this similarity might lack face validity (that is, the results are unexpected). The trials underpinning the model had their primary completion between 2011 and 2013 (see section\xa03.5). The clinical experts advised that there had been advancements in the management and treatment of advanced colorectal cancer in the decade since these trials took place. Clinical experts also explained that the COVID‑19 pandemic had impacted outcomes because of delays in diagnosis. They noted that there was likely to be real-world evidence available for people who have active cancer treatments in the NHS from the national cancer registry or Systemic Anti-Cancer Therapy (SACT) dataset, which would better reflect clinical practice. The committee agreed that using real-world evidence as a reference group would have more accurately reflected the QALY estimates. The committee would have preferred using a real-world dataset to derive the absolute event estimates for trifluridine–tipiracil. It would also have preferred using the hazard ratio from the network meta-analysis to estimate the relative effect for survival for those who had best supportive care.\n\n## QALY weighting\n\nThe committee considered 2 measures of QALY shortfall: absolute QALY shortfall and proportional QALY shortfall. Absolute QALY shortfall is the total health lost because of the condition. That is, the difference between the expected future health of people living without the condition and the future health which is lost by people living with a condition over their remaining lifetimes. Proportional QALY shortfall represents the fraction of health lost because of the condition. That is, the proportion of future health which is lost by people living with the condition compared with the expected future health of people living without the condition. Both the company's and EAG's estimates for proportional shortfall were above 0.95 for trifluridine–tipiracil and best supportive care, so the company considered that the 1.7 QALY weight should apply. The exact QALYs, and the absolute and proportional QALY shortfalls are confidential so cannot be reported here. The committee considered that there was uncertainty around the data used to estimate the QALYs for people living with the condition who had trifluridine–tipiracil. It would have preferred to see estimates using real-world data. The committee noted that the modifier for disease severity was not convincingly met for this population, and without additional data the committee would not be able to apply the 1.7 weighting. The committee then considered the estimates for people who would have best supportive care. Although it would have preferred to see QALY shortfall based on real-world data, it understood that people who had best supportive care in clinical practice would likely be less well, and have a worse prognosis, suggesting the estimates had greater face validity. The committee noted that all sensitivity analyses included estimates for a proportional shortfall above 0.95. The committee concluded that the modifier for disease severity for those who would have best supportive care was met and a weighting of 1.7 should be applied to the health benefits for regorafenib compared with best supportive care.\n\n# Cost-effectiveness estimates\n\n## Company and EAG cost-effectiveness estimates\n\nThe company's probabilistic incremental cost-effectiveness ratio (ICER) for regorafenib compared with trifluridine–tipiracil (including the commercial discount for regorafenib) is within what NICE normally considers an acceptable use of NHS resources, regardless of what severity weighting is applied. The committee recalled that a 1.7 weighting should be applied to health gains in the comparison with best supportive care. When the high severity weighting was applied, the company's cost-effectiveness estimates of regorafenib compared with best supportive care were also within the range NICE considers a cost-effective use of NHS resources. But the company's base case did not reflect the committee's preferred assumptions, which were:\n\nfully parametric survival models for overall survival estimates for regorafenib and best supportive care (generalised gamma)\n\nfully parametric survival models for progression-free survival estimates for regorafenib and best supportive care (log-logistic)\n\na fully parametric model for regorafenib time-on-treatment estimates (log-logistic)\n\nan equal RDI for regorafenib and trifluridine–tipiracil\n\ninclusion of grade\xa01 and\xa02 adverse events\n\nincluding subsequent treatments. The committee concluded that applying all its preferred assumptions impacted the cost-effectiveness estimates for regorafenib compared with best supportive care but had negligible impact on the estimates for regorafenib compared with trifluridine–tipiracil.\n\n# Other factors\n\n## Equality issues\n\nThe committee heard that no equalities concerns were raised by the stakeholders and did not consider any equality issues to have an impact on its decision making about treatment of mCRC with regorafenib.\n\n# Conclusion\n\n## Recommendation\n\nThe committee concluded that regorafenib was likely to be cost effective compared with both trifluridine–tipiracil and best supportive care. But there remain some uncertainties in the cost-effectiveness estimates of regorafenib compared with best supportive care. The committee considered input from clinical experts, which suggested that treatment sequencing (that is, which treatment to use first, either regorafenib or trifluridine–tipiracil) would be based on individual preference and potential for response. It noted that clinicians would also consider toxicities from previous lines of treatment as well as previous treatment response and patient choice. So, the committee concluded that having regorafenib as an additional treatment option is appropriate, because this allows clinicians to make the most appropriate decision for each patient. So, regorafenib is recommended for previously treated metastatic colorectal cancer."}	https://www.nice.org.uk/guidance/ta866	Evidence-based recommendations on regorafenib (Stivarga) for previously treated metastatic colorectal cancer in adults.
0f49113083435021880b2b55069212de7c3cb640	nice	Barrett's oesophagus and stage 1 oesophageal adenocarcinoma: monitoring and management	Barrett's oesophagus and stage 1 oesophageal adenocarcinoma: monitoring and management This guideline covers monitoring, treatment and follow-up for people aged 18 and over with Barrett’s oesophagus and stage 1 oesophageal adenocarcinoma. It includes advice on endoscopic and non-endoscopic techniques. It aims to improve outcomes by ensuring the most effective investigations and treatments are used. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The stages of cancer/oesophageal adenocarcinoma referred to in this guideline are based on the 8th edition of the Union for International Cancer Control (UICC) tumour node metastasis (TNM) classification of malignant tumours. # Information and support Offer a clinical consultation to people with newly diagnosed Barrett's oesophagus to discuss risk of cancer, endoscopic surveillance plans and symptom control. Give the person verbal and written information about their diagnosis, available treatments and patient support groups. Give them time to consider this information when making decisions about their care. After each surveillance procedure, provide the person with an endoscopy report that includes a lay summary of the findings and a reference to ongoing symptom control. Follow the recommendations on communication and information in the NICE guidelines on patient experience in adult NHS services and shared decision making. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support . Full details of the evidence and the committee's discussion are in evidence review A: patient information and support. Loading. Please wait. # Pharmacological interventions ## Symptom control Follow the recommendations on interventions for gastro-oesophageal reflux disease (GORD) in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults. ## Preventing disease progression Do not offer aspirin to people with Barrett's oesophagus to prevent progression to oesophageal dysplasia and cancer. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pharmacological interventions . Full details of the evidence and the committee's discussion are in evidence review B: pharmacological interventions to reduce progression to dysplasia or cancer. Loading. Please wait. # Endoscopic surveillance Discuss the benefits and risks of endoscopic surveillance with the person diagnosed with Barrett's oesophagus. Offer high resolution white light endoscopy with Seattle biopsy protocol for surveillance of Barrett's oesophagus. Take into account the health of the person and ensure the benefits of surveillance outweigh the risks. ## Frequency of endoscopic surveillance Offer high resolution white light endoscopic surveillance with Seattle protocol biopsies: every 2 to 3 years to people with long-segment (3 cm or longer) Barrett's oesophagus every 3 to 5 years to people with short-segment (less than 3 cm) Barrett's oesophagus with intestinal metaplasia. Assess a person's risk of cancer based on their age, sex, family history of oesophageal cancer and smoking history and tailor the frequency of endoscopic surveillance accordingly, within the intervals given in recommendation 1.3.3. Do not offer endoscopic surveillance to people with short-segment (less than 3 cm) Barrett's oesophagus without intestinal metaplasia provided the diagnosis has been confirmed at 2 endoscopies. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on endoscopic surveillance . Full details of the evidence and the committee's discussion are in: evidence reviews C: endoscopic surveillance using white light endoscopy, D: diagnostic accuracy of endoscopic surveillance techniques, E: non-endoscopic surveillance techniques and F: frequency and duration of endoscopic surveillance. Loading. Please wait. # Staging for suspected stage 1 oesophageal adenocarcinoma Offer endoscopic resection for staging, to people with suspected stage 1 oesophageal adenocarcinoma. Do not use CT before endoscopic resection for staging suspected T1 oesophageal adenocarcinoma. Do not use endoscopic ultrasonography (EUS) before endoscopic resection for staging suspected T1a oesophageal adenocarcinoma. Consider EUS for nodal staging, for people with suspected T1b oesophageal adenocarcinoma based on endoscopic appearances or diagnosed with T1b oesophageal adenocarcinoma based on histological examination of endoscopic resection specimens. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on staging for suspected stage 1 oesophageal adenocarcinoma . Full details of the evidence and the committee's discussion are in evidence review G: endoscopic and radiological staging techniques. Loading. Please wait. # Managing Barrett's oesophagus with dysplasia Offer endoscopic resection of visible oesophageal lesions as first-line treatment to people with high-grade dysplasia. Offer endoscopic ablation of any residual Barrett's oesophagus to people with high-grade dysplasia after treatment with endoscopic resection. Offer radiofrequency ablation to people with low-grade oesophageal dysplasia diagnosed from biopsies taken at 2 separate endoscopies. Two gastrointestinal pathologists should confirm the histological diagnosis. Consider endoscopic surveillance at 6 monthly intervals with dose optimisation of acid-suppressant medication for people diagnosed with indefinite dysplasia of the oesophagus. Offer endoscopic follow-up to people who have received endoscopic treatment for Barrett's oesophagus with dysplasia. Follow the NICE interventional procedures guidance on endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia and epithelial radiofrequency ablation for Barrett's oesophagus. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing Barrett's oesophagus with dysplasia . Full details of the evidence and the committee's discussion are in evidence reviews H: endoscopic treatment (high-grade dysplasia and stage 1 adenocarcinoma), I: endoscopic treatment (low-grade dysplasia and indefinite dysplasia) and J: endoscopic and radiological follow-up after treatment. Loading. Please wait. # Managing stage 1 oesophageal adenocarcinoma Offer a clinical consultation to people with stage 1 oesophageal adenocarcinoma to discuss and evaluate the suitability of treatment options, including endoscopic resection or oesophagectomy. Offer endoscopic resection as first-line treatment to people with T1a oesophageal adenocarcinoma. Offer endoscopic ablation of any residual Barrett's oesophagus to people with T1a oesophageal adenocarcinoma after treatment with endoscopic resection. Offer endoscopic follow-up to people who have received endoscopic treatment for stage 1 oesophageal adenocarcinoma. Offer oesophagectomy to people with T1b oesophageal adenocarcinoma who are fit for surgery and at high risk of cancer progression. For example, where there is: incomplete endoscopic resection evidence of lymphovascular invasion or deep submucosal invasion (more than 500 micron) on histological examination of endoscopic resection specimens. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing stage 1 oesophageal adenocarcinoma . Full details of the evidence and the committee's discussion are in evidence reviews J: endoscopic and radiological follow-up after treatment and K: oesophagectomy versus endoscopic treatment. Loading. Please wait. # Non-surgical treatment for T1b oesophageal adenocarcinoma Consider radiotherapy (alone or in combination with chemotherapy) for people with T1b oesophageal adenocarcinoma at high risk of cancer progression (for example, incomplete endoscopic resection, or evidence of lymphovascular invasion or deep submucosal invasion (more than 500 micron) on histological examination of endoscopic resection specimens) and who are unfit for oesophagectomy. Offer endoscopic follow-up to people who have received radiotherapy for T1b oesophageal adenocarcinoma. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on non-surgical treatment for T1b oesophageal adenocarcinoma . Full details of the evidence and the committee's discussion are in evidence reviews L: non-surgical treatment for T1b oesophageal adenocarcinoma and J: endoscopic and radiological follow-up after treatment. Loading. Please wait. # Anti-reflux surgery Do not offer anti-reflux surgery to people with Barrett's oesophagus to prevent progression to dysplasia or cancer. Follow the recommendations on laparoscopic fundoplication for gastro-oesophageal reflux disease in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anti-reflux surgery . Full details of the evidence and the committee's discussion are in evidence reviews M: anti-reflux surgery to induce remission of disease or prevent recurrence and N: anti-reflux surgery to reduce progression to dysplasia or cancer. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in this guideline. ## Barrett's oesophagus An oesophagus in which any portion of the normal distal squamous epithelial lining has been replaced by metaplastic columnar epithelium, which is clearly visible endoscopically (≥1 cm) above the gastro-oesophageal junction and confirmed histopathologically from oesophageal biopsies. ## Seattle biopsy protocol Entails four-quadrant random biopsies for every 2 cm of Barrett's oesophagus in addition to targeted biopsies on macroscopically visible lesions. ## Stage 1 adenocarcinoma Any oesophageal adenocarcinoma with T1 stage and no lymph node (N0) or distant metastasis (M0).# Recommendations for research The guideline committee has made the following recommendations for research. # Diagnostic accuracy of endoscopic surveillance What is the diagnostic accuracy of different endoscopic surveillance techniques including high resolution endoscopy and chromoendoscopy for use in adults? For a short explanation of why the committee made this recommendation for research, see the rationale section on endoscopic surveillance . Full details of the evidence and the committee's discussion are in evidence review F: frequency and duration of endoscopic surveillance techniques. Loading. Please wait. # Frequency and duration of endoscopic surveillance What is the usefulness of clinical and molecular biomarkers to inform the optimal frequency and duration of endoscopic surveillance for adults with Barrett's oesophagus? For a short explanation of why the committee made this recommendation for research, see the rationale section on endoscopic surveillance . Full details of the evidence and the committee's discussion are in evidence review F: frequency and duration of endoscopic surveillance techniques. Loading. Please wait. # Oesophagectomy What is the effectiveness of endoscopic resection with or without adjuvant chemoradiotherapy and oesophagectomy for adults with T1b oesophageal adenocarcinoma? For a short explanation of why the committee made this recommendation for research, see the rationale section on managing stage 1 oesophageal adenocarcinoma . Full details of the evidence and the committee's discussion are in evidence review K: oesophagectomy versus endoscopy treatment. Loading. Please wait. # Endoscopic treatments For adults with Barrett's oesophagus with dysplasia, what is the effectiveness of different endoscopic ablation techniques alone or in combination with endoscopic resection? For a short explanation of why the committee made this recommendation for research, see the rationale section on managing Barrett's oesophagus with dysplasia . Full details of the evidence and the committee's discussion are in evidence review H: endoscopic treatment (high-grade dysplasia and stage 1 adenocarcinoma). Loading. Please wait. For adults with stage 1 oesophageal adenocarcinoma, what is the effectiveness of different endoscopic ablation techniques alone or in combination with endoscopic resection? For a short explanation of why the committee made this recommendation for research, see the rationale section on managing stage 1 oesophageal adenocarcinoma . Full details of the evidence and the committee's discussion are in evidence review H: endoscopic treatment (high-grade dysplasia and stage 1 adenocarcinoma). Loading. Please wait. # Frequency and duration of endoscopic follow-up What is the optimal frequency and duration of endoscopic follow-up for patients who have received endoscopic treatment for Barrett's oesophagus with dysplasia? For a short explanation of why the committee made this recommendation for research, see the rationale section on managing Barrett's oesophagus with dysplasia . Full details of the evidence and the committee's discussion are in evidence review J: endoscopic and radiological follow-up after treatment. Loading. Please wait. What is the optimal frequency and duration of endoscopic follow-up for patients who have received endoscopic treatment for stage 1 oesophageal adenocarcinoma? For a short explanation of why the committee made this recommendation for research, see the rationale section on managing stage 1 oesophageal adenocarcinoma . Full details of the evidence and the committee's discussion are in evidence review J: endoscopic and radiological follow-up after treatment. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Information and support Recommendations 1.1.1 to 1.1.4 ## Why the committee made the recommendations Qualitative evidence highlighted knowledge gaps and uncertainties at the time of diagnosis of Barrett's oesophagus. The committee emphasised this reflected their experience with people they see in clinical practice. They agreed a clinical consultation should be offered following diagnosis to provide information and support on the risk of progression to cancer and symptom control, and general information about endoscopic surveillance. Providing information both verbally and in written form is helpful as information can be difficult to grasp at a single consultation and written information will enable people to revisit the information when needed. This should include general information about the diagnosis of Barrett's oesophagus, available treatments and any patient support groups. The use of complex medical terminology limits people's ability to understand information. The committee agreed it was important that each endoscopy report includes a lay summary of the findings and that this is given to the person. ## How the recommendations might affect practice The recommendations are in line with current practice and therefore are unlikely to have a substantial resource impact. Return to recommendations # Pharmacological interventions Recommendations 1.2.1 and 1.2.2 ## Why the committee made the recommendations Limited evidence showed that proton pump inhibitors (PPIs) had no clinically important effect on outcomes (including all-cause mortality, progression to any grade of dysplasia or cancer, and serious adverse events). The committee agreed there was insufficient evidence to recommend PPIs to prevent progression to oesophageal dysplasia and cancer and decided not to make a recommendation on this. The committee agreed there was insufficient evidence to recommend aspirin to prevent progression to oesophageal dysplasia and cancer and decided to make a do not offer recommendation. Evidence showed that participants taking aspirin were more likely to get adverse events than those who did not, but the difference was small and not conclusive. The committee noted this was in line with their clinical experience and knowledge that bleeding is more likely to be seen in people treated with aspirin. They agreed that the inconclusive results could be attributed to a protective effect from PPIs taken by people in both the aspirin and no aspirin study groups. Although the committee did not look for evidence on medication use for symptom control, they agreed that acid-suppressant medication such as PPIs are highly effective and widely used in current practice to control symptoms of gastro-oesophageal reflux disease in people with Barrett's oesophagus. They decided it was useful to provide a link to the relevant section of the NICE guideline on gastro-oesophageal reflux disease. ## How the recommendations might affect practice Aspirin is not currently used to prevent progression to oesophageal dysplasia and cancer. Therefore, the recommendations are not expected to result in a change in current practice or to have a resource impact. Return to recommendations # Endoscopic surveillance Recommendations 1.3.1 to 1.3.5 ## Why the committee made the recommendations Evidence showed there was a 30% reduction in mortality for people who received endoscopic surveillance compared to those that did not. Based on this and their clinical experience, the committee agreed it should be offered to people with Barrett's oesophagus provided the person's general health is adequate, and the benefits of surveillance outweigh the risks. The committee noted this is the current standard of care for endoscopic surveillance for Barrett's oesophagus. The committee agreed that the risk of complications of endoscopic surveillance should be considered on an individual basis because the frequency and consequences of complications will vary depending on a range of factors, including age, fraility and medical comorbidities. It was agreed that possible complications should be discussed with the person with Barrett's oesophagus. Evidence for electronic and conventional chromoendoscopy techniques (including narrow band imaging, acetic acid, methylene blue) as well as endoscopic brushing was obtained from people with dysplasia and early-stage cancer. This means that these techniques have not been validated in an unselected population with Barrett's oesophagus undergoing standard endoscopic surveillance and therefore could not be recommended. A recommendation for research was made to assess the effectiveness of these techniques for surveillance of Barrett's oesophagus. There was no evidence to support an optimal frequency for endoscopic surveillance as this will differ according to individual risk factors. However, the committee agreed to make a recommendation for frequency of surveillance based on length of segment, in line with the British Society of Gastroenterology (BSG) guidelines and current practice in the UK. The committee agreed that the frequency of surveillance should be tailored to each person based on a clinical assessment of their risk of cancer, with length of segment, being the factor most closely linked to risk of cancer, but age, sex, family history of oesophageal cancer and smoking also being important. In line with current practice, there was consensus that people with short-segment (less than 3 cm) Barrett's oesophagus without intestinal metaplasia (confirmed at 2 endoscopies) should not be offered endoscopic surveillance because the risk of disease progression is low in this population and there are risks associated with endoscopic surveillance. There was no evidence on the duration of endoscopic surveillance and the committee agreed not to make a recommendation on this. The committee emphasised that evidence of clinical and molecular biomarkers associated with a greater risk of progression to dysplasia or cancer could inform setting appropriate intervals for endoscopic surveillance and agreed to make a recommendation for research on biomarkers. There was evidence of benefit of using cytosponge to diagnose dysplasia and cancer but the quality was not sufficient to support its use at present. Balloon brushing is an old technique that is not currently used in clinical practice. Limited evidence on cytology obtained from balloon brushing showed it could detect oesophageal dysplasia and adenocarcinoma, but the committee agreed there was insufficient evidence to recommend its use in clinical practice. There was a lack of evidence on other non-endoscopic surveillance techniques and based on their clinical experience, the committee agreed it was not appropriate to recommend them. ## How the recommendations might affect practice Endoscopic surveillance is widely used for monitoring people with Barrett's oesophagus. Adherence to the biopsy protocols requires additional procedure time beyond that of a standard endoscopy, but many services have already increased the time allocation for Barrett's surveillance and overall resource impact is not expected to be significant. Back to recommendations # Staging for suspected stage 1 oesophageal adenocarcinoma Recommendations 1.4.1 to 1.4.4 ## Why the committee made the recommendations In the absence of evidence on endoscopic staging techniques, the committee drew upon their clinical experience to inform decision making. They agreed that endoscopic resection should be offered to people with suspected stage 1 oesophageal adenocarcinoma as it is the most accurate staging technique and is the gold standard in current practice as recommended by the British Society of Gastroenterology (BSG) guidelines. There are 2 techniques for resection of suspected stage 1 oesophageal adenocarcinoma: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). The evidence did not show superiority of 1 technique over the other so the recommendation does not specify which to use. The committee noted, based on their clinical experience, that ESD may offer an advantage in individuals with Barrett's oesophagus-related neoplasia (lesions larger than 15 mm, poorly lifting tumours and lesions at risk for submucosal invasion) but there was no reason to select it routinely over EMR for small slightly elevated lesions because ESD is a complex procedure and is associated with more complications. Limited evidence indicated poor diagnostic accuracy of CT as a staging technique for early stage oesophageal adenocarcinoma because the resolution of CT is inadequate in detecting very small tumours and small volume lymph node metastasis. Therefore, there was consensus that CT should not be used before endoscopic resection for staging suspected T1 oesophageal adenocarcinoma. Limited evidence on the mini-probe endoscopic ultrasonograph (mini-probe EUS) and the conventional radial endoscopic ultrasonograph (crEUS) showed they cannot distinguish well between T1a and T1b tumours but can detect lymph node metastasis with greater accuracy. Based on the evidence and their clinical experience, the committee agreed that EUS should not be used before endoscopic resection for staging suspected T1a oesophageal adenocarcinoma, as this carries a negligible risk of lymph node metastasis. EUS should be considered when an oesophageal lesion is suspected to be T1b cancer based on endoscopic appearances, for example sessile lesions with significant luminal component (Paris 0-Is) or depressed lesions (Paris 0-IIc). It should also be considered for people with confirmed T1b oesophageal adenocarcinoma, who have a significant risk of lymph node metastasis and may benefit from additional oncological treatment, such as radiotherapy alone or in combination with chemotherapy. ## How the recommendations might affect practice These recommendations are in line with current practice and therefore will not have a resource impact. Back to recommendations # Managing Barrett's oesophagus with dysplasia Recommendations 1.5.1 to 1.5.6 ## Why the committee made the recommendations The evidence showed that endoscopic treatment using a combination of endoscopic resection and endoscopic ablation or endoscopic ablation alone is effective to treat people with high-grade dysplasia and prevent progression to adenocarcinoma. Based on clinical experience the committee recommended that high-grade dysplasia be endoscopically resected, when oesophageal lesions are visible at endoscopy, and the residual Barrett's oesophagus be treated with endoscopic ablation. There are 2 techniques for resection of dysplastic lesions in Barrett's oesophagus: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). There is no evidence of superiority of 1 technique over the other so the recommendation does not specify which to use. The evidence indicated that both radiofrequency ablation (RFA) and argon plasma coagulation (APC) are effective in reducing the risk of recurring oesophageal lesions in people who have received an endoscopic resection for high-grade dysplasia. However, the committee noted that for very long segment Barrett's oesophagus RFA might be more practical than APC, which has a significantly smaller ablation catheter than RFA. Given that there is no evidence of superiority of one ablation technique over the other, the committee agreed further research was needed to determine the most effective endoscopic ablation technique to use and made a recommendation for research. Evidence showed that RFA in people with confirmed low-grade oesophageal dysplasia protects from progression to high-grade dysplasia or cancer. The committee noted this was in line with their experience and that low-grade dysplasia is primarily managed by RFA in current practice. Based on their clinical experience, the committee emphasised that for RFA to be offered, evidence of low-grade dysplasia from biopsies from 2 separate endoscopies and confirmation of the diagnosis by 2 gastrointestinal pathologists should be present. They noted this was in line with current practice where RFA takes place in specialist centres by endoscopists with appropriate experience and would not be considered in cases where there is evidence of low-grade oesophageal dysplasia from biopsies from only 1 endoscopy or where there is no confirmation by a second gastrointestinal pathologist. There was no evidence to support use of other ablation techniques for treating low-grade dysplasia. In the absence of clinical evidence on people with indefinite dysplasia of the oesophagus, the committee drew on their clinical experience to make a recommendation for this population. They emphasised that the risk of progression to high-grade oesophageal dysplasia or cancer is around 3 to 5 times higher than the risk in the non-dysplastic population and therefore endoscopic surveillance every 6 months would be appropriate. The committee also noted, based on their clinical experience, that indefinite dysplasia is often linked to excessive inflammation of the oesophagus, therefore optimisation of acid-suppressant medication is appropriate. There was no evidence comparing different strategies of endoscopic follow-up in people with Barrett's oesophagus with dysplasia and the committee drew upon their clinical experience to make a recommendation. They agreed that endoscopic follow-up is needed for people who have received endoscopic treatment for Barrett's oesophagus with dysplasia as the likelihood of recurrence is high. The committee noted this was in line with current practice. Based on their clinical experience, the committee agreed that the frequency of follow-up should be based on the likelihood of recurrence. In the absence of evidence, the committee decided to make a recommendation for research to assess the optimal frequency and duration of endoscopic follow-up for people who have received endoscopic treatment for Barrett's oesophagus with dysplasia ## How the recommendations might affect practice These recommendations are in line with current practice and therefore will not have a resource impact. Back to recommendations # Managing stage 1 oesophageal adenocarcinoma Recommendations 1.6.1 to 1.6.5 ## Why the committee made the recommendations The quality of the evidence was limited but reflected the committee's clinical experience that endoscopic resection and oesophagectomy are equally effective for treating stage 1 adenocarcinoma, and oesophagectomy is associated with a higher incidence of serious adverse events. There was a lack of evidence on how the 2 treatments affect quality of life so the committee drew on their own experience to consider this. As part of standard practice a clinical consultation would be offered to the person to discuss the treatment options and the advantages and disadvantages of both approaches. Endoscopic resection is less invasive and has fewer complications than oesophagectomy. The committee agreed that even after successful endoscopic treatment there remains a risk of recurrence of Barrett's oesophagus and oesophageal neoplasia. Therefore, endoscopic treatment comes with a greater need for ongoing endoscopic surveillance, which could lead to anxiety about recurrence and possibly impacts on quality of life. This was reinforced by a patient committee member. Despite this, the committee agreed endoscopic resection is still more likely to result in better quality of life post-treatment than oesophagectomy. Therefore, it should be offered as first-line treatment to people with T1a adenocarcinoma. There was evidence supporting the effectiveness of using endoscopic resection followed by endoscopic ablation to treat people with T1a adenocarcinoma of the oesophagus. The evidence indicated that both radiofrequency ablation (RFA) and argon plasma coagulation (APC) are effective in reducing the risk of recurring oesophageal lesions in people who have received an endoscopic resection for T1a adenocarcinoma. However, the committee noted that for very long segment of Barrett's oesophagus RFA might be more practical than APC, which has a significantly smaller ablation catheter than RFA. Given that there is no evidence of superiority of one technique over the other, the committee agreed further research was needed to determine the most effective endoscopic ablation technique to use and made a recommendation for research. The lack of specific evidence for people with T1b oesophageal adenocarcinoma was a concern for the committee who agreed this is where there is the most uncertainty over appropriate treatment. In the absence of evidence, the committee decided to make a recommendation to offer oesophagectomy rather than endoscopic resection for people with T1b oesophageal adenocarcinoma at high risk of cancer progression. This was based on their clinical experience that there is a greater risk of local recurrence in cases of incomplete endoscopic resection and a high risk of lymph node metastasis in cases with deep submucosal invasion (more than 500 micron) and lymphovascular invasion. They decided not to make a recommendation for people with T1b at low risk of cancer progression as it was less clear which treatment option would be best but made a recommendation for research to determine the effectiveness of endoscopic resection with or without adjuvant chemoradiotherapy and oesophagectomy for adults with T1b oesophageal adenocarcinoma. In the absence of evidence comparing endoscopic and radiological follow-up with standard endoscopy in people with stage 1 oesophageal adenocarcinoma, the committee drew upon their clinical experience to make a recommendation. They agreed that endoscopic follow-up is needed for people who have received endoscopic treatment for stage 1 oesophageal adenocarcinoma as the likelihood of recurrence is high. The committee noted this was in line with current practice. Based on their clinical experience, the committee agreed that the frequency of follow-up should be based on the likelihood of recurrence. In the absence of evidence, the committee decided to make a recommendation for research to assess the optimal frequency and duration of endoscopic follow-up for people who have received endoscopic treatment for stage 1 oesophageal adenocarcinoma. ## How the recommendations might affect practice The current recommendations are in line with current practice and therefore will not have a resource impact. Back to recommendations # Non-surgical treatment for T1b oesophageal adenocarcinoma Recommendations 1.7.1 and 1.7.2 ## Why the committee made the recommendations In the absence of evidence to guide decision making, the committee drew upon their clinical experience to make a recommendation on non-surgical treatment for T1b oesophageal adenocarcinoma. Using radiotherapy alone or in combination with chemotherapy to treat oesophageal adenocarcinoma is current practice. The committee agreed that radiotherapy alone or in combination with chemotherapy would be appropriate for people with T1b oesophageal adenocarcinoma at high risk of cancer progression as it is likely to reduce the risk of recurrence. They noted that chemotherapy alone is not a definitive treatment. The committee acknowledged the absence of evidence for endoscopic and radiological follow-up in people with stage 1 oesophageal adenocarcinoma but agreed it would be usual practice to offer endoscopic follow-up to people who have received radiotherapy treatment for T1b oesophageal adenocarcinoma as the risk of cancer progression is high. The committee made a consensus recommendation based on their clinical experience. ## How the recommendations might affect practice The current recommendations are in line with current practice and therefore are unlikely to have a significant resource impact. Back to recommendations # Anti-reflux surgery Recommendations 1.8.1 and 1.8.2 ## Why the committee made the recommendations In the absence of evidence of a clinical benefit of anti-reflux surgery to reduce progression to dysplasia or cancer, the committee agreed it should not be recommended for this reason. Although the committee did not look for evidence on medication use for symptom control, they agreed that anti-reflux surgery can provide an alternative option for people who are intolerant to or unwilling to take acid-suppressant medication such as proton pump inhibitors (PPIs) and should be considered for this population. They decided it was useful to provide a link to the relevant recommendation in the NICE guideline on gastro-oesophageal reflux disease. In the absence of evidence, the committee agreed not to make a recommendation for anti-reflux surgery to induce remission or prevent recurrence in people with stage 1 adenocarcinoma. People who fail to respond to radiofrequency ablation (RFA) are sometimes referred for anti-reflux surgery. However, the committee noted that in such cases other ablation therapies such as argon plasma coagulation (APC) could be considered instead of anti-reflux surgery. ## How the recommendations might affect practice The current recommendations are in line with current practice and therefore will not have a resource impact. Back to recommendations# Context Barrett's oesophagus is a condition in which squamous cells at the lower end of the lining of the oesophagus are replaced with columnar cells. It can be a precursor to oesophageal adenocarcinoma. Barrett's oesophagus is more common in older age groups, men, people who are white and people who are overweight. The risk of progression to cancer is low. Fewer than 1% of people with Barrett's oesophagus develop oesophageal adenocarcinoma each year. However, oesophageal adenocarcinoma has a poor prognosis because of late presentation, and its incidence is increasing possibly related to more people being overweight or obese. Effective treatments for Barrett's oesophagus could reduce the number of people presenting late with adenocarcinoma and improve overall outcomes. NICE published a guideline on ablative therapy for Barrett's oesophagus (CG106) in 2010, which included people with high-grade dysplasia only. The British Society of Gastroenterology published guidance in 2013 on managing Barrett's oesophagus and related early neoplasia. This emphasised the importance of minimum data set reporting, including length of Barrett's segments and also the requirement that dysplasia is confirmed by 2 gastrointestinal pathologists. An update to the 2010 NICE guideline was needed because of new evidence on chemoprevention, managing Barrett's oesophagus with low-grade dysplasia and evolving practice in stage 1 adenocarcinoma.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe stages of cancer/oesophageal adenocarcinoma referred to in this guideline are based on the 8th edition of the Union for International Cancer Control (UICC) tumour node metastasis (TNM) classification of malignant tumours.\n\n# Information and support\n\nOffer a clinical consultation to people with newly diagnosed Barrett's oesophagus to discuss risk of cancer, endoscopic surveillance plans and symptom control.\n\nGive the person verbal and written information about their diagnosis, available treatments and patient support groups. Give them time to consider this information when making decisions about their care.\n\nAfter each surveillance procedure, provide the person with an endoscopy report that includes a lay summary of the findings and a reference to ongoing symptom control.\n\nFollow the recommendations on communication and information in the NICE guidelines on patient experience in adult NHS services and shared decision making.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: patient information and support.\n\nLoading. Please wait.\n\n# Pharmacological interventions\n\n## Symptom control\n\nFollow the recommendations on interventions for gastro-oesophageal reflux disease (GORD) in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults.\n\n## Preventing disease progression\n\nDo not offer aspirin to people with Barrett's oesophagus to prevent progression to oesophageal dysplasia and cancer.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pharmacological interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: pharmacological interventions to reduce progression to dysplasia or cancer.\n\nLoading. Please wait.\n\n# Endoscopic surveillance\n\nDiscuss the benefits and risks of endoscopic surveillance with the person diagnosed with Barrett's oesophagus.\n\nOffer high resolution white light endoscopy with Seattle biopsy protocol for surveillance of Barrett's oesophagus. Take into account the health of the person and ensure the benefits of surveillance outweigh the risks.\n\n## Frequency of endoscopic surveillance\n\nOffer high resolution white light endoscopic surveillance with Seattle protocol biopsies:\n\nevery 2 to 3 years to people with long-segment (3 cm or longer) Barrett's oesophagus\n\nevery 3 to 5 years to people with short-segment (less than 3 cm) Barrett's oesophagus with intestinal metaplasia.\n\nAssess a person's risk of cancer based on their age, sex, family history of oesophageal cancer and smoking history and tailor the frequency of endoscopic surveillance accordingly, within the intervals given in recommendation 1.3.3.\n\nDo not offer endoscopic surveillance to people with short-segment (less than 3 cm) Barrett's oesophagus without intestinal metaplasia provided the diagnosis has been confirmed at 2 endoscopies.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on endoscopic surveillance\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews C: endoscopic surveillance using white light endoscopy,\xa0D: diagnostic accuracy of endoscopic surveillance techniques, E: non-endoscopic surveillance techniques and F: frequency and duration of endoscopic surveillance.\n\nLoading. Please wait.\n\n# Staging for suspected stage 1 oesophageal adenocarcinoma\n\nOffer endoscopic resection for staging, to people with suspected stage 1 oesophageal adenocarcinoma.\n\nDo not use CT before endoscopic resection for staging suspected T1 oesophageal adenocarcinoma.\n\nDo not use endoscopic ultrasonography (EUS) before endoscopic resection for staging suspected T1a oesophageal adenocarcinoma.\n\nConsider EUS for nodal staging, for people with suspected T1b oesophageal adenocarcinoma based on endoscopic appearances or diagnosed with T1b oesophageal adenocarcinoma based on histological examination of endoscopic resection specimens.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on staging for suspected stage 1 oesophageal adenocarcinoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: endoscopic and radiological staging techniques.\n\nLoading. Please wait.\n\n# Managing Barrett's oesophagus with dysplasia\n\nOffer endoscopic resection of visible oesophageal lesions as first-line treatment to people with high-grade dysplasia.\n\nOffer endoscopic ablation of any residual Barrett's oesophagus to people with high-grade dysplasia after treatment with endoscopic resection.\n\nOffer radiofrequency ablation to people with low-grade oesophageal dysplasia diagnosed from biopsies taken at 2 separate endoscopies. Two gastrointestinal pathologists should confirm the histological diagnosis.\n\nConsider endoscopic surveillance at 6 monthly intervals with dose optimisation of acid-suppressant medication for people diagnosed with indefinite dysplasia of the oesophagus.\n\nOffer endoscopic follow-up to people who have received endoscopic treatment for Barrett's oesophagus with dysplasia.\n\nFollow the NICE interventional procedures guidance on endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia and epithelial radiofrequency ablation for Barrett's oesophagus.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing Barrett's oesophagus with dysplasia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews\xa0H: endoscopic treatment (high-grade dysplasia and stage 1 adenocarcinoma), I: endoscopic treatment (low-grade dysplasia and indefinite dysplasia) and J: endoscopic and radiological follow-up after treatment.\n\nLoading. Please wait.\n\n# Managing stage 1 oesophageal adenocarcinoma\n\nOffer a clinical consultation to people with stage\xa01 oesophageal adenocarcinoma to discuss and evaluate the suitability of treatment options, including endoscopic resection or oesophagectomy.\n\nOffer endoscopic resection as first-line treatment to people with T1a oesophageal adenocarcinoma.\n\nOffer endoscopic ablation of any residual Barrett's oesophagus to people with T1a oesophageal adenocarcinoma after treatment with endoscopic resection.\n\nOffer endoscopic follow-up to people who have received endoscopic treatment for stage 1 oesophageal adenocarcinoma.\n\nOffer oesophagectomy to people with T1b oesophageal adenocarcinoma who are fit for surgery and at high risk of cancer progression. For example, where there is:\n\nincomplete endoscopic resection\n\nevidence of lymphovascular invasion or deep submucosal invasion (more than 500 micron) on histological examination of endoscopic resection specimens.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing stage 1 oesophageal adenocarcinoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews\xa0J: endoscopic and radiological follow-up after treatment and K: oesophagectomy versus endoscopic treatment.\n\nLoading. Please wait.\n\n# Non-surgical treatment for T1b oesophageal adenocarcinoma\n\nConsider radiotherapy (alone or in combination with chemotherapy) for people with T1b oesophageal adenocarcinoma at high risk of cancer progression (for example, incomplete endoscopic resection, or evidence of lymphovascular invasion or deep submucosal invasion (more than 500 micron) on histological examination of endoscopic resection specimens) and who are unfit for oesophagectomy.\n\nOffer endoscopic follow-up to people who have received radiotherapy for T1b oesophageal adenocarcinoma.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on non-surgical treatment for T1b oesophageal adenocarcinoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews\xa0L: non-surgical treatment for T1b oesophageal adenocarcinoma and J: endoscopic and radiological follow-up after treatment.\n\nLoading. Please wait.\n\n# Anti-reflux surgery\n\nDo not offer anti-reflux surgery to people with Barrett's oesophagus to prevent progression to dysplasia or cancer.\n\nFollow the recommendations on laparoscopic fundoplication for gastro-oesophageal reflux disease in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anti-reflux surgery\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews M: anti-reflux surgery to induce remission of disease or prevent recurrence and N: anti-reflux surgery to reduce progression to dysplasia or cancer.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in this guideline.\n\n## Barrett's oesophagus\n\nAn oesophagus in which any portion of the normal distal squamous epithelial lining has been replaced by metaplastic columnar epithelium, which is clearly visible endoscopically (≥1 cm) above the gastro-oesophageal junction and confirmed histopathologically from oesophageal biopsies.\n\n## Seattle biopsy protocol\n\nEntails four-quadrant random biopsies for every 2 cm of Barrett's oesophagus in addition to targeted biopsies on macroscopically visible lesions.\n\n## Stage\xa01 adenocarcinoma\n\nAny oesophageal adenocarcinoma with T1 stage and no lymph node (N0) or distant metastasis (M0).", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Diagnostic accuracy of endoscopic surveillance\n\nWhat is the diagnostic accuracy of different endoscopic surveillance techniques including high resolution endoscopy and chromoendoscopy for use in adults?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on endoscopic surveillance\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: frequency and duration of endoscopic surveillance techniques.\n\nLoading. Please wait.\n\n# Frequency and duration of endoscopic surveillance\n\nWhat is the usefulness of clinical and molecular biomarkers to inform the optimal frequency and duration of endoscopic surveillance for adults with Barrett's oesophagus?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on endoscopic surveillance\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: frequency and duration of endoscopic surveillance techniques.\n\nLoading. Please wait.\n\n# Oesophagectomy\n\nWhat is the effectiveness of endoscopic resection with or without adjuvant chemoradiotherapy and oesophagectomy for adults with T1b oesophageal adenocarcinoma?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing stage 1 oesophageal adenocarcinoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: oesophagectomy versus endoscopy treatment.\n\nLoading. Please wait.\n\n# Endoscopic treatments\n\nFor adults with Barrett's oesophagus with dysplasia, what is the effectiveness of different endoscopic ablation techniques alone or in combination with endoscopic resection?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing Barrett's oesophagus with dysplasia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: endoscopic treatment (high-grade dysplasia and stage 1 adenocarcinoma).\n\nLoading. Please wait.\n\nFor adults with stage 1 oesophageal adenocarcinoma, what is the effectiveness of different endoscopic ablation techniques alone or in combination with endoscopic resection?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing stage 1 oesophageal adenocarcinoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: endoscopic treatment (high-grade dysplasia and stage 1 adenocarcinoma).\n\nLoading. Please wait.\n\n# Frequency and duration of endoscopic follow-up\n\nWhat is the optimal frequency and duration of endoscopic follow-up for patients who have received endoscopic treatment for Barrett's oesophagus with dysplasia?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing Barrett's oesophagus with dysplasia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: endoscopic and radiological follow-up after treatment.\n\nLoading. Please wait.\n\nWhat is the optimal frequency and duration of endoscopic follow-up for patients who have received endoscopic treatment for stage 1 oesophageal adenocarcinoma?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing stage 1 oesophageal adenocarcinoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: endoscopic and radiological follow-up after treatment.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Information and support\n\nRecommendations 1.1.1 to 1.1.4\n\n## Why the committee made the recommendations\n\nQualitative evidence highlighted knowledge gaps and uncertainties at the time of diagnosis of Barrett's oesophagus. The committee emphasised this reflected their experience with people they see in clinical practice. They agreed a clinical consultation should be offered following diagnosis to provide information and support on the risk of progression to cancer and symptom control, and general information about endoscopic surveillance.\n\nProviding information both verbally and in written form is helpful as information can be difficult to grasp at a single consultation and written information will enable people to revisit the information when needed. This should include general information about the diagnosis of Barrett's oesophagus, available treatments and any patient support groups.\n\nThe use of complex medical terminology limits people's ability to understand information. The committee agreed it was important that each endoscopy report includes a lay summary of the findings and that this is given to the person.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice and therefore are unlikely to have a substantial resource impact.\n\nReturn to recommendations\n\n# Pharmacological interventions\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nLimited evidence showed that proton pump inhibitors (PPIs) had no clinically important effect on outcomes (including all-cause mortality, progression to any grade of dysplasia or cancer, and serious adverse events). The committee agreed there was insufficient evidence to recommend PPIs to prevent progression to oesophageal dysplasia and cancer and decided not to make a recommendation on this.\n\nThe committee agreed there was insufficient evidence to recommend aspirin to prevent progression to oesophageal dysplasia and cancer and decided to make a do not offer recommendation. Evidence showed that participants taking aspirin were more likely to get adverse events than those who did not, but the difference was small and not conclusive. The committee noted this was in line with their clinical experience and knowledge that bleeding is more likely to be seen in people treated with aspirin. They agreed that the inconclusive results could be attributed to a protective effect from PPIs taken by people in both the aspirin and no aspirin study groups.\n\nAlthough the committee did not look for evidence on medication use for symptom control, they agreed that acid-suppressant medication such as PPIs are highly effective and widely used in current practice to control symptoms of gastro-oesophageal reflux disease in people with Barrett's oesophagus. They decided it was useful to provide a link to the relevant section of the NICE guideline on gastro-oesophageal reflux disease.\n\n## How the recommendations might affect practice\n\nAspirin is not currently used to prevent progression to oesophageal dysplasia and cancer. Therefore, the recommendations are not expected to result in a change in current practice or to have a resource impact.\n\nReturn to recommendations\n\n# Endoscopic surveillance\n\nRecommendations 1.3.1 to 1.3.5\n\n## Why the committee made the recommendations\n\nEvidence showed there was a 30% reduction in mortality for people who received endoscopic surveillance compared to those that did not. Based on this and their clinical experience, the committee agreed it should be offered to people with Barrett's oesophagus provided the person's general health is adequate, and the benefits of surveillance outweigh the risks. The committee noted this is the current standard of care for endoscopic surveillance for Barrett's oesophagus.\n\nThe committee agreed that the risk of complications of endoscopic surveillance should be considered on an individual basis because the frequency and consequences of complications will vary depending on a range of factors, including age, fraility and medical comorbidities. It was agreed that possible complications should be discussed with the person with Barrett's oesophagus.\n\nEvidence for electronic and conventional chromoendoscopy techniques (including narrow band imaging, acetic acid, methylene blue) as well as endoscopic brushing was obtained from people with dysplasia and early-stage cancer. This means that these techniques have not been validated in an unselected population with Barrett's oesophagus undergoing standard endoscopic surveillance and therefore could not be recommended. A recommendation for research was made to assess the effectiveness of these techniques for surveillance of Barrett's oesophagus.\n\nThere was no evidence to support an optimal frequency for endoscopic surveillance as this will differ according to individual risk factors. However, the committee agreed to make a recommendation for frequency of surveillance based on length of segment, in line with the British Society of Gastroenterology (BSG) guidelines and current practice in the UK.\n\nThe committee agreed that the frequency of surveillance should be tailored to each person based on a clinical assessment of their risk of cancer, with length of segment, being the factor most closely linked to risk of cancer, but age, sex, family history of oesophageal cancer and smoking also being important.\n\nIn line with current practice, there was consensus that people with short-segment (less than 3 cm) Barrett's oesophagus without intestinal metaplasia (confirmed at 2 endoscopies) should not be offered endoscopic surveillance because the risk of disease progression is low in this population and there are risks associated with endoscopic surveillance.\n\nThere was no evidence on the duration of endoscopic surveillance and the committee agreed not to make a recommendation on this.\n\nThe committee emphasised that evidence of clinical and molecular biomarkers associated with a greater risk of progression to dysplasia or cancer could inform setting appropriate intervals for endoscopic surveillance and agreed to make a recommendation for research on biomarkers.\n\nThere was evidence of benefit of using cytosponge to diagnose dysplasia and cancer but the quality was not sufficient to support its use at present.\n\nBalloon brushing is an old technique that is not currently used in clinical practice. Limited evidence on cytology obtained from balloon brushing showed it could detect oesophageal dysplasia and adenocarcinoma, but the committee agreed there was insufficient evidence to recommend its use in clinical practice.\n\nThere was a lack of evidence on other non-endoscopic surveillance techniques and based on their clinical experience, the committee agreed it was not appropriate to recommend them.\n\n## How the recommendations might affect practice\n\nEndoscopic surveillance is widely used for monitoring people with Barrett's oesophagus. Adherence to the biopsy protocols requires additional procedure time beyond that of a standard endoscopy, but many services have already increased the time allocation for Barrett's surveillance and overall resource impact is not expected to be significant.\n\nBack to recommendations\n\n# Staging for suspected stage 1 oesophageal adenocarcinoma\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nIn the absence of evidence on endoscopic staging techniques, the committee drew upon their clinical experience to inform decision making. They agreed that endoscopic resection should be offered to people with suspected stage 1 oesophageal adenocarcinoma as it is the most accurate staging technique and is the gold standard in current practice as recommended by the British Society of Gastroenterology (BSG) guidelines.\n\nThere are 2 techniques for resection of suspected stage 1 oesophageal adenocarcinoma: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). The evidence did not show superiority of 1 technique over the other so the recommendation does not specify which to use.\n\nThe committee noted, based on their clinical experience, that ESD may offer an advantage in individuals with Barrett's oesophagus-related neoplasia (lesions larger than 15 mm, poorly lifting tumours and lesions at risk for submucosal invasion) but there was no reason to select it routinely over EMR for small slightly elevated lesions because ESD is a complex procedure and is associated with more complications.\n\nLimited evidence indicated poor diagnostic accuracy of CT as a staging technique for early stage oesophageal adenocarcinoma because the resolution of CT is inadequate in detecting very small tumours and small volume lymph node metastasis. Therefore, there was consensus that CT should not be used before endoscopic resection for staging suspected T1 oesophageal adenocarcinoma.\n\nLimited evidence on the mini-probe endoscopic ultrasonograph (mini-probe EUS) and the conventional radial endoscopic ultrasonograph (crEUS) showed they cannot distinguish well between T1a and T1b tumours but can detect lymph node metastasis with greater accuracy. Based on the evidence and their clinical experience, the committee agreed that EUS should not be used before endoscopic resection for staging suspected T1a oesophageal adenocarcinoma, as this carries a negligible risk of lymph node metastasis.\n\nEUS should be considered when an oesophageal lesion is suspected to be T1b cancer based on endoscopic appearances, for example sessile lesions with significant luminal component (Paris 0-Is) or depressed lesions (Paris 0-IIc). It should also be considered for people with confirmed T1b oesophageal adenocarcinoma, who have a significant risk of lymph node metastasis and may benefit from additional oncological treatment, such as radiotherapy alone or in combination with chemotherapy.\n\n## How the recommendations might affect practice\n\nThese recommendations are in line with current practice and therefore will not have a resource impact.\n\nBack to recommendations\n\n# Managing Barrett's oesophagus with dysplasia\n\nRecommendations 1.5.1 to 1.5.6\n\n## Why the committee made the recommendations\n\nThe evidence showed that endoscopic treatment using a combination of endoscopic resection and endoscopic ablation or endoscopic ablation alone is effective to treat people with high-grade dysplasia and prevent progression to adenocarcinoma. Based on clinical experience the committee recommended that high-grade dysplasia be endoscopically resected, when oesophageal lesions are visible at endoscopy, and the residual Barrett's oesophagus be treated with endoscopic ablation.\n\nThere are 2 techniques for resection of dysplastic lesions in Barrett's oesophagus: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). There is no evidence of superiority of 1 technique over the other so the recommendation does not specify which to use.\n\nThe evidence indicated that both radiofrequency ablation (RFA) and argon plasma coagulation (APC) are effective in reducing the risk of recurring oesophageal lesions in people who have received an endoscopic resection for high-grade dysplasia. However, the committee noted that for very long segment Barrett's oesophagus RFA might be more practical than APC, which has a significantly smaller ablation catheter than RFA. Given that there is no evidence of superiority of one ablation technique over the other, the committee agreed further research was needed to determine the most effective endoscopic ablation technique to use and made a recommendation for research.\n\nEvidence showed that RFA in people with confirmed low-grade oesophageal dysplasia protects from progression to high-grade dysplasia or cancer. The committee noted this was in line with their experience and that low-grade dysplasia is primarily managed by RFA in current practice.\n\nBased on their clinical experience, the committee emphasised that for RFA to be offered, evidence of low-grade dysplasia from biopsies from 2 separate endoscopies and confirmation of the diagnosis by 2 gastrointestinal pathologists should be present. They noted this was in line with current practice where RFA takes place in specialist centres by endoscopists with appropriate experience and would not be considered in cases where there is evidence of low-grade oesophageal dysplasia from biopsies from only 1 endoscopy or where there is no confirmation by a second gastrointestinal pathologist.\n\nThere was no evidence to support use of other ablation techniques for treating low-grade dysplasia.\n\nIn the absence of clinical evidence on people with indefinite dysplasia of the oesophagus, the committee drew on their clinical experience to make a recommendation for this population. They emphasised that the risk of progression to high-grade oesophageal dysplasia or cancer is around 3 to 5 times higher than the risk in the non-dysplastic population and therefore endoscopic surveillance every 6 months would be appropriate. The committee also noted, based on their clinical experience, that indefinite dysplasia is often linked to excessive inflammation of the oesophagus, therefore optimisation of acid-suppressant medication is appropriate.\n\nThere was no evidence comparing different strategies of endoscopic follow-up in people with Barrett's oesophagus with dysplasia and the committee drew upon their clinical experience to make a recommendation. They agreed that endoscopic follow-up is needed for people who have received endoscopic treatment for Barrett's oesophagus with dysplasia as the likelihood of recurrence is high. The committee noted this was in line with current practice.\n\nBased on their clinical experience, the committee agreed that the frequency of follow-up should be based on the likelihood of recurrence. In the absence of evidence, the committee decided to make a recommendation for research to assess the optimal frequency and duration of endoscopic follow-up for people who have received endoscopic treatment for Barrett's oesophagus with dysplasia\n\n## How the recommendations might affect practice\n\nThese recommendations are in line with current practice and therefore will not have a resource impact.\n\nBack to recommendations\n\n# Managing stage 1 oesophageal adenocarcinoma\n\nRecommendations 1.6.1 to 1.6.5\n\n## Why the committee made the recommendations\n\nThe quality of the evidence was limited but reflected the committee's clinical experience that endoscopic resection and oesophagectomy are equally effective for treating stage\xa01 adenocarcinoma, and oesophagectomy is associated with a higher incidence of serious adverse events. There was a lack of evidence on how the 2 treatments affect quality of life so the committee drew on their own experience to consider this. As part of standard practice a clinical consultation would be offered to the person to discuss the treatment options and the advantages and disadvantages of both approaches.\n\nEndoscopic resection is less invasive and has fewer complications than oesophagectomy. The committee agreed that even after successful endoscopic treatment there remains a risk of recurrence of Barrett's oesophagus and oesophageal neoplasia. Therefore, endoscopic treatment comes with a greater need for ongoing endoscopic surveillance, which could lead to anxiety about recurrence and possibly impacts on quality of life. This was reinforced by a patient committee member. Despite this, the committee agreed endoscopic resection is still more likely to result in better quality of life post-treatment than oesophagectomy. Therefore, it should be offered as first-line treatment to people with T1a adenocarcinoma.\n\nThere was evidence supporting the effectiveness of using endoscopic resection followed by endoscopic ablation to treat people with T1a adenocarcinoma of the oesophagus.\n\nThe evidence indicated that both radiofrequency ablation (RFA) and argon plasma coagulation (APC) are effective in reducing the risk of recurring oesophageal lesions in people who have received an endoscopic resection for T1a adenocarcinoma. However, the committee noted that for very long segment of Barrett's oesophagus RFA might be more practical than APC, which has a significantly smaller ablation catheter than RFA. Given that there is no evidence of superiority of one technique over the other, the committee agreed further research was needed to determine the most effective endoscopic ablation technique to use and made a recommendation for research.\n\nThe lack of specific evidence for people with T1b oesophageal adenocarcinoma was a concern for the committee who agreed this is where there is the most uncertainty over appropriate treatment. In the absence of evidence, the committee decided to make a recommendation to offer oesophagectomy rather than endoscopic resection for people with T1b oesophageal adenocarcinoma at high risk of cancer progression. This was based on their clinical experience that there is a greater risk of local recurrence in cases of incomplete endoscopic resection and a high risk of lymph node metastasis in cases with deep submucosal invasion (more than 500 micron) and lymphovascular invasion. They decided not to make a recommendation for people with T1b at low risk of cancer progression as it was less clear which treatment option would be best but made a recommendation for research to determine the effectiveness of endoscopic resection with or without adjuvant chemoradiotherapy and oesophagectomy for adults with T1b oesophageal adenocarcinoma.\n\nIn the absence of evidence comparing endoscopic and radiological follow-up with standard endoscopy in people with stage 1 oesophageal adenocarcinoma, the committee drew upon their clinical experience to make a recommendation. They agreed that endoscopic follow-up is needed for people who have received endoscopic treatment for stage 1 oesophageal adenocarcinoma as the likelihood of recurrence is high. The committee noted this was in line with current practice.\n\nBased on their clinical experience, the committee agreed that the frequency of follow-up should be based on the likelihood of recurrence. In the absence of evidence, the committee decided to make a recommendation for research to assess the optimal frequency and duration of endoscopic follow-up for people who have received endoscopic treatment for stage 1 oesophageal adenocarcinoma.\n\n## How the recommendations might affect practice\n\nThe current recommendations are in line with current practice and therefore will not have a resource impact.\n\nBack to recommendations\n\n# Non-surgical treatment for T1b oesophageal adenocarcinoma\n\nRecommendations 1.7.1 and 1.7.2\n\n## Why the committee made the recommendations\n\nIn the absence of evidence to guide decision making, the committee drew upon their clinical experience to make a recommendation on non-surgical treatment for T1b oesophageal adenocarcinoma.\n\nUsing radiotherapy alone or in combination with chemotherapy to treat oesophageal adenocarcinoma is current practice.\n\nThe committee agreed that radiotherapy alone or in combination with chemotherapy would be appropriate for people with T1b oesophageal adenocarcinoma at high risk of cancer progression as it is likely to reduce the risk of recurrence. They noted that chemotherapy alone is not a definitive treatment.\n\nThe committee acknowledged the absence of evidence for endoscopic and radiological follow-up in people with stage 1 oesophageal adenocarcinoma but agreed it would be usual practice to offer endoscopic follow-up to people who have received radiotherapy treatment for T1b oesophageal adenocarcinoma as the risk of cancer progression is high. The committee made a consensus recommendation based on their clinical experience.\n\n## How the recommendations might affect practice\n\nThe current recommendations are in line with current practice and therefore are unlikely to have a significant resource impact.\n\nBack to recommendations\n\n# Anti-reflux surgery\n\nRecommendations 1.8.1 and 1.8.2\n\n## Why the committee made the recommendations\n\nIn the absence of evidence of a clinical benefit of anti-reflux surgery to reduce progression to dysplasia or cancer, the committee agreed it should not be recommended for this reason.\n\nAlthough the committee did not look for evidence on medication use for symptom control, they agreed that anti-reflux surgery can provide an alternative option for people who are intolerant to or unwilling to take acid-suppressant medication such as proton pump inhibitors (PPIs) and should be considered for this population. They decided it was useful to provide a link to the relevant recommendation in the NICE guideline on gastro-oesophageal reflux disease. In the absence of evidence, the committee agreed not to make a recommendation for anti-reflux surgery to induce remission or prevent recurrence in people with stage 1 adenocarcinoma. People who fail to respond to radiofrequency ablation (RFA) are sometimes referred for anti-reflux surgery. However, the committee noted that in such cases other ablation therapies such as argon plasma coagulation (APC) could be considered instead of anti-reflux surgery.\n\n## How the recommendations might affect practice\n\nThe current recommendations are in line with current practice and therefore will not have a resource impact.\n\nBack to recommendations", 'Context': "Barrett's oesophagus is a condition in which squamous cells at the lower end of the lining of the oesophagus are replaced with columnar cells. It can be a precursor to oesophageal adenocarcinoma. Barrett's oesophagus is more common in older age groups, men, people who are white and people who are overweight. The risk of progression to cancer is low. Fewer than 1% of people with Barrett's oesophagus develop oesophageal adenocarcinoma each year.\n\nHowever, oesophageal adenocarcinoma has a poor prognosis because of late presentation, and its incidence is increasing possibly related to more people being overweight or obese. Effective treatments for Barrett's oesophagus could reduce the number of people presenting late with adenocarcinoma and improve overall outcomes.\n\nNICE published a guideline on ablative therapy for Barrett's oesophagus (CG106) in 2010, which included people with high-grade dysplasia only. The British Society of Gastroenterology published guidance in 2013 on managing Barrett's oesophagus and related early neoplasia. This emphasised the importance of minimum data set reporting, including length of Barrett's segments and also the requirement that dysplasia is confirmed by 2 gastrointestinal pathologists. An update to the 2010 NICE guideline was needed because of new evidence on chemoprevention, managing Barrett's oesophagus with low-grade dysplasia and evolving practice in stage 1 adenocarcinoma."}	https://www.nice.org.uk/guidance/ng231	This guideline covers monitoring, treatment and follow-up for people aged 18 and over with Barrett’s oesophagus and stage 1 oesophageal adenocarcinoma. It includes advice on endoscopic and non-endoscopic techniques. It aims to improve outcomes by ensuring the most effective investigations and treatments are used.
3fbdeb76674b34d4788ad7fd8d2524ca47cda521	nice	Transvenous obliteration for gastric varices	Transvenous obliteration for gastric varices Evidence-based recommendations on transvenous obliteration for gastric varices. This involves inserting a tube with a tiny balloon on the end into a vein in the thigh or neck. The tube is then passed into the enlarged vein in the stomach (gastric varix) and the balloon is inflated to stop blood flowing into the vein. The vein is then blocked using one of several techniques. The aim is to reduce the risk of bleeding. # Recommendations Evidence on the safety and efficacy of transvenous obliteration of gastric varices is adequate in the short term but limited in the long term. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do transvenous obliteration of gastric varices should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. This should include the risk of: balloon rupture and embolisation of sclerosant or device during the procedure an increase in portal vein pressure in the long term, which may exacerbate ascites and oesophageal varices. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Enter details about everyone having transvenous obliteration of gastric varices onto suitable registry databases where available and review local clinical outcomes. Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection should be discussed with a specialist centre that offers all of the standard treatments for portal hypertension and bleeding gastric varices, and that is experienced in managing acute and chronic liver disease. The procedure should only be done by clinicians with training in and experience of the procedure.# The condition, current treatments and procedure # The condition Varices are dilated veins. Gastric varices form in around 20% of people with portal hypertension. Portal hypertension can happen in cirrhosis or in people without cirrhosis who develop thrombosis of the splanchnic circulation, such as portal vein thrombosis. Gastric varices are prone to bleeding, and this is associated with high mortality and poor prognosis. # Current treatments Treatments for gastric varices include non-selective beta-blockers, balloon tamponade, band ligation, endoscopic cyanoacrylate or thrombin injection, transjugular intrahepatic portosystemic shunt and transvenous obliteration. # The procedure Cross-sectional imaging is done to identify and confirm the target shunt (gastrorenal shunt is usually present). Percutaneous venous access of the femoral or jugular vein is done using standard angiographic technique. An occlusion balloon catheter is inserted and navigated into the target shunt under fluoroscopic guidance. The balloon is inflated to block the shunt and venography is then done to define the variceal anatomy and type of varices. Sclerosant is slowly injected into the varices to fill the full extent of the varices, with the embolisation end point being minimal filling of the afferent vein or portal vasculature. The injection of sclerosant can be done with or without using a microcatheter for more selective injection. The occlusion balloon catheter is left in situ until satisfactory embolisation of the varices is achieved. This procedure is called balloon-occluded retrograde transvenous obliteration (BRTO). The aim is to obliterate the varices and manage acutely bleeding gastric varices or those at high risk of bleeding. Modified techniques, such as balloon-occluded antegrade transvenous obliteration (BATO, a collective term for portal venous access routes to the varices), vascular plug-assisted retrograde transvenous obliteration (PARTO) and coil-assisted retrograde transvenous obliteration (CARTO), follow a similar procedure to BRTO. However, for PARTO and CARTO, shunt occlusion is achieved by vascular plugging or coiling. These 2 techniques can reduce procedure time and eliminate the risk of balloon rupture.	{'Recommendations': "Evidence on the safety and efficacy of transvenous obliteration of gastric varices is adequate in the short term but limited in the long term. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do transvenous obliteration of gastric varices should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. This should include the risk of:\n\n\n\nballoon rupture and embolisation of sclerosant or device during the procedure\n\nan increase in portal vein pressure in the long term, which may exacerbate ascites and oesophageal varices.\n\n\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nEnter details about everyone having transvenous obliteration of gastric varices onto suitable registry databases where available and review local clinical outcomes.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be discussed with a specialist centre that offers all of the standard treatments for portal hypertension and bleeding gastric varices, and that is experienced in managing acute and chronic liver disease.\n\nThe procedure should only be done by clinicians with training in and experience of the procedure.", 'The condition, current treatments and procedure': '# The condition\n\nVarices are dilated veins. Gastric varices form in around 20% of people with portal hypertension. Portal hypertension can happen in cirrhosis or in people without cirrhosis who develop thrombosis of the splanchnic circulation, such as portal vein thrombosis. Gastric varices are prone to bleeding, and this is associated with high mortality and poor prognosis.\n\n# Current treatments\n\nTreatments for gastric varices include non-selective beta-blockers, balloon tamponade, band ligation, endoscopic cyanoacrylate or thrombin injection, transjugular intrahepatic portosystemic shunt and transvenous obliteration.\n\n# The procedure\n\nCross-sectional imaging is done to identify and confirm the target shunt (gastrorenal shunt is usually present). Percutaneous venous access of the femoral or jugular vein is done using standard angiographic technique. An occlusion balloon catheter is inserted and navigated into the target shunt under fluoroscopic guidance. The balloon is inflated to block the shunt and venography is then done to define the variceal anatomy and type of varices. Sclerosant is slowly injected into the varices to fill the full extent of the varices, with the embolisation end point being minimal filling of the afferent vein or portal vasculature. The injection of sclerosant can be done with or without using a microcatheter for more selective injection. The occlusion balloon catheter is left in situ until satisfactory embolisation of the varices is achieved. This procedure is called balloon-occluded retrograde transvenous obliteration (BRTO). The aim is to obliterate the varices and manage acutely bleeding gastric varices or those at high risk of bleeding.\n\nModified techniques, such as balloon-occluded antegrade transvenous obliteration (BATO, a collective term for portal venous access routes to the varices), vascular plug-assisted retrograde transvenous obliteration (PARTO) and coil-assisted retrograde transvenous obliteration (CARTO), follow a similar procedure to BRTO. However, for PARTO and CARTO, shunt occlusion is achieved by vascular plugging or coiling. These 2\xa0techniques can reduce procedure time and eliminate the risk of balloon rupture.'}	https://www.nice.org.uk/guidance/ipg751	Evidence-based recommendations on transvenous obliteration for gastric varices. This involves inserting a tube with a tiny balloon on the end into a vein in the thigh or neck. The tube is then passed into the enlarged vein in the stomach (gastric varix) and the balloon is inflated to stop blood flowing into the vein. The vein is then blocked using one of several techniques. The aim is to reduce the risk of bleeding.
11688361d79a4ce6a8a9491de17dd28a02dc1a13	nice	Biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer	Biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer Evidence-based recommendations on biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer. This involves pushing the rectum slightly away from the prostate by inserting a balloon or injecting a gel (spacer) between them. # Recommendations Evidence on the safety and efficacy of biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. The procedure should only be done by clinicians with training in and experience of transperineal interventional procedures. Further research could be in the form of randomised controlled trials or observational data studies including registry studies and real-world evidence. It should report details of patient selection, choice of radiotherapy technique and device used, improvement in quality of life, and long-term efficacy and safety. It should also identify high-risk groups who might benefit.# The condition, current treatments and procedure # The condition Prostate cancer is the most common cancer in men, and the second most common cancer in the UK. Most prostate cancers are either localised or locally advanced at diagnosis. Localised prostate cancer often does not cause any symptoms, but some people might have urinary problems or erectile dysfunction. Some people may not identify as men but may have a prostate. # Current treatments Current treatment options for localised or locally advanced prostate cancer include 'watchful waiting', active surveillance, radiotherapy, radical prostatectomy, transurethral resection of the prostate, cryotherapy, high-intensity focused ultrasound, androgen deprivation therapy and chemotherapy (as recommended in NICE's guideline on prostate cancer: diagnosis and management). Radiation therapy is an established curative treatment and can be either external-beam radiotherapy or brachytherapy (also called interstitial radiotherapy). Brachytherapy can be given at low or high dose rates. Low dose rate brachytherapy may be used alone or with external-beam radiotherapy. # The procedure Radiotherapy for prostate cancer can cause rectal damage because of the close proximity of the prostate and the rectum. Symptoms of rectal damage can include diarrhoea, incontinence, proctitis and ulceration of the rectal mucosa. Injecting a biodegradable substance (examples include polyethylene glycol hydrogel, hyaluronic acic and human collagen), or inserting and inflating a biodegradable balloon spacer in the space between the rectum and prostate is done to temporarily increase the distance between them. The aim is to reduce the amount of radiation delivered to the rectum and reduce the toxicity profile during prostate radiotherapy. The procedure can be done with the patient under general, spinal or local anaesthesia using transrectal ultrasound guidance. The patient is placed in the dorsal lithotomy position. For gel injection, a needle is advanced percutaneously via a transperineal approach into the space between the prostate and the rectum. Hydrodissection with saline may be used to separate the prostate and the rectum for some gels, but is not always necessary. After confirming the correct positioning of the needle, the gel is injected, filling the perirectal space. Some of the gels may polymerise to form a soft mass and some do not. The biodegradable gel absorbs slowly over several months. Some gels are reversible and can be dissolved using enzymes. For balloon spacer insertion, a small perineal incision is typically used to insert a dilator and introducer sheath. The dilator is advanced towards the prostate base over the needle, which is then removed. A biodegradable balloon is introduced through the introducer sheath and is filled with saline and sealed with a biodegradable plug. The balloon spacer degrades over several months.	{'Recommendations': "Evidence on the safety and efficacy of biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThe procedure should only be done by clinicians with training in and experience of transperineal interventional procedures.\n\nFurther research could be in the form of randomised controlled trials or observational data studies including registry studies and real-world evidence. It should report details of patient selection, choice of radiotherapy technique and device used, improvement in quality of life, and long-term efficacy and safety. It should also identify high-risk groups who might benefit.", 'The condition, current treatments and procedure': "# The condition\n\nProstate cancer is the most common cancer in men, and the second most common cancer in the UK. Most prostate cancers are either localised or locally advanced at diagnosis. Localised prostate cancer often does not cause any symptoms, but some people might have urinary problems or erectile dysfunction. Some people may not identify as men but may have a prostate.\n\n# Current treatments\n\nCurrent treatment options for localised or locally advanced prostate cancer include 'watchful waiting', active surveillance, radiotherapy, radical prostatectomy, transurethral resection of the prostate, cryotherapy, high-intensity focused ultrasound, androgen deprivation therapy and chemotherapy (as recommended in NICE's guideline on prostate cancer: diagnosis and management).\n\nRadiation therapy is an established curative treatment and can be either external-beam radiotherapy or brachytherapy (also called interstitial radiotherapy). Brachytherapy can be given at low or high dose rates. Low dose rate brachytherapy may be used alone or with external-beam radiotherapy.\n\n# The procedure\n\nRadiotherapy for prostate cancer can cause rectal damage because of the close proximity of the prostate and the rectum. Symptoms of rectal damage can include diarrhoea, incontinence, proctitis and ulceration of the rectal mucosa. Injecting a biodegradable substance (examples include polyethylene glycol hydrogel, hyaluronic acic and human collagen), or inserting and inflating a biodegradable balloon spacer in the space between the rectum and prostate is done to temporarily increase the distance between them. The aim is to reduce the amount of radiation delivered to the rectum and reduce the toxicity profile during prostate radiotherapy.\n\nThe procedure can be done with the patient under general, spinal or local anaesthesia using transrectal ultrasound guidance. The patient is placed in the dorsal lithotomy position. For gel injection, a needle is advanced percutaneously via a transperineal approach into the space between the prostate and the rectum. Hydrodissection with saline may be used to separate the prostate and the rectum for some gels, but is not always necessary. After confirming the correct positioning of the needle, the gel is injected, filling the perirectal space. Some of the gels may polymerise to form a soft mass and some do not. The biodegradable gel absorbs slowly over several months. Some gels are reversible and can be dissolved using enzymes. For balloon spacer insertion, a small perineal incision is typically used to insert a dilator and introducer sheath. The dilator is advanced towards the prostate base over the needle, which is then removed. A biodegradable balloon is introduced through the introducer sheath and is filled with saline and sealed with a biodegradable plug. The balloon spacer degrades over several months."}	https://www.nice.org.uk/guidance/ipg752	Evidence-based recommendations on biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer. This involves pushing the rectum slightly away from the prostate by inserting a balloon or injecting a gel (spacer) between them.
f6f4f9938999143d3f31feb8c860ccafe808cd7f	nice	Upadacitinib for treating active non-radiographic axial spondyloarthritis	Upadacitinib for treating active non-radiographic axial spondyloarthritis Evidence-based recommendations on upadacitinib (Rinvoq) for treating active non-radiographic axial spondyloarthritis in adults. # Recommendations Upadacitinib is recommended as an option for treating active non-radiographic axial spondyloarthritis with objective signs of inflammation (shown by elevated C-reactive protein or MRI) that is not controlled well enough with non-steroidal anti-inflammatory drugs (NSAIDs) in adults. It is recommended only if: tumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough and the company provides upadacitinib according to the commercial arrangement. Assess response to upadacitinib after 16 weeks of treatment. Continue treatment only if there is clear evidence of response, defined as a reduction in: the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pretreatment value or by 2 or more units and the spinal pain visual analogue scale (VAS) by 2 cm or more. Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the BASDAI and spinal pain VAS and make any adjustments needed. If patients and their clinicians consider upadacitinib to be 1 of a range of suitable treatments (including secukinumab and ixekizumab), discuss the advantages and disadvantages of the available treatments. After that discussion, if more than 1 treatment is suitable, choose the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements. These recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Usual treatment for active non-radiographic axial spondyloarthritis in adults that is not controlled well enough with NSAIDs, and when TNF-alpha inhibitors are not suitable or do not control the condition well enough, is secukinumab or ixekizumab. These are biological treatments. Upadacitinib is another biological treatment. Evidence from clinical trials shows that upadacitinib reduces symptoms and improves quality of life better than placebo. Indirect comparisons suggest that upadacitinib works as well as secukinumab and ixekizumab. A cost comparison suggests upadacitinib has similar costs and overall health benefits as secukinumab and ixekizumab. So upadacitinib is recommended.# Information about upadacitinib # Marketing authorisation indication Upadacitinib (RINVOQ, AbbVie) is indicated for 'the treatment of active non-radiographic axial spondyloarthritis in adult patients with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs)'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for upadacitinib. # Price The list price is £805.56 per 28‑tablet pack, with each tablet containing 15 mg of upadacitinib (excluding VAT; BNF online, accessed November 2022). The annual cost of treatment with one 15‑mg tablet per day is £10,501.05 (excluding VAT; BNF online, accessed November 2022). The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by AbbVie, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Decision problem ## Cost comparison The company proposed that upadacitinib should be considered in adults as an alternative to the currently NICE-recommended interleukin (IL)‑17 inhibitors secukinumab and ixekizumab for active non-radiographic axial spondyloarthritis that is not controlled well enough with conventional therapy and when TNF‑alpha inhibitors are not suitable or do not control the condition well enough. The committee agreed that the proposed population was consistent with previous recommendations for IL‑17 inhibitors for active non-radiographic axial spondyloarthritis, and with their use in clinical practice. The company presented a comparison with 2 NICE-recommended IL‑17 inhibitors (NICE technology appraisal guidance on secukinumab for treating non-radiographic axial spondyloarthritis and ixekizumab for treating axial spondyloarthritis). The committee agreed that this was consistent with the criteria for a cost-comparison evaluation. ## Comparators Secukinumab and ixekizumab are anti‑IL-17 injections recommended by NICE for treating non-radiographic axial spondyloarthritis. Upadacitinib is an oral JAK inhibitor. The clinical and patient experts highlighted the convenience of upadacitinib over IL‑17 inhibitors owing to its oral administration. They also suggested that upadacitinib would be especially helpful for people with needle phobias or dexterity issues that make self-injecting difficult. Clinical advice to the EAG suggested that secukinumab is chosen more often than ixekizumab for treating active non-radiographic axial spondyloarthritis. Secukinumab has been available for ankylosing spondylitis since 2016, suggesting that secukinumab is more established in NHS clinical practice than ixekizumab, which became available in 2021. The committee concluded that secukinumab and ixekizumab are appropriate comparators for upadacitinib, but that secukinumab was the more relevant comparator. # Clinical effectiveness ## Data sources Upadacitinib has been studied in 1 randomised controlled trial including 313 adults with active non-radiographic axial spondyloarthritis (SELECT‑AXIS 2, study 2). It was compared with placebo. In SELECT‑AXIS 2, study 2, upadacitinib was associated with statistically significant improvements compared with placebo in the primary and secondary outcomes, including the Assessment in Spondyloarthritis international Society 40% (ASAS40) response, BASDAI 50 score and total back pain score. Upadacitinib was associated with higher ASAS40 and BASDAI 50 responses and total back pain score improvement at week 14 than placebo. People having upadacitinib also had statistically significantly higher scores in the Ankylosing Spondylitis Quality of Life (ASQoL) measure. The committee concluded that upadacitinib was more clinically effective than placebo. ## Network meta-analysis The company did a series of network meta-analyses comparing clinical-effectiveness data for upadacitinib (SELECT‑AXIS 2, study 2) with data for secukinumab (PREVENT) and ixekizumab (COAST‑X). The analyses investigated measures of efficacy, including binary outcomes (ASAS40, BASDAI 50) and continuous outcomes (BASDAI and Bath Ankylosing Spondylitis Functional Index ). The EAG highlighted that although the median values favoured upadacitinib over ixekizumab (except for BASDAI 50 score) and secukinumab, the credible intervals were wide. It explained that the health benefits for all treatments could be similar, but could also differ. The clinical experts stated in their submission that they would expect upadacitinib to provide clinically meaningful benefits compared with IL‑17 inhibitors. The EAG also identified heterogeneity between the trials included in the network meta-analysis that may impact its validity, but acknowledged that there were no studies available that directly compared upadacitinib with either secukinumab or ixekizumab. The committee confirmed this and noted that uncertainties relating to heterogeneity were unlikely to be resolved by a more detailed cost–utility analysis. The committee concluded that the network meta-analysis was uncertain, but supported the company's position that upadacitinib has similar clinical effectiveness to secukinumab and ixekizumab. ## Safety comparisons between trials The company provided safety data comparing upadacitinib with placebo (SELECT‑AXIS 2, study 2), secukinumab (PREVENT) and ixekizumab (COAST‑X). The company and EAG agreed that the safety profiles of all treatments were broadly similar. However, the EAG highlighted that the company had only provided naive comparisons, and the differences between adverse event incidence between the trials was likely to be influenced by differences in trial design, length of follow up and differences in adverse event definitions in each trial. The committee agreed with the EAG. It concluded that it was difficult to draw definitive conclusions from the safety data, and formal modelling of the available safety data would have been helpful for decision making. # Cost comparison ## Cost-comparison estimates The company presented a base-case cost-comparison analysis that modelled the total costs of upadacitinib, secukinumab and ixekizumab over 5 years. It also provided a scenario analysis modelling the costs over 10 years. It considered that the clinical evidence available supported the assumption of clinical equivalence between upadacitinib, secukinumab and ixekizumab. The EAG was satisfied with the company's cost-comparison analysis methods, so did not provide its own cost-comparison estimates. Taking into account the confidential patient access schemes for upadacitinib, secukinumab and ixekizumab, the committee concluded that the total costs associated with upadacitinib were similar to or lower than those associated with secukinumab and ixekizumab. The discounts for all treatments are confidential, so the incremental costs cannot be shared here. # Conclusion ## Recommendation The committee concluded that the criteria for a cost comparison were met because: upadacitinib provided similar overall health benefits to those of secukinumab or ixekizumab, and the total costs associated with upadacitinib were similar to or lower than the total costs associated with secukinumab or ixekizumab. The committee therefore recommended upadacitinib as an option for treating active non-radiographic axial spondyloarthritis in adults.	{'Recommendations': 'Upadacitinib is recommended as an option for treating active non-radiographic axial spondyloarthritis with objective signs of inflammation (shown by elevated C-reactive protein or MRI) that is not controlled well enough with non-steroidal anti-inflammatory drugs (NSAIDs) in adults. It is recommended only if:\n\ntumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough and\n\nthe company provides upadacitinib according to the commercial arrangement.\n\nAssess response to upadacitinib after 16\xa0weeks of treatment. Continue treatment only if there is clear evidence of response, defined as a reduction in:\n\nthe Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pretreatment value or by 2 or more units and\n\nthe spinal pain visual analogue scale (VAS) by 2\xa0cm or more.\n\nTake into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the BASDAI and spinal pain VAS and make any adjustments needed.\n\nIf patients and their clinicians consider upadacitinib to be 1 of a range of suitable treatments (including secukinumab and ixekizumab), discuss the advantages and disadvantages of the available treatments. After that discussion, if more than 1 treatment is suitable, choose the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements.\n\nThese recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nUsual treatment for active non-radiographic axial spondyloarthritis in adults that is not controlled well enough with NSAIDs, and when TNF-alpha inhibitors are not suitable or do not control the condition well enough, is secukinumab or ixekizumab. These are biological treatments. Upadacitinib is another biological treatment.\n\nEvidence from clinical trials shows that upadacitinib reduces symptoms and improves quality of life better than placebo. Indirect comparisons suggest that upadacitinib works as well as secukinumab and ixekizumab.\n\nA cost comparison suggests upadacitinib has similar costs and overall health benefits as secukinumab and ixekizumab. So upadacitinib is recommended.', 'Information about upadacitinib': "# Marketing authorisation indication\n\nUpadacitinib (RINVOQ, AbbVie) is indicated for 'the treatment of active non-radiographic axial spondyloarthritis in adult patients with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for upadacitinib.\n\n# Price\n\nThe list price is £805.56 per 28‑tablet pack, with each tablet containing 15\xa0mg of upadacitinib (excluding VAT; BNF online, accessed November 2022). The annual cost of treatment with one 15‑mg tablet per day is £10,501.05 (excluding VAT; BNF online, accessed November 2022).\n\nThe company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by AbbVie, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Decision problem\n\n## Cost comparison\n\nThe company proposed that upadacitinib should be considered in adults as an alternative to the currently NICE-recommended interleukin (IL)‑17 inhibitors secukinumab and ixekizumab for active non-radiographic axial spondyloarthritis that is not controlled well enough with conventional therapy and when TNF‑alpha inhibitors are not suitable or do not control the condition well enough. The committee agreed that the proposed population was consistent with previous recommendations for IL‑17 inhibitors for active non-radiographic axial spondyloarthritis, and with their use in clinical practice. The company presented a comparison with 2 NICE-recommended IL‑17 inhibitors (NICE technology appraisal guidance on secukinumab for treating non-radiographic axial spondyloarthritis and ixekizumab for treating axial spondyloarthritis). The committee agreed that this was consistent with the criteria for a cost-comparison evaluation.\n\n## Comparators\n\nSecukinumab and ixekizumab are anti‑IL-17 injections recommended by NICE for treating non-radiographic axial spondyloarthritis. Upadacitinib is an oral JAK inhibitor. The clinical and patient experts highlighted the convenience of upadacitinib over IL‑17 inhibitors owing to its oral administration. They also suggested that upadacitinib would be especially helpful for people with needle phobias or dexterity issues that make self-injecting difficult. Clinical advice to the EAG suggested that secukinumab is chosen more often than ixekizumab for treating active non-radiographic axial spondyloarthritis. Secukinumab has been available for ankylosing spondylitis since 2016, suggesting that secukinumab is more established in NHS clinical practice than ixekizumab, which became available in 2021. The committee concluded that secukinumab and ixekizumab are appropriate comparators for upadacitinib, but that secukinumab was the more relevant comparator.\n\n# Clinical effectiveness\n\n## Data sources\n\nUpadacitinib has been studied in 1 randomised controlled trial including 313 adults with active non-radiographic axial spondyloarthritis (SELECT‑AXIS\xa02, study\xa02). It was compared with placebo. In SELECT‑AXIS\xa02, study\xa02, upadacitinib was associated with statistically significant improvements compared with placebo in the primary and secondary outcomes, including the Assessment in Spondyloarthritis international Society 40% (ASAS40) response, BASDAI\xa050 score and total back pain score. Upadacitinib was associated with higher ASAS40 and BASDAI\xa050 responses and total back pain score improvement at week\xa014 than placebo. People having upadacitinib also had statistically significantly higher scores in the Ankylosing Spondylitis Quality of Life (ASQoL) measure. The committee concluded that upadacitinib was more clinically effective than placebo.\n\n## Network meta-analysis\n\nThe company did a series of network meta-analyses comparing clinical-effectiveness data for upadacitinib (SELECT‑AXIS\xa02, study\xa02) with data for secukinumab (PREVENT) and ixekizumab (COAST‑X). The analyses investigated measures of efficacy, including binary outcomes (ASAS40, BASDAI\xa050) and continuous outcomes (BASDAI [change from baseline] and Bath Ankylosing Spondylitis Functional Index [change from baseline]). The EAG highlighted that although the median values favoured upadacitinib over ixekizumab (except for BASDAI\xa050 score) and secukinumab, the credible intervals were wide. It explained that the health benefits for all treatments could be similar, but could also differ. The clinical experts stated in their submission that they would expect upadacitinib to provide clinically meaningful benefits compared with IL‑17 inhibitors. The EAG also identified heterogeneity between the trials included in the network meta-analysis that may impact its validity, but acknowledged that there were no studies available that directly compared upadacitinib with either secukinumab or ixekizumab. The committee confirmed this and noted that uncertainties relating to heterogeneity were unlikely to be resolved by a more detailed cost–utility analysis. The committee concluded that the network meta-analysis was uncertain, but supported the company's position that upadacitinib has similar clinical effectiveness to secukinumab and ixekizumab.\n\n## Safety comparisons between trials\n\nThe company provided safety data comparing upadacitinib with placebo (SELECT‑AXIS\xa02, study\xa02), secukinumab (PREVENT) and ixekizumab (COAST‑X). The company and EAG agreed that the safety profiles of all treatments were broadly similar. However, the EAG highlighted that the company had only provided naive comparisons, and the differences between adverse event incidence between the trials was likely to be influenced by differences in trial design, length of follow up and differences in adverse event definitions in each trial. The committee agreed with the EAG. It concluded that it was difficult to draw definitive conclusions from the safety data, and formal modelling of the available safety data would have been helpful for decision making.\n\n# Cost comparison\n\n## Cost-comparison estimates\n\nThe company presented a base-case cost-comparison analysis that modelled the total costs of upadacitinib, secukinumab and ixekizumab over 5\xa0years. It also provided a scenario analysis modelling the costs over 10\xa0years. It considered that the clinical evidence available supported the assumption of clinical equivalence between upadacitinib, secukinumab and ixekizumab. The EAG was satisfied with the company's cost-comparison analysis methods, so did not provide its own cost-comparison estimates. Taking into account the confidential patient access schemes for upadacitinib, secukinumab and ixekizumab, the committee concluded that the total costs associated with upadacitinib were similar to or lower than those associated with secukinumab and ixekizumab. The discounts for all treatments are confidential, so the incremental costs cannot be shared here.\n\n# Conclusion\n\n## Recommendation\n\nThe committee concluded that the criteria for a cost comparison were met because:\n\nupadacitinib provided similar overall health benefits to those of secukinumab or ixekizumab, and\n\nthe total costs associated with upadacitinib were similar to or lower than the total costs associated with secukinumab or ixekizumab. The committee therefore recommended upadacitinib as an option for treating active non-radiographic axial spondyloarthritis in adults."}	https://www.nice.org.uk/guidance/ta861	Evidence-based recommendations on upadacitinib (Rinvoq) for treating active non-radiographic axial spondyloarthritis in adults.
cfdb6d4dc1316cddc4497735e370cb37c39d3f58	nice	Trastuzumab deruxtecan for treating HER2-positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments	Trastuzumab deruxtecan for treating HER2-positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments Evidence-based recommendations on trastuzumab deruxtecan (Enhertu) for treating HER2-positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments in adults. # Recommendations Trastuzumab deruxtecan is recommended with managed access as an option for treating HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments in adults. It is only recommended if the conditions in the managed access agreement for trastuzumab deruxtecan are followed. This recommendation is not intended to affect treatment with trastuzumab deruxtecan that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Standard treatment for HER2‑positive unresectable or metastatic breast cancer includes anti-HER2 treatments. After first-line treatment with trastuzumab and a taxane, standard treatment is trastuzumab emtansine. Trastuzumab deruxtecan would be an alternative anti-HER2 treatment after trastuzumab and a taxane. Clinical trial evidence shows that trastuzumab deruxtecan increases how long people have before their cancer gets worse compared with trastuzumab emtansine. There is not enough evidence yet to show if people live longer with trastuzumab deruxtecan compared with trastuzumab emtansine because the clinical trial is still ongoing. This means the cost-effectiveness estimates are highly uncertain and trastuzumab deruxtecan cannot be recommended for routine use in the NHS. Trastuzumab deruxtecan could be cost effective if further evidence shows that people live longer with treatment. Evidence from the trial and from NHS practice could help address the uncertainty about how long people live. So, trastuzumab deruxtecan is recommended for use with managed access.# Information about trastuzumab deruxtecan # Marketing authorisation indication Trastuzumab deruxtecan (Enhertu, Daiichi Sankyo) 'as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2‑positive breast cancer who have received one or more prior anti-HER2-based regimens'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for trastuzumab deruxtecan. # Price The list price for trastuzumab deruxtecan is £1,455 per vial containing 100 mg powder for concentrate for solution for infusion (excluding VAT; BNF online accessed October 2022). The company has a commercial arrangement. This makes trastuzumab deruxtecan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Daiichi Sankyo, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Details of the condition Some breast cancer cells have higher levels of a protein called human epidermal growth factor receptor 2 (HER2) on their surface which stimulates them to grow. This is known as HER2‑positive breast cancer and around 1 in 5 unresectable or metastatic breast cancers are HER2‑positive. The patient experts explained that being diagnosed with unresectable or metastatic breast cancer is extremely difficult for people and their family and friends. Many people feel uncertain, upset, and anxious, which can negatively affect mental health. People with unresectable or metastatic breast cancer have to organise their lives around hospital appointments and scans, which can constrain their everyday activities. There is no cure for unresectable or metastatic breast cancer. Treatment aims to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. Treatment is continued for as long as it works. The committee concluded that there is a high disease burden for people with HER2‑positive unresectable or metastatic breast cancer. # Clinical management ## Clinical need Clinical and patient experts explained that people with HER2‑positive unresectable or metastatic breast cancer who have had treatment with trastuzumab and a taxane have a high symptom burden. There is an unmet need for treatments that control disease progression, extend life, and have an acceptable safety profile. First-line treatment of HER2‑positive unresectable or metastatic breast cancer includes the anti-HER2 treatments pertuzumab and trastuzumab with docetaxel (see NICE's technology appraisal guidance on pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer), or trastuzumab with paclitaxel (see NICE's technology appraisal guidance on trastuzumab for the treatment of advanced breast cancer). Trastuzumab emtansine is an anti-HER2 treatment used at second line (see NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane). Non-targeted chemotherapy can also be used at second line (see NICE's guideline on advanced breast cancer: diagnosis and treatment) but the clinical experts confirmed that trastuzumab emtansine is the current standard treatment. Patient and clinical experts explained that new treatments with improved outcomes are needed. Patient experts highlighted the need for new treatments with acceptable tolerability that can extend how long people live and improve quality of life. The committee concluded that that there is an unmet need for alternative anti-HER2 treatments after 1 or more anti-HER2 treatments. ## Comparator The clinical experts confirmed that current standard care in the NHS for people with untreated HER2‑positive unresectable or metastatic breast cancer is trastuzumab and a taxane and that for second-line treatment current standard care is trastuzumab emtansine (see section 3.2). The committee concluded that trastuzumab emtansine is the relevant comparator for trastuzumab deruxtecan. # Clinical evidence ## Data source The clinical evidence was based on DESTINY‑Breast03, a phase 3, open-label, randomised controlled trial for people with HER2‑positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane. The trial was done in 169 centres in 15 countries, with a low number of people included from England. The EAG considered that this resulted in some uncertainty about how generalisable the DESTINY‑Breast03 results are to UK clinical practice. The clinical experts highlighted that the DESTINY‑Breast03 trial included people from different family backgrounds, including Asian and Black family backgrounds. The clinical experts confirmed that DESTINY‑Breast03 is generalisable to UK clinical practice. The committee concluded that, although there were low numbers of people in the trial from England, DESTINY‑Breast03 is generalisable to UK clinical practice. ## Subsequent treatments In its submission, the company explained that the proportion of people who had subsequent treatments in DESTINY‑Breast03 was higher than would be expected in NHS clinical practice based on its clinical expert opinion (the exact proportions are confidential and cannot be reported here). So, it assumed the proportion of people having subsequent treatments to be 66.7% in both the trastuzumab deruxtecan and trastuzumab emtansine arms, based on clinical expert opinion. In response to technical engagement, the company highlighted that its base case value is conservative, given that the same value is applied to both treatment arms. The EAG considered that there is uncertainty associated with clinical expert opinion but agreed the proportion of people having subsequent treatments should be 66.7% for both arms in the model. The committee acknowledged the uncertainty but concluded that an assumption that 66.7% of people would have subsequent treatments in both arms was acceptable for decision making. In its submission, the company used the same subsequent treatments from the trastuzumab deruxtecan arm and the trastuzumab emtansine arm of DESTINY‑Breast03 in its base case. The EAG considered that the subsequent treatment distributions from DESTINY‑Breast03 may not be reflective of the subsequent treatments used in NHS clinical practice. It considered that the subsequent treatments in the European subgroup in DESTINY‑Breast03 may be more applicable to NHS clinical practice. But it noted that the sample size for this subgroup is small and so is associated with uncertainty. In its response to technical engagement, the company provided 3 scenario analyses using different subsequent treatments based on: the European subgroup in DESTINY‑Breast03; UK clinical expert opinion; and the pooled subsequent treatment distribution from DESTINY‑Breast03. It noted these scenarios had a very small impact on the cost-effectiveness estimates and so it maintained its original base case using the subsequent treatment distributions directly from DESTINY‑Breast03. The EAG noted that using the scenario analyses provided by the company resulted in minor differences in the cost-effectiveness estimates. But each scenario was associated with uncertainty, and so it used the same estimates as in the company base case. The committee recognised the uncertainty, but it was satisfied that the various scenario analyses had a minor effect on the cost-effectiveness estimates. It concluded that using subsequent treatment distributions from DESTINY‑Breast03 was acceptable for decision making. ## Clinical effectiveness The primary endpoint of DESTINY‑Breast03 is progression-free survival, and overall survival is a secondary endpoint. At the May 2021 data cut-off, median progression-free survival by blinded independent central review was not reached in the trastuzumab deruxtecan arm compared with 6.8 months in the trastuzumab emtansine arm. The hazard ratio was 0.28 (p<0.001), showing trastuzumab deruxtecan was associated with a statistically significant improvement in progression-free survival compared with trastuzumab emtansine. Median overall survival was not reached in either arm. The median follow up was 16.2 months in the trastuzumab deruxtecan arm and 15.3 months in the trastuzumab emtansine arm. The clinical experts commented that it is rare for a treatment for metastatic breast cancer to demonstrate such a favourable hazard ratio for progression-free survival, and they would expect this to translate into an overall survival benefit. The committee concluded that based on the interim trial data, trastuzumab deruxtecan could be considered a promising treatment for people with HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments but that the evidence on long-term outcomes is limited. ## Long-term treatment effects The overall survival data from the DESTINY‑Breast03 study is immature. The median overall survival for both the trastuzumab deruxtecan and trastuzumab emtansine arms could not be estimated from the number of deaths at the May 2021 data cut-off. The clinical experts commented that they would expect the significant benefit in progression-free survival for trastuzumab deruxtecan to translate into a long-term survival benefit (see section 3.7). The company commented that progression-free survival is a good surrogate for overall survival. It said that trastuzumab deruxtecan was associated with a numerically lower risk of death compared with trastuzumab emtansine at the May 2021 data cut-off, with a hazard ratio of 0.55 (95% confidence interval 0.36 to 0.86). So, it assumed a long-term survival benefit for trastuzumab deruxtecan compared with trastuzumab emtansine in its base case. The EAG noted that because of the small number of deaths in the trastuzumab deruxtecan arm of DESTINY‑Breast03, there is a high level of uncertainty associated with assuming a long-term survival benefit. The committee accepted that it is unlikely that there is no overall survival benefit at all compared with trastuzumab emtansine. But, because the data is immature, it concluded the size of any overall survival benefit for trastuzumab deruxtecan was highly uncertain, resulting in significant uncertainty in the clinical-effectiveness and cost-effectiveness estimates. ## Adverse events The committee noted that trastuzumab deruxtecan is associated with side effects, including interstitial lung disease (ILD). The clinical experts confirmed that trastuzumab deruxtecan is associated with side effects that need careful management. But they explained that trastuzumab deruxtecan is available in the NHS for HER2‑positive unresectable or metastatic breast cancer at a later line in the treatment pathway. This means there is experience of using trastuzumab deruxtecan in the NHS and clinicians can effectively monitor and manage side effects, including ILD. The clinical experts advised that there is clinical enthusiasm to use trastuzumab deruxtecan at an earlier line in the treatment pathway for people with HER2‑positive unresectable or metastatic breast cancer. The patient experts commented that side effects do occur with trastuzumab deruxtecan and they can result in dose reductions, which make the side effects more manageable. But they explained that people will accept the side effects of trastuzumab deruxtecan given the benefit it may bring in reducing both tumour volume and symptoms. The committee concluded that trastuzumab deruxtecan is associated with side effects, which may impact on quality of life, but these are manageable for most people. # Cost-effectiveness evidence ## Company's modelling approach The company submitted a partitioned survival model to estimate the cost effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine. It has 3 health states: progression-free survival, progressed disease, and death. The committee considered that the partitioned survival model is a standard approach to estimate cost effectiveness of cancer drugs and is suitable for decision making. ## Progression-free survival The company fitted independent Weibull models to Kaplan–Meier curves to estimate progression-free survival in both arms. The EAG noted that the progression-free survival estimates from DESTINY‑Breast03 that were used to inform long-term extrapolations of progression-free survival in the economic model were associated with uncertainty because the data was immature. The EAG acknowledged that alternative extrapolations of the data only have a small effect on the cost-effectiveness estimates. The committee concluded that the company's approach to estimating progression-free survival was appropriate. ## Long-term overall survival In its submission, the company assumed a long-term survival benefit for trastuzumab deruxtecan compared with trastuzumab emtansine (see sections 3.7 and 3.8). In its base case, the company extrapolated overall survival beyond the end of the trial follow-up period using parametric survival models. The log-logistic model provided the best statistical fit to the DESTINY‑Breast03 trial data. But the company chose the generalised gamma curve for its base case based on clinical expert opinion. The EAG noted that there is considerable uncertainty in the company's predicted survival for trastuzumab deruxtecan. The company's extrapolated overall survival curve for trastuzumab deruxtecan relies on the assumption that the trend in overall survival seen within the trial will continue beyond the follow-up period. The EAG considered this an uncertain assumption given the immature survival data in DESTINY‑Breast03. It recognised that there is some separation of the overall survival curves between trastuzumab deruxtecan and trastuzumab emtansine. But it commented that there is insufficient evidence to prove a long-term difference in overall survival between them, in particular, if there is a continued benefit during disease progression after treatment has stopped. It commented that there is no survival data post-progression, meaning that it is not clear if there is a treatment effect after disease progression. In its base case, the EAG preferred an assumption that there is no survival benefit after progression. Instead, it used the estimated overall survival from the company's base case for the first 2 years and then adjusted the overall survival beyond 2 years. It used 2 years as the point to adjust overall survival because only 24 people were still in the trastuzumab deruxtecan arm of the trial by 2 years. This method consisted of increasing the mortality hazard ratio according to the implied progression-free survival mortality rate that was derived from the generalised gamma overall survival curve fitted for trastuzumab deruxtecan. The EAG assumed no difference in effectiveness between trastuzumab deruxtecan and trastuzumab emtansine in the progressed disease state beyond 2 years. At technical engagement, the company provided an alternative methodology incorporating further long-term data. Data was replicated from the trastuzumab emtansine arm of the EMILIA study, which compared trastuzumab emtansine with lapatinib and capecitabine. It had a median follow up of 47.8 months. Parametric survival models were fitted to the replicated data to inform the trastuzumab emtansine overall survival. The hazard ratio from DESTINY‑Breast03 was then applied to this curve to inform the trastuzumab deruxtecan overall survival. This alternative method resulted in similar cost-effectiveness estimates to the company's base case. The committee noted that only a small number of deaths occurred during the follow-up period of DESTINY‑Breast03. So, the long-term extrapolation of overall survival for trastuzumab deruxtecan is highly uncertain, with no data currently available to inform which extrapolation method is most appropriate. The committee concluded that the modelling of overall survival was highly uncertain and further data collection was needed to inform overall survival with trastuzumab deruxtecan. ## Utility values In its submission, the company noted that the number of post-progression observations from DESTINY‑Breast03 were limited. It also highlighted that post-progression utility values taken directly from the trial were implausibly high in comparison to previously accepted progressed disease utility values within the same population, based on clinical opinion. So, it used utility values which were derived from coefficients of the mixed model analysis from Lloyd et al. (2006). The company assumed that people who progress while on trastuzumab deruxtecan would have a better quality of life compared with those who progress while on trastuzumab emtansine. This is because of improved response rates and improved disease control. The EAG raised concerns about using Lloyd et al. (2006) to calculate coefficients for the utility values weighted by responder and non-responder from the DESTINY‑Breast03 trial. It noted Lloyd et al. (2006) does not provide any evidence for difference in utility values for people who have progressed after responding to initial treatment. It provides evidence for people who currently respond to treatment before progression. The EAG commented it could not find any evidence for a difference in utility values after progression. At technical engagement, the company provided scenario analyses as an alternative to assuming a utility benefit for trastuzumab deruxtecan across the entire progressed disease state. Instead, the difference in utility lasts for 4 or 6 months after progression, then the same utility value is assumed for both trastuzumab deruxtecan and trastuzumab emtansine. The committee noted the company's rationale that people on trastuzumab deruxtecan would have a higher quality of life post-progression than people on trastuzumab emtansine because of improved response rates and disease control. But the committee considered that there is no direct trial evidence to support such a utility benefit. It concluded that there was no direct evidence of a utility benefit post-progression and that post-progression utility values should be independent of previous treatment. ## Vial sharing In its submission, the company assumed that vial sharing is available in some UK centres. In its base case, the company assumed 50% vial sharing in line with the assumptions accepted in NICE's technology appraisal guidance on sacituzumab govitecan for treating unresectable triple-negative advanced breast cancer after 2 or more therapies and NICE's technology appraisal guidance on trastuzumab deruxtecan for treating HER2-positive unresectable or metastatic breast cancer after 2 or more anti-HER2 therapies. The EAG commented that 50% vial sharing could be an overestimate and that if vial sharing is carried out it is unlikely there would be perfect allocation of each dose. So, it preferred to use 10% vial sharing in its base case. The NHS England Cancer Drugs Fund clinical lead confirmed that vial sharing is encouraged by NHS England and that they expected vial sharing to occur regularly for trastuzumab deruxtecan because of dose banding, in which individual doses are rounded up or down. They commented that they would expect vial sharing to occur in at least 50% of cases. The committee concluded that vial sharing should be assumed to occur in 50% of cases. # Severity ## QALY weighting In its submission, the company provided evidence that HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments is a severe condition. The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company provided absolute and proportional quality-adjusted life year (QALY) shortfall estimates in line with NICE's health technology evaluations manual. Absolute QALY shortfall is the future health that is lost by people living with a condition, including quality and length of life, compared with the expected future health of people living without the condition, over their remaining lifetimes. Proportional QALY shortfall represents the proportion of future health that is lost by people living with the condition, including quality and length of life. To estimate the absolute and proportional QALY shortfalls, the company provided the QALYs of people without the condition over their remaining lifetime, based on the characteristics of people in the trial and the QALYs of people with the condition on current standard care. The company estimated that people with these characteristics without HER2‑positive unresectable or metastatic breast cancer would be expected to have remaining lifetime QALYs of 14.63. It used the Measuring and Valuing Health Study EQ‑5D‑3L value set and health state profiles from 2012 and 2014 Health Survey for England data. The EAG estimated the expected remaining lifetime QALYs to be 14.33 using Hernández-Alava et al. (2017) EQ‑5D‑5L to EQ‑5D‑3L mapping with health state profiles from Health Survey for England data for 2017 to 2018. The company's model estimated the expected remaining lifetime QALYs for people with the condition who have trastuzumab emtansine after trastuzumab and a taxane, by cross-walking EQ‑5D‑5L to EQ‑5D‑3L using the van Hout algorithm. This resulted in values for absolute QALY shortfall of 12 or above. The proportional QALY shortfall was estimated at less than 0.85. The company considered that the 1.2 QALY weight should apply (the exact QALYs, and the absolute and proportional QALY shortfalls are confidential so cannot be reported here). The EAG preferred to cross-walk EQ‑5D‑5L to EQ‑5D‑3L using the Hernández-Alava et al. (2017) algorithm which resulted in values for absolute QALY shortfall of less than 12 and a proportional QALY shortfall of less than 0.85. So, the EAG base case suggested that a severity QALY weighting does not apply (the exact QALYs, and the absolute and proportional QALY shortfalls, are confidential so cannot be reported here). The committee discussed the methods used by the company and the EAG to estimate the remaining lifetime QALYs for the general population and for people living with the condition. It noted NICE's position statement on the use of the EQ-5D-5L value set and was also aware that NICE's health technology evaluations manual states a preference for Hernández-Alava et al. (2017), as used by the ERG to cross-walk EQ‑5D‑5L to EQ‑5D‑3L. It considered there was high uncertainty around the methods used to estimate the remaining lifetime QALYs for the general population and for people living with the condition. The committee noted that the modifier for disease severity was not convincingly met but recognised that there were plausible cost-effectiveness estimates below £30,000 per QALY gained when the QALY weight was not applied and when the 1.2 QALY weight was applied. The committee concluded that it is uncertain whether the modifier for disease severity was convincingly met, but recognised it was met in some scenarios. # Cost-effectiveness estimates ## Company and EAG cost-effectiveness estimates Because of confidential discounts for trastuzumab deruxtecan, trastuzumab emtansine and subsequent treatments, the cost-effectiveness results are commercial in confidence and cannot be reported here. The committee preferred an analysis that included: % of people having subsequent treatments in both arms the distributions of subsequent treatments from DESTINY‑Breast03 treatment-independent post-progression utility values vial sharing in 50% of cases.The committee recalled the uncertainty in how the survival benefit of trastuzumab deruxtecan was modelled and that further data collection was needed to inform overall survival with trastuzumab deruxtecan (see section 3.8 and section 3.11). Using the committee's preferred assumptions and the company's preferred overall survival extrapolation resulted in an incremental cost-effectiveness ratio (ICER) above £30,000 per QALY gained. But the committee noted that using the committee's preferred assumptions with different methods of extrapolating overall survival resulted in ICERs below £30,000 per QALY gained. The committee considered these scenarios were plausible but uncertain. Using the committee's preferred assumptions and the EAG's preferred overall survival extrapolation, which assumed no long-term survival benefit for trastuzumab deruxtecan, resulted in an ICER that was above £30,000 per QALY gained. The committee agreed that this ICER is not implausible, because of the high degree of uncertainty of the long-term overall survival benefit of trastuzumab deruxtecan compared with trastuzumab emtansine. This is mainly related to the immaturity of the overall survival data. The committee recognised that the evidence base was immature and the most plausible cost-effectiveness estimates for trastuzumab deruxtecan are highly uncertain. It concluded that with the available data, the most plausible ICER had not been proven to be within the range usually considered a cost-effective use of resources, even when the severity modifier was applied. So, it concluded that trastuzumab deruxtecan could not be recommended for routine commissioning. # Managed access ## Recommendation with managed access Having concluded that trastuzumab deruxtecan could not be recommended for routine use, the committee then considered if it could be recommended with managed access for treating HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments. The committee considered whether a recommendation with managed access could be made, and discussed that: There is plausible potential to satisfy the criteria for routine use: the committee considered there are plausible ICERs below £30,000 per QALY both when the modifier for disease severity is applied and when it is not applied the company's model is structurally robust for decision making (see section 3.10). The key uncertainties relate to overall survival, which is a key driver of the cost-effectiveness results. New evidence could address the clinical uncertainty: data from DESTINY‑Breast03 is immature because only a small percentage of those recruited had had an event by the May 2021 data cut-off. The trial is ongoing and further data could help reduce uncertainties around long-term progression-free survival and overall survival the Systemic Anti-Cancer Therapy dataset could provide meaningful real-world data about time on treatment and overall survival for trastuzumab deruxtecan in the NHS. The company submitted a managed access proposal and expressed an interest in trastuzumab deruxtecan being considered for funding through managed access. The managed access feasibility assessment noted that trastuzumab deruxtecan would likely be eligible for use in the Cancer Drugs Fund.The committee considered that trastuzumab deruxtecan met the criteria to be considered for a recommendation with managed access. It recommended trastuzumab deruxtecan for use in managed access as an option for people with HER2‑positive unresectable or metastatic breast cancer, after 1 or more anti-HER2 treatments, if the conditions in the managed access agreement are followed. When the guidance is next reviewed the company should use the committee's preferred assumptions (unless new evidence indicates otherwise) as set out in sections 3.4 to 3.15. ## Innovation The company, patient experts and clinical experts considered trastuzumab deruxtecan to be innovative. They explained that it would be a step-change in improving clinical outcomes and managing HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments. The committee considered whether trastuzumab deruxtecan was innovative. It did not identify additional benefits of trastuzumab deruxtecan not captured in the economic modelling. So, the committee concluded that all additional benefits of trastuzumab deruxtecan had already been taken into account.	{'Recommendations': 'Trastuzumab deruxtecan is recommended with managed access as an option for treating HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments in adults. It is only recommended if the conditions in the managed access agreement for trastuzumab deruxtecan are followed.\n\nThis recommendation is not intended to affect treatment with trastuzumab deruxtecan that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard treatment for HER2‑positive unresectable or metastatic breast cancer includes anti-HER2 treatments. After first-line treatment with trastuzumab and a taxane, standard treatment is trastuzumab emtansine. Trastuzumab deruxtecan would be an alternative anti-HER2 treatment after trastuzumab and a taxane.\n\nClinical trial evidence shows that trastuzumab deruxtecan increases how long people have before their cancer gets worse compared with trastuzumab emtansine.\n\nThere is not enough evidence yet to show if people live longer with trastuzumab deruxtecan compared with trastuzumab emtansine because the clinical trial is still ongoing. This means the cost-effectiveness estimates are highly uncertain and trastuzumab deruxtecan cannot be recommended for routine use in the NHS.\n\nTrastuzumab deruxtecan could be cost effective if further evidence shows that people live longer with treatment. Evidence from the trial and from NHS practice could help address the uncertainty about how long people live. So, trastuzumab deruxtecan is recommended for use with managed access.', 'Information about trastuzumab deruxtecan': "# Marketing authorisation indication\n\nTrastuzumab deruxtecan (Enhertu, Daiichi Sankyo) 'as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2‑positive breast cancer who have received one or more prior anti-HER2-based regimens'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for trastuzumab deruxtecan.\n\n# Price\n\nThe list price for trastuzumab deruxtecan is £1,455 per vial containing 100\xa0mg powder for concentrate for solution for infusion (excluding VAT; BNF online accessed October\xa02022).\n\nThe company has a commercial arrangement. This makes trastuzumab deruxtecan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Daiichi Sankyo, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Details of the condition\n\nSome breast cancer cells have higher levels of a protein called human epidermal growth factor receptor\xa02 (HER2) on their surface which stimulates them to grow. This is known as HER2‑positive breast cancer and around 1 in 5 unresectable or metastatic breast cancers are HER2‑positive. The patient experts explained that being diagnosed with unresectable or metastatic breast cancer is extremely difficult for people and their family and friends. Many people feel uncertain, upset, and anxious, which can negatively affect mental health. People with unresectable or metastatic breast cancer have to organise their lives around hospital appointments and scans, which can constrain their everyday activities. There is no cure for unresectable or metastatic breast cancer. Treatment aims to stop progression of the disease, extend life, and maintain or improve quality of life for as long as possible. Treatment is continued for as long as it works. The committee concluded that there is a high disease burden for people with HER2‑positive unresectable or metastatic breast cancer.\n\n# Clinical management\n\n## Clinical need\n\nClinical and patient experts explained that people with HER2‑positive unresectable or metastatic breast cancer who have had treatment with trastuzumab and a taxane have a high symptom burden. There is an unmet need for treatments that control disease progression, extend life, and have an acceptable safety profile. First-line treatment of HER2‑positive unresectable or metastatic breast cancer includes the anti-HER2 treatments pertuzumab and trastuzumab with docetaxel (see NICE's technology appraisal guidance on pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer), or trastuzumab with paclitaxel (see NICE's technology appraisal guidance on trastuzumab for the treatment of advanced breast cancer). Trastuzumab emtansine is an anti-HER2 treatment used at second line (see NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane). Non-targeted chemotherapy can also be used at second line (see NICE's guideline on advanced breast cancer: diagnosis and treatment) but the clinical experts confirmed that trastuzumab emtansine is the current standard treatment. Patient and clinical experts explained that new treatments with improved outcomes are needed. Patient experts highlighted the need for new treatments with acceptable tolerability that can extend how long people live and improve quality of life. The committee concluded that that there is an unmet need for alternative anti-HER2 treatments after 1 or more anti-HER2 treatments.\n\n## Comparator\n\nThe clinical experts confirmed that current standard care in the NHS for people with untreated HER2‑positive unresectable or metastatic breast cancer is trastuzumab and a taxane and that for second-line treatment current standard care is trastuzumab emtansine (see section\xa03.2). The committee concluded that trastuzumab emtansine is the relevant comparator for trastuzumab deruxtecan.\n\n# Clinical evidence\n\n## Data source\n\nThe clinical evidence was based on DESTINY‑Breast03, a phase\xa03, open-label, randomised controlled trial for people with HER2‑positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane. The trial was done in 169 centres in 15 countries, with a low number of people included from England. The EAG considered that this resulted in some uncertainty about how generalisable the DESTINY‑Breast03 results are to UK clinical practice. The clinical experts highlighted that the DESTINY‑Breast03 trial included people from different family backgrounds, including Asian and Black family backgrounds. The clinical experts confirmed that DESTINY‑Breast03 is generalisable to UK clinical practice. The committee concluded that, although there were low numbers of people in the trial from England, DESTINY‑Breast03 is generalisable to UK clinical practice.\n\n## Subsequent treatments\n\nIn its submission, the company explained that the proportion of people who had subsequent treatments in DESTINY‑Breast03 was higher than would be expected in NHS clinical practice based on its clinical expert opinion (the exact proportions are confidential and cannot be reported here). So, it assumed the proportion of people having subsequent treatments to be 66.7% in both the trastuzumab deruxtecan and trastuzumab emtansine arms, based on clinical expert opinion. In response to technical engagement, the company highlighted that its base case value is conservative, given that the same value is applied to both treatment arms. The EAG considered that there is uncertainty associated with clinical expert opinion but agreed the proportion of people having subsequent treatments should be 66.7% for both arms in the model. The committee acknowledged the uncertainty but concluded that an assumption that 66.7% of people would have subsequent treatments in both arms was acceptable for decision making.\n\nIn its submission, the company used the same subsequent treatments from the trastuzumab deruxtecan arm and the trastuzumab emtansine arm of DESTINY‑Breast03 in its base case. The EAG considered that the subsequent treatment distributions from DESTINY‑Breast03 may not be reflective of the subsequent treatments used in NHS clinical practice. It considered that the subsequent treatments in the European subgroup in DESTINY‑Breast03 may be more applicable to NHS clinical practice. But it noted that the sample size for this subgroup is small and so is associated with uncertainty. In its response to technical engagement, the company provided 3 scenario analyses using different subsequent treatments based on: the European subgroup in DESTINY‑Breast03; UK clinical expert opinion; and the pooled subsequent treatment distribution from DESTINY‑Breast03. It noted these scenarios had a very small impact on the cost-effectiveness estimates and so it maintained its original base case using the subsequent treatment distributions directly from DESTINY‑Breast03. The EAG noted that using the scenario analyses provided by the company resulted in minor differences in the cost-effectiveness estimates. But each scenario was associated with uncertainty, and so it used the same estimates as in the company base case. The committee recognised the uncertainty, but it was satisfied that the various scenario analyses had a minor effect on the cost-effectiveness estimates. It concluded that using subsequent treatment distributions from DESTINY‑Breast03 was acceptable for decision making.\n\n## Clinical effectiveness\n\nThe primary endpoint of DESTINY‑Breast03 is progression-free survival, and overall survival is a secondary endpoint. At the May\xa02021 data cut-off, median progression-free survival by blinded independent central review was not reached in the trastuzumab deruxtecan arm compared with 6.8\xa0months in the trastuzumab emtansine arm. The hazard ratio was 0.28 (p<0.001), showing trastuzumab deruxtecan was associated with a statistically significant improvement in progression-free survival compared with trastuzumab emtansine. Median overall survival was not reached in either arm. The median follow up was 16.2\xa0months in the trastuzumab deruxtecan arm and 15.3\xa0months in the trastuzumab emtansine arm. The clinical experts commented that it is rare for a treatment for metastatic breast cancer to demonstrate such a favourable hazard ratio for progression-free survival, and they would expect this to translate into an overall survival benefit. The committee concluded that based on the interim trial data, trastuzumab deruxtecan could be considered a promising treatment for people with HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments but that the evidence on long-term outcomes is limited.\n\n## Long-term treatment effects\n\nThe overall survival data from the DESTINY‑Breast03 study is immature. The median overall survival for both the trastuzumab deruxtecan and trastuzumab emtansine arms could not be estimated from the number of deaths at the May\xa02021 data cut-off. The clinical experts commented that they would expect the significant benefit in progression-free survival for trastuzumab deruxtecan to translate into a long-term survival benefit (see section\xa03.7). The company commented that progression-free survival is a good surrogate for overall survival. It said that trastuzumab deruxtecan was associated with a numerically lower risk of death compared with trastuzumab emtansine at the May\xa02021 data cut-off, with a hazard ratio of 0.55 (95% confidence interval 0.36 to 0.86). So, it assumed a long-term survival benefit for trastuzumab deruxtecan compared with trastuzumab emtansine in its base case. The EAG noted that because of the small number of deaths in the trastuzumab deruxtecan arm of DESTINY‑Breast03, there is a high level of uncertainty associated with assuming a long-term survival benefit. The committee accepted that it is unlikely that there is no overall survival benefit at all compared with trastuzumab emtansine. But, because the data is immature, it concluded the size of any overall survival benefit for trastuzumab deruxtecan was highly uncertain, resulting in significant uncertainty in the clinical-effectiveness and cost-effectiveness estimates.\n\n## Adverse events\n\nThe committee noted that trastuzumab deruxtecan is associated with side effects, including interstitial lung disease (ILD). The clinical experts confirmed that trastuzumab deruxtecan is associated with side effects that need careful management. But they explained that trastuzumab deruxtecan is available in the NHS for HER2‑positive unresectable or metastatic breast cancer at a later line in the treatment pathway. This means there is experience of using trastuzumab deruxtecan in the NHS and clinicians can effectively monitor and manage side effects, including ILD. The clinical experts advised that there is clinical enthusiasm to use trastuzumab deruxtecan at an earlier line in the treatment pathway for people with HER2‑positive unresectable or metastatic breast cancer. The patient experts commented that side effects do occur with trastuzumab deruxtecan and they can result in dose reductions, which make the side effects more manageable. But they explained that people will accept the side effects of trastuzumab deruxtecan given the benefit it may bring in reducing both tumour volume and symptoms. The committee concluded that trastuzumab deruxtecan is associated with side effects, which may impact on quality of life, but these are manageable for most people.\n\n# Cost-effectiveness evidence\n\n## Company's modelling approach\n\nThe company submitted a partitioned survival model to estimate the cost effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine. It has 3 health states: progression-free survival, progressed disease, and death. The committee considered that the partitioned survival model is a standard approach to estimate cost effectiveness of cancer drugs and is suitable for decision making.\n\n## Progression-free survival\n\nThe company fitted independent Weibull models to Kaplan–Meier curves to estimate progression-free survival in both arms. The EAG noted that the progression-free survival estimates from DESTINY‑Breast03 that were used to inform long-term extrapolations of progression-free survival in the economic model were associated with uncertainty because the data was immature. The EAG acknowledged that alternative extrapolations of the data only have a small effect on the cost-effectiveness estimates. The committee concluded that the company's approach to estimating progression-free survival was appropriate.\n\n## Long-term overall survival\n\nIn its submission, the company assumed a long-term survival benefit for trastuzumab deruxtecan compared with trastuzumab emtansine (see sections\xa03.7 and 3.8). In its base case, the company extrapolated overall survival beyond the end of the trial follow-up period using parametric survival models. The log-logistic model provided the best statistical fit to the DESTINY‑Breast03 trial data. But the company chose the generalised gamma curve for its base case based on clinical expert opinion. The EAG noted that there is considerable uncertainty in the company's predicted survival for trastuzumab deruxtecan. The company's extrapolated overall survival curve for trastuzumab deruxtecan relies on the assumption that the trend in overall survival seen within the trial will continue beyond the follow-up period. The EAG considered this an uncertain assumption given the immature survival data in DESTINY‑Breast03. It recognised that there is some separation of the overall survival curves between trastuzumab deruxtecan and trastuzumab emtansine. But it commented that there is insufficient evidence to prove a long-term difference in overall survival between them, in particular, if there is a continued benefit during disease progression after treatment has stopped. It commented that there is no survival data post-progression, meaning that it is not clear if there is a treatment effect after disease progression. In its base case, the EAG preferred an assumption that there is no survival benefit after progression. Instead, it used the estimated overall survival from the company's base case for the first 2\xa0years and then adjusted the overall survival beyond 2\xa0years. It used 2\xa0years as the point to adjust overall survival because only 24 people were still in the trastuzumab deruxtecan arm of the trial by 2\xa0years. This method consisted of increasing the mortality hazard ratio according to the implied progression-free survival mortality rate that was derived from the generalised gamma overall survival curve fitted for trastuzumab deruxtecan. The EAG assumed no difference in effectiveness between trastuzumab deruxtecan and trastuzumab emtansine in the progressed disease state beyond 2\xa0years. At technical engagement, the company provided an alternative methodology incorporating further long-term data. Data was replicated from the trastuzumab emtansine arm of the EMILIA study, which compared trastuzumab emtansine with lapatinib and capecitabine. It had a median follow up of 47.8\xa0months. Parametric survival models were fitted to the replicated data to inform the trastuzumab emtansine overall survival. The hazard ratio from DESTINY‑Breast03 was then applied to this curve to inform the trastuzumab deruxtecan overall survival. This alternative method resulted in similar cost-effectiveness estimates to the company's base case. The committee noted that only a small number of deaths occurred during the follow-up period of DESTINY‑Breast03. So, the long-term extrapolation of overall survival for trastuzumab deruxtecan is highly uncertain, with no data currently available to inform which extrapolation method is most appropriate. The committee concluded that the modelling of overall survival was highly uncertain and further data collection was needed to inform overall survival with trastuzumab deruxtecan.\n\n## Utility values\n\nIn its submission, the company noted that the number of post-progression observations from DESTINY‑Breast03 were limited. It also highlighted that post-progression utility values taken directly from the trial were implausibly high in comparison to previously accepted progressed disease utility values within the same population, based on clinical opinion. So, it used utility values which were derived from coefficients of the mixed model analysis from Lloyd et al. (2006). The company assumed that people who progress while on trastuzumab deruxtecan would have a better quality of life compared with those who progress while on trastuzumab emtansine. This is because of improved response rates and improved disease control. The EAG raised concerns about using Lloyd et al. (2006) to calculate coefficients for the utility values weighted by responder and non-responder from the DESTINY‑Breast03 trial. It noted Lloyd et al. (2006) does not provide any evidence for difference in utility values for people who have progressed after responding to initial treatment. It provides evidence for people who currently respond to treatment before progression. The EAG commented it could not find any evidence for a difference in utility values after progression. At technical engagement, the company provided scenario analyses as an alternative to assuming a utility benefit for trastuzumab deruxtecan across the entire progressed disease state. Instead, the difference in utility lasts for 4\xa0or 6\xa0months after progression, then the same utility value is assumed for both trastuzumab deruxtecan and trastuzumab emtansine. The committee noted the company's rationale that people on trastuzumab deruxtecan would have a higher quality of life post-progression than people on trastuzumab emtansine because of improved response rates and disease control. But the committee considered that there is no direct trial evidence to support such a utility benefit. It concluded that there was no direct evidence of a utility benefit post-progression and that post-progression utility values should be independent of previous treatment.\n\n## Vial sharing\n\nIn its submission, the company assumed that vial sharing is available in some UK centres. In its base case, the company assumed 50% vial sharing in line with the assumptions accepted in NICE's technology appraisal guidance on sacituzumab govitecan for treating unresectable triple-negative advanced breast cancer after 2 or more therapies and NICE's technology appraisal guidance on trastuzumab deruxtecan for treating HER2-positive unresectable or metastatic breast cancer after 2 or more anti-HER2 therapies. The EAG commented that 50% vial sharing could be an overestimate and that if vial sharing is carried out it is unlikely there would be perfect allocation of each dose. So, it preferred to use 10% vial sharing in its base case. The NHS England Cancer Drugs Fund clinical lead confirmed that vial sharing is encouraged by NHS England and that they expected vial sharing to occur regularly for trastuzumab deruxtecan because of dose banding, in which individual doses are rounded up or down. They commented that they would expect vial sharing to occur in at least 50% of cases. The committee concluded that vial sharing should be assumed to occur in 50% of cases.\n\n# Severity\n\n## QALY weighting\n\nIn its submission, the company provided evidence that HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments is a severe condition. The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company provided absolute and proportional quality-adjusted life year (QALY) shortfall estimates in line with NICE's health technology evaluations manual. Absolute QALY shortfall is the future health that is lost by people living with a condition, including quality and length of life, compared with the expected future health of people living without the condition, over their remaining lifetimes. Proportional QALY shortfall represents the proportion of future health that is lost by people living with the condition, including quality and length of life. To estimate the absolute and proportional QALY shortfalls, the company provided the QALYs of people without the condition over their remaining lifetime, based on the characteristics of people in the trial and the QALYs of people with the condition on current standard care. The company estimated that people with these characteristics without HER2‑positive unresectable or metastatic breast cancer would be expected to have remaining lifetime QALYs of 14.63. It used the Measuring and Valuing Health Study EQ‑5D‑3L value set and health state profiles from 2012 and 2014 Health Survey for England data. The EAG estimated the expected remaining lifetime QALYs to be 14.33 using Hernández-Alava et al. (2017) EQ‑5D‑5L to EQ‑5D‑3L mapping with health state profiles from Health Survey for England data for 2017 to 2018. The company's model estimated the expected remaining lifetime QALYs for people with the condition who have trastuzumab emtansine after trastuzumab and a taxane, by cross-walking EQ‑5D‑5L to EQ‑5D‑3L using the van Hout algorithm. This resulted in values for absolute QALY shortfall of 12 or above. The proportional QALY shortfall was estimated at less than 0.85. The company considered that the 1.2 QALY weight should apply (the exact QALYs, and the absolute and proportional QALY shortfalls are confidential so cannot be reported here). The EAG preferred to cross-walk EQ‑5D‑5L to EQ‑5D‑3L using the Hernández-Alava et al. (2017) algorithm which resulted in values for absolute QALY shortfall of less than 12 and a proportional QALY shortfall of less than 0.85. So, the EAG base case suggested that a severity QALY weighting does not apply (the exact QALYs, and the absolute and proportional QALY shortfalls, are confidential so cannot be reported here). The committee discussed the methods used by the company and the EAG to estimate the remaining lifetime QALYs for the general population and for people living with the condition. It noted NICE's position statement on the use of the EQ-5D-5L value set and was also aware that NICE's health technology evaluations manual states a preference for Hernández-Alava et al. (2017), as used by the ERG to cross-walk EQ‑5D‑5L to EQ‑5D‑3L. It considered there was high uncertainty around the methods used to estimate the remaining lifetime QALYs for the general population and for people living with the condition. The committee noted that the modifier for disease severity was not convincingly met but recognised that there were plausible cost-effectiveness estimates below £30,000 per QALY gained when the QALY weight was not applied and when the 1.2 QALY weight was applied. The committee concluded that it is uncertain whether the modifier for disease severity was convincingly met, but recognised it was met in some scenarios.\n\n# Cost-effectiveness estimates\n\n## Company and EAG cost-effectiveness estimates\n\nBecause of confidential discounts for trastuzumab deruxtecan, trastuzumab emtansine and subsequent treatments, the cost-effectiveness results are commercial in confidence and cannot be reported here. The committee preferred an analysis that included:\n\n% of people having subsequent treatments in both arms\n\nthe distributions of subsequent treatments from DESTINY‑Breast03\n\ntreatment-independent post-progression utility values\n\nvial sharing in 50% of cases.The committee recalled the uncertainty in how the survival benefit of trastuzumab deruxtecan was modelled and that further data collection was needed to inform overall survival with trastuzumab deruxtecan (see section\xa03.8 and section\xa03.11). Using the committee's preferred assumptions and the company's preferred overall survival extrapolation resulted in an incremental cost-effectiveness ratio (ICER) above £30,000 per QALY gained. But the committee noted that using the committee's preferred assumptions with different methods of extrapolating overall survival resulted in ICERs below £30,000 per QALY gained. The committee considered these scenarios were plausible but uncertain. Using the committee's preferred assumptions and the EAG's preferred overall survival extrapolation, which assumed no long-term survival benefit for trastuzumab deruxtecan, resulted in an ICER that was above £30,000 per QALY gained. The committee agreed that this ICER is not implausible, because of the high degree of uncertainty of the long-term overall survival benefit of trastuzumab deruxtecan compared with trastuzumab emtansine. This is mainly related to the immaturity of the overall survival data. The committee recognised that the evidence base was immature and the most plausible cost-effectiveness estimates for trastuzumab deruxtecan are highly uncertain. It concluded that with the available data, the most plausible ICER had not been proven to be within the range usually considered a cost-effective use of resources, even when the severity modifier was applied. So, it concluded that trastuzumab deruxtecan could not be recommended for routine commissioning.\n\n# Managed access\n\n## Recommendation with managed access\n\nHaving concluded that trastuzumab deruxtecan could not be recommended for routine use, the committee then considered if it could be recommended with managed access for treating HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments. The committee considered whether a recommendation with managed access could be made, and discussed that:\n\nThere is plausible potential to satisfy the criteria for routine use:\n\n\n\nthe committee considered there are plausible ICERs below £30,000 per QALY both when the modifier for disease severity is applied and when it is not applied\n\nthe company's model is structurally robust for decision making (see section\xa03.10).\n\n\n\nThe key uncertainties relate to overall survival, which is a key driver of the cost-effectiveness results.\n\nNew evidence could address the clinical uncertainty:\n\n\n\ndata from DESTINY‑Breast03 is immature because only a small percentage of those recruited had had an event by the May\xa02021 data cut-off. The trial is ongoing and further data could help reduce uncertainties around long-term progression-free survival and overall survival\n\nthe Systemic Anti-Cancer Therapy dataset could provide meaningful real-world data about time on treatment and overall survival for trastuzumab deruxtecan in the NHS.\n\n\n\nThe company submitted a managed access proposal and expressed an interest in trastuzumab deruxtecan being considered for funding through managed access. The managed access feasibility assessment noted that trastuzumab deruxtecan would likely be eligible for use in the Cancer Drugs Fund.The committee considered that trastuzumab deruxtecan met the criteria to be considered for a recommendation with managed access. It recommended trastuzumab deruxtecan for use in managed access as an option for people with HER2‑positive unresectable or metastatic breast cancer, after 1 or more anti-HER2 treatments, if the conditions in the managed access agreement are followed. When the guidance is next reviewed the company should use the committee's preferred assumptions (unless new evidence indicates otherwise) as set out in sections\xa03.4 to 3.15.\n\n## Innovation\n\nThe company, patient experts and clinical experts considered trastuzumab deruxtecan to be innovative. They explained that it would be a step-change in improving clinical outcomes and managing HER2‑positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments. The committee considered whether trastuzumab deruxtecan was innovative. It did not identify additional benefits of trastuzumab deruxtecan not captured in the economic modelling. So, the committee concluded that all additional benefits of trastuzumab deruxtecan had already been taken into account."}	https://www.nice.org.uk/guidance/ta862	Evidence-based recommendations on trastuzumab deruxtecan (Enhertu) for treating HER2-positive unresectable or metastatic breast cancer after 1 or more anti-HER2 treatments in adults.
2429c1b6be485afd887c1d5c5d07dc4b1629cb6f	nice	Nintedanib for treating idiopathic pulmonary fibrosis when forced vital capacity is above 80% predicted	Nintedanib for treating idiopathic pulmonary fibrosis when forced vital capacity is above 80% predicted Evidence-based recommendations on nintedanib (Ofev) for treating idiopathic pulmonary fibrosis in adults when forced vital capacity is above 80% predicted. # Recommendations Nintedanib is recommended as an option for treating idiopathic pulmonary fibrosis in adults, only if: they have a forced vital capacity of above 80% predicted the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with nintedanib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations This technology appraisal is for treating idiopathic pulmonary fibrosis in people with a forced vital capacity (FVC) above 80% predicted. Nintedanib is also recommended for people with an FVC between 50% and 80% predicted (NICE technology appraisal guidance 379). Currently, the only option for people with idiopathic pulmonary fibrosis with an FVC above 80% predicted is best supportive care. Clinical trial evidence shows that nintedanib slows the decrease of lung function compared with placebo in people with idiopathic pulmonary fibrosis with an FVC above 80% predicted. Also, long-term evidence suggests that the effect of nintedanib is maintained over time. The most likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So, nintedanib is recommended.# Information about nintedanib # Marketing authorisation indication Nintedanib (Ofev, Boehringer Ingelheim) is indicated 'for the treatment of idiopathic pulmonary fibrosis'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for nintedanib. # Price The price of nintedanib is £2,151.10 per pack of 60 capsules, each containing 150 mg (excluding VAT; BNF online accessed October 2022). The company has a commercial arrangement. This makes nintedanib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Boehringer Ingelheim, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Review objectives The committee reviewed existing and new data on the clinical and cost effectiveness of nintedanib. It also considered evidence on the nature of idiopathic pulmonary fibrosis and the benefits of nintedanib for people with the condition and clinical experts. The committee also took into account the effective use of NHS resources. This evaluation reviews part of NICE's previous technology appraisal guidance on nintedanib. This is to take into account new evidence relating to people with a forced vital capacity (FVC) above 80% predicted. This review only considers part of nintedanib's marketing authorisation (people with a FVC above 80% predicted). # The condition ## Unmet need Idiopathic pulmonary fibrosis is a chronic, progressive lung disease characterised by scarring (fibrosis) of lung tissues. Most people with idiopathic pulmonary fibrosis experience breathlessness and coughing, which are associated with a progressive decline in lung function. The median survival from diagnosis is 2 to 5 years. Patient experts explained that the physical symptoms of the condition severely impacts people's quality of life affecting mobility, mental health, and ability to complete usual activities. The committee discussed the treatments for idiopathic pulmonary fibrosis in current NHS practice. The clinical experts explained that they offer treatment with pirfenidone (NICE's technology appraisal guidance on pirfenidone for treating idiopathic pulmonary fibrosis) or nintedanib (NICE's technology appraisal guidance on nintedanib for treating idiopathic pulmonary fibrosis, from now TA379) to people with an FVC between 50% and 80% predicted. This reflects NICE's technology appraisal guidance on pirfenidone and nintedanib for treating idiopathic pulmonary fibrosis. The clinical experts noted that they would offer best supportive care to people with an FVC above 80% predicted because NICE does not recommend pirfenidone or nintedanib in this population. Clinicians would like to offer active treatments to people with an FVC above 80% predicted. The committee concluded that the only treatment option for people with idiopathic pulmonary fibrosis who have an FVC above 80% predicted is best supportive care. It recognised the unmet need of these people. # Clinical effectiveness ## Evidence sources The company did an updated systematic literature review to identify new data available since TA379. Data from relevant subgroups within 5 identified trials comparing nintedanib with placebo were included in the company's submission: phase 3 INPULSIS 1 and 2 randomised controlled trials (RCTs) phase 2 TOMORROW RCT INPULSIS‑ON open-label extension study TOMORROW open-label extension study.The EAG raised concerns that the inclusion and exclusion criteria in the company's systematic literature review were unclear, which may have caused relevant observational studies to be excluded. In particular, the EAG raised concerns about excluding Lancaster et al. (2020), which reports the results of a phase 3b clinical trial comparing nintedanib with placebo. The company explained that this was excluded from the literature review because it is not a pivotal trial and because of methodological limitations caused by protocol amendments. For example, the company noted that the primary analysis was done at 6 months instead of 52 weeks, which may have introduced bias into the study. However, the EAG believed that limitations of the study would not significantly bias the results and the data could have been used to inform survival estimations in the model. The company explained that the results of Lancaster et al. are consistent with data from the TOMORROW and INPULSIS studies. Because of this, the company considered that including the data from Lancaster et al. (2020) would have a minimal effect on the results in its submission. The committee concluded that further transparency on the company's systematic literature review methodology would have been useful to reduce uncertainty, but there was enough evidence for reasonable decision making. ## Results The results for the clinical effectiveness of nintedanib in people with idiopathic pulmonary fibrosis with an FVC above 80% predicted came from post-hoc subgroup analyses of the INPULSIS and TOMORROW trials (see section 3.3). The pooled results from the INPULSIS trials showed a reduced decline in FVC of 128.4 ml per year for nintedanib compared with placebo in people with idiopathic pulmonary fibrosis with an FVC above 80% predicted. Results from the TOMORROW trial showed a reduced decline in FVC of 176 ml per year for nintedanib compared with placebo in people with idiopathic pulmonary fibrosis with an FVC of above 80% predicted. There was no statistically significant difference in the reduction in decline for the FVC above 80% predicted subgroup compared with the whole population. The committee noted that the annual rate of decline in FVC in INPULSIS‑ON was consistent with what was observed in the INPULSIS trials, which suggested that the effects of nintedanib persist beyond 4 years. The results from the TOMORROW open-label extension also showed similar results. Long-term efficacy in reducing disease progression was also sustained in people who needed dose adjustments. The committee concluded that results from all the trials indicated that nintedanib gave a sustained improvement in patient outcomes compared with placebo in people with an FVC above 80% predicted. # Survival modelling ## Overall survival population The company stated that the network meta-analysis (NMA) done as part of TA379 had not been updated for this evaluation. The company said that this was because no new relevant nintedanib RCTs had been identified. However, unlike the previous evaluation, only results for the comparison with placebo were considered relevant to this population and considered within this evaluation. The EAG noted that the NMA was done for the whole trial population and not specifically for people with an FVC above 80% predicted. The company explained that this was because no significant treatment effect by subgroup was observed for primary or secondary endpoints (see section 3.4). This meant the results for the overall population are expected to be similar to those expected in people with an FVC above 80% predicted. The EAG noted that the INPULSIS trials were not designed to investigate the effects of nintedanib in subgroups and so it is plausible that the non-significant results are because of a lack of statistical power. Also, the EAG suggested that overall survival for people with an FVC above 80% predicted should have been used to reflect the lower mortality rate in this group. Because of this, the EAG preferred to include overall survival results for people with an FVC above 80% predicted in its base case. The committee recognised that analysis of people with an FVC above 80% predicted may be more relevant, but also noted that subgroup analysis would reduce sample sizes and increase uncertainty. So, the committee concluded that scenarios with both EAG and company approaches would be relevant to consider in decision making. ## Overall survival extrapolation The committee noted that the duration of follow-up data for nintedanib is about 5.5 years (which is longer than in the analyses used in TA379). The EAG explained that in the data for people with an FVC above 80% predicted, the survival curves were similar in the nintedanib group and the best supportive care group at 52 weeks. At this point in the trials, people having placebo were allowed to switch to nintedanib, significantly reducing the number of people having placebo and available for survival analysis beyond this point. The EAG noted that this increased the uncertainty of survival data in the placebo arm. Therefore, the EAG's preferred approach was to assume that survival in the nintedanib arm and the best supportive care arm was equivalent until the average predicted FVC of the subgroup reached that of the whole trial population. After this point, survival in the best supportive care arm was assumed to follow the extrapolated curve from the whole trial population for the best supportive care arm. This was modelled to happen after 5.5 years in the EAG's base case. However, the EAG also presented scenario analyses assuming that overall survival remained the same in both treatment groups for 1 year and for 3 years. The company disagreed with the EAG's survival data extrapolation. It believed that the approach did not match with real-world data. Also, the company suggested that modelling equal survival for nintedanib and the best supportive care arm implied that nintedanib was not effective for the first 5.5 years. It noted that lung function decline is a key predictor of survival. So, assuming equal survival in both arms does not take into account the data showing that nintedanib reduces the rate of lung function decline (see section 3.4). The committee noted that nintedanib showed a higher survival probability at 5 years (60% instead of 40%) than was predicted in the original evaluation. It considered that the EAG's approach may be conservative because the trial results suggested there could be a survival difference between the arms. The committee also noted that, despite the survival data in the placebo arm being more uncertain, the length of follow up was typical for a technology appraisal and the nintedanib arm had far more data than was usual. The committee concluded that both the company's approach and the EAG's approach should be considered. # Economic model ## Model structure The company presented a Markov model to estimate the cost effectiveness of nintedanib compared with standard care in people with idiopathic pulmonary fibrosis with an FVC above 80% predicted. The structure of the model was the same as was submitted in TA379. The model used a lifetime horizon and a cycle length of 3 months. The health states in the model used 2 measures: predicted FVC (separated by 10 percentage point increments) and the occurrence of an acute exacerbation. People changed health states if they experienced a loss of lung function, exacerbation, both a loss of lung function and exacerbation, or death. People who moved to a lower predicted FVC health state could not move back to a higher health state. Similarly, people who experienced exacerbation were unable to move back to a non-exacerbation health state. The model also allowed for people to experience adverse events. The EAG considered the model structure reasonable. However, it noted that the company model does not include general population mortality and uses a 50‑year time horizon. The EAG suggested that a 35‑year time horizon may be more suitable because the starting age of the patient population in the model was 67 years old. The committee concluded that the company's model was acceptable for decision making, but noted that it was more appropriate to use a 35‑year time horizon. ## Stopping rule In TA379, a stopping rule was implemented for people whose predicted FVC percentage decreased by 10% or more in a 12‑month period. This stopping rule was not implemented by the company in this evaluation of people with an FVC above 80% predicted. The committee recalled that in TA379, nintedanib could not be considered cost effective without a stopping rule. In this evaluation, the company removed the stopping rule from their analyses and explained that expert clinical advice input suggested that the stopping rule would be difficult to implement. It was also noted that in NICE's technology appraisal guidance on nintedanib for treating progressive fibrosing interstitial lung diseases, clinical experts advised they would stop treatment with nintedanib if disease progression was not sufficiently slowed, even without a formal stopping rule. Clinical experts advised the EAG that people tend to stop taking nintedanib because of tolerability issues or advancing disease with high symptom burden. Also, they advised that predicted FVC was not usually used as the only measure for stopping treatment with nintedanib. They noted that predicted FVC can vary significantly for an individual patient. The EAG also did scenario analysis including the stopping rule. The committee acknowledged the expert opinion and concluded that if nintedanib was a cost-effective use of NHS resources without a formal stopping rule in this evaluation, then no stopping rule would be applied. # Cost-effectiveness estimates ## Results The company's base-case incremental cost-effectiveness ratio (ICER) compared with best supportive care was below £20,000 per quality-adjusted life-year (QALY) gained, when commercial arrangements for nintedanib and all the comparators were included. The exact ICERs are considered confidential and cannot be reported here. Also, the ICER was below £30,000 per QALY gained when considering the EAG's base case which used: the survival data from the subgroup of people with an FVC above 80% predicted (see section 3.5) the same extrapolation for the nintedanib and placebo arms for the first 5.5 years of the model (see section 3.6) a time horizon of 35 years (see section 3.7).The committee agreed with the EAG's use of the survival data for the subgroup with an FVC above 80% predicted (see section 3.5) and the reduced time horizon (see section 3.7). However, the committee believed that the EAG's extrapolation of the survival data may be conservative (see section 3.6). The committee also considered key scenario analysis such as different extrapolations of survival data. To understand the level of uncertainty, it considered probabilistic sensitivity analyses on both the corrected company base case and the EAG's base case. The results indicated that, using the corrected company base case, nintedanib was likely to be cost effective at a threshold of £20,000 per QALY gained. Even with the conservative approach taken by the EAG, nintedanib was likely to be cost effective at a threshold of £30,000 per QALY gained. Overall, the committee concluded that nintedanib was likely to be a cost-effective use of NHS resources. # Other factors ## Equality issues No equality issues were identified. NICE's advice about conditions with a high degree of severity did not apply. # Conclusion ## Recommendation All the ICERs considered by the committee were in the range normally considered a cost-effective use of NHS resources. So, nintedanib is recommended for treating idiopathic pulmonary fibrosis in people with an FVC above 80% predicted.	{'Recommendations': 'Nintedanib is recommended as an option for treating idiopathic pulmonary fibrosis in adults, only if:\n\nthey have a forced vital capacity of above 80% predicted\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with nintedanib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThis technology appraisal is for treating idiopathic pulmonary fibrosis in people with a forced vital capacity (FVC) above 80% predicted. Nintedanib is also recommended for people with an FVC between 50% and 80% predicted (NICE technology appraisal guidance 379). Currently, the only option for people with idiopathic pulmonary fibrosis with an FVC above 80% predicted is best supportive care.\n\nClinical trial evidence shows that nintedanib slows the decrease of lung function compared with placebo in people with idiopathic pulmonary fibrosis with an FVC above 80% predicted. Also, long-term evidence suggests that the effect of nintedanib is maintained over time.\n\nThe most likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. So, nintedanib is recommended.', 'Information about nintedanib': "# Marketing authorisation indication\n\nNintedanib (Ofev, Boehringer Ingelheim) is indicated 'for the treatment of idiopathic pulmonary fibrosis'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for nintedanib.\n\n# Price\n\nThe price of nintedanib is £2,151.10 per pack of 60\xa0capsules, each containing 150\xa0mg (excluding VAT; BNF online accessed October 2022).\n\nThe company has a commercial arrangement. This makes nintedanib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Boehringer Ingelheim, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Review objectives\n\nThe committee reviewed existing and new data on the clinical and cost effectiveness of nintedanib. It also considered evidence on the nature of idiopathic pulmonary fibrosis and the benefits of nintedanib for people with the condition and clinical experts. The committee also took into account the effective use of NHS resources. This evaluation reviews part of NICE's previous technology appraisal guidance on nintedanib. This is to take into account new evidence relating to people with a forced vital capacity (FVC) above 80% predicted. This review only considers part of nintedanib's marketing authorisation (people with a FVC above 80% predicted).\n\n# The condition\n\n## Unmet need\n\nIdiopathic pulmonary fibrosis is a chronic, progressive lung disease characterised by scarring (fibrosis) of lung tissues. Most people with idiopathic pulmonary fibrosis experience breathlessness and coughing, which are associated with a progressive decline in lung function. The median survival from diagnosis is 2\xa0to 5\xa0years. Patient experts explained that the physical symptoms of the condition severely impacts people's quality of life affecting mobility, mental health, and ability to complete usual activities. The committee discussed the treatments for idiopathic pulmonary fibrosis in current NHS practice. The clinical experts explained that they offer treatment with pirfenidone (NICE's technology appraisal guidance on pirfenidone for treating idiopathic pulmonary fibrosis) or nintedanib (NICE's technology appraisal guidance on nintedanib for treating idiopathic pulmonary fibrosis, from now TA379) to people with an FVC between 50% and 80% predicted. This reflects NICE's technology appraisal guidance on pirfenidone and nintedanib for treating idiopathic pulmonary fibrosis. The clinical experts noted that they would offer best supportive care to people with an FVC above 80% predicted because NICE does not recommend pirfenidone or nintedanib in this population. Clinicians would like to offer active treatments to people with an FVC above 80% predicted. The committee concluded that the only treatment option for people with idiopathic pulmonary fibrosis who have an FVC above 80% predicted is best supportive care. It recognised the unmet need of these people.\n\n# Clinical effectiveness\n\n## Evidence sources\n\nThe company did an updated systematic literature review to identify new data available since TA379. Data from relevant subgroups within 5 identified trials comparing nintedanib with placebo were included in the company's submission:\n\nphase\xa03 INPULSIS 1 and 2 randomised controlled trials (RCTs)\n\nphase 2 TOMORROW RCT\n\nINPULSIS‑ON open-label extension study\n\nTOMORROW open-label extension study.The EAG raised concerns that the inclusion and exclusion criteria in the company's systematic literature review were unclear, which may have caused relevant observational studies to be excluded. In particular, the EAG raised concerns about excluding Lancaster et al. (2020), which reports the results of a phase\xa03b clinical trial comparing nintedanib with placebo. The company explained that this was excluded from the literature review because it is not a pivotal trial and because of methodological limitations caused by protocol amendments. For example, the company noted that the primary analysis was done at 6\xa0months instead of 52\xa0weeks, which may have introduced bias into the study. However, the EAG believed that limitations of the study would not significantly bias the results and the data could have been used to inform survival estimations in the model. The company explained that the results of Lancaster et al. are consistent with data from the TOMORROW and INPULSIS studies. Because of this, the company considered that including the data from Lancaster et al. (2020) would have a minimal effect on the results in its submission. The committee concluded that further transparency on the company's systematic literature review methodology would have been useful to reduce uncertainty, but there was enough evidence for reasonable decision making.\n\n## Results\n\nThe results for the clinical effectiveness of nintedanib in people with idiopathic pulmonary fibrosis with an FVC above 80% predicted came from post-hoc subgroup analyses of the INPULSIS and TOMORROW trials (see section\xa03.3). The pooled results from the INPULSIS trials showed a reduced decline in FVC of 128.4\xa0ml per year for nintedanib compared with placebo in people with idiopathic pulmonary fibrosis with an FVC above 80% predicted. Results from the TOMORROW trial showed a reduced decline in FVC of 176\xa0ml per year for nintedanib compared with placebo in people with idiopathic pulmonary fibrosis with an FVC of above 80% predicted. There was no statistically significant difference in the reduction in decline for the FVC above 80% predicted subgroup compared with the whole population. The committee noted that the annual rate of decline in FVC in INPULSIS‑ON was consistent with what was observed in the INPULSIS trials, which suggested that the effects of nintedanib persist beyond 4\xa0years. The results from the TOMORROW open-label extension also showed similar results. Long-term efficacy in reducing disease progression was also sustained in people who needed dose adjustments. The committee concluded that results from all the trials indicated that nintedanib gave a sustained improvement in patient outcomes compared with placebo in people with an FVC above 80% predicted.\n\n# Survival modelling\n\n## Overall survival population\n\nThe company stated that the network meta-analysis (NMA) done as part of TA379 had not been updated for this evaluation. The company said that this was because no new relevant nintedanib RCTs had been identified. However, unlike the previous evaluation, only results for the comparison with placebo were considered relevant to this population and considered within this evaluation. The EAG noted that the NMA was done for the whole trial population and not specifically for people with an FVC above 80% predicted. The company explained that this was because no significant treatment effect by subgroup was observed for primary or secondary endpoints (see section\xa03.4). This meant the results for the overall population are expected to be similar to those expected in people with an FVC above 80% predicted. The EAG noted that the INPULSIS trials were not designed to investigate the effects of nintedanib in subgroups and so it is plausible that the non-significant results are because of a lack of statistical power. Also, the EAG suggested that overall survival for people with an FVC above 80% predicted should have been used to reflect the lower mortality rate in this group. Because of this, the EAG preferred to include overall survival results for people with an FVC above 80% predicted in its base case. The committee recognised that analysis of people with an FVC above 80% predicted may be more relevant, but also noted that subgroup analysis would reduce sample sizes and increase uncertainty. So, the committee concluded that scenarios with both EAG and company approaches would be relevant to consider in decision making.\n\n## Overall survival extrapolation\n\nThe committee noted that the duration of follow-up data for nintedanib is about 5.5\xa0years (which is longer than in the analyses used in TA379). The EAG explained that in the data for people with an FVC above 80% predicted, the survival curves were similar in the nintedanib group and the best supportive care group at 52\xa0weeks. At this point in the trials, people having placebo were allowed to switch to nintedanib, significantly reducing the number of people having placebo and available for survival analysis beyond this point. The EAG noted that this increased the uncertainty of survival data in the placebo arm. Therefore, the EAG's preferred approach was to assume that survival in the nintedanib arm and the best supportive care arm was equivalent until the average predicted FVC of the subgroup reached that of the whole trial population. After this point, survival in the best supportive care arm was assumed to follow the extrapolated curve from the whole trial population for the best supportive care arm. This was modelled to happen after 5.5\xa0years in the EAG's base case. However, the EAG also presented scenario analyses assuming that overall survival remained the same in both treatment groups for 1\xa0year and for 3\xa0years. The company disagreed with the EAG's survival data extrapolation. It believed that the approach did not match with real-world data. Also, the company suggested that modelling equal survival for nintedanib and the best supportive care arm implied that nintedanib was not effective for the first 5.5\xa0years. It noted that lung function decline is a key predictor of survival. So, assuming equal survival in both arms does not take into account the data showing that nintedanib reduces the rate of lung function decline (see section\xa03.4). The committee noted that nintedanib showed a higher survival probability at 5\xa0years (60% instead of 40%) than was predicted in the original evaluation. It considered that the EAG's approach may be conservative because the trial results suggested there could be a survival difference between the arms. The committee also noted that, despite the survival data in the placebo arm being more uncertain, the length of follow up was typical for a technology appraisal and the nintedanib arm had far more data than was usual. The committee concluded that both the company's approach and the EAG's approach should be considered.\n\n# Economic model\n\n## Model structure\n\nThe company presented a Markov model to estimate the cost effectiveness of nintedanib compared with standard care in people with idiopathic pulmonary fibrosis with an FVC above 80% predicted. The structure of the model was the same as was submitted in TA379. The model used a lifetime horizon and a cycle length of 3\xa0months. The health states in the model used 2 measures: predicted FVC (separated by 10\xa0percentage point increments) and the occurrence of an acute exacerbation. People changed health states if they experienced a loss of lung function, exacerbation, both a loss of lung function and exacerbation, or death. People who moved to a lower predicted FVC health state could not move back to a higher health state. Similarly, people who experienced exacerbation were unable to move back to a non-exacerbation health state. The model also allowed for people to experience adverse events. The EAG considered the model structure reasonable. However, it noted that the company model does not include general population mortality and uses a 50‑year time horizon. The EAG suggested that a 35‑year time horizon may be more suitable because the starting age of the patient population in the model was 67\xa0years old. The committee concluded that the company's model was acceptable for decision making, but noted that it was more appropriate to use a 35‑year time horizon.\n\n## Stopping rule\n\nIn TA379, a stopping rule was implemented for people whose predicted FVC percentage decreased by 10% or more in a 12‑month period. This stopping rule was not implemented by the company in this evaluation of people with an FVC above 80% predicted. The committee recalled that in TA379, nintedanib could not be considered cost effective without a stopping rule. In this evaluation, the company removed the stopping rule from their analyses and explained that expert clinical advice input suggested that the stopping rule would be difficult to implement. It was also noted that in NICE's technology appraisal guidance on nintedanib for treating progressive fibrosing interstitial lung diseases, clinical experts advised they would stop treatment with nintedanib if disease progression was not sufficiently slowed, even without a formal stopping rule. Clinical experts advised the EAG that people tend to stop taking nintedanib because of tolerability issues or advancing disease with high symptom burden. Also, they advised that predicted FVC was not usually used as the only measure for stopping treatment with nintedanib. They noted that predicted FVC can vary significantly for an individual patient. The EAG also did scenario analysis including the stopping rule. The committee acknowledged the expert opinion and concluded that if nintedanib was a cost-effective use of NHS resources without a formal stopping rule in this evaluation, then no stopping rule would be applied.\n\n# Cost-effectiveness estimates\n\n## Results\n\nThe company's base-case incremental cost-effectiveness ratio (ICER) compared with best supportive care was below £20,000 per quality-adjusted life-year (QALY) gained, when commercial arrangements for nintedanib and all the comparators were included. The exact ICERs are considered confidential and cannot be reported here. Also, the ICER was below £30,000 per QALY gained when considering the EAG's base case which used:\n\nthe survival data from the subgroup of people with an FVC above 80% predicted (see section\xa03.5)\n\nthe same extrapolation for the nintedanib and placebo arms for the first 5.5\xa0years of the model (see section\xa03.6)\n\na time horizon of 35\xa0years (see section\xa03.7).The committee agreed with the EAG's use of the survival data for the subgroup with an FVC above 80% predicted (see section\xa03.5) and the reduced time horizon (see section\xa03.7). However, the committee believed that the EAG's extrapolation of the survival data may be conservative (see section\xa03.6). The committee also considered key scenario analysis such as different extrapolations of survival data. To understand the level of uncertainty, it considered probabilistic sensitivity analyses on both the corrected company base case and the EAG's base case. The results indicated that, using the corrected company base case, nintedanib was likely to be cost effective at a threshold of £20,000 per QALY gained. Even with the conservative approach taken by the EAG, nintedanib was likely to be cost effective at a threshold of £30,000 per QALY gained. Overall, the committee concluded that nintedanib was likely to be a cost-effective use of NHS resources.\n\n# Other factors\n\n## Equality issues\n\nNo equality issues were identified. NICE's advice about conditions with a high degree of severity did not apply.\n\n# Conclusion\n\n## Recommendation\n\nAll the ICERs considered by the committee were in the range normally considered a cost-effective use of NHS resources. So, nintedanib is recommended for treating idiopathic pulmonary fibrosis in people with an FVC above 80% predicted."}	https://www.nice.org.uk/guidance/ta864	Evidence-based recommendations on nintedanib (Ofev) for treating idiopathic pulmonary fibrosis in adults when forced vital capacity is above 80% predicted.
ae2374db7d963f4ab461804043a4d28c79639519	nice	Somatrogon for treating growth disturbance in children and young people aged 3 years and over	Somatrogon for treating growth disturbance in children and young people aged 3 years and over Evidence-based recommendations on somatrogon (Ngenla) for treating growth disturbance in children and young people aged 3 years and over. # Recommendations Somatrogon is recommended, within its marketing authorisation, as an option for treating growth disturbance caused by growth hormone deficiency in children and young people aged 3 years and over. If people with the condition and their clinicians consider somatrogon to be 1 of a range of suitable treatments (including any preparation of somatropin) discuss the advantages and disadvantages of the available treatments. After that discussion, if more than 1 treatment is suitable, choose the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements. Why these recommendations were made Growth disturbance caused by growth hormone deficiency is usually treated with somatropin, available in multiple preparations, which are already recommended in NICE's technology appraisal guidance on somatropin. Somatragon works in a similar way, but it is a weekly injection instead of a daily one. Evidence from clinical trials shows that somatrogon is as effective as one preparation of somatropin (Genotropin). The cost modelling used a range of dosages of somatropin (0.023 to 0.039 mg/kg per day), which clinical experts advised is the range of dosages used in the NHS. Using this range of dosages, a cost comparison suggests the costs of somatrogon are similar to those of the somatropin preparations. So somatrogon is recommended. For all evidence see the committee papers. To see what NICE did for somatropin, see the committee discussion in NICE's guidance on somatropin.# Information about somatrogon # Marketing authorisation indication Somatrogon (Ngenla, Pfizer) is indicated for 'the treatment of children and adolescents from 3 years of age with growth disturbance due to insufficient secretion of growth hormone'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for somatrogon. # Price £166.08 per 1.2-ml vial containing 24 mg of somatrogon or £415.20 for a 1.2-ml vial containing 60 mg of somatrogon (excluding VAT, company submission, December 2022). At the recommended dose of 0.66 mg per kg per week the estimated annual cost for a 40 kg patient is £9,500. Costs may vary in different settings because of negotiated procurement discounts.	{'Recommendations': "Somatrogon is recommended, within its marketing authorisation, as an option for treating growth disturbance caused by growth hormone deficiency in children and young people aged 3 years and over.\n\nIf people with the condition and their clinicians consider somatrogon to be 1 of a range of suitable treatments (including any preparation of somatropin) discuss the advantages and disadvantages of the available treatments. After that discussion, if more than 1 treatment is suitable, choose the least expensive. Take account of administration costs, dosage, price per dose and commercial arrangements.\n\nWhy these recommendations were made\n\nGrowth disturbance caused by growth hormone deficiency is usually treated with somatropin, available in multiple preparations, which are already recommended in NICE's technology appraisal guidance on somatropin. Somatragon works in a similar way, but it is a weekly injection instead of a daily one.\n\nEvidence from clinical trials shows that somatrogon is as effective as one preparation of somatropin (Genotropin).\n\nThe cost modelling used a range of dosages of somatropin (0.023 to 0.039 mg/kg per day), which clinical experts advised is the range of dosages used in the NHS.\n\nUsing this range of dosages, a cost comparison suggests the costs of somatrogon are similar to those of the somatropin preparations. So somatrogon is recommended.\n\nFor all evidence see the committee papers. To see what NICE did for somatropin, see the committee discussion in NICE's guidance on somatropin.", 'Information about somatrogon': "# Marketing authorisation indication\n\nSomatrogon (Ngenla, Pfizer) is indicated for 'the treatment of children and adolescents from 3 years of age with growth disturbance due to insufficient secretion of growth hormone'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for somatrogon.\n\n# Price\n\n£166.08 per 1.2-ml vial containing 24\xa0mg of somatrogon or £415.20 for a 1.2-ml vial containing 60\xa0mg of somatrogon (excluding VAT, company submission, December 2022). At the recommended dose of 0.66\xa0mg per kg per week the estimated annual cost for a 40\xa0kg patient is £9,500. Costs may vary in different settings because of negotiated procurement discounts."}	https://www.nice.org.uk/guidance/ta863	Evidence-based recommendations on somatrogon (Ngenla) for treating growth disturbance in children and young people aged 3 years and over.
4f82f8baa42f8022e23b8b2d3a1236abeb59faab	nice	Devices for remote monitoring of Parkinson's disease	Devices for remote monitoring of Parkinson's disease Evidence-based recommendations on Kinesia 360 and KinesiaU (Great Lakes NeuroTechnologies), PDMonitor (PD Neurotechnology), Personal KinetiGraph (Global Kinetics) and STAT‑ON (Sense4care) for remote monitoring of Parkinson’s disease. # Recommendations Kinesia 360, KinesiaU, PDMonitor, Personal KinetiGraph (PKG) and STAT‑ON are conditionally recommended as options for remote monitoring of Parkinson's disease to inform treatment if: further evidence is generated, including: the impact on resources associated with using the technologies (for people with Parkinson's disease and their carers; see section 4.1) the size of impact of using the technologies on symptoms or health-related quality of life (for people with Parkinson's disease and their carers) and how long this lasts for (see section 4.2) how frequently the devices are used, and under what circumstances, in the NHS (see section 4.3), and cost impact is managed (see recommendation 1.2). Commissioners should consider the available payment options for the technologies when deciding which to use (for example, pay per use, a subscription model or outright purchase). They should take into account the fact that the technologies may not be needed any more if further data shows they are not cost effective. Clinicians should consider features of the devices and how they are used when identifying which may be most suitable for a person, particularly for people with restricted movement, missing limbs, or people who are frail or have cognitive impairment. Clinicians should also support people to set up and operate the remote monitoring devices if needed. Why the committee made these recommendations Monitoring symptoms of Parkinson's disease is important to help clinicians make decisions about a person's care. But this can be difficult in current practice because symptoms can come and go and may be difficult to remember or describe. Review appointments may also be infrequent. Sometimes people with Parkinson's disease may struggle to accurately assess their symptoms, and how severe they think they are may differ from the view of their carer (care partner). More objective monitoring of symptoms is therefore an unmet need. Using these devices could help clinicians to better determine when changes to treatment are needed. This may help better manage symptoms of Parkinson's disease and improve quality of life for people with Parkinson's disease and their carers. There is a lack of evidence about how much of an impact using the devices in the NHS would have on quality of life for both people with Parkinson's disease and their carers. The devices could help save NHS resources, but it is unclear by how much, and which resources. The amount of evidence for each device varies, and no studies compared 1 device against another. PKG has the most evidence, but how effective it would be when used in the NHS is not certain; this is because in the main trial, people who did and did not have the device had more check ups than they would in the NHS. The device was also used more frequently than would be expected in NHS care. Having early conditional access to these technologies could improve management of symptoms and quality of life for people with Parkinson's disease and their carers. Data should be collected so that the clinical and cost effectiveness of the technologies can be fully assessed. So, the devices are conditionally recommended as an option to help monitor Parkinson's disease. Clinicians should take into account whether people need help to use the devices, and if 1 device is more suited to a person than others. The devices can only be used if the cost impact is managed by considering the different payment options for the technologies.# The tests # Clinical need and practice ## Parkinson's disease Parkinson's disease is a condition that affects the brain, resulting in a progressive loss of coordination and movement problems. It is caused by a loss of the cells in the brain that are responsible for producing dopamine, which helps to control and coordinate body movements. People with Parkinson's disease experience a range of motor symptoms, which can fluctuate in severity during the day and between days. Motor symptoms may include dyskinesia (involuntary movement), bradykinesia (slowness) and tremor; non-motor symptoms include sleep disturbances. Starting or adjusting treatment helps to control symptoms. However, these treatments can themselves cause motor-related side effects. An important consideration in decisions about treatment is the need to balance the benefits of treatment with the potential side effects. ## Current care pathway NICE's guideline on Parkinson's disease recommends that people diagnosed with Parkinson's disease are seen every 6 to 12 months to review their diagnosis. More frequent follow ups may be needed to optimise medication dosage, or for people who need more advanced treatments. Current practice for monitoring motor symptoms includes using validated questionnaires, history taking and clinical observation. It can be difficult to assess the symptoms of some people with Parkinson's disease because they can have difficulty communicating, remembering or recording their symptoms. Examination at a single point in time, for example at a clinic appointment, may over or underestimate symptom severity or incidence, given that motor fluctuations can vary over time. ## Potential value of technologies Devices that can monitor and record symptoms of Parkinson's disease could identify people who could benefit from changes to their care. By objectively measuring these symptoms over several days, the technologies may more accurately estimate a person's symptoms and help to inform medication decisions. At scoping, clinical experts highlighted that functionality to measure dyskinesia and bradykinesia was particularly important for this. Better-informed treatment decisions could lead to improved quality of life. Improved motor symptoms could reduce falls and hip fractures. The technologies could also help improve communication between people with Parkinson's disease and clinicians when discussing symptoms and potential changes to care. The technologies may also allow more remote monitoring of Parkinson's disease. This could help to alleviate the stress and anxiety of attending clinic appointments. Objective monitoring of symptoms could also reduce the length and number of clinic appointments, thereby freeing up NHS resources. # The interventions The technologies all have remote monitoring capability, are automated monitors (do not require the user to perform tests), measure dyskinesia, help assess bradykinesia and can be used outside a clinical setting in the absence of a healthcare professional. The devices are intended for use together with clinical assessment. They have regulatory approval and are available to the NHS. ## Kinesia 360 The Kinesia 360 motor assessment system (Great Lakes NeuroTechnologies) monitors movement to quantify motor symptoms and assess activity. The system comprises sensors worn on the wrist and ankle, a tablet, and a charge pad. Kinesia 360 measures various aspects of bradykinesia, dyskinesia and tremor. It has a 16‑hour battery life, so typically someone will wear the sensors during the day and recharge the device overnight. Algorithms are used to automatically calculate severity scores, which healthcare professionals can view through web-based reports. Data is automatically downloaded from the device and uploaded to the Kinesia Web Portal during recharging. The mobile application also includes electronic diaries for capturing patient-reported outcomes and customisable medication diaries. Healthcare staff can be trained in Kinesia 360 in about 30 minutes. The monthly device subscription costs £224. ## KinesiaU The KinesiaU motor assessment system (Great Lakes NeuroTechnologies) comprises a smartwatch and smartphone application. Symptoms can be measured through continuous recording or through specific active tasks (which can be done while being monitored continuously). The system rates the severity of tremor, slowness and dyskinesia symptoms into good, mild, moderate and severe categories (averaged for the selected time range). The product is to be used only under the direction of a qualified clinician. Reports can be produced throughout the day and over the course of days, weeks and months to assess response to therapy and activities. Users can view or share reports in real time using the smartphone application. Healthcare professionals can access reports remotely through the KinesiaU provider portal. The mobile application also includes customisable medication and exercise diaries, which can be added to the report. Healthcare staff can be trained in KinesiaU in about 30 minutes. The monthly subscription costs £64 per patient. ## PDMonitor The PDMonitor system (PD Neurotechnology) consists of a SmartBox, 5 sensors and a PDMonitor mobile application. The sensors are worn on both wrists, both ankles and the waist, and acquire movement data for assessing motor symptoms. The system measures activity, posture, bradykinesia, freezing of gait, gait disturbances, wrist tremor, leg tremor, dyskinesia and 'on' periods (when the Parkinson's disease responds to treatment and motor performance is normal) and 'off' periods (when medication becomes less effective). It also provides a summary of measured daily activity. The duration and frequency of use is decided by the healthcare professional. The PDMonitor SmartBox is a docking station for charging the monitoring devices. It also collects, stores and processes data and uploads it to the PD Neurotechnology storage service. Healthcare professionals can access reports through the mobile application, which also includes medication, diet and self-reported symptom diaries. The company offers training for healthcare professionals, and there is a user manual for the physician tool. The device can be purchased outright for £12,000. During consultation, the company added that an alternative pricing model is available: a yearly subscription of £350 per month, and discounts available based on volume. ## Personal KinetiGraph (PKG) The PKG Movement Recording System (Global Kinetics) is a wrist-worn PKG watch that continuously measures movement over a 6‑day period. The PKG measures bradykinesia, dyskinesia, tremors, motor fluctuations, and immobility, and records when the watch is not being worn. It also monitors movement during sleep. The PKG watch is returned by the user to the company (using a prepaid addressed envelope), which extracts the data and generates reports for users and healthcare professionals to view online. As well as providing the raw data, algorithm-generated movement scores are provided for the whole 6‑day period. The report includes summary graphs showing measurements over time and a summary of results, along with a suggested target range for interpretation. The watch has medication reminders and users can record when they have taken their medication. The company provides education and training to healthcare professionals. It advises that healthcare professionals should review an average of 15 to 20 PKGs to be proficient, supported by an eLearning module, which takes approximately 1 to 2 hours. The device costs £225 per use per patient. ## STAT-ON The STAT‑ON system (Sense4care) consists of a monitoring device, a base charger, a belt with a waist-worn inertia recorder attached, and a mobile application. The system must be configured by a healthcare professional through the mobile application. The smartphone application connects to the STAT‑ON device via Bluetooth. Results are stored in its internal memory. The device measures dyskinesia, 'on' and 'off' periods, gait parameters (including bradykinesia and freezing of gait), falls, energy expenditure and posture. It does not measure tremor. The user wears the device for a minimum of 5 days (ideally for 7 days), totalling a minimum of 24 hours over the 5 days, to collect enough data. After this, a report can be generated. The device collects data and uses algorithms to process it. It produces a report containing detailed data analyses, as well as summaries of activity and prevalence of symptoms during the monitored period. Healthcare professionals can download the report using the mobile application. The application also has medication reminders, and people can record when they have taken their medication. Training sessions last 1.5 hours. Quick guides, videos and graphical training documents are provided for healthcare professionals to understand how the system is configured and how to interpret the report. The annual subscription cost is £1,600. ## The comparator The comparator is clinical judgement of motor and non-motor symptoms based on information including clinical history and patient diaries, which may include rating scale tools and activity trackers. The Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr scale can be used to describe and assess symptoms related to Parkinson's disease.# Committee discussion The diagnostics advisory committee considered evidence on Kinesia 360, KinesiaU, PDMonitor, Personal KinetiGraph (PKG), and STAT‑ON for remote monitoring of Parkinson's disease from several sources, including a diagnostics assessment report and an overview of that report. Full details are in the project documents for this guidance on the NICE website. # People with Parkinson's disease could benefit from remote monitoring technologies The external assessment group (EAG) identified 8 papers that reported patient or carer opinions on PKG, 2 papers on STAT‑ON, 1 on Kinesia 360 and 1 on KinesiaU. Patient experts explained the potential benefits of easy-to-use and unobtrusive remote monitoring options for Parkinson's disease. This included contributing to a 'feeling of normality', prolonging a level of independence, acting as an urgency signal to accelerate further care, and reducing anxiety around in-person visits. It could also help with describing symptoms to healthcare professionals, which can be very difficult, particularly when trying to describe how symptoms change over time. A patient expert also explained that the reports the technologies generate can help them understand their condition. The committee noted that remote monitoring technologies could make remote care easier, so that healthcare professionals could do appointments by telephone or video call, so people did not have to travel as often to meet in person. This would reduce travel costs and could reduce how much their condition feels like a medical condition, particularly in the earlier stages. However, the patient experts said that the disease can be isolating for people with Parkinson's disease and their carers, and that face-to-face appointments can help with this. The committee also noted that the technologies may not be suitable for everyone with Parkinson's disease, for example for people who are particularly frail, use a wheelchair, are confined to bed, or have missing limbs or cognitive or sensory impairment. In some cases, additional support may be needed to help people to use the remote monitoring devices. The committee noted that the devices differ in how they work and where sensors are worn, so some may be more suited to some people than others, for example people with missing limbs or with restricted movement. It recognised that offering face-to-face appointments is still essential, and that remote assessment would not replace this, but could offer more flexible options for care for some people. The clinical experts commented that the technologies should be considered as complementary to face-to-face appointments. The clinical experts emphasised the importance of making training and other user-support resources accessible, and making sure that they are suitable for people with hearing loss or visual impairment. The clinical experts also said that the time between review appointments can be very variable and prolonged, so having the option of using the remote monitoring devices could provide reassurance and a safety net for checking symptoms between clinic appointments. The committee concluded that devices for remote monitoring offer a range of potential benefits to people with Parkinson's disease. # Carers could benefit from remote technologies monitoring symptoms The patient experts said that current methods of assessing symptoms can rely heavily on observations made by carers, and their ability to communicate these to clinical experts. The size of responsibility for this causes a lot of stress and anxiety, particularly as the condition progresses and if the carer is the main source of information about changes in symptoms. The person with Parkinson's disease and their carer may disagree about the extent of symptoms, which can be difficult. A technology that objectively reviews symptoms could help discussions and take pressure off the carer. The patient experts also said that if someone with Parkinson's disease does not have a carer living with them, or if their carer has cognitive issues, then the potential value of the technologies would be much greater. The committee recognised that a carer's quality of life is affected by the severity of Parkinson's symptoms, and the responsibilities of managing medication and hospital visits. The patient experts explained that caring for people with Parkinson's disease can mean that carers put off managing their own health issues, and that this can affect a carer's health-related quality of life considerably, and so increase costs to the NHS. Travel for in-person appointments can be difficult for carers who may need to take time off work, particularly if they are the only earner, so being able to use remote appointments more would help. The committee recognised that objective remote monitoring technologies may help alleviate stress and anxiety for carers, assist in communication with healthcare professionals, and could save time at hospital appointments by providing a starting point for discussions. It concluded that it was important to consider any impact of the technologies on carers in its decision making. # The technologies could be used in many different ways in the NHS and how they would fit into the care pathway is not clear The clinical experts explained that the technologies could be used in many different ways in the NHS. For example, before regularly scheduled appointments with healthcare professionals, after treatment changes to help titrate dosage, to indicate if a further review appointment with a healthcare professional is needed, or for people who are having issues with symptoms. They said that centres currently using these technologies did so in very different ways. The clinical experts noted that it was important that the technologies were integrated into care pathways, including training for clinical teams and for people with Parkinson's disease and their carers. This could mean that care pathways are changed. How the technologies would be used if adopted was not clear and could have a big impact on clinical and cost effectiveness. Studies identified by the EAG that compared the devices with standard care used the technologies in different ways: Woodrow et al. (2020) used the PKG at 5‑week intervals for up to 25 weeks; Isaacson et al. (2021) used the Kinesia 360 to optimise rotigotine dosage when motor symptoms were not controlled well enough. There was little data showing the impact of the devices if they were used in ways that could be adopted by the NHS, for example to identify people who need a review appointment with a healthcare professional. The EAG explained that there was little evidence on the technologies when used in the UK. It also pointed out that how the technologies are used would affect how often they are used, and that this greatly affected cost-effectiveness estimates (see section 3.9). The committee concluded that the technologies could be used in many different ways in the NHS and how they would fit into the care pathway is not clear. # The level of care in Parkinson's disease varies and remote monitoring may become increasingly important The clinical and patient experts explained that, although NICE's guideline on Parkinson's disease recommends that people with Parkinson's disease have a review every 6 to 12 months, this does not always happen in practice. They said the level of care varies across the NHS. The clinical experts added that the number of people with Parkinson's disease is increasing, which will place further pressure on the healthcare system. There are also backlogs for review appointments because of COVID‑19 disruptions. Patient experts said the technologies could be a way for people with difficulties accessing services to have assessments. They said it was also a way to identify issues during the lengthy gaps between reviews (see section 3.1). The committee noted that the size of benefit of adopting the technologies may vary depending on current local care. It also noted that increasing pressures on NHS services may mean that the technologies are likely to become increasingly beneficial. # Clinical effectiveness ## The reference standard in identified accuracy studies is imperfect and may underestimate technology performance The EAG said that there is no clearly established reference standard for measuring Parkinson's disease symptoms, beyond clinician and patient assessment, that could be used to establish test accuracy. A potential benefit of the technologies is that they may more accurately evaluate symptoms than patient recall or clinical opinion, so a reference standard based on patient recall or clinical opinion (as used in accuracy studies identified by the EAG in its systematic review) could underestimate technology performance. The committee noted that accuracy estimates may not be the best outcome for assessing the performance of these technologies. ## There is limited evidence on how much the technologies can improve symptoms or health-related quality of life Only 3 studies had data comparing clinical outcomes with the technologies against not using the technologies. Two of these (which assessed the Kinesia 360) were small randomised controlled trials. The largest study (which assessed the PKG and was by Woodrow et al.) reported clinical improvements in terms of statistically significant reductions in the Unified Parkinson's Disease Rating Scale (UPDRS) 3 (motor examination), UPDRS 4 (complications of therapy), total UPDRS score and PDQ‑39 (Parkinson's Disease Questionnaire 39). The committee noted that the trial was not randomised. It understood that there could have been a systematic difference between the centres included in the trial and their catchment areas because people were allocated to PKG based on the centre they attended. The clinical experts also pointed out that the PKG was used every 5 weeks in the Woodrow et al. study, which would not be realistic in the NHS. Standard care in the study's comparator arms also may not represent NHS care. Because the length of follow up from the available studies was relatively short, there was also a lack of data on how long any benefit of the devices lasted once they were not used any more. Also, the EAG did not identify any data specifically on the populations who were identified in the scope as likely to have particular benefit from the technologies. These included people with communication barriers and people from black, Asian and minority ethnic family backgrounds, because symptoms can vary by family background. The committee concluded that, while the identified studies gave some indication of how the technologies could benefit people with Parkinson's disease, there was considerable uncertainty about the likely size of this benefit if the technologies were adopted in the NHS. ## Most of the evidence is in people having maintenance therapy The clinical and patient experts suggested that the technologies may be particularly useful for people who are eligible for more advanced therapies such as deep brain stimulation. But the EAG said the only evidence on the devices' comparative effectiveness was in the maintenance stage of Parkinson's disease. The committee understood that the devices may perform differently in these different populations. ## How much remote monitoring devices would change decisions about care in the NHS is uncertain The clinical experts said that, as well as changes to medication, symptoms can be managed with other changes to care like physiotherapy and exercise. Only the PKG had data on how the technologies can change decisions about care. The proportion of people who had a change in clinical management as a result of the PKG varied considerably (between 31.8% and 79%). A UK study reported that the PKG provided additional information in 45.5% of cases. In studies of clinician opinion, between 4% and 41% agreed that the PKG provided enough additional information to consider making treatment adjustments. The committee concluded that there was uncertainty about how much using remote monitoring devices would change care for people in the NHS. # Cost effectiveness ## Device cost is a major driver of cost effectiveness In the EAG's model, the intervention arm resulted in a higher cost than standard care. Device cost had the biggest impact on this. The EAG said that the device cost depended on how the devices were modelled as being used (see section 3.3) and the cost per use. The technologies have differing payment mechanisms: pay per use, a subscription model or outright purchase of the device. The committee noted that the payment options differed in terms of upfront investment and how reversible a decision to use a technology would be. The committee recalled that the technologies could be used in various ways in the NHS and noted that the EAG had modelled use at varying frequencies. This included one-time use (at baseline) and routine use (every 6 months) in its base cases, and a recurrent use scenario analysis (at 6 and 18 months in place of clinic appointments). How frequently the technologies were used substantially affected device-related costs and the cost-effectiveness estimates. ## Because of the uncertainty about the devices' impact on health-related quality of life, their cost effectiveness is also uncertain The committee recalled that there was uncertainty about the size of impact that device use would have on symptoms if used in the NHS (see section 3.6). The EAG used the Woodrow et al. trial to inform the estimates of health-related quality of life in its model. It also had to make assumptions about how long any benefit would last after using the devices. Sensitivity analyses showed that the cost-effectiveness estimates were very sensitive to this assumption. The committee concluded that the size and longevity of the benefits of device-guided decisions about care was very uncertain, and consequently so were the cost-effectiveness estimates produced by the EAG's model. ## Chaudhuri et al. (2022) is likely to have overestimated how device use would affect resource use and how long any benefit would last for Cost-effectiveness modelling reported by Chaudhuri et al. (2022) estimated that the PKG would be cost saving by £17,362, whereas in the EAG's model the PKG incurred costs. Both models compared the PKG with standard care. The committee questioned the approach used in Chaudhuri et al., which took scores with PKG use on the UPDRS from Woodrow et al. and converted them to the Hoehn and Yahr scale. They then used this to calculate resource costs. The committee noted that the EAG had been unable to verify or validate the approach used by Chaudhuri et al. It was also not clear if the symptom improvements observed from using the technologies could realistically translate into the large-scale changes in healthcare use predicted by this model. A clinical expert said that it was very unlikely that remote monitoring devices would have the effect shown on the Hoehn and Yahr scale. The EAG added that in Woodrow et al., device use did not have a statistically significant effect on the Hoehn and Yahr scores (-0.044, standard error 0.097 for adjusted data). It also said that in the Chaudhuri et al. model, the PKG's effect on symptoms was assumed to last for 5 years with only limited waning of effect after that, although there was no evidence for this. Clinical experts noted that there are no disease-modifying treatments available for Parkinson's disease that can stop progression. The committee concluded that the Chaudhuri et al. model was likely to have overestimated how much the PKG can reduce healthcare-associated resource costs, and how long the benefit from PKG-guided care on symptoms would last for. ## The broader impact of remote monitoring device use on resources is uncertain A UK survey reported that people with Parkinson's disease interact with 18 different healthcare professions. The EAG had suggested that more data on this could identify further areas in which remote monitoring device-aided care could reduce costs. The patient experts also explained that the cost of providing care to people with Parkinson's disease can differ significantly according to whether they have a live-in carer, a paid carer or no carer at all. Costs related to social care were not included in the EAG's model because of a lack of data. Any impact of remote monitoring devices on these costs, for example delaying when someone with Parkinson's disease goes into a care home, could have been missed. The companies said that the EAG's model did not include costs related to falls and hip fractures prevented, which they said could be an uncaptured benefit if the devices did improve symptom management. The EAG explained that there was a lack of data to inform this. Also, because of a lack of data, its analysis was constrained to the management phase of Parkinson's disease. It understood that falls, hip fractures and social care costs are largely confined to the advanced stages of the disease. The committee concluded that the EAG's model may have underestimated the impact of using remote monitoring devices on some resources and associated costs. However, other costs related to implementing the devices, for example interconnectivity, may be higher in practice. ## The EAG's model did not capture the potential impact of remote monitoring on carers The committee recalled that remote monitoring devices could benefit carers (see section 3.2). But, because of a lack of data, the EAG's model did not include costs or health-related quality of life for them. The committee noted that relatively small improvements in quality-adjusted life years (QALYs) resulting from device use (perhaps related to carer benefits) could have a large impact on the cost-effectiveness results, depending on the analysis used. The committee concluded that there was considerable uncertainty about how much the remote monitoring devices could affect carers, and noted that this had not been captured in the EAG's model. ## The value of the technology may be underestimated, or was not estimated, by the EAG's model for some groups There was not enough evidence for the EAG to be able to do subgroup analyses for people who have communication barriers, people from black, Asian and minority ethnic family backgrounds, or people from different socio-economic backgrounds. These populations were identified at scoping as being potentially likely to gain additional benefits from the technologies. The patient experts noted that remote monitoring may also benefit people who are having difficulty attending consultations, or getting care because services are at full capacity. The EAG had also not been able to model how remote monitoring devices might work for people being considered for advanced therapies such as deep brain stimulation, because there was not enough evidence. ## Remote monitoring technologies have considerable promise, but more data is needed to estimate their true cost effectiveness The committee recognised the promise that remote monitoring devices offer to people with Parkinson's disease and their carers (see section 3.1 and section 3.2). These devices could also help with increasing capacity pressures on the NHS. But their cost effectiveness is very uncertain, and to estimate it more accurately, there are several areas of uncertainty for which more data is needed (see section 4). The PKG has the most evidence, but the committee recalled that there was uncertainty about how well data from the main trial for this technology (Woodrow et al.) represents how well the device would work in the NHS (see section 3.6). The committee noted that the technologies differed in how sensors are worn (see sections 2.6 to 2.21) and the algorithms they use. Because of this, the EAG stated that clinical benefits observed for 1 technology could not be assumed for the other technologies. No identified studies compared the performance of 1 technology against another. A lot of identified data was on test accuracy. The committee recalled its concern about the suitability of accuracy estimates for assessing the performance of these technologies (see section 3.5). It also recalled the uncertainty in how much remote monitoring devices would change decisions about care in the NHS (see section 3.8). The committee concluded that, to assess performance, further data is needed for all technologies on the size of impact of using all of the technologies on symptoms or health-related quality of life (see section 4.2). ## The remote monitoring technologies can be used in the NHS while further data is collected The committee considered the risks associated with using the technologies in the NHS while further data is collected. The clinical and patient experts said that their main concern about potentially worse patient outcomes was if use of the devices was poorly implemented. For example, if they were used to entirely replace face-to-face appointments, and were not integrated into care pathways. They also said that remote monitoring devices were already being used in some NHS centres. The committee noted that the overall cost impact of using the devices was uncertain and was largely dictated by how much the companies charged, and the different payment mechanisms (see section 3.9). The committee concluded that this was important for commissioners to consider, because the devices were likely to differ in terms of ongoing or irrecoverable costs if a later decision was made to stop using the technologies, for example if further data collection showed they did not work as well as anticipated. # Research considerations ## More data collection is needed in populations that represent the potential use and benefits of the devices in the NHS There was no or limited data for several populations who could particularly benefit from the remote monitoring technologies (see section 3.14), including people who might be helped by advanced therapies.# Evidence generation recommendations # More data on how much remote monitoring devices affect resource use would help decision making There is uncertainty about how much remote monitoring devices would affect resource use in the NHS and personal social services. Some impacts may not have been included in the external assessment group's (EAG) model because of a lack of data (see section 3.12), including resource use related to carers (see section 3.13). Adopting the technologies may change how care is provided (see section 3.4) so their effect on resources is hard to estimate without direct data. So, the committee recommended collecting data on how much using the devices affects resource use, to inform cost-effectiveness estimates. Data on time dedicated to training and spent reviewing device results should also be collected. The broader impact on services provided by Parkinson's specialist teams and carers should be considered. # More data to help inform estimates of the impact on health-related quality of life would help decision making How much using remote monitoring devices to guide decisions about care affects symptoms, and therefore health-related quality of life, is uncertain. How long after using the devices any impact would last is also uncertain. This had a sizeable influence on cost-effectiveness estimates (see section 3.10). Data on this came from studies that did not represent likely NHS practice (see section 3.6), which is itself uncertain (see section 3.3), and from assumptions made by the EAG because of lack of data. For its model, the EAG used a published algorithm from Chandler et al. (2020) to estimate quality-adjusted life years (QALYs) from the Unified Parkinson's Disease Rating Scale (UPDRS) domain scores. The clinical experts said that health-related quality of life questionnaires like the PDQ‑39 are increasingly used in trials to assess health-related quality of life for people with Parkinson's disease. The committee also recognised that the effect of the devices on the health-related quality of life of carers had not been included in the EAG's model because of a lack of data (see section 3.13). # Data should be collected on how often the remote monitoring devices are used and for what reasons How frequently the remote monitoring devices were modelled as being used substantially affected the cost-effectiveness estimates in the EAG's model (see section 3.9). There are many ways the devices could be used in the NHS (see section 3.3) and no data was available to compare different approaches. So, it is currently not possible to highlight particular approaches that are likely to be more clinically and cost effective. Centres using the devices should therefore collect data on how often they are used and under what circumstances. For example, regularly in advance of scheduled review appointments, to indicate when such appointments are needed, or targeted to people having issues with symptoms. This will help assess the clinical and cost effectiveness of the different uses of the devices in NHS practice.	{'Recommendations': "Kinesia\xa0360, KinesiaU, PDMonitor, Personal KinetiGraph (PKG) and STAT‑ON are conditionally recommended as options for remote monitoring of Parkinson's disease to inform treatment if:\n\nfurther evidence is generated, including:\n\n\n\nthe impact on resources associated with using the technologies (for people with Parkinson's disease and their carers; see section 4.1)\n\nthe size of impact of using the technologies on symptoms or health-related quality of life (for people with Parkinson's disease and their carers) and how long this lasts for (see section 4.2)\n\nhow frequently the devices are used, and under what circumstances, in the NHS (see section 4.3), and\n\n\n\ncost impact is managed (see recommendation 1.2).\n\nCommissioners should consider the available payment options for the technologies when deciding which to use (for example, pay per use, a subscription model or outright purchase). They should take into account the fact that the technologies may not be needed any more if further data shows they are not cost effective.\n\nClinicians should consider features of the devices and how they are used when identifying which may be most suitable for a person, particularly for people with restricted movement, missing limbs, or people who are frail or have cognitive impairment. Clinicians should also support people to set up and operate the remote monitoring devices if needed.\n\nWhy the committee made these recommendations\n\nMonitoring symptoms of Parkinson's disease is important to help clinicians make decisions about a person's care. But this can be difficult in current practice because symptoms can come and go and may be difficult to remember or describe. Review appointments may also be infrequent. Sometimes people with Parkinson's disease may struggle to accurately assess their symptoms, and how severe they think they are may differ from the view of their carer (care partner). More objective monitoring of symptoms is therefore an unmet need. Using these devices could help clinicians to better determine when changes to treatment are needed. This may help better manage symptoms of Parkinson's disease and improve quality of life for people with Parkinson's disease and their carers.\n\nThere is a lack of evidence about how much of an impact using the devices in the NHS would have on quality of life for both people with Parkinson's disease and their carers. The devices could help save NHS resources, but it is unclear by how much, and which resources. The amount of evidence for each device varies, and no studies compared 1 device against another. PKG has the most evidence, but how effective it would be when used in the NHS is not certain; this is because in the main trial, people who did and did not have the device had more check ups than they would in the NHS. The device was also used more frequently than would be expected in NHS care.\n\nHaving early conditional access to these technologies could improve management of symptoms and quality of life for people with Parkinson's disease and their carers. Data should be collected so that the clinical and cost effectiveness of the technologies can be fully assessed. So, the devices are conditionally recommended as an option to help monitor Parkinson's disease. Clinicians should take into account whether people need help to use the devices, and if 1 device is more suited to a person than others. The devices can only be used if the cost impact is managed by considering the different payment options for the technologies.", 'The tests': "# Clinical need and practice\n\n## Parkinson's disease\n\nParkinson's disease is a condition that affects the brain, resulting in a progressive loss of coordination and movement problems. It is caused by a loss of the cells in the brain that are responsible for producing dopamine, which helps to control and coordinate body movements. People with Parkinson's disease experience a range of motor symptoms, which can fluctuate in severity during the day and between days. Motor symptoms may include dyskinesia (involuntary movement), bradykinesia (slowness) and tremor; non-motor symptoms include sleep disturbances. Starting or adjusting treatment helps to control symptoms. However, these treatments can themselves cause motor-related side effects. An important consideration in decisions about treatment is the need to balance the benefits of treatment with the potential side effects.\n\n## Current care pathway\n\nNICE's guideline on Parkinson's disease recommends that people diagnosed with Parkinson's disease are seen every 6 to 12\xa0months to review their diagnosis. More frequent follow ups may be needed to optimise medication dosage, or for people who need more advanced treatments. Current practice for monitoring motor symptoms includes using validated questionnaires, history taking and clinical observation. It can be difficult to assess the symptoms of some people with Parkinson's disease because they can have difficulty communicating, remembering or recording their symptoms. Examination at a single point in time, for example at a clinic appointment, may over or underestimate symptom severity or incidence, given that motor fluctuations can vary over time.\n\n## Potential value of technologies\n\nDevices that can monitor and record symptoms of Parkinson's disease could identify people who could benefit from changes to their care. By objectively measuring these symptoms over several days, the technologies may more accurately estimate a person's symptoms and help to inform medication decisions. At scoping, clinical experts highlighted that functionality to measure dyskinesia and bradykinesia was particularly important for this.\n\nBetter-informed treatment decisions could lead to improved quality of life. Improved motor symptoms could reduce falls and hip fractures. The technologies could also help improve communication between people with Parkinson's disease and clinicians when discussing symptoms and potential changes to care.\n\nThe technologies may also allow more remote monitoring of Parkinson's disease. This could help to alleviate the stress and anxiety of attending clinic appointments. Objective monitoring of symptoms could also reduce the length and number of clinic appointments, thereby freeing up NHS resources.\n\n# The interventions\n\nThe technologies all have remote monitoring capability, are automated monitors (do not require the user to perform tests), measure dyskinesia, help assess bradykinesia and can be used outside a clinical setting in the absence of a healthcare professional. The devices are intended for use together with clinical assessment. They have regulatory approval and are available to the NHS.\n\n## Kinesia 360\n\nThe Kinesia\xa0360 motor assessment system (Great Lakes NeuroTechnologies) monitors movement to quantify motor symptoms and assess activity. The system comprises sensors worn on the wrist and ankle, a tablet, and a charge pad. Kinesia\xa0360 measures various aspects of bradykinesia, dyskinesia and tremor. It has a 16‑hour battery life, so typically someone will wear the sensors during the day and recharge the device overnight.\n\nAlgorithms are used to automatically calculate severity scores, which healthcare professionals can view through web-based reports. Data is automatically downloaded from the device and uploaded to the Kinesia Web Portal during recharging. The mobile application also includes electronic diaries for capturing patient-reported outcomes and customisable medication diaries.\n\nHealthcare staff can be trained in Kinesia\xa0360 in about 30\xa0minutes. The monthly device subscription costs £224.\n\n## KinesiaU\n\nThe KinesiaU motor assessment system (Great Lakes NeuroTechnologies) comprises a smartwatch and smartphone application. Symptoms can be measured through continuous recording or through specific active tasks (which can be done while being monitored continuously). The system rates the severity of tremor, slowness and dyskinesia symptoms into good, mild, moderate and severe categories (averaged for the selected time range). The product is to be used only under the direction of a qualified clinician.\n\nReports can be produced throughout the day and over the course of days, weeks and months to assess response to therapy and activities. Users can view or share reports in real time using the smartphone application. Healthcare professionals can access reports remotely through the KinesiaU provider portal. The mobile application also includes customisable medication and exercise diaries, which can be added to the report.\n\nHealthcare staff can be trained in KinesiaU in about 30\xa0minutes. The monthly subscription costs £64 per patient.\n\n## PDMonitor\n\nThe PDMonitor system (PD Neurotechnology) consists of a SmartBox, 5\xa0sensors and a PDMonitor mobile application. The sensors are worn on both wrists, both ankles and the waist, and acquire movement data for assessing motor symptoms. The system measures activity, posture, bradykinesia, freezing of gait, gait disturbances, wrist tremor, leg tremor, dyskinesia and 'on' periods (when the Parkinson's disease responds to treatment and motor performance is normal) and 'off' periods (when medication becomes less effective). It also provides a summary of measured daily activity. The duration and frequency of use is decided by the healthcare professional.\n\nThe PDMonitor SmartBox is a docking station for charging the monitoring devices. It also collects, stores and processes data and uploads it to the PD Neurotechnology storage service. Healthcare professionals can access reports through the mobile application, which also includes medication, diet and self-reported symptom diaries.\n\nThe company offers training for healthcare professionals, and there is a user manual for the physician tool. The device can be purchased outright for £12,000. During consultation, the company added that an alternative pricing model is available: a yearly subscription of £350 per month, and discounts available based on volume.\n\n## Personal KinetiGraph (PKG)\n\nThe PKG Movement Recording System (Global Kinetics) is a wrist-worn PKG watch that continuously measures movement over a 6‑day period. The PKG measures bradykinesia, dyskinesia, tremors, motor fluctuations, and immobility, and records when the watch is not being worn. It also monitors movement during sleep.\n\nThe PKG watch is returned by the user to the company (using a prepaid addressed envelope), which extracts the data and generates reports for users and healthcare professionals to view online. As well as providing the raw data, algorithm-generated movement scores are provided for the whole 6‑day period. The report includes summary graphs showing measurements over time and a summary of results, along with a suggested target range for interpretation. The watch has medication reminders and users can record when they have taken their medication.\n\nThe company provides education and training to healthcare professionals. It advises that healthcare professionals should review an average of 15\xa0to 20 PKGs to be proficient, supported by an eLearning module, which takes approximately 1 to 2\xa0hours. The device costs £225 per use per patient.\n\n## STAT-ON\n\nThe STAT‑ON system (Sense4care) consists of a monitoring device, a base charger, a belt with a waist-worn inertia recorder attached, and a mobile application. The system must be configured by a healthcare professional through the mobile application. The smartphone application connects to the STAT‑ON device via Bluetooth. Results are stored in its internal memory. The device measures dyskinesia, 'on' and 'off' periods, gait parameters (including bradykinesia and freezing of gait), falls, energy expenditure and posture. It does not measure tremor. The user wears the device for a minimum of 5\xa0days (ideally for 7\xa0days), totalling a minimum of 24\xa0hours over the 5\xa0days, to collect enough data. After this, a report can be generated.\n\nThe device collects data and uses algorithms to process it. It produces a report containing detailed data analyses, as well as summaries of activity and prevalence of symptoms during the monitored period. Healthcare professionals can download the report using the mobile application. The application also has medication reminders, and people can record when they have taken their medication.\n\nTraining sessions last 1.5\xa0hours. Quick guides, videos and graphical training documents are provided for healthcare professionals to understand how the system is configured and how to interpret the report. The annual subscription cost is £1,600.\n\n## The comparator\n\nThe comparator is clinical judgement of motor and non-motor symptoms based on information including clinical history and patient diaries, which may include rating scale tools and activity trackers. The Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr scale can be used to describe and assess symptoms related to Parkinson's disease.", 'Committee discussion': "The diagnostics advisory committee considered evidence on Kinesia\xa0360, KinesiaU, PDMonitor, Personal KinetiGraph (PKG), and STAT‑ON for remote monitoring of Parkinson's disease from several sources, including a diagnostics assessment report and an overview of that report. Full details are in the project documents for this guidance on the NICE website.\n\n# People with Parkinson's disease could benefit from remote monitoring technologies\n\nThe external assessment group (EAG) identified 8 papers that reported patient or carer opinions on PKG, 2 papers on STAT‑ON, 1 on Kinesia\xa0360 and 1 on KinesiaU. Patient experts explained the potential benefits of easy-to-use and unobtrusive remote monitoring options for Parkinson's disease. This included contributing to a 'feeling of normality', prolonging a level of independence, acting as an urgency signal to accelerate further care, and reducing anxiety around in-person visits. It could also help with describing symptoms to healthcare professionals, which can be very difficult, particularly when trying to describe how symptoms change over time. A patient expert also explained that the reports the technologies generate can help them understand their condition. The committee noted that remote monitoring technologies could make remote care easier, so that healthcare professionals could do appointments by telephone or video call, so people did not have to travel as often to meet in person. This would reduce travel costs and could reduce how much their condition feels like a medical condition, particularly in the earlier stages. However, the patient experts said that the disease can be isolating for people with Parkinson's disease and their carers, and that face-to-face appointments can help with this. The committee also noted that the technologies may not be suitable for everyone with Parkinson's disease, for example for people who are particularly frail, use a wheelchair, are confined to bed, or have missing limbs or cognitive or sensory impairment. In some cases, additional support may be needed to help people to use the remote monitoring devices. The committee noted that the devices differ in how they work and where sensors are worn, so some may be more suited to some people than others, for example people with missing limbs or with restricted movement. It recognised that offering face-to-face appointments is still essential, and that remote assessment would not replace this, but could offer more flexible options for care for some people. The clinical experts commented that the technologies should be considered as complementary to face-to-face appointments. The clinical experts emphasised the importance of making training and other user-support resources accessible, and making sure that they are suitable for people with hearing loss or visual impairment. The clinical experts also said that the time between review appointments can be very variable and prolonged, so having the option of using the remote monitoring devices could provide reassurance and a safety net for checking symptoms between clinic appointments. The committee concluded that devices for remote monitoring offer a range of potential benefits to people with Parkinson's disease.\n\n# Carers could benefit from remote technologies monitoring symptoms\n\nThe patient experts said that current methods of assessing symptoms can rely heavily on observations made by carers, and their ability to communicate these to clinical experts. The size of responsibility for this causes a lot of stress and anxiety, particularly as the condition progresses and if the carer is the main source of information about changes in symptoms. The person with Parkinson's disease and their carer may disagree about the extent of symptoms, which can be difficult. A technology that objectively reviews symptoms could help discussions and take pressure off the carer. The patient experts also said that if someone with Parkinson's disease does not have a carer living with them, or if their carer has cognitive issues, then the potential value of the technologies would be much greater. The committee recognised that a carer's quality of life is affected by the severity of Parkinson's symptoms, and the responsibilities of managing medication and hospital visits. The patient experts explained that caring for people with Parkinson's disease can mean that carers put off managing their own health issues, and that this can affect a carer's health-related quality of life considerably, and so increase costs to the NHS. Travel for in-person appointments can be difficult for carers who may need to take time off work, particularly if they are the only earner, so being able to use remote appointments more would help. The committee recognised that objective remote monitoring technologies may help alleviate stress and anxiety for carers, assist in communication with healthcare professionals, and could save time at hospital appointments by providing a starting point for discussions. It concluded that it was important to consider any impact of the technologies on carers in its decision making.\n\n# The technologies could be used in many different ways in the NHS and how they would fit into the care pathway is not clear\n\nThe clinical experts explained that the technologies could be used in many different ways in the NHS. For example, before regularly scheduled appointments with healthcare professionals, after treatment changes to help titrate dosage, to indicate if a further review appointment with a healthcare professional is needed, or for people who are having issues with symptoms. They said that centres currently using these technologies did so in very different ways. The clinical experts noted that it was important that the technologies were integrated into care pathways, including training for clinical teams and for people with Parkinson's disease and their carers. This could mean that care pathways are changed. How the technologies would be used if adopted was not clear and could have a big impact on clinical and cost effectiveness. Studies identified by the EAG that compared the devices with standard care used the technologies in different ways: Woodrow et al. (2020) used the PKG at 5‑week intervals for up to 25\xa0weeks; Isaacson et al. (2021) used the Kinesia\xa0360 to optimise rotigotine dosage when motor symptoms were not controlled well enough. There was little data showing the impact of the devices if they were used in ways that could be adopted by the NHS, for example to identify people who need a review appointment with a healthcare professional. The EAG explained that there was little evidence on the technologies when used in the UK. It also pointed out that how the technologies are used would affect how often they are used, and that this greatly affected cost-effectiveness estimates (see section 3.9). The committee concluded that the technologies could be used in many different ways in the NHS and how they would fit into the care pathway is not clear.\n\n# The level of care in Parkinson's disease varies and remote monitoring may become increasingly important\n\nThe clinical and patient experts explained that, although NICE's guideline on Parkinson's disease recommends that people with Parkinson's disease have a review every 6 to 12\xa0months, this does not always happen in practice. They said the level of care varies across the NHS. The clinical experts added that the number of people with Parkinson's disease is increasing, which will place further pressure on the healthcare system. There are also backlogs for review appointments because of COVID‑19 disruptions. Patient experts said the technologies could be a way for people with difficulties accessing services to have assessments. They said it was also a way to identify issues during the lengthy gaps between reviews (see section 3.1). The committee noted that the size of benefit of adopting the technologies may vary depending on current local care. It also noted that increasing pressures on NHS services may mean that the technologies are likely to become increasingly beneficial.\n\n# Clinical effectiveness\n\n## The reference standard in identified accuracy studies is imperfect and may underestimate technology performance\n\nThe EAG said that there is no clearly established reference standard for measuring Parkinson's disease symptoms, beyond clinician and patient assessment, that could be used to establish test accuracy. A potential benefit of the technologies is that they may more accurately evaluate symptoms than patient recall or clinical opinion, so a reference standard based on patient recall or clinical opinion (as used in accuracy studies identified by the EAG in its systematic review) could underestimate technology performance. The committee noted that accuracy estimates may not be the best outcome for assessing the performance of these technologies.\n\n## There is limited evidence on how much the technologies can improve symptoms or health-related quality of life\n\nOnly 3 studies had data comparing clinical outcomes with the technologies against not using the technologies. Two of these (which assessed the Kinesia\xa0360) were small randomised controlled trials. The largest study (which assessed the PKG and was by Woodrow et al.) reported clinical improvements in terms of statistically significant reductions in the Unified Parkinson's Disease Rating Scale (UPDRS)\xa03 (motor examination), UPDRS\xa04 (complications of therapy), total UPDRS score and PDQ‑39 (Parkinson's Disease Questionnaire 39). The committee noted that the trial was not randomised. It understood that there could have been a systematic difference between the centres included in the trial and their catchment areas because people were allocated to PKG based on the centre they attended. The clinical experts also pointed out that the PKG was used every 5\xa0weeks in the Woodrow et al. study, which would not be realistic in the NHS. Standard care in the study's comparator arms also may not represent NHS care. Because the length of follow up from the available studies was relatively short, there was also a lack of data on how long any benefit of the devices lasted once they were not used any more. Also, the EAG did not identify any data specifically on the populations who were identified in the scope as likely to have particular benefit from the technologies. These included people with communication barriers and people from black, Asian and minority ethnic family backgrounds, because symptoms can vary by family background. The committee concluded that, while the identified studies gave some indication of how the technologies could benefit people with Parkinson's disease, there was considerable uncertainty about the likely size of this benefit if the technologies were adopted in the NHS.\n\n## Most of the evidence is in people having maintenance therapy\n\nThe clinical and patient experts suggested that the technologies may be particularly useful for people who are eligible for more advanced therapies such as deep brain stimulation. But the EAG said the only evidence on the devices' comparative effectiveness was in the maintenance stage of Parkinson's disease. The committee understood that the devices may perform differently in these different populations.\n\n## How much remote monitoring devices would change decisions about care in the NHS is uncertain\n\nThe clinical experts said that, as well as changes to medication, symptoms can be managed with other changes to care like physiotherapy and exercise. Only the PKG had data on how the technologies can change decisions about care. The proportion of people who had a change in clinical management as a result of the PKG varied considerably (between 31.8% and 79%). A UK study reported that the PKG provided additional information in 45.5% of cases. In studies of clinician opinion, between 4% and 41% agreed that the PKG provided enough additional information to consider making treatment adjustments. The committee concluded that there was uncertainty about how much using remote monitoring devices would change care for people in the NHS.\n\n# Cost effectiveness\n\n## Device cost is a major driver of cost effectiveness\n\nIn the EAG's model, the intervention arm resulted in a higher cost than standard care. Device cost had the biggest impact on this. The EAG said that the device cost depended on how the devices were modelled as being used (see section 3.3) and the cost per use. The technologies have differing payment mechanisms: pay per use, a subscription model or outright purchase of the device. The committee noted that the payment options differed in terms of upfront investment and how reversible a decision to use a technology would be. The committee recalled that the technologies could be used in various ways in the NHS and noted that the EAG had modelled use at varying frequencies. This included one-time use (at baseline) and routine use (every 6\xa0months) in its base cases, and a recurrent use scenario analysis (at 6 and 18\xa0months in place of clinic appointments). How frequently the technologies were used substantially affected device-related costs and the cost-effectiveness estimates.\n\n## Because of the uncertainty about the devices' impact on health-related quality of life, their cost effectiveness is also uncertain\n\nThe committee recalled that there was uncertainty about the size of impact that device use would have on symptoms if used in the NHS (see section 3.6). The EAG used the Woodrow\xa0et\xa0al. trial to inform the estimates of health-related quality of life in its model. It also had to make assumptions about how long any benefit would last after using the devices. Sensitivity analyses showed that the cost-effectiveness estimates were very sensitive to this assumption. The committee concluded that the size and longevity of the benefits of device-guided decisions about care was very uncertain, and consequently so were the cost-effectiveness estimates produced by the EAG's model.\n\n## Chaudhuri et al. (2022) is likely to have overestimated how device use would affect resource use and how long any benefit would last for\n\nCost-effectiveness modelling reported by Chaudhuri et al. (2022) estimated that the PKG would be cost saving by £17,362, whereas in the EAG's model the PKG incurred costs. Both models compared the PKG with standard care. The committee questioned the approach used in Chaudhuri et al., which took scores with PKG use on the UPDRS from Woodrow et al. and converted them to the Hoehn and Yahr scale. They then used this to calculate resource costs. The committee noted that the EAG had been unable to verify or validate the approach used by Chaudhuri et al. It was also not clear if the symptom improvements observed from using the technologies could realistically translate into the large-scale changes in healthcare use predicted by this model. A clinical expert said that it was very unlikely that remote monitoring devices would have the effect shown on the Hoehn and Yahr scale. The EAG added that in Woodrow et al., device use did not have a statistically significant effect on the Hoehn and Yahr scores (-0.044, standard error 0.097 for adjusted data). It also said that in the Chaudhuri et al. model, the PKG's effect on symptoms was assumed to last for 5 years with only limited waning of effect after that, although there was no evidence for this. Clinical experts noted that there are no disease-modifying treatments available for Parkinson's disease that can stop progression. The committee concluded that the Chaudhuri et al. model was likely to have overestimated how much the PKG can reduce healthcare-associated resource costs, and how long the benefit from PKG-guided care on symptoms would last for.\n\n## The broader impact of remote monitoring device use on resources is uncertain\n\nA UK survey reported that people with Parkinson's disease interact with 18 different healthcare professions. The EAG had suggested that more data on this could identify further areas in which remote monitoring device-aided care could reduce costs. The patient experts also explained that the cost of providing care to people with Parkinson's disease can differ significantly according to whether they have a live-in carer, a paid carer or no carer at all. Costs related to social care were not included in the EAG's model because of a lack of data. Any impact of remote monitoring devices on these costs, for example delaying when someone with Parkinson's disease goes into a care home, could have been missed. The companies said that the EAG's model did not include costs related to falls and hip fractures prevented, which they said could be an uncaptured benefit if the devices did improve symptom management. The EAG explained that there was a lack of data to inform this. Also, because of a lack of data, its analysis was constrained to the management phase of Parkinson's disease. It understood that falls, hip fractures and social care costs are largely confined to the advanced stages of the disease. The committee concluded that the EAG's model may have underestimated the impact of using remote monitoring devices on some resources and associated costs. However, other costs related to implementing the devices, for example interconnectivity, may be higher in practice.\n\n## The EAG's model did not capture the potential impact of remote monitoring on carers\n\nThe committee recalled that remote monitoring devices could benefit carers (see section 3.2). But, because of a lack of data, the EAG's model did not include costs or health-related quality of life for them. The committee noted that relatively small improvements in quality-adjusted life years (QALYs) resulting from device use (perhaps related to carer benefits) could have a large impact on the cost-effectiveness results, depending on the analysis used. The committee concluded that there was considerable uncertainty about how much the remote monitoring devices could affect carers, and noted that this had not been captured in the EAG's model.\n\n## The value of the technology may be underestimated, or was not estimated, by the EAG's model for some groups\n\nThere was not enough evidence for the EAG to be able to do subgroup analyses for people who have communication barriers, people from black, Asian and minority ethnic family backgrounds, or people from different socio-economic backgrounds. These populations were identified at scoping as being potentially likely to gain additional benefits from the technologies. The patient experts noted that remote monitoring may also benefit people who are having difficulty attending consultations, or getting care because services are at full capacity. The EAG had also not been able to model how remote monitoring devices might work for people being considered for advanced therapies such as deep brain stimulation, because there was not enough evidence.\n\n## Remote monitoring technologies have considerable promise, but more data is needed to estimate their true cost effectiveness\n\nThe committee recognised the promise that remote monitoring devices offer to people with Parkinson's disease and their carers (see section 3.1 and section 3.2). These devices could also help with increasing capacity pressures on the NHS. But their cost effectiveness is very uncertain, and to estimate it more accurately, there are several areas of uncertainty for which more data is needed (see section 4). The PKG has the most evidence, but the committee recalled that there was uncertainty about how well data from the main trial for this technology (Woodrow et al.) represents how well the device would work in the NHS (see section 3.6). The committee noted that the technologies differed in how sensors are worn (see sections 2.6 to 2.21) and the algorithms they use. Because of this, the EAG stated that clinical benefits observed for 1 technology could not be assumed for the other technologies. No identified studies compared the performance of 1 technology against another. A lot of identified data was on test accuracy. The committee recalled its concern about the suitability of accuracy estimates for assessing the performance of these technologies (see section 3.5). It also recalled the uncertainty in how much remote monitoring devices would change decisions about care in the NHS (see section 3.8). The committee concluded that, to assess performance, further data is needed for all technologies on the size of impact of using all of the technologies on symptoms or health-related quality of life (see section 4.2).\n\n## The remote monitoring technologies can be used in the NHS while further data is collected\n\nThe committee considered the risks associated with using the technologies in the NHS while further data is collected. The clinical and patient experts said that their main concern about potentially worse patient outcomes was if use of the devices was poorly implemented. For example, if they were used to entirely replace face-to-face appointments, and were not integrated into care pathways. They also said that remote monitoring devices were already being used in some NHS centres. The committee noted that the overall cost impact of using the devices was uncertain and was largely dictated by how much the companies charged, and the different payment mechanisms (see section 3.9). The committee concluded that this was important for commissioners to consider, because the devices were likely to differ in terms of ongoing or irrecoverable costs if a later decision was made to stop using the technologies, for example if further data collection showed they did not work as well as anticipated.\n\n# Research considerations\n\n## More data collection is needed in populations that represent the potential use and benefits of the devices in the NHS\n\nThere was no or limited data for several populations who could particularly benefit from the remote monitoring technologies (see section 3.14), including people who might be helped by advanced therapies.", 'Evidence generation recommendations': "# More data on how much remote monitoring devices affect resource use would help decision making\n\nThere is uncertainty about how much remote monitoring devices would affect resource use in the NHS and personal social services. Some impacts may not have been included in the external assessment group's (EAG) model because of a lack of data (see section 3.12), including resource use related to carers (see section 3.13). Adopting the technologies may change how care is provided (see section 3.4) so their effect on resources is hard to estimate without direct data. So, the committee recommended collecting data on how much using the devices affects resource use, to inform cost-effectiveness estimates. Data on time dedicated to training and spent reviewing device results should also be collected. The broader impact on services provided by Parkinson's specialist teams and carers should be considered.\n\n# More data to help inform estimates of the impact on health-related quality of life would help decision making\n\nHow much using remote monitoring devices to guide decisions about care affects symptoms, and therefore health-related quality of life, is uncertain. How long after using the devices any impact would last is also uncertain. This had a sizeable influence on cost-effectiveness estimates (see section 3.10). Data on this came from studies that did not represent likely NHS practice (see section 3.6), which is itself uncertain (see section 3.3), and from assumptions made by the EAG because of lack of data. For its model, the EAG used a published algorithm from Chandler et al. (2020) to estimate quality-adjusted life years (QALYs) from the Unified Parkinson's Disease Rating Scale (UPDRS) domain scores. The clinical experts said that health-related quality of life questionnaires like the PDQ‑39 are increasingly used in trials to assess health-related quality of life for people with Parkinson's disease. The committee also recognised that the effect of the devices on the health-related quality of life of carers had not been included in the EAG's model because of a lack of data (see section 3.13).\n\n# Data should be collected on how often the remote monitoring devices are used and for what reasons\n\nHow frequently the remote monitoring devices were modelled as being used substantially affected the cost-effectiveness estimates in the EAG's model (see section 3.9). There are many ways the devices could be used in the NHS (see section 3.3) and no data was available to compare different approaches. So, it is currently not possible to highlight particular approaches that are likely to be more clinically and cost effective. Centres using the devices should therefore collect data on how often they are used and under what circumstances. For example, regularly in advance of scheduled review appointments, to indicate when such appointments are needed, or targeted to people having issues with symptoms. This will help assess the clinical and cost effectiveness of the different uses of the devices in NHS practice."}	https://www.nice.org.uk/guidance/dg51	Evidence-based recommendations on Kinesia 360 and KinesiaU (Great Lakes NeuroTechnologies), PDMonitor (PD Neurotechnology), Personal KinetiGraph (Global Kinetics) and STAT‑ON (Sense4care) for remote monitoring of Parkinson’s disease.
b6a3e92c6f7ced02d0ae905ae333191f9c75e52d	nice	Delirium: prevention, diagnosis and management in hospital and long-term care	Delirium: prevention, diagnosis and management in hospital and long-term care This guideline covers diagnosing and treating delirium in people aged 18 and over in hospital and in long-term residential care or a nursing home. It also covers identifying people at risk of developing delirium in these settings and preventing onset. It aims to improve diagnosis of delirium and reduce hospital stays and complications. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Think delirium Be aware that people in hospital or long-term care may be at risk of delirium. This can have serious consequences (such as increased risk of dementia and/or death) and, for people in hospital, may increase their length of stay in hospital and their risk of new admission to long-term care. For recommendations on managing delirium in palliative care, see the NICE guideline on care of dying adults in the last days of life. # Risk factor assessment When people first present to hospital or long-term care, assess them for the following risk factors. If any of these risk factors are present, the person is at risk of delirium. Age 65 years or older. Cognitive impairment (past or present) and/or dementia (for guidance on diagnosing dementia, see the section on diagnosis in the NICE guideline on dementia). If cognitive impairment is suspected, confirm it using a standardised and validated cognitive impairment measure. Current hip fracture. Severe illness (a clinical condition that is deteriorating or is at risk of deterioration; for further information on recognising and responding to acute illness in adults in hospital, see the NICE guideline on acutely ill adults in hospital). Observe people at every opportunity for any changes in the risk factors for delirium. # Indicators of delirium: at presentation At presentation, assess people at risk for recent (within hours or days) changes or fluctuations that may indicate delirium. These may be reported by the person at risk, or a carer or relative. These changes may affect: cognitive function: for example, worsened concentration, slow responses, confusion perception: for example, visual or auditory hallucinations physical function: for example, reduced mobility, reduced movement, restlessness, agitation, changes in appetite, sleep disturbance social behaviour: for example, difficulty engaging with or following requests, withdrawal, or alterations in communication, mood and/or attitude.If any of these changes are present, the person should have an assessment (see recommendation 1.6.1). Be particularly vigilant for changes that may indicate hypoactive delirium, which are often missed, such as withdrawal, slow responses, reduced mobility and movement, worsened concentration and reduced appetite. # Preventing delirium Ensure that people at risk of delirium are cared for by a team of healthcare professionals who are familiar to the person at risk. Avoid moving people within and between wards or rooms unless absolutely necessary. Give a tailored multicomponent intervention package: within 24 hours of admission, assess people at risk for clinical factors contributing to delirium based on the results of this assessment, provide a multicomponent intervention tailored to the person's individual needs and care setting as described in recommendations 1.4.4 to 1.4.13. The tailored multicomponent intervention package should be delivered by a multidisciplinary team trained and competent in delirium prevention. Address cognitive impairment and/or disorientation by: providing appropriate lighting and clear signage; a clock (consider providing a 24-hour clock in critical care) and a calendar should also be easily visible to the person at risk talking to the person to reorientate them by explaining where they are, who they are and what your role is introducing cognitively stimulating activities (for example, reminiscence) facilitating regular visits from family and friends. Address dehydration and/or constipation by: ensuring adequate fluid intake to prevent dehydration by encouraging the person to drink; consider offering subcutaneous or intravenous fluids if necessary taking advice if necessary, when managing fluid balance in people with comorbidities (for example, heart failure or chronic kidney disease). Assess for hypoxia and optimise oxygen saturation if necessary, as clinically appropriate.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. Address infection by: looking for and treating infection avoiding unnecessary catheterisation implementing infection control procedures in line with the NICE guideline on healthcare-associated infections. Address immobility or limited mobility through the following actions: Encourage people to: mobilise soon after surgery walk (provide appropriate walking aids if needed; these should be accessible at all times). Encourage all people, including those unable to walk, to carry out active range-of-motion exercises. Address pain by: assessing for pain looking for non-verbal signs of pain, particularly in those with communication difficulties (for example, people with learning difficulties or dementia, or people on a ventilator or who have a tracheostomy) starting and reviewing appropriate pain management in any person in whom pain is identified or suspected. Carry out a medication review for people taking multiple drugs, taking into account both the type and number of medications. For information on medicines optimisation see the NICE guideline on medicines optimisation. Address poor nutrition by: following the advice given on nutrition in the NICE guideline on nutrition support for adults if people have dentures, ensuring they fit properly. Address sensory impairment by: resolving any reversible cause of the impairment, such as impacted ear wax ensuring hearing and visual aids are available to and used by people who need them, and that they are in good working order. Promote good sleep patterns and sleep hygiene by: avoiding nursing or medical procedures during sleeping hours, if possible scheduling medication rounds to avoid disturbing sleep reducing noise to a minimum during sleep periods. # Indicators of delirium: daily observations Observe, at least daily, all people in hospital or long-term care for recent (within hours or days) changes or fluctuations indicating delirium (for example, see recommendation 1.3.1). These may be reported by the person at risk, or a carer or relative. If any of these changes are present the person should have an assessment using an appropriate tool (see recommendation 1.6.1). Ensure that any changes that may indicate delirium are documented in the person's record or notes. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indicators of delirium: daily observations . Full details of the evidence and the committee's discussion are in evidence review A: diagnostic accuracy of tests to identify delirium. Loading. Please wait. # Assessment and diagnosis If indicators of delirium are identified, a health or social care practitioner who is competent to do so should carry out an assessment using the 4AT. In critical care or in the recovery room after surgery use the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or Intensive Care Delirium Screening Checklist (ICDSC) instead of the 4AT. If the assessment described in recommendation 1.6.1 indicates delirium, a healthcare professional with the relevant expertise should make the final diagnosis. This could be the same person who made the assessment. If there is difficulty distinguishing between the diagnoses of delirium, dementia or delirium superimposed on dementia, manage the delirium first. Ensure that the diagnosis of delirium is documented both in the person's record or notes, and in their primary care health record. For a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on assessment and diagnosis . Full details of the evidence and the committee's discussion are in evidence review A: diagnostic accuracy of tests to identify delirium. Loading. Please wait. # Treating delirium ## Initial management In people diagnosed with delirium, identify and manage the possible underlying cause or combination of causes. Ensure effective communication and reorientation (for example explaining where the person is, who they are and what your role is) and provide reassurance for people diagnosed with delirium. Consider involving family, friends and carers to help with this. Provide a suitable care environment (see recommendation 1.4.1 in the section on preventing delirium). ## Distressed people If a person with delirium is distressed or considered a risk to themselves or others, first use verbal and non-verbal techniques to de-escalate the situation. For more information on de-escalation techniques, see the NICE guideline on violence and aggression. Distress may be less evident in people with hypoactive delirium, who can still become distressed by, for example, psychotic symptoms. If a person with delirium is distressed or considered a risk to themselves or others, and verbal and non-verbal de-escalation techniques are ineffective or inappropriate, consider giving short-term haloperidol (usually for 1 week or less). Start at the lowest clinically appropriate dose and titrate cautiously according to symptoms. Take into account the Medicines and Healthcare products Regulatory Agency's advice about the risks of using haloperidol for the acute treatment of delirium in older people, including the risks of cardiac and neurological side effects (especially in people living with Parkinson's disease or dementia with Lewy bodies). ## If delirium does not resolve For people in whom delirium does not resolve: re-evaluate for underlying causes follow up and assess for possible dementia (see the NICE guideline on dementia). # Information and support Offer information to people who are at risk of delirium or who have delirium, and their family and/or carers, which: informs them that delirium is common and usually temporary describes people's experience of delirium encourages people at risk and their families and/or carers to tell their healthcare team about any sudden changes or fluctuations in behaviour encourages the person who has had delirium to share their experience of delirium with the healthcare professional during recovery advises the person of any support groups. Ensure that information provided meets the cultural, cognitive and language needs of the person. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## Health or social care practitioners Health and social care staff across the wider care team. This could include registered nurses and care workers (also called care assistants or support workers), social workers, therapists, case managers, GPs, lead clinicians, community nurses and allied professionals, such as physiotherapists, occupational therapists and dietitians. ## Healthcare professionals Health professionals regulated or licensed with a professional body to provide care and support, for example, generalist and specialist doctors registered with the General Medical Council, and nurses registered with the Nursing and Midwifery Council. ## Hyperactive delirium A subtype of delirium characterised by people who have heightened arousal and can be restless, agitated or aggressive. ## Hypoactive delirium A subtype of delirium characterised by people who become withdrawn, quiet and sleepy. ## Long-term care Residential care in a home that may include skilled nursing care and help with everyday activities. This includes nursing homes and residential homes.# Recommendations for research The guideline committee has made the following key recommendations for research. # Delirium assessment tools What is the diagnostic accuracy, and ease of implementation, of different delirium assessment tools: for people with pre-existing cognitive impairment, for example dementia, learning disability or severe depression for people who do not speak English as a first language in different settings, for example emergency departments, residential care homes or virtual consultations when delivered by different types of health and social care practitioners, for example healthcare assistants or allied health professionals such as paramedics? For a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and diagnosis . Full details of the evidence and the committee's discussion are in evidence review A: diagnostic accuracy of tests to identify delirium. Loading. Please wait. # Pharmacological prevention In people in hospital who are at high risk of delirium, which medication (atypical antipsychotics, typical antipsychotics, benzodiazepines or acetylcholinesterase inhibitors), compared with placebo or each other, is more clinically and cost effective in preventing the development of delirium? ## Why this is important The serious nature of delirium and its consequences makes it important to establish all methods of prevention. Pharmacological agents may be a simple preventive treatment for delirium, but there is uncertainty about effectiveness and side effects so they should be used with caution. The evidence is limited: 3 low-quality studies were found, each of which was unrepresentative either of the population or the medication used, but there was some indication of clinical effectiveness. A large randomised trial (with at least 100 people in each arm) should be conducted in people in hospital who are at high risk of delirium to compare atypical antipsychotics, typical antipsychotics, benzodiazepines or acetylcholinesterase inhibitors with placebo, or each other, for preventing delirium. The included populations should be defined in terms of their delirium risk (for example people at high risk could be those with 2 or more risk factors for delirium). The primary outcome should be the incidence of delirium, measured at least daily using a validated diagnostic tool. The severity and duration of delirium should also be recorded, together with adverse effects of the medication, notably extrapyramidal symptoms and stroke. # Pharmacological treatment In people in hospital who have delirium, which is the most effective medication (atypical antipsychotics, typical antipsychotics or benzodiazepines) compared with placebo or each other for treating delirium? ## Why this is important Pharmacological interventions are currently used in clinical practice to manage the symptoms of delirium but the evidence for this is limited. One moderate-quality study showed that typical and atypical antipsychotics were clinically and cost effective compared with placebo, but there is no evidence for benzodiazepines. Pharmacological agents that alter the course of delirium or control particular symptoms might be useful in treating delirium, but we need to determine whether the medication should be given routinely or for selected symptoms, and what adverse events may occur. A large randomised trial (with at least 100 people in each arm) should be conducted in people in hospital with delirium to compare atypical antipsychotics, typical antipsychotics, or benzodiazepines with placebo, or each other, for the treatment of delirium. The outcomes should be recovery from delirium (complete response), and the duration and severity of delirium, measured using a validated diagnostic tool. Adverse events, notably extrapyramidal symptoms and stroke, should also be recorded. # Multicomponent intervention For people in long-term care, is a multicomponent non-pharmacological intervention more clinically and cost effective than usual care in preventing the development of delirium? ## Why this is important Although there is moderate-quality evidence of clinical and cost effectiveness for multicomponent interventions for the prevention of delirium in people in hospital, there is no evidence in a long-term care setting. It is anticipated that such an intervention would benefit this long-term care population. A large, adequately powered, randomised trial, or a large, adequately powered, cluster randomised trial should be conducted in people in long-term care to compare a multicomponent intervention with usual care. The multicomponent intervention should include assessment by a trained and competent healthcare professional, who would recommend actions tailored to the person's needs. The intervention should include the recommended interventions to prevent delirium, particularly reorientation, medication review, hydration and sleep hygiene. The primary outcome should be the incidence of delirium, measured at least daily using a validated diagnostic tool. The severity and duration of delirium should also be recorded using a validated tool, together with the consequences of delirium, including admission to hospital. # Delirium in long-term care How common is delirium and what are its adverse outcomes in people in long-term care? ## Why this is important Although there is evidence for adverse outcomes consequent to delirium in hospital, there is very little evidence from long-term care. It is important to determine whether people in long-term care, who already have a high risk of death, dementia and other adverse outcomes, have a further increased risk of these outcomes if they develop delirium. The risk of hospital admission as a consequence of delirium is also unknown. A large cohort study should be conducted in people in long-term care to determine: the prevalence of delirium in this setting, and if the presence of delirium is a prognostic factor for death, dementia, admission to hospital, falls and other adverse outcomes. The multivariate analysis conducted in this study should take into consideration the potential significant risk factors and confounding factors identified in the guideline. Such a study would also inform cost-effectiveness analyses for the prevention and treatment of delirium. # Education programme Does a staff education programme (compared with an educational leaflet or usual care) reduce the incidence of delirium and improve the recognition and recording of delirium in people in hospital? ## Why this is important There is some evidence from multicomponent prevention studies to suggest that an education programme for healthcare professionals who care for people at risk of delirium reduces the incidence of delirium. However, the quality of this evidence is poor. There is a need to determine whether education has an important preventive effect on the incidence of delirium. There is also a need to find out if an educational programme increases awareness of delirium, so that delirium is recorded accurately, which is not the case in the UK at present. A cluster randomised trial should be carried out, with whole hospitals randomised to the educational interventions (thereby reducing the trial contamination effects of staff vicariously picking up education from colleagues randomised to the education programme arm). The primary outcomes (incidence of delirium and recording of delirium in the person's healthcare record) should be measured at a minimum of 3 timepoints before and after the intervention.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Indicators of delirium: daily observations Recommendations 1.5.1 to 1.5.2 ## Why the committee made the recommendations The committee agreed with the recommendation in the previous version of the guideline that all staff should be observing the people in their care and should be alert for changes indicating delirium. They noted that some simple tools like the Single Question to Identify Delirium (SQiD) might be useful to help practitioners notice any changes. They did not add SQiD specifically to the recommendation because they agreed that it is just one of many ways to encourage observation and that many places already have systems set up for this. They noted that in some settings the recording of these observations could be inconsistent, and that routine recording of changes that might indicate delirium was important. ## How the recommendations might affect practice Better recording of the indicators of delirium will improve the chances of these changes being noticed and acted upon. Return to recommendations # Assessment and diagnosis Recommendations 1.6.1 to 1.6.2 ## Why the committee made the recommendations The committee agreed that once a change that might indicate delirium has been noted and recorded, a member of staff competent to do so should carry out a formal assessment. Several assessment tools had high enough sensitivity and specificity to be useful in clinical practice. However, the committee agreed that implementation issues need to be considered as well. For example, who can do the test, how long does it take and how much training is needed? Balancing the evidence for accuracy and cost effectiveness with the practicality of implementing the tests, the committee agreed that the 4AT was the best option for most settings. It is among the most accurate of the tools reviewed, quick and simple to use, and has a broader range of evidence to support it. The committee agreed that a range of health and social care practitioners would be able to carry out the 4AT and that special training is not needed, although practitioners should be assessed as competent in its use. They also discussed that some specialist professionals may not need to use a screening tool to carry out an assessment and diagnose delirium, but that it would generally be considered good practice. Overall, they agreed that its use will help ensure that delirium is picked up promptly in different care settings, especially those where a healthcare professional may not be immediately available. For critical care and post-surgical settings, the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC) worked best because they were specifically designed for those settings. However, the committee noted that training is needed for both CAM-ICU and ICDSC before practitioners can use them. If the assessment shows delirium is likely, the committee agreed that the final diagnosis should be carried out by a healthcare professional with the necessary experience and expertise, for example, a specialist nurse, a GP, lead clinician or a member of the frailty team. Depending on the circumstances, this might be the same person who carried out the 4AT. If there is uncertainty about the diagnosis, a specialist such as a geriatrician or psychiatrist, may need to be involved. The committee agreed that although the evidence allowed them to make recommendations overall, further, more specific, research on the accuracy and ease of use of different assessment tools in different settings, for different patient groups (including those with dementia, cognitive impairments, learning disabilities or affective disorders) and by different healthcare practitioners, would help to make future guidance more specific. They therefore made a recommendation for research on delirium assessment tools. ## How the recommendations might affect practice The committee noted that the assessment tools they recommended are already the most commonly used in practice. The change from healthcare professional in the previous version of this guideline to health or social care practitioner in this version will potentially reduce the workload for healthcare professionals who previously had to carry out assessments for delirium. Return to recommendations# Context Delirium (sometimes called 'acute confusional state') is a common clinical syndrome characterised by disturbed consciousness, cognitive function or perception, which has an acute onset and fluctuating course. It usually develops over 1 to 2 days. It is a serious condition that is associated with poor outcomes. However, it can be prevented and treated if dealt with urgently. A person may already have delirium when they present to hospital or long-term care or it may develop during a hospital admission or residential stay in long-term care. Delirium can be hypoactive or hyperactive but some people show signs of both (mixed). People with hyperactive delirium have heightened arousal and can be restless, agitated and aggressive. People with hypoactive delirium become withdrawn, quiet and sleepy. Hypoactive and mixed delirium can be more difficult to recognise. It can be difficult to distinguish between delirium and dementia and some people may have both conditions. Older people and people with dementia, severe illness or a hip fracture are more at risk of delirium. The prevalence of delirium in people on medical wards in hospital is about 20% to 30%, and 10% to 50% of people having surgery develop delirium. In long-term care the prevalence is under 20%. But reporting of delirium is poor in the UK, indicating that awareness and reporting procedures need to be improved. There is a significant burden associated with this condition. Compared with people who do not develop delirium, people who develop delirium may: need to stay longer in hospital or in critical care have an increased incidence of dementia have more hospital-acquired complications, such as falls and pressure sores be more likely to need to be admitted to long-term care if they are in hospital be more likely to die. This clinical guideline describes methods of preventing, identifying, diagnosing and treating delirium. In particular, the guideline focuses on preventing delirium in people identified to be at risk, using a targeted, multicomponent, non-pharmacological intervention that addresses a number of modifiable risk factors ('clinical factors'). If delirium is prevented, it should generate cost savings. This guideline does not cover children and young people (younger than 18 years), people receiving end-of-life care, or people with intoxication and/or withdrawing from drugs or alcohol, and people with delirium associated with these states.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Think delirium\n\nBe aware that people in hospital or long-term care may be at risk of delirium. This can have serious consequences (such as increased risk of dementia and/or death) and, for people in hospital, may increase their length of stay in hospital and their risk of new admission to long-term care. For recommendations on managing delirium in palliative care, see the NICE guideline on care of dying adults in the last days of life. \n\n# Risk factor assessment\n\nWhen people first present to hospital or long-term care, assess them for the following risk factors. If any of these risk factors are present, the person is at risk of delirium.\n\nAge 65\xa0years or older.\n\nCognitive impairment (past or present) and/or dementia (for guidance on diagnosing dementia, see the section on diagnosis in the NICE guideline on dementia). If cognitive impairment is suspected, confirm it using a standardised and validated cognitive impairment measure.\n\nCurrent hip fracture.\n\nSevere illness (a clinical condition that is deteriorating or is at risk of deterioration; for further information on recognising and responding to acute illness in adults in hospital, see the NICE guideline on acutely ill adults in hospital). \n\nObserve people at every opportunity for any changes in the risk factors for delirium. \n\n# Indicators of delirium: at presentation\n\nAt presentation, assess people at risk for recent (within hours or days) changes or fluctuations that may indicate delirium. These may be reported by the person at risk, or a carer or relative. These changes may affect:\n\ncognitive function: for example, worsened concentration, slow responses, confusion\n\nperception: for example, visual or auditory hallucinations\n\nphysical function: for example, reduced mobility, reduced movement, restlessness, agitation, changes in appetite, sleep disturbance\n\nsocial behaviour: for example, difficulty engaging with or following requests, withdrawal, or alterations in communication, mood and/or attitude.If any of these changes are present, the person should have an assessment (see recommendation 1.6.1). [2010, amended 2023]\n\nBe particularly vigilant for changes that may indicate hypoactive delirium, which are often missed, such as withdrawal, slow responses, reduced mobility and movement, worsened concentration and reduced appetite. \n\n# Preventing delirium\n\nEnsure that people at risk of delirium are cared for by a team of healthcare professionals who are familiar to the person at risk. Avoid moving people within and between wards or rooms unless absolutely necessary. \n\nGive a tailored multicomponent intervention package:\n\nwithin 24\xa0hours of admission, assess people at risk for clinical factors contributing to delirium\n\nbased on the results of this assessment, provide a multicomponent intervention tailored to the person's individual needs and care setting as described in recommendations 1.4.4 to 1.4.13. \n\nThe tailored multicomponent intervention package should be delivered by a multidisciplinary team trained and competent in delirium prevention. \n\nAddress cognitive impairment and/or disorientation by:\n\nproviding appropriate lighting and clear signage; a clock (consider providing a 24-hour clock in critical care) and a calendar should also be easily visible to the person at risk\n\ntalking to the person to reorientate them by explaining where they are, who they are and what your role is\n\nintroducing cognitively stimulating activities (for example, reminiscence)\n\nfacilitating regular visits from family and friends. \n\nAddress dehydration and/or constipation by:\n\nensuring adequate fluid intake to prevent dehydration by encouraging the person to drink; consider offering subcutaneous or intravenous fluids if necessary\n\ntaking advice if necessary, when managing fluid balance in people with comorbidities (for example, heart failure or chronic kidney disease). \n\nAssess for hypoxia and optimise oxygen saturation if necessary, as clinically appropriate.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. \n\nAddress infection by:\n\nlooking for and treating infection\n\navoiding unnecessary catheterisation\n\nimplementing infection control procedures in line with the NICE guideline on healthcare-associated infections. \n\nAddress immobility or limited mobility through the following actions:\n\nEncourage people to:\n\n\n\nmobilise soon after surgery\n\nwalk (provide appropriate walking aids if needed; these should be accessible at all times).\n\n\n\nEncourage all people, including those unable to walk, to carry out active range-of-motion exercises. \n\nAddress pain by:\n\nassessing for pain\n\nlooking for non-verbal signs of pain, particularly in those with communication difficulties (for example, people with learning difficulties or dementia, or people on a ventilator or who have a tracheostomy)\n\nstarting and reviewing appropriate pain management in any person in whom pain is identified or suspected. \n\nCarry out a medication review for people taking multiple drugs, taking into account both the type and number of medications. For information on medicines optimisation see the NICE guideline on medicines optimisation. \n\nAddress poor nutrition by:\n\nfollowing the advice given on nutrition in the NICE guideline on nutrition support for adults\n\nif people have dentures, ensuring they fit properly. \n\nAddress sensory impairment by:\n\nresolving any reversible cause of the impairment, such as impacted ear wax\n\nensuring hearing and visual aids are available to and used by people who need them, and that they are in good working order. \n\nPromote good sleep patterns and sleep hygiene by:\n\navoiding nursing or medical procedures during sleeping hours, if possible\n\nscheduling medication rounds to avoid disturbing sleep\n\nreducing noise to a minimum during sleep periods. \n\n# Indicators of delirium: daily observations\n\nObserve, at least daily, all people in hospital or long-term care for recent (within hours or days) changes or fluctuations indicating delirium (for example, see recommendation 1.3.1). These may be reported by the person at risk, or a carer or relative. If any of these changes are present the person should have an assessment using an appropriate tool (see recommendation 1.6.1). [2010, amended 2023]\n\nEnsure that any changes that may indicate delirium are documented in the person's record or notes. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indicators of delirium: daily observations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: diagnostic accuracy of tests to identify delirium.\n\nLoading. Please wait.\n\n# Assessment and diagnosis\n\nIf indicators of delirium are identified, a health or social care practitioner who is competent to do so should carry out an assessment using the 4AT. In critical care or in the recovery room after surgery use the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or Intensive Care Delirium Screening Checklist (ICDSC) instead of the 4AT. \n\nIf the assessment described in recommendation 1.6.1 indicates delirium, a healthcare professional with the relevant expertise should make the final diagnosis. This could be the same person who made the assessment. \n\nIf there is difficulty distinguishing between the diagnoses of delirium, dementia or delirium superimposed on dementia, manage the delirium first. \n\nEnsure that the diagnosis of delirium is documented both in the person's record or notes, and in their primary care health record. \n\nFor a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on assessment and diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: diagnostic accuracy of tests to identify delirium.\n\nLoading. Please wait.\n\n# Treating delirium\n\n## Initial management\n\nIn people diagnosed with delirium, identify and manage the possible underlying cause or combination of causes. \n\nEnsure effective communication and reorientation (for example explaining where the person is, who they are and what your role is) and provide reassurance for people diagnosed with delirium. Consider involving family, friends and carers to help with this. Provide a suitable care environment (see recommendation 1.4.1 in the section on preventing delirium). \n\n## Distressed people\n\nIf a person with delirium is distressed or considered a risk to themselves or others, first use verbal and non-verbal techniques to de-escalate the situation. For more information on de-escalation techniques, see the NICE guideline on violence and aggression. Distress may be less evident in people with hypoactive delirium, who can still become distressed by, for example, psychotic symptoms. \n\nIf a person with delirium is distressed or considered a risk to themselves or others, and verbal and non-verbal de-escalation techniques are ineffective or inappropriate, consider giving short-term haloperidol (usually for 1\xa0week or less). Start at the lowest clinically appropriate dose and titrate cautiously according to symptoms. Take into account the Medicines and Healthcare products Regulatory Agency's advice about the risks of using haloperidol for the acute treatment of delirium in older people, including the risks of cardiac and neurological side effects (especially in people living with Parkinson's disease or dementia with Lewy bodies). \n\n## If delirium does not resolve\n\nFor people in whom delirium does not resolve:\n\nre-evaluate for underlying causes\n\nfollow up and assess for possible dementia (see the NICE guideline on dementia). \n\n# Information and support\n\nOffer information to people who are at risk of delirium or who have delirium, and their family and/or carers, which:\n\ninforms them that delirium is common and usually temporary\n\ndescribes people's experience of delirium\n\nencourages people at risk and their families and/or carers to tell their healthcare team about any sudden changes or fluctuations in behaviour\n\nencourages the person who has had delirium to share their experience of delirium with the healthcare professional during recovery\n\nadvises the person of any support groups. \n\nEnsure that information provided meets the cultural, cognitive and language needs of the person. \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Health or social care practitioners\n\nHealth and social care staff across the wider care team. This could include registered nurses and care workers (also called care assistants or support workers), social workers, therapists, case managers, GPs, lead clinicians, community nurses and allied professionals, such as physiotherapists, occupational therapists and dietitians.\n\n## Healthcare professionals\n\nHealth professionals regulated or licensed with a professional body to provide care and support, for example, generalist and specialist doctors registered with the General Medical Council, and nurses registered with the Nursing and Midwifery Council.\n\n## Hyperactive delirium\n\nA subtype of delirium characterised by people who have heightened arousal and can be restless, agitated or aggressive.\n\n## Hypoactive delirium\n\nA subtype of delirium characterised by people who become withdrawn, quiet and sleepy.\n\n## Long-term care\n\nResidential care in a home that may include skilled nursing care and help with everyday activities. This includes nursing homes and residential homes.", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\n# Delirium assessment tools\n\nWhat is the diagnostic accuracy, and ease of implementation, of different delirium assessment tools:\n\nfor people with pre-existing cognitive impairment, for example dementia, learning disability or severe depression\n\nfor people who do not speak English as a first language\n\nin different settings, for example emergency departments, residential care homes or virtual consultations\n\nwhen delivered by different types of health and social care practitioners, for example healthcare assistants or allied health professionals such as paramedics? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on assessment and diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: diagnostic accuracy of tests to identify delirium.\n\nLoading. Please wait.\n\n# Pharmacological prevention\n\nIn people in hospital who are at high risk of delirium, which medication (atypical antipsychotics, typical antipsychotics, benzodiazepines or acetylcholinesterase inhibitors), compared with placebo or each other, is more clinically and cost effective in preventing the development of delirium? \n\n## Why this is important\n\nThe serious nature of delirium and its consequences makes it important to establish all methods of prevention. Pharmacological agents may be a simple preventive treatment for delirium, but there is uncertainty about effectiveness and side effects so they should be used with caution. The evidence is limited: 3 low-quality studies were found, each of which was unrepresentative either of the population or the medication used, but there was some indication of clinical effectiveness. A large randomised trial (with at least 100\xa0people in each arm) should be conducted in people in hospital who are at high risk of delirium to compare atypical antipsychotics, typical antipsychotics, benzodiazepines or acetylcholinesterase inhibitors with placebo, or each other, for preventing delirium. The included populations should be defined in terms of their delirium risk (for example people at high risk could be those with 2 or more risk factors for delirium). The primary outcome should be the incidence of delirium, measured at least daily using a validated diagnostic tool. The severity and duration of delirium should also be recorded, together with adverse effects of the medication, notably extrapyramidal symptoms and stroke.\n\n# Pharmacological treatment\n\nIn people in hospital who have delirium, which is the most effective medication (atypical antipsychotics, typical antipsychotics or benzodiazepines) compared with placebo or each other for treating delirium? \n\n## Why this is important\n\nPharmacological interventions are currently used in clinical practice to manage the symptoms of delirium but the evidence for this is limited. One moderate-quality study showed that typical and atypical antipsychotics were clinically and cost effective compared with placebo, but there is no evidence for benzodiazepines. Pharmacological agents that alter the course of delirium or control particular symptoms might be useful in treating delirium, but we need to determine whether the medication should be given routinely or for selected symptoms, and what adverse events may occur. A large randomised trial (with at least 100\xa0people in each arm) should be conducted in people in hospital with delirium to compare atypical antipsychotics, typical antipsychotics, or benzodiazepines with placebo, or each other, for the treatment of delirium. The outcomes should be recovery from delirium (complete response), and the duration and severity of delirium, measured using a validated diagnostic tool. Adverse events, notably extrapyramidal symptoms and stroke, should also be recorded.\n\n# Multicomponent intervention\n\nFor people in long-term care, is a multicomponent non-pharmacological intervention more clinically and cost effective than usual care in preventing the development of delirium? \n\n## Why this is important\n\nAlthough there is moderate-quality evidence of clinical and cost effectiveness for multicomponent interventions for the prevention of delirium in people in hospital, there is no evidence in a long-term care setting. It is anticipated that such an intervention would benefit this long-term care population. A large, adequately powered, randomised trial, or a large, adequately powered, cluster randomised trial should be conducted in people in long-term care to compare a multicomponent intervention with usual care. The multicomponent intervention should include assessment by a trained and competent healthcare professional, who would recommend actions tailored to the person's needs. The intervention should include the recommended interventions to prevent delirium, particularly reorientation, medication review, hydration and sleep hygiene. The primary outcome should be the incidence of delirium, measured at least daily using a validated diagnostic tool. The severity and duration of delirium should also be recorded using a validated tool, together with the consequences of delirium, including admission to hospital.\n\n# Delirium in long-term care\n\nHow common is delirium and what are its adverse outcomes in people in long-term care? \n\n## Why this is important\n\nAlthough there is evidence for adverse outcomes consequent to delirium in hospital, there is very little evidence from long-term care. It is important to determine whether people in long-term care, who already have a high risk of death, dementia and other adverse outcomes, have a further increased risk of these outcomes if they develop delirium. The risk of hospital admission as a consequence of delirium is also unknown. A large cohort study should be conducted in people in long-term care to determine:\n\nthe prevalence of delirium in this setting, and\n\nif the presence of delirium is a prognostic factor for death, dementia, admission to hospital, falls and other adverse outcomes.\n\nThe multivariate analysis conducted in this study should take into consideration the potential significant risk factors and confounding factors identified in the guideline. Such a study would also inform cost-effectiveness analyses for the prevention and treatment of delirium.\n\n# Education programme\n\nDoes a staff education programme (compared with an educational leaflet or usual care) reduce the incidence of delirium and improve the recognition and recording of delirium in people in hospital? \n\n## Why this is important\n\nThere is some evidence from multicomponent prevention studies to suggest that an education programme for healthcare professionals who care for people at risk of delirium reduces the incidence of delirium. However, the quality of this evidence is poor. There is a need to determine whether education has an important preventive effect on the incidence of delirium. There is also a need to find out if an educational programme increases awareness of delirium, so that delirium is recorded accurately, which is not the case in the UK at present. A cluster randomised trial should be carried out, with whole hospitals randomised to the educational interventions (thereby reducing the trial contamination effects of staff vicariously picking up education from colleagues randomised to the education programme arm). The primary outcomes (incidence of delirium and recording of delirium in the person's healthcare record) should be measured at a minimum of 3\xa0timepoints before and after the intervention.", 'Rationale and impact': 'These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Indicators of delirium: daily observations\n\nRecommendations 1.5.1 to 1.5.2\n\n## Why the committee made the recommendations\n\nThe committee agreed with the recommendation in the previous version of the guideline that all staff should be observing the people in their care and should be alert for changes indicating delirium. They noted that some simple tools like the Single Question to Identify Delirium (SQiD) might be useful to help practitioners notice any changes. They did not add SQiD specifically to the recommendation because they agreed that it is just one of many ways to encourage observation and that many places already have systems set up for this. They noted that in some settings the recording of these observations could be inconsistent, and that routine recording of changes that might indicate delirium was important.\n\n## How the recommendations might affect practice\n\nBetter recording of the indicators of delirium will improve the chances of these changes being noticed and acted upon.\n\nReturn to recommendations\n\n# Assessment and diagnosis\n\nRecommendations 1.6.1 to 1.6.2\n\n## Why the committee made the recommendations\n\nThe committee agreed that once a change that might indicate delirium has been noted and recorded, a member of staff competent to do so should carry out a formal assessment.\n\nSeveral assessment tools had high enough sensitivity and specificity to be useful in clinical practice. However, the committee agreed that implementation issues need to be considered as well. For example, who can do the test, how long does it take and how much training is needed?\n\nBalancing the evidence for accuracy and cost effectiveness with the practicality of implementing the tests, the committee agreed that the 4AT was the best option for most settings. It is among the most accurate of the tools reviewed, quick and simple to use, and has a broader range of evidence to support it.\n\nThe committee agreed that a range of health and social care practitioners would be able to carry out the 4AT and that special training is not needed, although practitioners should be assessed as competent in its use. They also discussed that some specialist professionals may not need to use a screening tool to carry out an assessment and diagnose delirium, but that it would generally be considered good practice. Overall, they agreed that its use will help ensure that delirium is picked up promptly in different care settings, especially those where a healthcare professional may not be immediately available.\n\nFor critical care and post-surgical settings, the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC) worked best because they were specifically designed for those settings. However, the committee noted that training is needed for both CAM-ICU and ICDSC before practitioners can use them.\n\nIf the assessment shows delirium is likely, the committee agreed that the final diagnosis should be carried out by a healthcare professional with the necessary experience and expertise, for example, a specialist nurse, a GP, lead clinician or a member of the frailty team. Depending on the circumstances, this might be the same person who carried out the 4AT. If there is uncertainty about the diagnosis, a specialist such as a geriatrician or psychiatrist, may need to be involved.\n\nThe committee agreed that although the evidence allowed them to make recommendations overall, further, more specific, research on the accuracy and ease of use of different assessment tools in different settings, for different patient groups (including those with dementia, cognitive impairments, learning disabilities or affective disorders) and by different healthcare practitioners, would help to make future guidance more specific. They therefore made a recommendation for research on delirium assessment tools.\n\n## How the recommendations might affect practice\n\nThe committee noted that the assessment tools they recommended are already the most commonly used in practice. The change from healthcare professional in the previous version of this guideline to health or social care practitioner in this version will potentially reduce the workload for healthcare professionals who previously had to carry out assessments for delirium.\n\nReturn to recommendations', 'Context': "Delirium (sometimes called 'acute confusional state') is a common clinical syndrome characterised by disturbed consciousness, cognitive function or perception, which has an acute onset and fluctuating course. It usually develops over 1 to 2\xa0days. It is a serious condition that is associated with poor outcomes. However, it can be prevented and treated if dealt with urgently.\n\nA person may already have delirium when they present to hospital or long-term care or it may develop during a hospital admission or residential stay in long-term care. Delirium can be hypoactive or hyperactive but some people show signs of both (mixed). People with hyperactive delirium have heightened arousal and can be restless, agitated and aggressive. People with hypoactive delirium become withdrawn, quiet and sleepy. Hypoactive and mixed delirium can be more difficult to recognise.\n\nIt can be difficult to distinguish between delirium and dementia and some people may have both conditions.\n\nOlder people and people with dementia, severe illness or a hip fracture are more at risk of delirium. The prevalence of delirium in people on medical wards in hospital is about 20% to 30%, and 10% to 50% of people having surgery develop delirium. In long-term care the prevalence is under 20%. But reporting of delirium is poor in the UK, indicating that awareness and reporting procedures need to be improved.\n\nThere is a significant burden associated with this condition. Compared with people who do not develop delirium, people who develop delirium may:\n\nneed to stay longer in hospital or in critical care\n\nhave an increased incidence of dementia\n\nhave more hospital-acquired complications, such as falls and pressure sores\n\nbe more likely to need to be admitted to long-term care if they are in hospital\n\nbe more likely to die.\n\nThis clinical guideline describes methods of preventing, identifying, diagnosing and treating delirium. In particular, the guideline focuses on preventing delirium in people identified to be at risk, using a targeted, multicomponent, non-pharmacological intervention that addresses a number of modifiable risk factors ('clinical factors').\n\nIf delirium is prevented, it should generate cost savings.\n\nThis guideline does not cover children and young people (younger than 18\xa0years), people receiving end-of-life care, or people with intoxication and/or withdrawing from drugs or alcohol, and people with delirium associated with these states."}	https://www.nice.org.uk/guidance/cg103	This guideline covers diagnosing and treating delirium in people aged 18 and over in hospital and in long-term residential care or a nursing home. It also covers identifying people at risk of developing delirium in these settings and preventing onset. It aims to improve diagnosis of delirium and reduce hospital stays and complications.
df2c7ac0461f29064344d68a2fbe5a43227f8f6d	nice	Maribavir for treating refractory cytomegalovirus infection after transplant	Maribavir for treating refractory cytomegalovirus infection after transplant Evidence-based recommendations on maribavir (Livtencity) for cytomegalovirus infection in adults after transplant. # Recommendations Maribavir is recommended, within its marketing authorisation, as an option for treating cytomegalovirus (CMV) infection that is refractory to treatment including cidofovir, foscarnet, ganciclovir or valganciclovir in adults who have had a haematopoietic stem cell transplant or solid organ transplant. It is recommended only if the company provides it according to the commercial arrangement. Why the committee made these recommendations After a transplant, for CMV infection that does not respond well enough to treatment, usual treatment is cidofovir, foscarnet, ganciclovir or valganciclovir, or combinations of these. Clinical evidence suggests that maribavir gets rid of CMV infection better than usual treatment, but this is uncertain because of the way the trial was done. The most likely cost-effectiveness estimates are also uncertain. But they are towards the lower end of the range that NICE considers an acceptable use of NHS resources, and current treatment options are limited. So maribavir is recommended.# Information about maribavir # Marketing authorisation indication Maribavir (Livtencity) is indicated for 'the treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT)'. The dosage schedule is available in the summary of product characteristics for maribavir. # Price The list price of 56 x 200 mg maribavir tablets is £11,550 (excluding VAT; company source). The company has a commercial arrangement. This makes maribavir available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need ## There are limited treatment options for CMV and an oral treatment given at home would be beneficial Cytomegalovirus (CMV) is present in approximately 60% to 70% of the population. Although it is generally mild and treatable, CMV can become active when a person's immunity is weakened, such as by immunosuppressive chemotherapy or after a transplant. Latent CMV can also be transferred from a transplant donor to the recipient. Currently, there are few treatments for CMV after a transplant, and treatment resistance can be an issue. Several antiviral therapies, including valganciclovir, ganciclovir, foscarnet and cidofovir, are used off-label. But there are no licensed medicines in the UK for treating CMV infection after a solid organ transplant (SOT) or allogeneic haematopoietic stem cell transplant (HSCT) if the infection is refractory to treatment. The patient experts explained that CMV reactivation can substantially negatively affect mental health and physical wellbeing in people and their families. Hospital admissions to treat CMV reactivation can be stressful, especially after the heavy burden of transplant procedures. Refractory or resistant CMV infections can have serious effects on quality of life. Intravenous treatments are needed several times a day, which can result in extended hospitalisation. Other comorbidities and further infections can develop during treatment for CMV. All of this can delay recovery. The clinical experts explained that foscarnet can be associated with kidney damage, making it less suitable for people who have had a kidney transplant or who have impaired renal function. Cidofovir can cause neutropenia. These risks mean that, in some people whose infection is resistant or refractory to ganciclovir and valganciclovir, these medicines have to be reused because of a lack of alternative treatment options. The patient experts suggested that the psychological benefits of being able to have treatment at home would greatly improve the recovery process from both CMV infection and transplant, avoid the unpleasant side effects of current treatment options, and also reduce costs to the NHS. The clinical experts considered that maribavir would be especially suitable for people with refractory CMV whose comorbidities mean that side effects from current second-line antiviral options would be particularly unfavourable. The committee concluded that current treatment options are limited, and an oral treatment given at home would be beneficial. # Clinical evidence ## The conduct and design of SOLSTICE could bias the results The main clinical evidence came from SOLSTICE. This was a phase 3, randomised, open-label, active-controlled trial with a 20‑week follow up. Its aim was to evaluate the efficacy and safety of maribavir (n=235) compared with any of the investigator-assigned antiviral treatments (IAT, n=117). These included intravenous ganciclovir, foscarnet, cidofovir and oral valganciclovir. The choice of IAT was at the investigators' discretion and could include monotherapy or combination therapy with any of the 4 treatments. The ERG noted some concerns around the design and conduct of the trial. The open-label design meant that participants and investigators were aware of the choice of treatment from the start of the study. In the comparator arm, the investigators could choose treatment based on medical history and the clinical course of previous treatment for CMV. The investigators decided whether participants should continue previous therapy at the same or an increased dose, change treatment or select combination therapy. The investigators could also decide whether immunosuppressant therapy should be changed. The ERG considered this could lead to bias, especially for assessing recurrence. At the investigators' discretion, people having IAT could stop treatment after the third week (because of lack of efficacy or toxicity) and receive maribavir treatment instead, known as the rescue arm. The ERG thought that the rescue arm may introduce bias to some outcomes. The committee considered that 3 weeks of treatment may not be long enough to assess whether efficacy is maintained. The clinical experts explained that in clinical practice, people are likely to stay on treatment for longer before stopping. The committee concluded that some aspects of the conduct and design of SOLSTICE could bias the results. ## Results of SOLSTICE may not be generalisable to clinical practice The committee considered how generalisable SOLSTICE was to clinical practice. It discussed the following concerns: One of the clinical experts advised that as time since transplant increases, the risk of CMV reactivation and other events decreases as people recover and the need for immunosuppressant therapy reduces. The mean and median time since transplant at randomisation were longer than would be expected in clinical practice for the SOT subgroup, and imbalanced between the treatment arms for SOT and HSCT. The impact of this was greater in the HSCT population because the time between transplant and randomisation was shorter than in the SOT group. There was no clear reason why the baseline characteristics should be imbalanced, given the data presented. The committee considered whether this was because of individual participant characteristics, or because of the way the trial was done. It agreed further details of the data distribution would be helpful. The length of time since transplant at randomisation in the SOT subgroup and the imbalance between treatment arms in the HSCT population would likely have a large impact on the generalisability of the SOLSTICE results to clinical practice. The ERG noted that many people having IAT had retreatment with an anti-CMV treatment to which their infection was resistant. It considered this would underestimate clearance in people having IAT compared with clinical practice and overestimate the relative effect of maribavir. Clinical advice to the ERG had suggested that resistance would be assessed if an infection did not respond adequately to a specific anti-CMV treatment, and that an alternative treatment would be offered. Continued treatment when resistance has been confirmed is likely to lead to a lower chance of CMV clearance than changing to an alternative treatment. At technical engagement, the company did a sensitivity analysis that excluded people who received IAT to which their infection was resistant at baseline. These results suggested that the benefit of maribavir was sustained. The company suggested that many people may have treatment to which their infection is resistant, because resistance testing is not routine practice, and because alternative treatment options may not be available because of the renal toxicity associated with some treatments (see section 3.1). It considered this would explain why investigators continued treatment even if the virus had a mutation that was known to confer resistance. The clinical experts confirmed that this was plausible. The ERG considered there was a large amount of missing data for clearance and clinically relevant recurrence during the trial period. At technical engagement, the company accepted there was potential for bias because of premature treatment discontinuations. It did several sensitivity analyses to control for the missing data, which showed a statistically significant benefit of maribavir compared with IAT. The company did not provide additional analyses for recurrence data because it believed there was very little missing recurrence data. Missing data could affect both clearance and recurrence outcomes. The committee considered that more data was missing in the IAT arm because of treatment discontinuation and the option for people to join the rescue arm. This missing data potentially reduced the usefulness of the time-to-event data on clearance and recurrence that would otherwise have been helpful to inform the committee's view on the effectiveness of maribavir. The committee concluded that the results from SOLSTICE may not be generalisable to clinical practice. ## SOLSTICE data suggests that maribavir improves clearance compared with IAT, but the results are highly uncertain The primary outcome in SOLSTICE was viral clearance at week 8. In the intention to treat population, 55.7% of people who had maribavir had confirmed CMV viraemia clearance at the end of week 8 compared with 23.9% who had IAT. After adjusting for transplant type (SOT versus HSCT) and baseline plasma CMV DNA viral load (low versus intermediate or high), the difference was 32.8% (95% confidence interval 22.8% to 42.7%; p<0.001). At the end of the trial, in people whose infection responded by week 8, fewer people on maribavir had a clinically relevant recurrence than those who had IAT, although the difference was not statistically significant. There was no statistically significant difference in all-cause mortality between treatment arms. More deaths occurred in the HSCT group than in the SOT group, and there was a small difference in favour of maribavir for SOT, but in favour of IAT for HSCT. The committee concluded that SOLSTICE suggests an advantage for maribavir achieving clearance. But because of uncertainties in the SOLSTICE data (see sections 3.1 and 3.2), it could not be sure that the data was robust enough to confirm the size of this benefit. # The company's economic model ## The health states used in the company's model are appropriate The company used a 2‑stage Markov model to estimate the cost effectiveness of maribavir compared with IAT. Each health state was associated with different costs, quality of life and mortality risks. The stage 1 model included 3 health states: clinically significant CMV, no clinically significant CMV, and death. All people entered the model with clinically significant CMV. When the CMV infection cleared they could move to the no clinically significant CMV state or experience a CMV recurrence. Tunnel states were used to estimate time-dependent transitions between clinically significant and no clinically significant CMV. The stage 2 model comprised 2 health states: alive and dead. People could die at any point during either stage. The model had a lifetime time horizon, with stage 1 lasting 78 weeks. At the first meeting, the committee agreed that the overall model structure and health states used by the company in both stages of the model were appropriate, but that it had some concerns about the duration of stage 1 of the model (see section 3.9). In response to consultation, the company updated its stage 1 Markov model by restricting it from 78 weeks to 39.2 weeks (see section 3.9). The committee concluded that the company's modelling of maribavir was appropriate. ## The company's updated model using OTUS data is suitable for decision making The company used data from OTUS to update its stage 1 model at technical engagement. OTUS is a retrospective real-world evidence analysis of CMV infection that is refractory or resistant to treatment, with a longer follow up than SOLSTICE. The company used the OTUS data to populate the model beyond the 20‑week duration of SOLSTICE. This included modelling recurrences for the first 20 weeks based on SOLSTICE data, then using OTUS data to model outcomes for the remaining stage 1 time horizon. The ERG considered OTUS to be more generalisable to clinical practice than SOLSTICE, but had concerns with the way the company used the OTUS data, which assumed that the populations and outcomes in OTUS and SOLSTICE were interchangeable. The ERG highlighted that the ratio of SOT to HSCT procedures, percentage of clearance, and time since transplant differed between the 2 sources. The ERG preferred to use OTUS to model the probability of clearance and recurrence for IAT in the stage 1 Markov model, with the outcomes for maribavir estimated by applying a relative treatment effect taken from SOLSTICE. OTUS could also be used to inform risk of mortality, time since transplant and event rates of complications such as graft failure and graft-versus-host disease. In a scenario analysis done by the company using the OTUS data, clearance rates were adjusted for 8‑week mortality. The ERG was unclear about why this had been done, and preferred to use data that had not been adjusted for mortality at 8 weeks. The committee preferred the ERG's approach. At the first meeting, it agreed that using OTUS data as far as possible, with the relative treatment effect of maribavir from SOLSTICE, would be more robust for modelling outcomes in the stage 1 Markov model, and that data from OTUS should not be adjusted for mortality at 8 weeks. In response to consultation, the company incorporated OTUS data in its revised analyses, with the relative treatment effect of maribavir from SOLSTICE. The company noted the uncertainties of incorporating 2 data sources in the model, but maintained that SOLSTICE was the most reliable data source to estimate the treatment effect of maribavir compared with standard care. The ERG commented that the company had not provided the underlying data for clearance events for the SOT population, and queried the company's estimate of probability of clearance for the HSCT population. Ahead of the second committee meeting, the company submitted additional data from OTUS. The ERG was satisfied with the company's update and noted that it had a minimal effect on the incremental cost-effectiveness ratio (ICER). The committee concluded that the data used in the company's model was suitable for decision making. ## Using a treatment-independent risk of recurrence is suitable for decision making The company modelled different risks of CMV recurrence dependent on the treatment received. People having maribavir had a lower probability of CMV recurrence than those receiving IAT, even if they had experienced clearance for the same amount of time. The ERG stated that the risk of CMV recurrence should depend on the time spent in clearance rather than the treatment received, and included this in its updated model. One of the clinical experts advised that clearance with maribavir may be greater than with IAT, meaning reinfection is less likely to occur. The committee considered this reasonable, but had not seen any supporting evidence. It agreed at the first meeting that the risk of recurrence should not be treatment specific. In response to consultation, the company noted that there was evidence of an effect of maribavir on the risk of CMV recurrence. But despite this, it updated its base case and applied treatment-independent recurrence risk. The ERG agreed that the company's approach was in line with the committee's preferences. The committee concluded that using a treatment-independent risk of recurrence is suitable for decision making. ## Restricting the model to 2 CMV recurrences is appropriate The company's model included multiple CMV recurrences based on OTUS data, which showed up to 6 recurrences after SOT and 4 recurrences after HSCT. The company assumed that the risk of third and further recurrences in the model was the same as that for second recurrences. The ERG noted that in OTUS, the risk of subsequent recurrences decreased with the number of recurrences and that the benefit of maribavir may be overestimated. The ERG limited its model to 2 recurrences because no robust data was identified to inform the risk of recurrence beyond this point. The committee accepted that the risk of CMV recurrence is likely to decrease with the number of recurrences, but that more than 2 recurrences are plausible. At the first meeting it agreed that the company's model likely overestimated the number of CMV recurrences, and that it would have preferred to have seen recurrence risk decrease as the number of recurrences increased. In response to consultation, the company updated its base case, restricting the stage 1 Markov model to 39.2 weeks (see section 3.9) and 2 CMV recurrences. The company noted that the OTUS data provided evidence for multiple recurrences and that the ERG's approach of limiting the number of recurrences in the model was conservative. The company highlighted that, because it had updated its base case in this way, it was now fully aligned with the committee's preferences. The ERG agreed. The committee concluded that restricting the model to 2 recurrences was likely to be conservative, but in the absence of further data, this was the most suitable approach for decision making. ## Restricting the stage 1 Markov model to 39.2 weeks is appropriate for decision making The company originally used 20‑week data from SOLSTICE to model CMV recurrences up to 52 weeks, meaning its stage 1 Markov model had a duration of 52 weeks. But based on the OTUS data (which provided evidence for multiple recurrences over a longer time), the company increased the duration of the stage 1 model to 78 weeks. The ERG was unclear about the company's reasoning for using 78 weeks. The company explained that OTUS data in the SOT population provided evidence that would allow the stage 1 model to be extended beyond 78 weeks, but had applied 78 weeks as a pragmatic option because of heterogeneity in the treatment pathway at longer time horizons and to mitigate uncertainty. The ERG highlighted there were few third (or further) recurrences in OTUS and so to model further recurrences the company had to use the risk of second recurrence from OTUS (see section 3.8). This created uncertainty in the modelling. The ERG thought that the duration of the stage 1 Markov model should reflect the time frame over which the first and second recurrences happened in OTUS (39.2 weeks) because the data for this was robust. It included this assumption in its base case. The committee recognised there was some uncertainty around the appropriate duration of the stage 1 Markov model. But it considered that if OTUS was used as the main source of data for the IAT arm of the model, the stage 1 Markov model should accurately reflect the time to last recurrence in OTUS. The committee agreed at the first meeting that the stage 1 Markov model should align with the duration of time that CMV recurrences can be accurately modelled. It specified that more than 2 CMV recurrences should be modelled, with the risk of recurrence decreasing as the number of recurrences increases, if data was available to model this. In the absence of robust data, the stage 1 Markov model should be restricted to 39.2 weeks and 2 CMV recurrences, and scenario analyses should be done to show the potential impact of further CMV recurrences, with a stage 1 duration of between 39.2 and 78 weeks. In response to consultation, the company accepted the committee's preference, and updated its base case to restrict the stage 1 Markov model to 39.2 weeks and 2 CMV recurrences. The company commented that the OTUS data was a robust source for modelling recurrences over time and that including a maximum of 2 recurrences was conservative. The committee noted that the company had not provided any scenario analyses showing the potential impact of more than 2 CMV recurrences with a stage 1 duration of between 39.2 and 78 weeks, as requested at the first meeting. The ERG was satisfied that the company had updated the model correctly. The committee concluded that the company's updated model was suitable for decision making. ## Maribavir may have an impact on mortality, but this is highly uncertain and the magnitude of the impact is unknown The company had originally modelled survival in the stage 1 Markov model using individual patient data from SOLSTICE to estimate the risk of mortality in the clinically significant CMV and no clinically significant CMV health states. But the ERG noted that the Kaplan–Meier data, which incorporated the difference in CMV events across treatment arms, showed no statistically significant difference in overall mortality between maribavir and IAT (see section 3.4). So this was inconsistent with the company's approach of assuming there was a difference in mortality for clinically significant CMV compared with no clinically significant CMV. At technical engagement, the company reiterated its view that the SOLSTICE data was the most appropriate source. It provided Kaplan–Meier data for time to all-cause mortality from SOLSTICE (adjusted to account for people in the IAT arm crossing over to have rescue treatment). The company did not explain how the adjustment was done, so the ERG could not validate the adjusted survival data. The company considered that its analysis supported using the unadjusted SOLSTICE data in the model. It reiterated its view that SOLSTICE suggested that mortality for maribavir was lower than for IAT, and that this justified using CMV-related mortality risks taken from SOLSTICE in the model. Additionally, the company provided 2 scenario analyses based on OTUS and using published data to inform mortality risks for people who had clinically significant CMV and no clinically significant CMV. The ERG noted that the scenario using the published data (Hakimi et al. for the SOT population and Camargo et al. for the HSCT population) did not include populations that fully aligned with either SOLSTICE or the decision problem. At the first meeting, the committee recognised there was a lot of uncertainty in the assumptions for mortality in the stage 1 model, but that SOLSTICE had not shown a survival benefit. It considered that mortality should not differ based on treatment, so there should be no life year gain with maribavir in the model. It agreed that risk of mortality in the stage 1 model should be the same for the maribavir and IAT groups. In response to consultation, the company disagreed with the committee's preference, and maintained that SOLSTICE provided clear evidence of a difference in survival associated with a response to CMV treatment. It provided further evidence including a Kaplan–Meier plot of overall survival by clearance status at week 8 from SOLSTICE, which showed a statistically significant difference in the hazard rate of death between CMV clearance at week 8 (in either treatment group) compared with no CMV clearance. It also provided data from TAK620‑5004, a retrospective study collecting follow-up data at 12 months from SOT and HSCT recipients randomised to the maribavir arm in the SOLSTICE study. This data showed numerically lower overall mortality than that seen in published estimates, 12 months after treatment for refractory or resistant CMV after a transplant. The company updated its base case using the published data from Hakimi and Camargo to inform mortality risks for people with clinically significant CMV and no clinically significant CMV. The ERG noted that the risk of mortality associated with CMV was likely higher in the 2 sources used in the company's base case than in SOLSTICE and OTUS, and that the company's base case represented the best-case scenario. The ERG would have preferred this data to come from OTUS had it been available. It agreed with the company that clinically significant CMV is associated with increased mortality, but not with the magnitude modelled by the company. To help with decision making, the ERG provided 2 scenarios: a worst-case scenario with no additional risk of mortality from CMV (aligned with the committee's preference after the first meeting) and a midpoint in which people with CMV were arbitrarily assumed to have twice the risk of mortality than people without CMV. The committee acknowledged that although eliminating clinically significant CMV may reduce mortality, this did not mean that maribavir would reduce mortality. It was also aware that assuming a mortality benefit associated with no CMV substantially affected the cost-effectiveness results. The committee accepted that it was very likely that CMV clearance would have an impact on mortality, but the magnitude of the impact was very uncertain. It commented that it was likely that the upper bound of that magnitude was from the published data sources used by the company. The committee concluded that the true value was likely to lie somewhere in between no benefit and that upper bound, and that the company's base case was likely optimistic. ## The mean time since transplant should be used at model entry Time since transplant at entry to the model affected both the risk of mortality and the risk of CMV recurrence. In its base case, the company used the median time since transplant from SOLSTICE to inform the baseline characteristics of the modelled population. It suggested this was reasonable because the mean and median values were not the same and outliers could influence the mean estimate. The ERG preferred to use the mean time since transplant to fully reflect the whole population. The committee was aware that time since transplant had a substantial effect on outcomes and would have preferred to see data on the distribution of this (see section 3.3). In the absence of this information, it agreed at the first meeting that it was more appropriate to use the mean value. In response to consultation, the company agreed, and updated the model. The committee concluded that the updated model was suitable for decision making. ## The impact of leukaemia recurrence and graft failure should be included in the economic model The committee discussed the inclusion of disease complications in the model: The company base case originally did not include recurrences of leukaemia, but the ERG recommended doing this based on NICE's technology appraisal guidance on letermovir for preventing cytomegalovirus disease after a stem cell transplant. At technical engagement, the company did a scenario analysis that included the costs of leukaemia recurrence for 6 months and leukaemia relapse-related mortality. The ERG included this analysis in its base case. To estimate the probability of graft failure, the company used estimates from Hakimi et al. (2017), which reported that people with a CMV episode at 6 months or more after transplant have a 5.12% chance of graft failure, compared with 1.69% for people without CMV, over 1 year. After technical engagement, the ERG recommended that the company used graft failure data from OTUS, if the data was used to populate much of the model. The company investigated the events of graft failure in OTUS and noted that the impact of updating the model to include this data was small. The ERG agreed, and in its base case used the data from Hakimi et al.The committee agreed at the first meeting that disease complications should be included in the model, and accepted the ERG's approach of modelling recurrences of leukaemia and graft failure. In response to consultation, the company incorporated leukaemia recurrences into its model, but noted that this could lead to double counting of mortality. Graft failure was already captured in its base case. The ERG agreed that the company's approach was in line with the committee's preferences, and the committee concluded that the model was suitable for decision making. ## The impact of graft-versus-host disease should be included in the model The company base case originally included graft-versus-host disease. The ERG considered that people who have had an HSCT and go on to develop graft-versus-host disease have a higher probability of death, so this complication should be included in the model. The company noted the difficulty in identifying a causal relationship between graft-versus-host disease and CMV from the current literature, but provided a scenario including graft-versus-host disease (without a higher mortality risk). At the first meeting, the committee noted that although a causal relationship could not be identified, the effects on overall mortality could have a large impact on the cost-effectiveness estimates. The company noted that data from OTUS is likely to become available in the future that will provide more information on graft-versus-host disease. The ERG included the company's scenario in its base case. The committee accepted the ERG's approach to including graft-versus-host disease in the model. In response to consultation, the company updated its base case to include graft-versus-host disease. The company also updated the model to account for time since transplant. The ERG disagreed with the company's estimation of the risk of graft-versus-host disease, noting that this may not differ by CMV status, and provided a scenario to explore this. It also noted that the company did not include the impact of graft-versus-host disease on survival, but given that the stage 1 Markov model now had a shorter time horizon (see section 3.9), the impact on the ICER of excluding this was likely to be small. The committee recognised that although developing graft-versus-host disease has not been directly associated with CMV infection, population data suggests that there is a higher incidence of graft-versus-host disease in people who also have CMV. But the committee was aware that clearing CMV may not lead to a lower risk of developing graft-versus-host disease in the future. On balance, it concluded that the company's approach to modelling graft-versus-host disease by CMV status was likely to be reasonable, but the uncertainty meant that the ERG's scenario was also plausible. # Costs in the economic model ## The model should include different intravenous administration costs for first and subsequent administrations The company assumed that the daily intravenous (IV) administration cost used for various IATs was equal to an NHS reference cost for complex chemotherapy at first attendance. The ERG had noted this cost should only apply to the first administration of IV IATs, when a central line would be inserted, but that the same line could be used for subsequent administrations so subsequent costs would be lower. The ERG judged that the administration costs applied for IV treatments in the IAT arm had been overestimated in the model. It suggested that a lower reference cost for subsequent elements of a chemotherapy cycle should be used for subsequent administration of IV IATs. It did a scenario analysis that explored the impact of using first and subsequent administration NHS reference costs, and another in which daily administration costs for IV treatments were based on the hourly cost of a critical care nurse. At the first meeting, the committee considered that both approaches were plausible, but that using the first and subsequent IV administration NHS reference costs would be most appropriate. In response to consultation, the company updated its base case, amending the administration cost to account for the reduced cost of subsequent treatment. The committee concluded that the company's approach was in line with its preferences. ## The cost of hospitalisation for people with clinically significant CMV is likely to be higher than for people without clinically significant CMV The committee considered whether the hospitalisation costs for people with clinically significant CMV would be different to the costs for those without clinically significant CMV. The company had applied a higher unit hospitalisation cost for clinically significant CMV than for no clinically significant CMV. This was based on weighted average NHS reference costs for a non-elective long stay for infectious diseases with or without interventions. The ERG preferred to apply an equal unit hospitalisation cost for clinically significant CMV and no clinically significant CMV, because it considered that the difference in costs would have already been incorporated into CMV treatment costs in the model. The committee considered that people hospitalised with clinically significant CMV would need extra care and incur greater costs (beyond treatment costs) than people hospitalised without clinically significant CMV. It concluded that the company's approach was appropriate. # Utility values in the economic model ## Utilities are appropriately captured in the model The ERG originally highlighted concerns about the company's approach to modelling estimated EQ‑5D‑3L values from the EQ‑5D‑5L data in SOLSTICE. At technical engagement, the company clarified the multiple imputation method it used. This was based on the approach used in NICE's technology appraisal guidance on letermovir for preventing cytomegalovirus disease after a stem cell transplant. The committee was satisfied with this approach. The ERG also noted that the utility values applied for the stage 2 Markov model were slightly inconsistent with those applied in the stage 1 Markov model. It noted that the values might underestimate the health-related quality of life of people who did not have clinically significant CMV after SOT, and overestimate the quality of life in people after HSCT. The committee recognised this slight inconsistency, but in the absence of further data considered the utilities used were appropriate. # Cost effectiveness ## Because of the uncertainty, an acceptable ICER is around £20,000 per QALY gained NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be around £20,000 per QALY gained. ## The cost-effectiveness estimates are uncertain but are likely within the range NICE considers an acceptable use of NHS resources The company's updated base-case ICER for maribavir compared with IAT was around £20,000 per QALY gained. This included confidential commercial arrangements for maribavir and the comparators, so the exact ICERs cannot be reported here. The company's base case included the following assumptions, which were preferred by the committee: including graft-versus-host disease by CMV status, assuming CMV increases the probability of graft-versus-host disease (section 3.13) modelling mortality using the ERG's midpoint scenario, in which people with CMV were arbitrarily assumed to have twice the risk of mortality than people without CMV (section 3.10) using the latest OTUS data to estimate the probability of clearance at week 8 (section 3.6).The committee considered the uncertainty associated with the cost-effectiveness estimates. But it concluded that the most plausible ICER was around £20,000 per QALY gained. # Innovation ## Maribavir is innovative in that it is an oral treatment that can be taken at home, but all of the benefits are captured in the modelling The committee agreed that there is an unmet need for an effective and tolerable treatment for CMV infection that is refractory to treatment in adults who have had an SOT or HSCT. It considered that having an oral treatment was innovative and reduced the need for people to be in hospital to receive treatment, but that these benefits were captured in the model. # Equalities ## No relevant equalities issues were identified The company stated that people from some minority ethnic family backgrounds are more likely to develop comorbidities and therefore would be more likely to need a transplant. They may also wait longer for a suitable organ donor. It also considered that older people have fewer treatment options because of toxicity. Both of these groups can need high levels of immunosuppression and so have an increased risk of CMV infection and graft rejection. Risk of transplant, time to transplant and age at transplant are not issues that can be addressed in a technology appraisal of a treatment for CMV. The company did not investigate whether treatment with maribavir works better in any particular groups. The committee concluded that no equalities issues were identified that could be addressed by this appraisal. # Conclusion ## Maribavir is recommended The committee recognised that there are limited treatment options for CMV infection that is refractory to treatment and that an oral treatment given at home would be beneficial. It acknowledged that SOLSTICE data suggests that maribavir improves clearance compared with IAT, but the results were highly uncertain. It considered that there was uncertainty in the cost-effectiveness estimates, but that the most likely estimates were within the range NICE usually considers a cost-effective use of NHS resources. So, maribavir is recommended for treating CMV infection that is refractory to treatment in adults who have had a SOT or HSCT.	{'Recommendations': 'Maribavir is recommended, within its marketing authorisation, as an option for treating cytomegalovirus (CMV) infection that is refractory to treatment including cidofovir, foscarnet, ganciclovir or valganciclovir in adults who have had a haematopoietic stem cell transplant or solid organ transplant. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nAfter a transplant, for CMV infection that does not respond well enough to treatment, usual treatment is cidofovir, foscarnet, ganciclovir or valganciclovir, or combinations of these.\n\nClinical evidence suggests that maribavir gets rid of CMV infection better than usual treatment, but this is uncertain because of the way the trial was done.\n\nThe most likely cost-effectiveness estimates are also uncertain. But they are towards the lower end of the range that NICE considers an acceptable use of NHS resources, and current treatment options are limited. So maribavir is recommended.', 'Information about maribavir': "# Marketing authorisation indication\n\nMaribavir (Livtencity) is indicated for 'the treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT)'.\n\nThe dosage schedule is available in the summary of product characteristics for maribavir.\n\n# Price\n\nThe list price of 56\xa0x\xa0200\xa0mg maribavir tablets is £11,550 (excluding VAT; company source). The company has a commercial arrangement. This makes maribavir available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## There are limited treatment options for CMV and an oral treatment given at home would be beneficial\n\nCytomegalovirus (CMV) is present in approximately 60% to 70% of the population. Although it is generally mild and treatable, CMV can become active when a person's immunity is weakened, such as by immunosuppressive chemotherapy or after a transplant. Latent CMV can also be transferred from a transplant donor to the recipient. Currently, there are few treatments for CMV after a transplant, and treatment resistance can be an issue. Several antiviral therapies, including valganciclovir, ganciclovir, foscarnet and cidofovir, are used off-label. But there are no licensed medicines in the UK for treating CMV infection after a solid organ transplant (SOT) or allogeneic haematopoietic stem cell\xa0transplant (HSCT) if the infection is refractory to treatment. The patient experts explained that CMV reactivation can substantially negatively affect mental health and physical wellbeing in people and their families. Hospital admissions to treat CMV reactivation can be stressful, especially after the heavy burden of transplant procedures. Refractory or resistant CMV infections can have serious effects on quality of life. Intravenous treatments are needed several times a day, which can result in extended hospitalisation. Other comorbidities and further infections can develop during treatment for CMV. All of this can delay recovery. The clinical experts explained that foscarnet can be associated with kidney damage, making it less suitable for people who have had a kidney transplant or who have impaired renal function. Cidofovir can cause neutropenia. These risks mean that, in some people whose infection is resistant or refractory to ganciclovir and valganciclovir, these medicines have to be reused because of a lack of alternative treatment options. The patient experts suggested that the psychological benefits of being able to have treatment at home would greatly improve the recovery process from both CMV infection and transplant, avoid the unpleasant side effects of current treatment options, and also reduce costs to the NHS. The clinical experts considered that maribavir would be especially suitable for people with refractory CMV whose comorbidities mean that side effects from current second-line antiviral options would be particularly unfavourable. The committee concluded that current treatment options are limited, and an oral treatment given at home would be beneficial.\n\n# Clinical evidence\n\n## The conduct and design of SOLSTICE could bias the results\n\nThe main clinical evidence came from SOLSTICE. This was a phase\xa03, randomised, open-label, active-controlled trial with a 20‑week follow\xa0up. Its aim was to evaluate the efficacy and safety of maribavir (n=235) compared with any of the investigator-assigned antiviral treatments (IAT, n=117). These included intravenous ganciclovir, foscarnet, cidofovir and oral valganciclovir. The choice of IAT was at the investigators' discretion and could include monotherapy or combination therapy with any of the 4\xa0treatments. The ERG noted some concerns around the design and conduct of the trial. The open-label design meant that participants and investigators were aware of the choice of treatment from the start of the study. In the comparator arm, the investigators could choose treatment based on medical history and the clinical course of previous treatment for CMV. The investigators decided whether participants should continue previous therapy at the same or an increased dose, change treatment or select combination therapy. The investigators could also decide whether immunosuppressant therapy should be changed. The ERG considered this could lead to bias, especially for assessing recurrence. At the investigators' discretion, people having IAT could stop treatment after the third week (because of lack of efficacy or toxicity) and receive maribavir treatment instead, known as the rescue arm. The ERG thought that the rescue arm may introduce bias to some outcomes. The committee considered that 3\xa0weeks of treatment may not be long enough to assess whether efficacy is maintained. The clinical experts explained that in clinical practice, people are likely to stay on treatment for longer before stopping. The committee concluded that some aspects of the conduct and design of SOLSTICE could bias the results.\n\n## Results of SOLSTICE may not be generalisable to clinical practice\n\nThe committee considered how generalisable SOLSTICE was to clinical practice. It discussed the following concerns:\n\nOne of the clinical experts advised that as time since transplant increases, the risk of CMV reactivation and other events decreases as people recover and the need for immunosuppressant therapy reduces. The mean and median time since transplant at randomisation were longer than would be expected in clinical practice for the SOT subgroup, and imbalanced between the treatment arms for SOT and HSCT. The impact of this was greater in the HSCT population because the time between transplant and randomisation was shorter than in the SOT group. There was no clear reason why the baseline characteristics should be imbalanced, given the data presented. The committee considered whether this was because of individual participant characteristics, or because of the way the trial was done. It agreed further details of the data distribution would be helpful. The length of time since transplant at randomisation in the SOT subgroup and the imbalance between treatment arms in the HSCT population would likely have a large impact on the generalisability of the SOLSTICE results to clinical practice.\n\nThe ERG noted that many people having IAT had retreatment with an anti-CMV treatment to which their infection was resistant. It considered this would underestimate clearance in people having IAT compared with clinical practice and overestimate the relative effect of maribavir. Clinical advice to the ERG had suggested that resistance would be assessed if an infection did not respond adequately to a specific anti-CMV treatment, and that an alternative treatment would be offered. Continued treatment when resistance has been confirmed is likely to lead to a lower chance of CMV clearance than changing to an alternative treatment. At technical engagement, the company did a sensitivity analysis that excluded people who received IAT to which their infection was resistant at baseline. These results suggested that the benefit of maribavir was sustained. The company suggested that many people may have treatment to which their infection is resistant, because resistance testing is not routine practice, and because alternative treatment options may not be available because of the renal toxicity associated with some treatments (see section 3.1). It considered this would explain why investigators continued treatment even if the virus had a mutation that was known to confer resistance. The clinical experts confirmed that this was plausible.\n\nThe ERG considered there was a large amount of missing data for clearance and clinically relevant recurrence during the trial period. At technical engagement, the company accepted there was potential for bias because of premature treatment discontinuations. It did several sensitivity analyses to control for the missing data, which showed a statistically significant benefit of maribavir compared with IAT. The company did not provide additional analyses for recurrence data because it believed there was very little missing recurrence data. Missing data could affect both clearance and recurrence outcomes. The committee considered that more data was missing in the IAT arm because of treatment discontinuation and the option for people to join the rescue arm. This missing data potentially reduced the usefulness of the time-to-event data on clearance and recurrence that would otherwise have been helpful to inform the committee's view on the effectiveness of maribavir. The committee concluded that the results from SOLSTICE may not be generalisable to clinical practice.\n\n## SOLSTICE data suggests that maribavir improves clearance compared with IAT, but the results are highly uncertain\n\nThe primary outcome in SOLSTICE was viral clearance at week\xa08. In the intention to treat population, 55.7% of people who had maribavir had confirmed CMV viraemia clearance at the end of week\xa08 compared with 23.9% who had IAT. After adjusting for transplant type (SOT versus HSCT) and baseline plasma CMV DNA viral load (low versus intermediate or high), the difference was 32.8% (95% confidence interval [CI] 22.8% to 42.7%; p<0.001). At the end of the trial, in people whose infection responded by week\xa08, fewer people on maribavir had a clinically relevant recurrence than those who had IAT, although the difference was not statistically significant. There was no statistically significant difference in all-cause mortality between treatment arms. More deaths occurred in the HSCT group than in the SOT group, and there was a small difference in favour of maribavir for SOT, but in favour of IAT for HSCT. The committee concluded that SOLSTICE suggests an advantage for maribavir achieving clearance. But because of uncertainties in the SOLSTICE data (see sections 3.1 and 3.2), it could not be sure that the data was robust enough to confirm the size of this benefit.\n\n# The company's economic model\n\n## The health states used in the company's model are appropriate\n\nThe company used a 2‑stage Markov model to estimate the cost effectiveness of maribavir compared with IAT. Each health state was associated with different costs, quality of life and mortality risks. The stage\xa01 model included 3 health states: clinically significant CMV, no clinically significant CMV, and death. All people entered the model with clinically significant CMV. When the CMV infection cleared they could move to the no clinically significant CMV state or experience a CMV recurrence. Tunnel states were used to estimate time-dependent transitions between clinically significant and no clinically significant CMV. The stage\xa02 model comprised 2 health states: alive and dead. People could die at any point during either stage. The model had a lifetime time horizon, with stage\xa01 lasting 78\xa0weeks. At the first meeting, the committee agreed that the overall model structure and health states used by the company in both stages of the model were appropriate, but that it had some concerns about the duration of stage\xa01 of the model (see section 3.9). In response to consultation, the company updated its stage\xa01 Markov model by restricting it from 78\xa0weeks to 39.2\xa0weeks (see section 3.9). The committee concluded that the company's modelling of maribavir was appropriate.\n\n## The company's updated model using OTUS data is suitable for decision making\n\nThe company used data from OTUS to update its stage\xa01 model at technical engagement. OTUS is a retrospective real-world evidence analysis of CMV infection that is refractory or resistant to treatment, with a longer follow\xa0up than SOLSTICE. The company used the OTUS data to populate the model beyond the 20‑week duration of SOLSTICE. This included modelling recurrences for the first 20\xa0weeks based on SOLSTICE data, then using OTUS data to model outcomes for the remaining stage\xa01 time horizon. The ERG considered OTUS to be more generalisable to clinical practice than SOLSTICE, but had concerns with the way the company used the OTUS data, which assumed that the populations and outcomes in OTUS and SOLSTICE were interchangeable. The ERG highlighted that the ratio of SOT to HSCT procedures, percentage of clearance, and time since transplant differed between the 2 sources. The ERG preferred to use OTUS to model the probability of clearance and recurrence for IAT in the stage\xa01 Markov model, with the outcomes for maribavir estimated by applying a relative treatment effect taken from SOLSTICE. OTUS could also be used to inform risk of mortality, time since transplant and event rates of complications such as graft failure and graft-versus-host disease. In a scenario analysis done by the company using the OTUS data, clearance rates were adjusted for 8‑week mortality. The ERG was unclear about why this had been done, and preferred to use data that had not been adjusted for mortality at 8\xa0weeks. The committee preferred the ERG's approach. At the first meeting, it agreed that using OTUS data as far as possible, with the relative treatment effect of maribavir from SOLSTICE, would be more robust for modelling outcomes in the stage\xa01 Markov model, and that data from OTUS should not be adjusted for mortality at 8\xa0weeks. In response to consultation, the company incorporated OTUS data in its revised analyses, with the relative treatment effect of maribavir from SOLSTICE. The company noted the uncertainties of incorporating 2\xa0data sources in the model, but maintained that SOLSTICE was the most reliable data source to estimate the treatment effect of maribavir compared with standard care. The ERG commented that the company had not provided the underlying data for clearance events for the SOT population, and queried the company's estimate of probability of clearance for the HSCT population. Ahead of the second committee meeting, the company submitted additional data from OTUS. The ERG was satisfied with the company's update and noted that it had a minimal effect on the incremental cost-effectiveness ratio (ICER). The committee concluded that the data used in the company's model was suitable for decision making.\n\n## Using a treatment-independent risk of recurrence is suitable for decision making\n\nThe company modelled different risks of CMV recurrence dependent on the treatment received. People having maribavir had a lower probability of CMV recurrence than those receiving IAT, even if they had experienced clearance for the same amount of time. The ERG stated that the risk of CMV recurrence should depend on the time spent in clearance rather than the treatment received, and included this in its updated model. One of the clinical experts advised that clearance with maribavir may be greater than with IAT, meaning reinfection is less likely to occur. The committee considered this reasonable, but had not seen any supporting evidence. It agreed at the first meeting that the risk of recurrence should not be treatment specific. In response to consultation, the company noted that there was evidence of an effect of maribavir on the risk of CMV recurrence. But despite this, it updated its base case and applied treatment-independent recurrence risk. The ERG agreed that the company's approach was in line with the committee's preferences. The committee concluded that using a treatment-independent risk of recurrence is suitable for decision making.\n\n## Restricting the model to 2 CMV recurrences is appropriate\n\nThe company's model included multiple CMV recurrences based on OTUS data, which showed up to 6 recurrences after SOT and 4\xa0recurrences after HSCT. The company assumed that the risk of third and further recurrences in the model was the same as that for second recurrences. The ERG noted that in OTUS, the risk of subsequent recurrences decreased with the number of recurrences and that the benefit of maribavir may be overestimated. The ERG limited its model to 2\xa0recurrences because no robust data was identified to inform the risk of recurrence beyond this point. The committee accepted that the risk of CMV recurrence is likely to decrease with the number of recurrences, but that more than 2\xa0recurrences are plausible. At the first meeting it agreed that the company's model likely overestimated the number of CMV recurrences, and that it would have preferred to have seen recurrence risk decrease as the number of recurrences increased. In response to consultation, the company updated its base case, restricting the stage\xa01 Markov model to 39.2\xa0weeks (see section 3.9) and 2 CMV recurrences. The company noted that the OTUS data provided evidence for multiple recurrences and that the ERG's approach of limiting the number of recurrences in the model was conservative. The company highlighted that, because it had updated its base case in this way, it was now fully aligned with the committee's preferences. The ERG agreed. The committee concluded that restricting the model to 2 recurrences was likely to be conservative, but in the absence of further data, this was the most suitable approach for decision making.\n\n## Restricting the stage\xa01 Markov model to 39.2\xa0weeks is appropriate for decision making\n\nThe company originally used 20‑week data from SOLSTICE to model CMV recurrences up to 52\xa0weeks, meaning its stage\xa01 Markov model had a duration of 52\xa0weeks. But based on the OTUS data (which provided evidence for multiple recurrences over a longer time), the company increased the duration of the stage\xa01 model to 78\xa0weeks. The ERG was unclear about the company's reasoning for using 78\xa0weeks. The company explained that OTUS data in the SOT population provided evidence that would allow the stage 1\xa0model to be extended beyond 78\xa0weeks, but had applied 78\xa0weeks as a pragmatic option because of heterogeneity in the treatment pathway at longer time horizons and to mitigate uncertainty. The ERG highlighted there were few third (or further) recurrences in OTUS and so to model further recurrences the company had to use the risk of second recurrence from OTUS (see section\xa03.8). This created uncertainty in the modelling. The ERG thought that the duration of the stage\xa01 Markov model should reflect the time frame over which the first and second recurrences happened in OTUS (39.2\xa0weeks) because the data for this was robust. It included this assumption in its base case. The committee recognised there was some uncertainty around the appropriate duration of the stage\xa01 Markov model. But it considered that if OTUS was used as the main source of data for the IAT arm of the model, the stage\xa01 Markov model should accurately reflect the time to last recurrence in OTUS. The committee agreed at the first meeting that the stage\xa01 Markov model should align with the duration of time that CMV recurrences can be accurately modelled. It specified that more than 2 CMV recurrences should be modelled, with the risk of recurrence decreasing as the number of recurrences increases, if data was available to model this. In the absence of robust data, the stage\xa01 Markov model should be restricted to 39.2\xa0weeks and 2 CMV recurrences, and scenario analyses should be done to show the potential impact of further CMV recurrences, with a stage\xa01 duration of between 39.2 and 78\xa0weeks. In response to consultation, the company accepted the committee's preference, and updated its base case to restrict the stage\xa01 Markov model to 39.2\xa0weeks and 2 CMV recurrences. The company commented that the OTUS data was a robust source for modelling recurrences over time and that including a maximum of 2\xa0recurrences was conservative. The committee noted that the company had not provided any scenario analyses showing the potential impact of more than 2 CMV recurrences with a stage\xa01 duration of between 39.2 and 78\xa0weeks, as requested at the first meeting. The ERG was satisfied that the company had updated the model correctly. The committee concluded that the company's updated model was suitable for decision making.\n\n## Maribavir may have an impact on mortality, but this is highly uncertain and the magnitude of the impact is unknown\n\nThe company had originally modelled survival in the stage\xa01 Markov model using individual patient data from SOLSTICE to estimate the risk of mortality in the clinically significant CMV and no clinically significant CMV health states. But the ERG noted that the Kaplan–Meier data, which incorporated the difference in CMV events across treatment arms, showed no statistically significant difference in overall mortality between maribavir and IAT (see section\xa03.4). So this was inconsistent with the company's approach of assuming there was a difference in mortality for clinically significant CMV compared with no clinically significant CMV. At technical engagement, the company reiterated its view that the SOLSTICE data was the most appropriate source. It provided Kaplan–Meier data for time to all-cause mortality from SOLSTICE (adjusted to account for people in the IAT arm crossing over to have rescue treatment). The company did not explain how the adjustment was done, so the ERG could not validate the adjusted survival data. The company considered that its analysis supported using the unadjusted SOLSTICE data in the model. It reiterated its view that SOLSTICE suggested that mortality for maribavir was lower than for IAT, and that this justified using CMV-related mortality risks taken from SOLSTICE in the model. Additionally, the company provided 2 scenario analyses based on OTUS and using published data to inform mortality risks for people who had clinically significant CMV and no clinically significant CMV. The ERG noted that the scenario using the published data (Hakimi et al. for the SOT population and Camargo et al. for the HSCT population) did not include populations that fully aligned with either SOLSTICE or the decision problem. At the first meeting, the committee recognised there was a lot of uncertainty in the assumptions for mortality in the stage 1 model, but that SOLSTICE had not shown a survival benefit. It considered that mortality should not differ based on treatment, so there should be no life year gain with maribavir in the model. It agreed that risk of mortality in the stage\xa01 model should be the same for the maribavir and IAT groups. In response to consultation, the company disagreed with the committee's preference, and maintained that SOLSTICE provided clear evidence of a difference in survival associated with a response to CMV treatment. It provided further evidence including a Kaplan–Meier plot of overall survival by clearance status at week\xa08 from SOLSTICE, which showed a statistically significant difference in the hazard rate of death between CMV clearance at week\xa08 (in either treatment group) compared with no CMV clearance. It also provided data from TAK620‑5004, a retrospective study collecting follow-up data at 12\xa0months from SOT and HSCT recipients randomised to the maribavir arm in the SOLSTICE study. This data showed numerically lower overall mortality than that seen in published estimates, 12\xa0months after treatment for refractory or resistant CMV after a transplant. The company updated its base case using the published data from Hakimi and Camargo to inform mortality risks for people with clinically significant CMV and no clinically significant CMV. The ERG noted that the risk of mortality associated with CMV was likely higher in the 2 sources used in the company's base case than in SOLSTICE and OTUS, and that the company's base case represented the best-case scenario. The ERG would have preferred this data to come from OTUS had it been available. It agreed with the company that clinically significant CMV is associated with increased mortality, but not with the magnitude modelled by the company. To help with decision making, the ERG provided 2 scenarios: a worst-case scenario with no additional risk of mortality from CMV (aligned with the committee's preference after the first meeting) and a midpoint in which people with CMV were arbitrarily assumed to have twice the risk of mortality than people without CMV. The committee acknowledged that although eliminating clinically significant CMV may reduce mortality, this did not mean that maribavir would reduce mortality. It was also aware that assuming a mortality benefit associated with no CMV substantially affected the cost-effectiveness results. The committee accepted that it was very likely that CMV clearance would have an impact on mortality, but the magnitude of the impact was very uncertain. It commented that it was likely that the upper bound of that magnitude was from the published data sources used by the company. The committee concluded that the true value was likely to lie somewhere in between no benefit and that upper bound, and that the company's base case was likely optimistic.\n\n## The mean time since transplant should be used at model entry\n\nTime since transplant at entry to the model affected both the risk of mortality and the risk of CMV recurrence. In its base case, the company used the median time since transplant from SOLSTICE to inform the baseline characteristics of the modelled population. It suggested this was reasonable because the mean and median values were not the same and outliers could influence the mean estimate. The ERG preferred to use the mean time since transplant to fully reflect the whole population. The committee was aware that time since transplant had a substantial effect on outcomes and would have preferred to see data on the distribution of this (see section 3.3). In the absence of this information, it agreed at the first meeting that it was more appropriate to use the mean value. In response to consultation, the company agreed, and updated the model. The committee concluded that the updated model was suitable for decision making.\n\n## The impact of leukaemia recurrence and graft failure should be included in the economic model\n\nThe committee discussed the inclusion of disease complications in the model:\n\nThe company base case originally did not include recurrences of leukaemia, but the ERG recommended doing this based on NICE's technology appraisal guidance on letermovir for preventing cytomegalovirus disease after a stem cell transplant. At technical engagement, the company did a scenario analysis that included the costs of leukaemia recurrence for 6\xa0months and leukaemia relapse-related mortality. The ERG included this analysis in its base case.\n\nTo estimate the probability of graft failure, the company used estimates from Hakimi et al. (2017), which reported that people with a CMV episode at 6\xa0months or more after transplant have a 5.12% chance of graft failure, compared with 1.69% for people without CMV, over 1 year. After technical engagement, the ERG recommended that the company used graft failure data from OTUS, if the data was used to populate much of the model. The company investigated the events of graft failure in OTUS and noted that the impact of updating the model to include this data was small. The ERG agreed, and in its base case used the data from Hakimi et al.The committee agreed at the first meeting that disease complications should be included in the model, and accepted the ERG's approach of modelling recurrences of leukaemia and graft failure. In response to consultation, the company incorporated leukaemia recurrences into its model, but noted that this could lead to double counting of mortality. Graft failure was already captured in its base case. The ERG agreed that the company's approach was in line with the committee's preferences, and the committee concluded that the model was suitable for decision making.\n\n## The impact of graft-versus-host disease should be included in the model\n\nThe company base case originally included graft-versus-host disease. The ERG considered that people who have had an HSCT and go on to develop graft-versus-host disease have a higher probability of death, so this complication should be included in the model. The company noted the difficulty in identifying a causal relationship between graft-versus-host disease and CMV from the current literature, but provided a scenario including graft-versus-host disease (without a higher mortality risk). At the first meeting, the committee noted that although a causal relationship could not be identified, the effects on overall mortality could have a large impact on the cost-effectiveness estimates. The company noted that data from OTUS is likely to become available in the future that will provide more information on graft-versus-host disease. The ERG included the company's scenario in its base case. The committee accepted the ERG's approach to including graft-versus-host disease in the model. In response to consultation, the company updated its base case to include graft-versus-host disease. The company also updated the model to account for time since transplant. The ERG disagreed with the company's estimation of the risk of graft-versus-host disease, noting that this may not differ by CMV status, and provided a scenario to explore this. It also noted that the company did not include the impact of graft-versus-host disease on survival, but given that the stage\xa01 Markov model now had a shorter time horizon (see section 3.9), the impact on the ICER of excluding this was likely to be small. The committee recognised that although developing graft-versus-host disease has not been directly associated with CMV infection, population data suggests that there is a higher incidence of graft-versus-host disease in people who also have CMV. But the committee was aware that clearing CMV may not lead to a lower risk of developing graft-versus-host disease in the future. On balance, it concluded that the company's approach to modelling graft-versus-host disease by CMV status was likely to be reasonable, but the uncertainty meant that the ERG's scenario was also plausible.\n\n# Costs in the economic model\n\n## The model should include different intravenous administration costs for first and subsequent administrations\n\nThe company assumed that the daily intravenous (IV) administration cost used for various IATs was equal to an NHS reference cost for complex chemotherapy at first attendance. The ERG had noted this cost should only apply to the first administration of IV IATs, when a central line would be inserted, but that the same line could be used for subsequent administrations so subsequent costs would be lower. The ERG judged that the administration costs applied for IV treatments in the IAT arm had been overestimated in the model. It suggested that a lower reference cost for subsequent elements of a chemotherapy cycle should be used for subsequent administration of IV IATs. It did a scenario analysis that explored the impact of using first and subsequent administration NHS reference costs, and another in which daily administration costs for IV treatments were based on the hourly cost of a critical care nurse. At the first meeting, the committee considered that both approaches were plausible, but that using the first and subsequent IV administration NHS reference costs would be most appropriate. In response to consultation, the company updated its base case, amending the administration cost to account for the reduced cost of subsequent treatment. The committee concluded that the company's approach was in line with its preferences.\n\n## The cost of hospitalisation for people with clinically significant CMV is likely to be higher than for people without clinically significant CMV\n\nThe committee considered whether the hospitalisation costs for people with clinically significant CMV would be different to the costs for those without clinically significant CMV. The company had applied a higher unit hospitalisation cost for clinically significant CMV than for no clinically significant CMV. This was based on weighted average NHS reference costs for a non-elective long stay for infectious diseases with or without interventions. The ERG preferred to apply an equal unit hospitalisation cost for clinically significant CMV and no clinically significant CMV, because it considered that the difference in costs would have already been incorporated into CMV treatment costs in the model. The committee considered that people hospitalised with clinically significant CMV would need extra care and incur greater costs (beyond treatment costs) than people hospitalised without clinically significant CMV. It concluded that the company's approach was appropriate.\n\n# Utility values in the economic model\n\n## Utilities are appropriately captured in the model\n\nThe ERG originally highlighted concerns about the company's approach to modelling estimated EQ‑5D‑3L values from the EQ‑5D‑5L data in SOLSTICE. At technical engagement, the company clarified the multiple imputation method it used. This was based on the approach used in NICE's technology appraisal guidance on letermovir for preventing cytomegalovirus disease after a stem cell transplant. The committee was satisfied with this approach. The ERG also noted that the utility values applied for the stage\xa02 Markov model were slightly inconsistent with those applied in the stage\xa01 Markov model. It noted that the values might underestimate the health-related quality of life of people who did not have clinically significant CMV after SOT, and overestimate the quality of life in people after HSCT. The committee recognised this slight inconsistency, but in the absence of further data considered the utilities used were appropriate.\n\n# Cost effectiveness\n\n## Because of the uncertainty, an acceptable ICER is around £20,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be around £20,000 per QALY gained.\n\n## The cost-effectiveness estimates are uncertain but are likely within the range NICE considers an acceptable use of NHS resources\n\nThe company's updated base-case ICER for maribavir compared with IAT was around £20,000 per QALY gained. This included confidential commercial arrangements for maribavir and the comparators, so the exact ICERs cannot be reported here. The company's base case included the following assumptions, which were preferred by the committee:\n\nincluding graft-versus-host disease by CMV status, assuming CMV increases the probability of graft-versus-host disease (section 3.13)\n\nmodelling mortality using the ERG's midpoint scenario, in which people with CMV were arbitrarily assumed to have twice the risk of mortality than people without CMV (section\xa03.10)\n\nusing the latest OTUS data to estimate the probability of clearance at week\xa08 (section 3.6).The committee considered the uncertainty associated with the cost-effectiveness estimates. But it concluded that the most plausible ICER was around £20,000 per QALY gained.\n\n# Innovation\n\n## Maribavir is innovative in that it is an oral treatment that can be taken at home, but all of the benefits are captured in the modelling\n\nThe committee agreed that there is an unmet need for an effective and tolerable treatment for CMV infection that is refractory to treatment in adults who have had an SOT or HSCT. It considered that having an oral treatment was innovative and reduced the need for people to be in hospital to receive treatment, but that these benefits were captured in the model.\n\n# Equalities\n\n## No relevant equalities issues were identified\n\nThe company stated that people from some minority ethnic family backgrounds are more likely to develop comorbidities and therefore would be more likely to need a transplant. They may also wait longer for a suitable organ donor. It also considered that older people have fewer treatment options because of toxicity. Both of these groups can need high levels of immunosuppression and so have an increased risk of CMV infection and graft rejection. Risk of transplant, time to transplant and age at transplant are not issues that can be addressed in a technology appraisal of a treatment for CMV. The company did not investigate whether treatment with maribavir works better in any particular groups. The committee concluded that no equalities issues were identified that could be addressed by this appraisal.\n\n# Conclusion\n\n## Maribavir is recommended\n\nThe committee recognised that there are limited treatment options for CMV infection that is refractory to treatment and that an oral treatment given at home would be beneficial. It acknowledged that SOLSTICE data suggests that maribavir improves clearance compared with IAT, but the results were highly uncertain. It considered that there was uncertainty in the cost-effectiveness estimates, but that the most likely estimates were within the range NICE usually considers a cost-effective use of NHS resources. So, maribavir is recommended for treating CMV infection that is refractory to treatment in adults who have had a SOT or HSCT."}	https://www.nice.org.uk/guidance/ta860	Evidence-based recommendations on maribavir (Livtencity) for cytomegalovirus infection in adults after transplant.
ee99a2ba05e5a5567c105abe5f6c6a8c3b88a869	nice	Trabeculectomy with a biodegradable collagen matrix implant for glaucoma	Trabeculectomy with a biodegradable collagen matrix implant for glaucoma Evidence-based recommendations on trabeculectomy with a biodegradable collagen matrix implant for glaucoma. This involves cutting a small flap in the white of the eye and putting a patch over the flap to help healing and prevent scarring. Fluid slowly drains out of the flap and the patch dissolves over time. The aim is to reduce pressure in the eye and slow or stop damage to sight. # Recommendations Evidence on the safety and efficacy of trabeculectomy with biodegradable collagen matrix implant for glaucoma is adequate to support using this procedure, provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).# The condition, current treatments and procedure # The condition Glaucoma is usually a chronic condition associated with raised intraocular pressure. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic. But, as the condition progresses, it causes visual field impairment and, if untreated, blindness. There are several types of glaucoma but the most common type of glaucoma in the UK is primary (or chronic) open-angle glaucoma. # Current treatments NICE's guideline on glaucoma describes its diagnosis and management. Treatment usually involves eye drops containing different drugs that either reduce aqueous humour production or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy, laser trabeculoplasty and cyclodiode laser treatment may also be used. # The procedure Trabeculectomy with an adjunctive biodegradable collagen matrix aims to modify wound healing and improve the drainage of aqueous humour to lower intraocular pressure. It reduces or avoids the use of antimetabolites and antifibrotic agents (mitomycin C, 5‑fluorouracil). In this procedure, with the person under local (intracameral) anaesthesia, the conjunctiva is lifted (or an opening is created) to access the sclera, and then a partial-thickness scleral flap is dissected. Within the scleral bed, a full-thickness opening (or a perforating scleral entrance) is created into the anterior chamber, to allow drainage of aqueous humour. Sometimes trabecular meshwork and adjacent structures are also removed. The scleral flap is then sutured loosely with 1 or 2 loops, to allow the aqueous fluid to drain into the subconjunctival space through the scleral hole. Cohesive viscoelastic is injected under the scleral flap. Then a subconjunctival biodegradable collagen matrix implant is placed directly on top of the scleral flap, and the conjunctiva is sutured (using continuous sutures) and closed around it.	{'Recommendations': "Evidence on the safety and efficacy of trabeculectomy with biodegradable collagen matrix implant for glaucoma is adequate to support using this procedure, provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).", 'The condition, current treatments and procedure': "# The condition\n\nGlaucoma is usually a chronic condition associated with raised intraocular pressure. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic. But, as the condition progresses, it causes visual field impairment and, if untreated, blindness. There are several types of glaucoma but the most common type of glaucoma in the UK is primary (or chronic) open-angle glaucoma.\n\n# Current treatments\n\nNICE's guideline on glaucoma describes its diagnosis and management. Treatment usually involves eye drops containing different drugs that either reduce aqueous humour production or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy, laser trabeculoplasty and cyclodiode laser treatment may also be used.\n\n# The procedure\n\nTrabeculectomy with an adjunctive biodegradable collagen matrix aims to modify wound healing and improve the drainage of aqueous humour to lower intraocular pressure. It reduces or avoids the use of antimetabolites and antifibrotic agents (mitomycin\xa0C, 5‑fluorouracil).\n\nIn this procedure, with the person under local (intracameral) anaesthesia, the conjunctiva is lifted (or an opening is created) to access the sclera, and then a partial-thickness scleral flap is dissected. Within the scleral bed, a full-thickness opening (or a perforating scleral entrance) is created into the anterior chamber, to allow drainage of aqueous humour. Sometimes trabecular meshwork and adjacent structures are also removed. The scleral flap is then sutured loosely with 1\xa0or 2\xa0loops, to allow the aqueous fluid to drain into the subconjunctival space through the scleral hole. Cohesive viscoelastic is injected under the scleral flap. Then a subconjunctival biodegradable collagen matrix implant is placed directly on top of the scleral flap, and the conjunctiva is sutured (using continuous sutures) and closed around it."}	https://www.nice.org.uk/guidance/ipg750	Evidence-based recommendations on trabeculectomy with a biodegradable collagen matrix implant for glaucoma. This involves cutting a small flap in the white of the eye and putting a patch over the flap to help healing and prevent scarring. Fluid slowly drains out of the flap and the patch dissolves over time. The aim is to reduce pressure in the eye and slow or stop damage to sight.
037486ea99e055c6e3286c0e83d8735f1ac62b12	nice	Tobacco: preventing uptake, promoting quitting and treating dependence	Tobacco: preventing uptake, promoting quitting and treating dependence This guideline covers support to stop smoking for everyone aged 12 and over, and help to reduce people's harm from smoking if they are not ready to stop in one go. It also covers ways to prevent children, young people and young adults aged 24 and under from taking up smoking. The guideline brings together and updates all NICE's previous guidelines on using tobacco, including smokeless tobacco. It covers nicotine replacement therapy and e-cigarettes to help people stop smoking or reduce their harm from smoking. It does not cover using tobacco products such as ‘heat not burn’ tobacco. # Recommendations on preventing uptake People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences. In this guideline, we use the following terms for age groups: children: aged 5 to 11 young people: aged 12 to 17 young adults: aged 18 to 24 adults: aged 18 and over. Unless otherwise stated, the recommendations on preventing uptake are for children and those aged 24 and under. At the time of publication (November 2021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking. These recommendations aim to prevent children, young people and young adults from taking up smoking. They cover anti-smoking mass-media and digital campaigns, measures to prevent tobacco being sold to and bought for children and young people, and prevention interventions in educational settings. # Organising and planning national, regional or local mass-media campaigns These recommendations are for commissioners and organisers of mass-media campaigns. Develop national, regional or local mass-media campaigns to prevent the uptake of smoking among young people under 18. Work in partnership with: the NHS, national, regional and local government and non-governmental organisations, children and young people, media professionals, healthcare professionals, public relations agencies and local anti-tobacco activists. Integrate regional and local campaigns to prevent smoking in children and young people with any national communications strategy to tackle tobacco use. Think about targeting campaigns towards groups that epidemiological data identify as having higher than average or stagnant rates of smoking. Base the campaigns on research that identifies and helps to understand the target audiences. Base campaign messages on strategic research and qualitative before-and-after testing with the target audiences. Repeat the messages in various ways and regularly update them to keep the audience's attention. Use a range of media channels to get unpaid press coverage and generate as much publicity as possible. Reach specific audiences by: using regional and local channels using the full range of media used by children and young people. Share effective practice in campaigns to prevent smoking in children and young people, including effective local and regional media messages, locally, regionally and nationally. Run campaigns to prevent smoking in children and young people for 3 to 5 years. Use process and outcome measures to ensure campaigns are being delivered correctly and effectively. For recommendations on the principles of evaluation, see NICE's guideline on behaviour change: general approaches. # Campaign strategies to prevent uptake and denormalise tobacco use These recommendations are for local authorities, trading standards bodies, organisers and planners of national, regional and local mass-media campaigns, and commissioners and planners. Assess whether an advocacy campaign is needed to support policy related to illegal tobacco sales. If an advocacy campaign is needed, base it on good practice. Use a range of strategies to reduce the attractiveness of tobacco and contribute to changing society's attitude towards tobacco use, so that smoking is not considered the norm by any group. This could include: generating news by writing articles, commissioning newsworthy research and issuing press releases using posters, brochures and other materials using digital media. As part of an advocacy campaign, provide a clear, published statement on how to deal with underage tobacco sales. Do not develop or deliver mass-media or access-restriction campaigns in conjunction with (or supported by) tobacco organisations. Actively discourage use of enforcement and related campaigns developed by tobacco organisations. # Helping retailers avoid illegal tobacco sales These recommendations are for local authorities and trading standards bodies. Provide retailers with training and guidance on how to avoid illegal sales. This includes encouraging them to: ask for proof of age from anyone who appears younger than 18 who attempts to buy cigarettes, and get it verified (examples of proof include a passport or driving licence, or cards bearing the nationally accredited 'PASS' hologram) inform Trading Standards of each tobacco sale refused on the grounds of age. Make it as difficult as possible for young people under 18 to get cigarettes and other tobacco products. In particular, exercise a statutory duty under the Children and Young Persons (Protection from Tobacco) Act (1991) to prevent underage sales by: prosecuting retailers who persistently break the law making test purchases each year, using local data to detect breaches in the law and auditing the breaches regularly to ensure consistent good practice across all local authorities. Work with other agencies to: identify areas where underage tobacco sales are a particular problem improve inspection and enforcement activities related to illegal tobacco sales. Run campaigns for retailers to publicise legislation prohibiting underage tobacco sales. These could include: details of possible fines that retailers can face details of where tobacco is being sold illegally successful local prosecutions health information. Ensure efforts to reduce illegal tobacco sales by retailers are sustained. # Coordinated approach to school-based interventions This recommendation is for schools, commissioners, local authorities, careers services or integrated youth support services, and local tobacco control alliances. Ensure smoking prevention interventions in schools and other educational establishments are: part of a local tobacco control strategy evidence-based linked to the school or educational establishment's smokefree policy consistent with regional and national tobacco control strategies integrated into the curriculum. See also NICE's guideline on behaviour change: general approaches. # Whole-school or organisation-wide smokefree policies These recommendations are for everyone working in and with primary and secondary schools and further education colleges. Develop a whole-school or organisation-wide smokefree policy in consultation with young people and staff: Include smoking prevention activities (led by adults or young people). Include staff training and development. Take account of children and young people's cultural, special educational or physical needs. (For example, by providing material in alternative formats such as pictures, large print, Braille, audio and video.) Ensure the policy forms part of the wider strategy on wellbeing, relationships education, relationships and sex education (RSE), health education, drug education and behaviour. Apply the policy to everyone using the premises (grounds as well as buildings), for any purpose, at any time. Do not allow any areas in the grounds to be designated for smoking (with the exception of caretakers' homes, as specified by law). Widely publicise the policy and ensure it is easily accessible so that everyone using the premises is aware of its content. (This includes making a printed version available.) See also NICE's guidelines on alcohol interventions in secondary and further education and social, emotional and mental wellbeing in primary and secondary education. # Adult-led interventions in schools These recommendations are for everyone working in and with primary and secondary schools and further education colleges. Integrate information about the health effects of tobacco use, as well as the legal, economic and social aspects of smoking, into the curriculum. For example, classroom discussions about tobacco could be relevant when teaching subjects such as biology, chemistry, citizenship, geography, mathematics and media studies. Include accurate information about smoking in the curriculum, including its prevalence and its consequences. Tobacco use by adults and peers should be discussed and challenged. Aim to: develop decision-making skills through active learning techniques include strategies for enhancing self-esteem and resisting the pressure to smoke from the media, family members, peers and the tobacco industry. As part of the curriculum on tobacco, alcohol and drug misuse, discourage children, young people and young adults who do not smoke from experimenting with or regularly using e-cigarettes. Talk about e‑cigarettes separately from tobacco products. When discussing e‑cigarettes, make it clear why children, young people and young adults who do not smoke should avoid e‑cigarettes to avoid inadvertently making them desirable. Provide additional 'booster' activities to support classroom education on tobacco until school leaving age. Activities might include school health fairs and guest speakers. Ensure smoking prevention interventions are delivered by teachers and higher-level teaching assistants who are both credible and competent in the subject, or by external experts. The latter should be trained to work with children and young people on tobacco issues. Interventions should be: entertaining, factual and interactive tailored to age and ability sensitive to family origin, culture and gender non-judgemental. Involve children and young people in schools in the design of interventions to prevent the uptake of smoking. Encourage parents and carers to become involved. For example, let them know about classwork or ask them to help with homework assignments. For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on adult-led interventions in schools . Full details of the evidence and the committee's discussion are in evidence review F and G: e-cigarettes and young people. Loading. Please wait. # Peer-led interventions in schools This recommendation is for everyone working in and with secondary schools and further education colleges. Consider evidence-based, peer-led interventions aimed at preventing the uptake of smoking. They should: link to relevant parts of the curriculum be delivered both in class and informally, outside the classroom be led by young people nominated by the students themselves (the peer leaders could be the same age or older) ensure peer leaders receive support from adults who have the appropriate expertise during the course of the programme ensure young people can consider and, if necessary, challenge peer and family norms on smoking, discuss the risks associated with it and the benefits of not smoking. See also NICE's guideline on alcohol interventions in secondary and further education.# Recommendations on promoting quitting People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences. In this guideline, we use the following terms for age groups: children: aged 5 to 11 young people: aged 12 to 17 young adults: aged 18 to 24 adults: aged 18 and over. At the time of publication (November 2021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking. These recommendations promote options to help people stop smoking or using smokeless tobacco or, if they do not want or are not ready to stop in one go, to reduce their harm. # Using medicinally licensed nicotine-containing products ## Raising awareness These recommendations are for people working in public health, and others with tobacco control and providing advice about harm reduction as part of their remit. Raise public awareness of the harm caused by smoking and secondhand smoke. Make it clear that smoking causes a range of diseases and conditions including cancer, chronic obstructive pulmonary disease and cardiovascular disease. Provide information on how people who smoke can reduce the risk of illness and death (to themselves and others) by using 1 or more medicinally licensed nicotine-containing products. Explain that they could be used as a partial or complete substitute for tobacco, either temporarily or in the long term. Provide the following information about nicotine: smoking is highly addictive mainly because it delivers nicotine very quickly to the brain and this makes stopping smoking difficult most smoking-related health problems are caused by other components in tobacco smoke, not by the nicotine nicotine levels in medicinally licensed nicotine-containing products are much lower than in tobacco, and the way these products deliver nicotine makes them less addictive than smoking. Provide the following information about the effectiveness and safety of medicinally licensed nicotine-containing products: any risks from using medicinally licensed nicotine-containing products are much lower than those of smoking; nicotine replacement therapy (NRT) products have been demonstrated in trials to be safe to use for at least 5 years lifetime use of medicinally licensed nicotine-containing products is likely to be considerably less harmful than smoking. Provide information on using medicinally licensed nicotine-containing products, including: what forms they take how to use them effectively when trying to stop or cut down smoking long-term use to reduce the risk of relapsing where to get them the cost compared with smoking. For recommendations on what information to provide about nicotine-containing e‑cigarettes, see the section on advice on nicotine-containing e-cigarettes. ## Point-of-sale promotion These recommendations are for manufacturers and retailers of medicinally licensed nicotine-containing products, including tobacco retailers. Encourage people who smoke to consider stopping or, if they do not want or are not ready to stop in one go, to consider the harm-reduction approaches outlined in box 1. # Promoting stop-smoking support ## Developers of communications strategies Coordinate communications strategies to support the delivery of stop-smoking support, telephone quitlines, school-based interventions, tobacco control policy changes and any other activities designed to help people to stop smoking. Develop and deliver communications strategies about stopping smoking in partnership with the NHS, national, regional and local government and non-governmental organisations. The strategies should: Use the best available evidence of effectiveness, such as Cochrane reviews. Be developed and evaluated using audience research. Use 'why to' and 'how to' stop messages that are non-judgemental, empathetic and respectful. For example, use testimonials from people who smoke or used to smoke. Involve community pharmacies in local campaigns and maintain links with other professional groups such as dentists, fire services and voluntary groups. Ensure campaigns are sufficiently extensive and sustained to have a reasonable chance of success. Think about targeting and tailoring campaigns towards groups that epidemiological data identify as having higher than average or stagnant rates of smoking, to address inequalities. ## Schools Make information on local stop-smoking support easily available to staff and students. Include details on the type of help available and when, where and how to access the services. ## Employers Make information on local stop-smoking support easily available at work. Include details on the type of help available and when, where and how to access the services. Publicise these interventions. Be responsive to individual needs and preferences of employees. If feasible, and if there is sufficient demand, provide on-site stop-smoking support. Allow staff to attend stop-smoking support during working hours without loss of pay. Negotiate a smokefree workplace policy with employees or their representatives. This should: State whether or not smoking breaks may be taken during working hours and, if so, where, how often and for how long. Include a stop-smoking policy developed in collaboration with staff and their representatives. Direct people who wish to stop smoking to local stop-smoking support. ## Employees and their representatives Encourage employers to provide advice, guidance and support to help employees who want to stop smoking. # Promoting support for people to stop using smokeless tobacco These recommendations are for public sector, voluntary and community organisations, health and social care professionals and faith groups. They are particularly relevant to South Asian communities in areas of identified need. Work in partnership with existing community initiatives to raise awareness of local smokeless tobacco cessation services and how to access them. Ensure any material used to raise awareness of the services: Uses the names that the smokeless tobacco products are known by locally, as well as the term 'smokeless tobacco'. Gives information about the health risks associated with smokeless tobacco and the availability of services to help people quit. Challenges the perceived benefits – and the relative priority that users may place on these benefits (compared with the health risks). For example, some people think smokeless tobacco is an appropriate way to ease indigestion or relieve dental pain, or help freshen the breath. Addresses the needs of people whose first language is not English (by providing translations). Addresses a range of communication needs by providing material in alternative formats, for example pictures, large print, Braille, audio and video. Includes information for specific South Asian subgroups (for example, older Bangladeshi women) who are known to have high rates of smokeless tobacco use. Discusses the concept of addiction in a way that is sensitive to culture and religion (for example, it may be better to refer to users as having developed a 'habit', rather than being 'addicted'). Does not stigmatise users of smokeless tobacco products within their own community, or in the eyes of the general community. Use existing local South Asian information networks (including culturally specific TV and radio channels), and traditional sources of health advice within South Asian communities to provide information on smokeless tobacco. Use venues and events that members of local South Asian communities frequent to publicise, provide or consult on cessation services with them. (Examples include educational establishments and premises where prayer groups or cultural events are held.) Raise awareness among those who work with children and young people about smokeless tobacco use. This includes: providing teachers with information on the harm that smokeless tobacco causes and that also challenges the perceived benefits – and the priority that users may place on these perceived benefits encouraging teachers to discuss with their students the reasons why people use smokeless tobacco; this could take place as part of drug education, or within any other relevant part of the curriculum. # Recommendations on treating tobacco dependence People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences. In this guideline, we use the following terms for age groups: children: aged 5 to 11 young people: aged 12 to 17 young adults: aged 18 to 24 adults: aged 18 and over. Unless otherwise stated, the recommendations on treating tobacco dependence are for people over the age of 12 who want to stop smoking or reduce harm from smoking. At the time of publication (November 2021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking. These recommendations aim to help people aged 12 or over (unless otherwise stated) to stop smoking or, if they do not want or are not ready to stop in one go, to reduce their harm from smoking. They cover interventions and services delivered in a range of settings, including NHS primary and secondary care, and emphasise the importance of targeting vulnerable groups who find giving up smoking hard or who smoke a lot. Pregnant women are mainly covered in the section on treating tobacco dependence in pregnant women. # Identifying and quantifying people's smoking ## Identifying people who smoke These recommendations are for health and social care professionals and those providing stop-smoking support or advice (for recommendations about pregnant women see the section on identifying pregnant women who smoke and referring them for stop-smoking support). At every opportunity, ask people if they smoke or have recently stopped smoking. If they smoke, advise them to stop smoking in a way that is sensitive to their preferences and needs, and advise them that stopping smoking in one go is the best approach. Explain how stop-smoking support can help. Discuss any stop-smoking aids the person has used before, including personally purchased nicotine-containing products. Offer advice on using nicotine-containing products on general sale, including over-the-counter nicotine replacement therapy (NRT) and nicotine-containing e-cigarettes. If someone does not want, or is not ready, to stop smoking in one go: find out about the person's smoking behaviour and level of nicotine dependence by asking how many cigarettes they smoke – and how soon after waking make sure they understand that stopping smoking reduces the risks of developing smoking-related illnesses or worsening conditions affected by smoking ask them to think about adopting a harm-reduction approach (see the section on supporting people who do not want, or are not ready, to stop smoking in one go) encourage them to seek help to stop smoking completely in the future leave the offer of help open and offer support again the next time they are in contact. Record smoking status and all actions, discussions and decisions related to advice, referrals or interventions about stopping smoking. Ask about their smoking status at the next available opportunity. ## Identifying smoking among carers, family and other household members These recommendations are for anyone who is responsible for providing health and support services (including stop-smoking support) to people using acute, maternity or mental health services. At the earliest opportunity, ask if any of the following people smoke: partners of pregnant women parents or carers of people using acute or mental health services anyone else in the household. If partners, parents, other household members and carers do not smoke, give them positive feedback if they are present. If they do smoke: encourage them to stop if they are present, and refer them to a hospital or local stop-smoking support using local arrangements if they want to stop or cut down their smoking if they are not present, ask the person using services to suggest they contact stop-smoking support and provide contact details. During contact with partners, parents, other household members and carers of people using acute, maternity and mental health services: provide clear advice about the danger of smoking and secondhand smoke, including to pregnant women and babies – before and after birth recommend not smoking around the patient, pregnant woman, mother or baby (this includes not smoking in the house). # Stop-smoking interventions These recommendations are for people providing stop-smoking support or advice. For training requirements see the National Centre for Smoking Cessation and Training (NCSCT) standard for training in smoking cessation treatments. For recommendations on digital and mobile health interventions for stopping smoking, see NICE's guideline on behaviour change: digital and mobile health interventions. See recommendation 1.14.23 for advice on people's use of prescribed medicines that are affected by smoking (or stopping smoking). Tell people who smoke that a range of interventions is available to help them stop smoking. Explain how to access them and refer people to stop-smoking support if appropriate. Ensure the following are accessible to adults who smoke: behavioural interventions: behavioural support (individual and group) very brief advice medicinally licensed products: bupropion (see BNF information on bupropion hydrochloride) nicotine replacement therapy – short and long acting varenicline (see NICE's technology appraisal guidance on varenicline for smoking cessation and the BNF information on varenicline) nicotine-containing e-cigarettes Allen Carr's Easyway in-person group seminar.In August 2022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. Consider NRT for young people aged 12 and over who are smoking and dependent on tobacco. If this is prescribed, offer it with behavioural support. Do not offer varenicline or bupropion to people under 18. Offer behavioural support to people who smoke regardless of which option they choose to help them stop smoking, unless they have chosen the Allen Carr Easyway in-person group seminar. Explain how to access this support. Discuss with people which options to use to stop smoking, taking into account: their preferences, health and social circumstances any medicines they are taking any contraindications and the potential for adverse effects their previous experience of stop-smoking aids.Also see the advice in the recommendations on medicinally licensed products, and the recommendations on nicotine-containing e-cigarettes. Advise people (as appropriate for their age) that the following options, when combined with behavioural support, are more likely to result in them successfully stopping smoking: varenicline (offered in line with NICE's technology appraisal guidance on varenicline for smoking cessation) a combination of short-acting and long-acting NRT nicotine-containing e‑cigarettes.In August 2022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. Advise people (as appropriate for their age) that the options that are less likely to result in them successfully stopping smoking, when combined with behavioural support, are: bupropion short-acting NRT used without long-acting NRT long-acting NRT used without short-acting NRT. For adults, prescribe or provide bupropion, varenicline or NRT before they stop smoking: For bupropion agree a quit date set within the first 2 weeks of treatment, reassess the person shortly before the prescription ends. For varenicline agree a quit date and start the treatment 1 to 2 weeks before this date, reassess the person shortly before the prescription ends. For NRT agree a quit date and ensure the person has NRT ready to start the day before the quit date. In August 2022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. For a short explanation of why the committee made the 2021 and 2022 recommendations and how they might affect practice, see the rationale and impact section on stop-smoking interventions . Full details of the evidence and the committee's discussion are in: evidence review L: barriers and facilitators to using e-cigarettes for cessation or harm reduction evidence review M: long-term health effects of e-cigarettes evidence review K: cessation and harm-reduction treatments evidence review P: effectiveness and cost-effectiveness of Allen Carr's Easyway. Loading. Please wait. ## Advice on medicinally licensed products These recommendations are for people providing stop-smoking support or advice. Emphasise that: most smoking-related health problems are caused by other components in tobacco smoke, not by the nicotine any risks from using medicinally licensed nicotine-containing products or other stop-smoking pharmacotherapies are much lower than those of smoking. Explain how to use medicinally licensed nicotine-containing products correctly. This includes ensuring people know how to achieve a high enough dose to: control cravings prevent compensatory smoking achieve their goals on stopping or reducing the amount they smoke. Advise people using short-acting NRT to replace each cigarette with the product they are using, for example a lozenge or piece of gum. Ideally, they should use this before the usual time they would have had the cigarette, to allow for the slower nicotine release from these products. ## Advice on nicotine-containing e-cigarettes These recommendations are for people providing stop-smoking support or advice to adults. Give clear, consistent and up-to-date information about nicotine-containing e‑cigarettes to adults who are interested in using them to stop smoking (for example, see the NCSCT e-cigarette guide and Public Health England's information on e-cigarettes and vaping). Advise adults how to use nicotine-containing e‑cigarettes. This includes explaining that: e‑cigarettes are not licensed medicines but are regulated by the Tobacco and Related Products Regulations (2016) there is not enough evidence to know whether there are long-term harms from e‑cigarette use use of e‑cigarettes is likely to be substantially less harmful than smoking any smoking is harmful, so people using e‑cigarettes should stop smoking tobacco completely. Discuss: how long the person intends to use nicotine-containing e‑cigarettes for using them for long enough to prevent a return to smoking and how to stop using them when they are ready to do so. Ask adults using nicotine-containing e‑cigarettes about any side effects or safety concerns that they may experience. Report these to the MHRA Yellow Card scheme, and let people know they can report side effects directly. Explain to adults who choose to use nicotine-containing e‑cigarettes the importance of getting enough nicotine to overcome withdrawal symptoms, and explain how to get enough nicotine. For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on advice on nicotine-containing e-cigarettes . Full details of the evidence and the committee's discussion are in: evidence review L: barriers and facilitators to using e-cigarettes for cessation or harm reduction evidence review M: long-term health effects of e-cigarettes evidence review K: cessation and harm-reduction treatments. Loading. Please wait. ## Telephone quitlines Ensure publicly sponsored telephone stop-smoking quitlines offer a rapid, positive and authoritative response. If possible, give callers whose first language is not English access to information and support in their chosen language. Ensure all staff giving advice through stop-smoking quitlines receive stop-smoking training (at least in brief interventions to help people stop smoking). Train staff who offer counselling through stop-smoking quitlines so that they meet the NCSCT Training Standard (individual behavioural counselling). Preferably, they should also have a relevant counselling qualification. Training should comply with the NCSCT Training Standard for training in smoking cessation treatments or its updates. # Support to stop smoking in primary care and community settings This recommendation is for health and social care professionals in primary care and community settings. See recommendation 1.14.23 for advice on people's use of prescribed medicines that are affected by smoking (or stopping smoking). Other recommendations to support pregnant women to stop smoking are in the section on treating tobacco dependence in pregnant women. For people who want to stop smoking: discuss with them how they can stop (NCSCT programmes explain how to do this) provide stop-smoking interventions and advice; see the section on stop-smoking interventions if you are unable to provide stop-smoking interventions, refer them to local stop-smoking support, if available if they opt out of a referral to stop-smoking support, refer them to a professional who can offer pharmacotherapy and very brief advice. # Support to stop smoking in secondary care services These recommendations are for health and social care professionals in all acute, maternity and mental health services (including both inpatient and community mental health services, health visitors and midwives). Other recommendations to support pregnant women to stop smoking are in the section on treating tobacco dependence in pregnant women. ## Information on stopping smoking for those using acute, maternity and mental health services These recommendations are about information and support before any secondary care admission. Give people information about the smokefree policy before their appointment, procedure or hospital stay. This should cover: the short- and long-term health benefits of stopping smoking at any time; for example, stopping smoking at any time before surgery has no ill effects (although people may experience short-term withdrawal symptoms such as headaches or irritability from quitting), and people who stop in the 8 weeks before surgery can benefit significantly the risks of secondhand smoke the fact that all buildings and grounds are smokefree so they must not smoke while admitted to, using or visiting these services (see the section on policy) the types of support available to help them stop smoking completely or temporarily before, during and after an admission or appointment (see the sections on behavioural support in acute and mental health services and supporting people who have to stop smoking temporarily) about the different pharmacotherapies that can help with stopping smoking and temporary abstinence, where to obtain them (including from GPs) and how to use them. Before a planned or likely admission to an inpatient setting, work with the person to include how they will manage their smoking on admission or entry to the secondary care setting in their personal care plan. Encourage people being referred for elective surgery to stop smoking before their surgery. Refer them to local stop-smoking support. Provide information and take the opportunity to provide advice to visitors about the benefits of stopping smoking and how to contact local stop-smoking support. ## Referring to behavioural support in acute, maternity and mental health services Offer and, if the person agrees, arrange for them to receive behavioural support to stop smoking during either their current outpatient visit or their inpatient stay. For people using secondary care services in the community, staff trained to provide behavioural support to stop smoking should offer and provide support. Other staff should offer and, if accepted, arrange a referral to local stop-smoking support. ## Behavioural support in acute and mental health services These recommendations are for healthcare professionals, stop-smoking advisers and others trained to provide behavioural support to stop smoking. For pregnant women, see the section on providing support to stop smoking for pregnant women. Discuss current and past smoking behaviour and develop a personal stop-smoking plan as part of a review of the person's health and wellbeing. Provide information about the different types of stop-smoking options and how to use them. Provide information about the types of behavioural support to stop smoking available. Offer and arrange or supply prescriptions of stop-smoking options (see the sections on stop-smoking interventions and stop-smoking pharmacotherapies in acute and mental health services). Offer to measure people's exhaled carbon monoxide level during each contact and use these measurements to motivate them to stop smoking and provide feedback on their progress. Alert the person's other healthcare providers and prescribers to changes in smoking behaviour because dosages of other medicines may need adjusting (see the section on drug dosages for people who have stopped smoking). For people who smoke who are admitted to secondary care, as well as following the recommendations in this section: Provide immediate support if necessary, otherwise within 24 hours of admission. Provide support (on site) as often and for as long as needed during admission. Offer weekly sessions, preferably face to face, for at least 4 weeks after discharge. If it is not possible to provide this support after discharge, arrange a referral to local stop-smoking support. For people who smoke who are receiving secondary care services in the community or at outpatient clinics (including preoperative assessments) follow the recommendations in this section and: Provide immediate support at the outpatient site. Offer weekly sessions, preferably face to face, for at least 4 weeks after the date they stopped smoking. Arrange a referral to local stop-smoking support if the person prefers. ## Stop-smoking pharmacotherapies in acute and mental health services For pregnant women, see recommendations on nicotine replacement therapy and other pharmacological support in the pregnancy section. Also see the recommendations on smoking in the physical health section of NICE's guideline on psychosis and schizophrenia in adults. If stop-smoking pharmacotherapy is accepted, make sure it is provided immediately. Advise people to remove nicotine replacement therapy patches 24 hours before microvascular reconstructive surgery and surgery using vasopressin injections. When people are discharged from hospital, ensure they have enough stop-smoking pharmacotherapy to last at least 1 week or until their next contact with stop-smoking support. Tell them about local policies on indoor and outdoor use of nicotine-containing e-cigarettes. See also the section on stop-smoking interventions. ## Stop-smoking support in mental health services For people with severe mental health conditions who may need additional support to stop smoking, offer: delivery by a specialist adviser with mental health expertise support that is tailored in duration and intensity to the person's needs. See also the section on stop-smoking interventions. For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on stop-smoking support in mental health services . Full details of the evidence and the committee's discussion are in evidence review O: tailored interventions for those with mental health conditions. Loading. Please wait. ## Supporting people who have to stop smoking temporarily These recommendations are for health and social care professionals, stop-smoking advisers and voluntary and community organisations. For those who need to abstain temporarily to use acute and mental health services: tell them about the different types of medicinally licensed nicotine-containing products and how to use them and encourage the use of medicinally licensed nicotine-containing products to help them abstain and, if possible, prescribe them. Provide behavioural support alongside medicinally licensed nicotine-containing products to maintain abstinence from smoking while in secondary care. Offer behavioural support to people who want or need to abstain from smoking temporarily in all settings, including closed institutions for example. Support could include: -ne-to-one or group sessions by specialist services discussing why it is important to reduce the harm caused by smoking (to others as well as themselves) encouraging people to consider other times or situations when they could stop. ## Medicine dosages for people who have stopped smoking These recommendations are for people who prescribe stop-smoking pharmacotherapies, and for pharmacists, and health and social care professionals in acute, maternity and mental health services (including both inpatient and community mental health services). Monitor people's use of prescribed medicines that are affected by smoking (or stopping smoking) for efficacy and adverse effects. Adjust the dosage as appropriate. Medicines that are affected include: clozapine, olanzapine, theophylline and warfarin. Refer to specific information for individual medicines, such as in the BNF or summaries of product characteristics in the electronic medicines compendium. Discuss with people who use secondary care and their carers that it might be possible to reduce the dose of some prescribed medicines when they stop smoking. Also advise them to seek medical advice if they notice any side effects from changing the amount they smoke. ## Making stop-smoking options available in hospital These recommendations are for hospital pharmacists and managers. Ensure hospital pharmacies stock the medicinally licensed products recommended in the section on stop-smoking interventions for patients and staff. Ensure people using secondary care have access to stop-smoking pharmacotherapies at all times. See also recommendation 1.22.14. ## Supporting staff in secondary care and closed institutions to stop smoking These recommendations are for providers of secondary care and stop-smoking support, and managers of closed institutions and other services where smoking is not permitted. Advise all staff who smoke to stop. Ensure systems are in place for staff who smoke to receive advice and guidance on how to stop in one go. Encourage staff to use stop-smoking support to stop or cut down the amount they smoke. Provide contact details for community support if preferred. See also the section on stop-smoking interventions and the NCSCT's service and delivery guidance 2014. ## Supporting staff in secondary care and closed institutions to reduce their harm from smoking and comply with smokefree policies These recommendations are for providers of secondary care, and managers of closed institutions and other services where smoking is not permitted. For staff in secondary care and closed institutions who do not want, or are not ready, to stop smoking in one go: Ask them if they would like to think about reducing the harm from smoking (see box 1). Advise them to use medicinally licensed nicotine-containing products to help them not to smoke immediately before and during working hours. Advise them where to get them. Offer and provide behavioural support to help staff in secondary care and closed institutions not to smoke during working hours. # Supporting people who do not want, or are not ready, to stop smoking in one go to reduce their harm from smoking These recommendations are for providers of stop-smoking support and other specially trained professionals. ## Choosing a harm-reduction approach Advise people that stopping smoking in one go is the best approach. If someone does not want, or is not ready, to stop smoking in one go, ask if they would like to think about reducing the harm from smoking. If they agree, help them to identify why they smoke, their smoking triggers and their smoking behaviour. Use this information to work through the approaches outlined in box 1. Suggest which approaches to stopping smoking might be most suitable, based on the person's smoking behaviour, previous attempts to stop and their health and social circumstances. Briefly discuss the merits of each approach to help them choose. Cutting down before stopping smoking with the help of 1 or more medicinally licensed nicotine-containing products (the products may be used as long as needed to prevent relapse to previous levels of smoking) without using medicinally licensed nicotine-containing products. Smoking reduction with the help of 1 or more medicinally licensed nicotine-containing products (the products may be used as long as needed to prevent relapse to previous levels of smoking) without using medicinally licensed nicotine-containing products. Temporarily not smoking with the help of 1 or more medicinally licensed nicotine-containing products without using medicinally licensed nicotine-containing products. ## Medicinally licensed nicotine-containing products for harm reduction These recommendations are for health and social care professionals, stop-smoking advisers and voluntary and community organisations. Reassure people who smoke that medicinally licensed nicotine-containing products are a safe, effective way to reduce the amount they smoke or to cut down before stopping. Also: advise them that these products can be used as a complete or partial substitute for tobacco, either in the short or long term explain that using these products also helps avoid compensatory smoking and increases their chances of stopping in the longer term reassure them that it is better to use these products and reduce the amount they smoke than to continue smoking at their current level. Advise people that medicinally licensed nicotine-containing products can be used for as long as they help stop them going back to previous levels of smoking (see box 1). If possible, supply or prescribe medicinally licensed nicotine-containing products. Otherwise, encourage people to ask their GP or pharmacist for them, or tell them where they can buy the products themselves. If more intensive support is needed, refer to stop-smoking support. ## Behavioural support for harm reduction These recommendations are for stop-smoking advisers and those trained to provide behavioural support to help people stop smoking, including telephone quitlines and internet support sites. Use the information gathered about smoking behaviour (see the section on identifying and quantifying people's smoking) to help people set goals and discuss reduction strategies. This may include: increasing the time interval between cigarettes delaying the first cigarette of the day choosing periods during the day, or specific occasions, when they will not smoke. Help people who are cutting down before stopping smoking to set a specific quit date. Normally this quit date should be within 6 weeks of them starting behavioural support, although the sooner the better. Help them to develop a schedule detailing how much they aim to cut down (and when) in the lead up to that date. Help people who are aiming to reduce the amount they smoke (but not intending to stop) to set a date when they will have achieved their goal. Help them to develop a schedule for this or to identify specific periods of time (or specific events) when they will not smoke. Tell people who are not prepared to stop smoking that the health benefits from reducing the amount they smoke are unclear. But advise them that if they reduce their smoking now, they are more likely to stop smoking in the future. Explain that this is particularly true if they use medicinally licensed nicotine-containing products to help reduce the amount they smoke. If necessary, advise people how to use medicinally licensed nicotine-containing products effectively. ## Harm-reduction self-help materials Provide self-help materials in a range of formats and languages, tailored to meet the needs of groups in which smoking is widespread and many people are dependent on tobacco, for example, those listed as being at high risk of harm in the section on commissioning and designing services. Self-help materials for people who smoke should include advice about the areas covered in the section on choosing a harm-reduction approach, as well as details of where to find more help and support. Use social media websites to publicise self-help materials. ## Manufacturer information supplied with medicinally licensed nicotine-containing products Provide consumers with clear, accurate information on the health risks of any medicinally licensed nicotine-containing product, compared with continuing to smoke and not smoking. Include details on long-term use. Provide simple, clear instructions on how to use medicinally licensed nicotine-containing products to support the harm-reduction approaches outlined in box 1. Think about providing information on the outer packaging as well as in the enclosed leaflet for medicinally licensed nicotine-containing products. Package medicinally licensed nicotine-containing products in a way that makes it as easy as possible for people to take the recommended dose for the right amount of time. # Stopping use of smokeless tobacco ## Identifying people who use smokeless tobacco and offering referral These recommendations are for GPs, dentists, pharmacists and other healthcare professionals, particularly those providing services for South Asian communities. Ask people if they use smokeless tobacco, using the names that the various products are known by locally. If necessary, use visual aids to show them what the products look like. (This may be necessary if the person does not speak English well or does not understand the terms being used.) Record the outcome in the person's notes. If someone uses smokeless tobacco, ensure they are aware of the health risks (for example, the risk of cardiovascular disease, oropharyngeal cancers and periodontal disease). Use a brief intervention to advise them to stop. Refer people who use smokeless tobacco who want to quit to local specialist tobacco cessation services (see the section on stop-smoking interventions). This includes services specifically for South Asian groups, where they are available. Record the person's response to any attempts to encourage or help them to stop using smokeless tobacco in their notes (as well as recording whether they smoke). ## Providing support to stop using smokeless tobacco These recommendations are for people providing support or advice as part of a comprehensive specialist tobacco cessation service. Use the local names when referring to smokeless tobacco products. Provide advice on how to quit to people who use smokeless tobacco (or recommend that they get advice to help them quit). Offer people who use smokeless tobacco help to prevent a relapse after an attempt to stop. If possible, check the success of the attempt by using a cotinine test (saliva examination). Monitor for any possible increase in tobacco smoking or use of areca nut. Advise people on how to cope with the potential adverse effects of quitting smokeless tobacco. This may include, for example, referring people for help to cope with oral pain, as well as providing general support to cope with withdrawal symptoms. Check whether smokeless tobacco users also smoke tobacco and, if that is the case, provide help to quit them both. ## Developing services for people using smokeless tobacco These recommendations are for people who commission, plan and run services to help people stop using tobacco. As part of the local joint strategic needs assessment, gather information on where, when and how often smokeless tobacco cessation services are promoted and provided to local South Asian communities – and by whom. Aim to get an overview of the services on offer. Consult with local voluntary and community organisations that work with, or alongside, South Asian communities to understand their specific issues and needs in relation to smokeless tobacco (see the section on working with local South Asian communities). Collect and analyse data on the use of smokeless tobacco among local South Asian communities. For example, collect data from local South Asian voluntary and community organisations, dental health professionals and primary and secondary care services. This data should provide information on: prevalence and incidence of smokeless tobacco use and detail on the people who use it (for example, their age, family origin, gender, language, religion, disability status and socioeconomic status) people who use smokeless tobacco and do not use cessation services types of smokeless tobacco used perceived level of health risk associated with these products circumstances in which these products are used locally proportion and demographics of people who both smoke and use smokeless tobacco products. When collecting and analysing information on smokeless tobacco, use consistent terminology to describe the products. Note any local variation in the terminology used by retailers and consumers. Think about working with neighbouring local authorities to analyse routinely collected data from a wider geographical area on the health problems associated with smokeless tobacco among local South Asian communities. In particular, collect and analyse data on the rate of oropharyngeal cancers. Note any demographic patterns. Data could be gathered from local cancer registers, Hospital Episode Statistics, joint strategic needs assessments and local cancer networks. Collect information from tobacco cessation services on the number of South Asian people who have recently sought help to give up smoking or smokeless tobacco. Depending on the level of detail available, data should be broken down demographically (for example, by age, family origin, gender, religion and socioeconomic status). These recommendations are for public sector, voluntary and community organisations, health and social care professionals and faith groups. Work with local South Asian communities to plan, design, coordinate, implement and publicise activities to help them stop using smokeless tobacco: Develop relationships and build trust between relevant organisations, communities and people by involving them in all aspects of planning. Take account of existing and past activities to address smokeless tobacco use and other health issues among these communities. Also see NICE's guideline on community engagement: improving health and wellbeing and reducing health inequalities. Work with local South Asian communities to understand how to make smokeless tobacco cessation services more accessible. For example, if smokeless tobacco cessation services are provided within existing mainstream stop-smoking support, find out what would make it easier for South Asian people to use the service. These recommendations are for directors of public health and those responsible for commissioning and managing tobacco cessation services. If local needs assessment shows that it is necessary, commission a range of services to help South Asian people stop using smokeless tobacco. Services should be in line with any existing local agreements or local enhanced service arrangements. Provide services for South Asian users of smokeless tobacco either within existing stop-smoking support or, for example, as: Part of services offered within a range of healthcare and community settings (for example, GP or dental surgeries, community pharmacies and community centres – see the section on identifying people who use smokeless tobacco and offering referral). A stand-alone service tailored to local needs (see the section on providing support to stop using smokeless tobacco). This might cater for specific groups such as South Asian women, speakers of a specific language or people who use a certain type of smokeless tobacco product. (The latter type of service could be named after the product, for example, it could be called a 'gutkha' cessation service.) Ensure local smokeless tobacco cessation services are coordinated and integrated with other tobacco control, prevention and cessation activities, as part of a comprehensive local tobacco control strategy. The services (and activities to promote them) should also be coordinated with, or linked to, national stop-smoking initiatives and other related national initiatives (for example, dental health campaigns). Ensure smokeless tobacco cessation services are part of a wider approach to addressing the health needs facing South Asian communities. They should be planned in partnership with relevant local voluntary and community organisations and user groups, and in consultation with local South Asian communities. Ensure smokeless tobacco cessation services take into account the fact that some people who use smokeless tobacco products also smoke. Ensure smokeless tobacco cessation services take into account the needs of people: from different local South Asian communities (for example, by using staff with relevant language skills or translators, or by providing translated materials or resources in a non-written format) who may be particularly concerned about confidentiality who may not realise smokeless tobacco is harmful who may not know help is available who may find it difficult to use existing local services because of their social circumstances, gender, language, culture or lifestyle. Regularly monitor and evaluate all local smokeless tobacco cessation services (and activities to promote them). Ensure they are effective and acceptable to service users. If necessary, adjust services to meet local need more effectively. The following outcomes should be reported: number of quit attempts percentage of successful quit attempts at 4 weeks percentage of quit attempts leading to an adverse or unintended consequence (such as someone switching to, or increasing, their use of smoked tobacco or areca nut-only products). # Adherence and relapse prevention These recommendations are for people providing stop-smoking support or advice. ## Supporting people trying to stop smoking Discuss ways of preventing a relapse to smoking. This could include talking about coping strategies and practical ways of making it easier to prevent a relapse to smoking. Do this at an early stage and at each contact. Offer the opportunity for a further course of varenicline, NRT or bupropion to prevent a relapse to smoking.In November 2021, this was an off-label use of bupropion. See NICE's information on prescribing medicines. In August 2022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on supporting people trying to stop smoking . Full details of the evidence and the committee's discussion are in evidence review N: smoking relapse prevention. Loading. Please wait. ## Supporting people cutting down or stopping temporarily If people who set out to reduce the amount they smoke or to stop temporarily have been successful, assess how motivated they are to: maintain that level reduce the amount they smoke even more stop completely. At appropriate intervals, measure people's exhaled breath for carbon monoxide to gauge their progress and help motivate them to stop smoking. Ask them whether daily activities, for example climbing the stairs or walking uphill, have become easier. Use this feedback to prompt discussion about the benefits of cutting down and, if appropriate, to encourage them to cut down even more or stop completely. Offer medicinally licensed nicotine-containing products, as needed, to help prevent a relapse among people who have reduced the amount they smoke. ## Reviewing the approach for people trying to stop smoking, cutting down or stopping temporarily For people attempting to stop smoking and those reducing their harm, offer follow‑up appointments and review the approach taken at each contact. Encourage people who have not achieved their quitting or harm-reduction goals to try again. Remind them that various interventions are available to help them and discuss which option to use next. See the sections on stop-smoking interventions and on supporting people who do not want, or are not ready, to stop smoking in one go to reduce their harm from smoking. For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on reviewing the approach . Full details of the evidence and the committee's discussion are in evidence review N: smoking relapse prevention. Loading. Please wait.# Recommendations on treating tobacco dependence in pregnant women People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences. At the time of publication (November 2021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking. These recommendations aim to help women stop smoking during pregnancy and in the first year after childbirth. Other recommendations relevant to pregnant women are in the section on support to stop smoking in secondary care services. # Identifying pregnant women who smoke and referring them for stop-smoking support These recommendations are for healthcare professionals providing maternity care. Provide routine carbon monoxide testing at the first antenatal appointment and at the 36-week appointment to assess every pregnant woman's exposure to tobacco smoke. Provide carbon monoxide testing at all other antenatal appointments if the pregnant woman: smokes or is quitting or used to smoke or tested with 4 parts per million (ppm) or above at the first antenatal appointment. Provide an opt-out referral to receive stop-smoking support for all pregnant women who: say they smoke or have stopped smoking in the past 2 weeks or have a carbon monoxide reading of 4 ppm or above or have previously been provided with an opt-out referral but have not yet engaged with stop-smoking support. See also the section on identifying smoking among carers, family and other household members. Explain to the woman: that it is normal practice to refer all pregnant women who smoke or have recently quit that the carbon monoxide test will allow her to see a physical measure of her smoking and exposure to other people's smoking what her carbon monoxide reading means, taking into consideration the time since she last smoked and the number of cigarettes smoked (and when) on the day of the test. If the pregnant woman does not smoke but has a carbon monoxide level of 3 ppm or more, help her to identify the source of carbon monoxide and reduce it. (Other sources include household or other secondhand smoke, heating appliances or traffic emissions.) If the pregnant woman has a high carbon monoxide reading (more than 10 ppm) but says she does not smoke: advise her about possible carbon monoxide poisoning ask her to contact the Gas Emergency Line (0800 111 999) for gas safety advice phrase any further questions about smoking sensitively to encourage a frank discussion. Record carbon monoxide level and any feedback given in the pregnant woman's antenatal records. If her antenatal records are not available locally, use local protocols to record this information. For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on identifying pregnant women who smoke and referring them for stop-smoking support . Full details of the evidence and the committee's discussion are in evidence review H: opt-out stop-smoking support. Loading. Please wait. # Following up women who have been referred for stop smoking support These recommendations are for people providing stop-smoking support or advice. Contact all pregnant women who have been referred for help. Discuss smoking and pregnancy and the issues they face, using an impartial, person-centred approach. Invite them to use the service. If necessary (and resources permit), make at least 3 contacts using different methods. Advise the maternity booking midwife of the outcome. Try to see pregnant women who cannot be contacted by other methods. This could happen during a routine antenatal care visit (for example, when they attend for a scan). Provide information about the risks of smoking to an unborn child and the benefits of stopping for both mother and baby. Address any factors that prevent pregnant women from using stop-smoking support. This could include: a lack of confidence in their ability to quit lack of knowledge about the services on offer difficulty accessing them lack of suitable childcare fear of failure and concerns about being stigmatised. If pregnant women are reluctant to attend the stop-smoking service, think about providing structured self-help materials or giving details of telephone quitlines or NHS online stop-smoking support. Also think about offering to visit them at home, or at another venue, if it is difficult for them to attend specialist services. Address any concerns pregnant women and their partners or family may have about stopping smoking and offer personalised information, advice and support on how to stop. Send information on smoking and pregnancy to women who opt out during the initial telephone call. This should include details on how to get help to quit at a later date. # Providing support to stop smoking These recommendations are for people providing stop-smoking support or advice. Provide the pregnant woman with intensive and ongoing support (brief interventions alone are unlikely to be sufficient) throughout pregnancy and beyond. This includes regularly monitoring her smoking status using carbon monoxide tests. Use carbon monoxide measurements to encourage her to quit and as a way to provide positive feedback once a quit attempt has been made. Biochemically validate that the pregnant woman has quit on the date she set and 4 weeks after. If possible, use urine or saliva cotinine tests, as these are more accurate than carbon monoxide tests. (They can detect exposure over the past few days rather than hours.) When carrying out tests, check whether the pregnant woman is using nicotine replacement therapy (NRT) as this may raise her cotinine levels. Take into account that no measure can be 100% accurate. Some people may smoke so infrequently – or inhale so little – that their intake cannot reliably be distinguished from that from passive smoking. If the pregnant woman stopped smoking in the 2 weeks before her maternity booking appointment, continue to provide support in line with the recommendations above and stop-smoking support practice protocols. Establish links with contraceptive services, fertility clinics and antenatal and postnatal services so that everyone working in those organisations knows about local stop-smoking support. Ensure they understand what these services offer and how to refer people to them. For pregnant women taking prescribed medicines, also see the section on medicine dosages for people who have stopped smoking. ## Nicotine replacement therapy and other pharmacological support Consider NRT alongside behavioural support to help women stop smoking in pregnancy (see BNF information on NRT). Consider NRT at the earliest opportunity in pregnancy and continue to provide it after pregnancy if the woman needs it to prevent a relapse to smoking, including if the pregnancy does not continue (see BNF information on NRT). Give pregnant women clear and consistent information about NRT. Explain: that it may help them stop smoking and reduce their cravings how to use NRT correctly, including how to get a high enough dose of nicotine to control cravings, prevent compensatory smoking and stop successfully. Advise pregnant women who are using nicotine patches to remove them before going to bed. Emphasise to pregnant women that: most smoking-related health problems are caused by other components in tobacco smoke, not by the nicotine any risks from using NRT are much lower than those of smoking nicotine levels in NRT are much lower than in tobacco, and the way these products deliver nicotine makes them considerably less addictive than smoking. Do not offer varenicline or bupropion to pregnant or breastfeeding women. For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on nicotine replacement therapy and other pharmacological support . Full details of the evidence and the committee's discussion are in evidence review J: nicotine replacement therapy and e-cigarettes in pregnancy: update. Loading. Please wait. ## Incentives to stop smoking These recommendations are for providers of stop-smoking support. In addition to NRT and behavioural support, offer voucher incentives to support women to stop smoking during pregnancy, as follows: refer women to an incentive scheme at the first maternity booking appointment or at the next available opportunity provide vouchers only for abstinence validated using a biochemical method, such as a carbon monoxide test with a reading of less than 4 ppm stagger incentives until at least the end of pregnancy (incentives totalling around £400 have been shown to be effective) do not exclude women who have relapsed or those whose pregnancy does not continue from continuing to take part in the scheme and try again ensure vouchers cannot be used to buy products that could be harmful during pregnancy (for example, alcohol and cigarettes). Consider providing voucher incentives jointly to the pregnant woman and to a friend or family member that she has chosen to support her during her quit attempt. Ensure staff are trained to promote and deliver incentive schemes to pregnant women to stop smoking. For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on incentives to stop smoking . Full details of the evidence and the committee's discussion are in evidence review I: incentives during pregnancy. Loading. Please wait. ## Enabling all pregnant women to access stop-smoking support These recommendations are to help providers of stop-smoking support reach all pregnant women, including those whose circumstances may make it more difficult to use services (for example, because of cultural or sociodemographic factors, age or language). Involve pregnant women who find it difficult to use or access existing stop-smoking support in the planning and development of services. Collaborate with the family nurse partnership and other outreach schemes to identify additional opportunities for providing intensive and ongoing support to pregnant women to stop smoking. (Note: family nurses make frequent home visits.) Work in partnership with agencies that support pregnant women who have complex social and emotional needs. This includes substance misuse services, youth and teenage pregnancy support and mental health services. ## Helping partners and others in the household who smoke These recommendations are for providers of stop-smoking support. See also the section on identifying smoking among carers, family and other household members. Offer pregnant women's partners who smoke help to stop. Use an intervention that comprises 3 or more elements and multiple contacts. Discuss with them which options to use – and in which order, taking into account: their preferences contraindications and the potential for adverse effects from stop-smoking pharmacotherapies the likelihood that they will follow the course of treatment their previous experience of stop-smoking aids do not favour one course of treatment over another; together, choose the one that seems most likely to succeed taking into account the above. # Recommendations on policy, commissioning and training People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences. In this guideline, we use the following terms for age groups: children: aged 5 to 11 young people: aged 12 to 17 young adults: aged 18 to 24 adults: aged 18 and over. At the time of publication (November 2021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking. These recommendations are for people with responsibility for developing smokefree policy, and for commissioning and training services. # Policy Develop a policy for smokefree grounds in collaboration with secondary care staff and people who use secondary care services, including services in the community, or their representatives. The policy should: set out a clear timeframe to establish or reinstate smokefree grounds identify the roles and responsibilities of staff ban staff from supervising or helping people to take smoking breaks identify the resources needed to support the policy ban the sale of tobacco products be periodically reviewed and updated, in line with all other organisational policies. Ensure smokefree implementation plans include: support for staff and people who use secondary care services to stop smoking completely or temporarily training for staff (see the section on training for healthcare staff) removing shelters or other designated outdoor smoking areas staff, contractor and volunteer contracts that do not allow smoking during work hours or when recognisable as an employee (for example, when in uniform, wearing identification, or handling hospital business) how secondary care staff can work with people who use services and carers to protect themselves from tobacco smoke when they visit people's homes. (In accordance with smokefree legislation, employers must take action to reduce the risk to the health and safety of their employees from secondhand smoke to as low a level as is reasonably practicable.) Ensure policies, procedures and resources are in place to: help comply with, and resolve immediately, any breaches of smokefree policies, including a process for staff to report incidents support staff to encourage others to comply with the smokefree policy work with people who use services, carers, visitors and staff to overcome any problems that may result from smoking restrictions (supported by 'personal care plans' as covered in the section on information on stopping smoking for those using acute, maternity and mental health services). Ensure all staff are aware of the smokefree policy and comply with it. ## Communicating the smokefree policy Develop, deliver and maintain a communications strategy on local smokefree policy requirements. This could include newsletters, pamphlets, posters and signage (smokefree signs for vehicles or areas that are enclosed or substantially enclosed must comply with regulations under the Health and Safety at Work etc Act 1974). Include information for people who use secondary care services, their parents or carers, staff and visitors, and the wider local population. Also include: clear, consistent messages about the need to keep buildings and grounds smokefree positive messages about the health benefits of a smokefree environment the fact that health and social care professionals have a duty to provide a safe, healthy environment for staff and people who use or visit secondary care services information about stop-smoking support and how to access services, including support to temporarily stop, for staff and people who use secondary care services the fact that staff are not allowed to smoke at any time during working hours or when recognisable as an employee, contractor or volunteer (for example, when in uniform, wearing identification, or handling hospital business). ## Closed institutions Include management of smoking in the care plan of people in closed institutions who smoke. Develop a policy to ensure effective stop-smoking interventions are provided and promoted in prisons, military establishments and long-stay health centres, such as mental healthcare units. Use Department of Health and Social Care guidance to develop the policy. See also the sections on employers, support to stop smoking in secondary care services and supporting people who do not want, or are not ready, to stop smoking in one go to reduce their harm from smoking. ## Ensuring local tobacco control strategies include secondary care These recommendations are for people with responsibility for planning, commissioning and running tobacco control strategies. Ensure the joint strategic needs assessment: takes into account the impact of smoking on local communities identifies expected numbers of particular groups of people who are at very high risk of tobacco-related harm (for example, those listed as being at high risk of harm in the section on commissioning and designing services) identifies the proportion of people at very high risk reached by services and the numbers who successfully stop smoking. Make it clear in the local tobacco control strategy that people working in secondary care should: communicate key messages about tobacco-related harm to everyone who uses services develop policies and support to help people stop smoking identify people who want to stop smoking and, if appropriate, refer them to a stop-smoking adviser implement a comprehensive smokefree policy that includes the grounds of the establishment. Develop a local stop-smoking care pathway and referral procedure to ensure there is continuity of care between primary, community and secondary care. # Commissioning and designing services These recommendations are for directors and senior managers in settings where stop-smoking support is needed, and commissioners, providers and managers of stop-smoking support. Use integrated care systems plans, health and wellbeing strategies, and other relevant local strategies and plans to make the range of interventions in the section on stop-smoking interventions accessible to adults who smoke. Ensure service specifications require providers of stop-smoking support to offer nicotine replacement therapy (NRT) for as long as needed to help prevent a relapse to smoking. Use the government's local tobacco control profiles to estimate smoking prevalence among the local population. Prioritise groups at high risk of tobacco-related harm. These may include: people with mental health conditions (for example, see NICE's guideline on depression in adults) people who misuse substances (for example, see NICE's guideline on coexisting severe mental illness and substance misuse: community health and social care services) people with health conditions caused or made worse by smoking (for example, see NICE's guidelines on cardiovascular disease: identifying and supporting people most at risk of dying early, type 1 diabetes in adults, asthma and chronic obstructive pulmonary disease) people with a smoking-related illness (see NICE's guideline on lung cancer) populations with a high prevalence of smoking-related morbidity or a particularly high susceptibility to harm communities or groups with particularly high smoking prevalence (such as manual workers, travellers and LGBT+ people) people with a low socioeconomic status pregnant women who smoke. For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on commissioning and designing services . Full details of the evidence and the committee's discussion are in: evidence review N: smoking relapse prevention evidence review K: cessation and harm-reduction treatments. Loading. Please wait. ## Providing stop-smoking support to employers Offer support to employers who want to help their employees to stop smoking. If appropriate and feasible, provide support on the employer's premises. If initial demand exceeds the resources available, focus on the following: small and medium-sized enterprises enterprises with a high proportion of employees on low pay enterprises with a high proportion of employees at high risk of tobacco-related harm. ## Harm reduction within stop-smoking support Ensure investment in harm-reduction approaches does not detract from, but supports and extends the reach and impact of, existing stop-smoking support. Develop stop-smoking referral and treatment pathways to ensure a range of approaches and interventions is available to support people who opt for a harm-reduction approach (see box 1). Ensure service specifications require providers of stop-smoking support to offer medicinally licensed nicotine-containing products on a long-term basis to help people maintain a lower level of smoking. ## Stop-smoking support in secondary care Ensure all secondary care buildings and grounds are smokefree. Ensure the NHS standard contract and local authority contract includes smokefree strategies. Ensure all hospitals have on-site stop-smoking support. Ensure stop-smoking medicinally licensed products are included in secondary care formularies. Include NICE-recommended nicotine-containing products as options for sale in secondary care settings (for example, in hospital shops). Ensure secondary care service specifications and service-level agreements require: all staff to be trained to give advice on stopping smoking and to make a referral to behavioural support relevant staff to undertake regular continuing professional development in how to provide behavioural support to stop smoking. Monitor and audit the implementation and impact of recommendations for secondary care services. This may include recording: individual smoking status (including for pregnant women at the time of giving birth) number of referrals uptake of interventions prescribing of stop-smoking pharmacotherapies ‑week quit rates staff training. Ensure the needs of higher-risk groups identified in the joint strategic needs assessment are being met (see the section on ensuring local tobacco control strategies include secondary care). Ensure secondary care providers have enough resources to maintain a smokefree policy. Ensure secondary care pathways cover the following actions: identifying people who smoke providing advice on likely smoking-related complications providing advice on how to stop smoking proactively referring people to stop-smoking support. Secondary care directors and managers leading on stop-smoking support should assign a clinical or medical director to lead on stop-smoking support for people who use, or work in, secondary care services. As well as implementing the recommendations in this guideline on providing and commissioning stop-smoking support in secondary care, the designated lead should ensure: the organisation has an annual improvement programme for stop-smoking support given to people who use, or work in, secondary care services stop-smoking support (for patients and staff) is promoted and communicated effectively (see the section on communicating the smokefree policy) to start a cultural change within the organisation the quality of stop-smoking support continues to improve performance monitoring and feedback on outcomes is provided to all staff. For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on stop-smoking support in secondary care . Full details of the evidence and the committee's discussion are in evidence review K: cessation and harm-reduction treatments. Loading. Please wait. ## Referral systems for people who smoke Ensure there are systems for consistently recording and maintaining records of smoking status. All patient records should: provide a prompt for action (including referral to stop-smoking support) be stored for easy access and audit. Make sure there is a robust system (preferably electronic) to support continuity of care between secondary care and local stop-smoking support for people moving in and out of secondary care. ## Monitoring stop-smoking services by commissioners and managers Set targets for stop-smoking services, including the number of people using the service and the proportion who successfully stop smoking. Performance targets should include: treating at least 5% of the estimated local population who smoke each year achieving a stop-smoking rate of at least 35% at 4 weeks, based on everyone who starts treatment and defining success as not having smoked (confirmed by carbon monoxide monitoring of exhaled breath) in the fourth week after the quit date. Check self-reported smoking abstinence using a carbon monoxide test. Define success as the person having less than 10 parts per million (ppm) of carbon monoxide in their exhaled breath at 4 weeks after the quit date. This does not imply that treatment should stop at 4 weeks. Monitor performance data for stop-smoking services routinely and independently. Make the results publicly available. Audit exceptional results (for example, 4‑week smoking quit rates lower than 35% or above 70%). Use the audit to determine the reasons for unusual performance as well as to identify good practice and ensure it is being followed. Assess the performance of providers that support people who want to reduce the harm from smoking. Additional measures could include: numbers attending the services (for comparison with the numbers attending before harm-reduction options were offered) classifying the harm-reduction approaches used (see box 1) characteristics of people using the service (such as demographic data, cigarette usage, level of dependency and previous attempts to stop) type and amount of medicinally licensed nicotine-containing products supplied or prescribed, and over-the-counter sales of these products number of people setting a quit date. # Training ## Training to prevent uptake of smoking This recommendation is for those with responsibility for improving the health and wellbeing of children, young people and young adults who attend school. Work in partnership with those involved in smoking prevention and stop-smoking activities to design, deliver, monitor and evaluate smoking prevention training and interventions. Partners could include: national and local education agencies training agencies local authorities tobacco control alliances school nursing service voluntary sector organisations local health improvement services providers of stop-smoking support universities. See also NICE's guidelines on behaviour change: general approaches and alcohol interventions in secondary and further education. ## Training on stopping smoking Train all frontline healthcare staff to offer very brief advice on how to stop smoking in accordance with the section on support to stop smoking in primary care and community settings. Also train them to make referrals, if necessary and possible, to local stop-smoking support. Frontline secondary care staff should also be trained to refer people for behavioural support. Provide additional, specialised training on providing stop-smoking support for those working with specific groups, for example people with mental health conditions and pregnant women who smoke. Encourage and train healthcare professionals to ask people about smoking and to advise them of the dangers of exposure to secondhand smoke. Ensure staff working in closed institutions recognise that some people see smoking as an integral part of their lives. Also ensure staff recognise the issues arising from being forced to stop, as opposed to doing this voluntarily. Ensure staff recognise how the closed environment may restrict the techniques and coping mechanisms that people would normally use to stop smoking or reduce the amount they smoke. Provide the support needed for their circumstances. This includes prescribing or supplying medicinally licensed nicotine-containing products. Ensure staff understand that if someone reduces the amount they smoke, or stops completely, this can affect psychotropic and some other medications (see the summaries of product characteristics for individual drugs in the electronic medicines compendium for further details). Ensure arrangements are in place to adjust their medication accordingly. See the section on medicine dosages for people who have stopped smoking. Do not allow staff with health and social care or custodial responsibilities to smoke during working hours in locations where the people in their care are not allowed to smoke. Ensure all midwives are trained to assess and record people's smoking status and their readiness to quit. They should also: know about the health risks of smoking and the benefits of quitting understand why it can be difficult to stop know about the treatments that can help people to quit, including nicotine replacement therapy know how to refer people who smoke to local services for treatment. See the National Centre for Smoking Cessation and Training's (NCSCT) module on very brief advice on smoking for pregnant women. Ensure all healthcare and other professionals who work with pregnant women are trained in the same skills to support women to stop smoking, and to the same standard, as midwives. This includes: GPs, practice nurses health visitors -bstetricians paediatricians sonographers midwives (including young people's lead midwives) family nurses those working in fertility clinics, dental facilities and community pharmacies those working in youth and teenage pregnancy services, children's centres, social services and voluntary and community organisations. Ensure that all healthcare and other professionals who work with pregnant women (see recommendation 1.23.10): understand the impact that smoking can have on a woman and her unborn child understand the dangers of exposing a pregnant woman and her unborn child – and other children – to secondhand smoke. Train all midwives who deliver intensive stop-smoking interventions (one-to-one or group support) to the same standard as stop-smoking advisers. The minimum standard for these interventions is set by the NCSCT. Also provide additional, specialised training and offer them ongoing support and training updates. See the NCSCT's specialty module on pregnancy and the postpartum period. Ensure that midwives and specialist stop-smoking advisers who work with pregnant women: know how to ask them questions in a way that encourages them to be open about their smoking always recommend quitting rather than cutting down have received accredited training in the use of carbon monoxide monitors. Ensure training for health, dental health and allied professionals (for example, community pharmacists) covers: the fact that smokeless tobacco may be used locally – and the need to keep abreast of statistics on local prevalence the reasons why, and how, members of the South Asian community use smokeless tobacco (including the cultural context for its use) the health risks associated with smokeless tobacco the fact that some people of South Asian family origin may be less used to a preventive approach to health than the general population the local names used for smokeless tobacco products, while emphasising the need to use the term 'smokeless tobacco' as well when talking to users about them. Ensure training helps professionals to: recognise the signs of smokeless tobacco use know how to ask someone, in a sensitive and culturally aware manner, whether they use smokeless tobacco provide information in a culturally sensitive way on the harm smokeless tobacco causes (this includes being able to challenge any perceived benefits – and the relative priority that users may place on these benefits) deliver a brief intervention and refer people to tobacco cessation services if they want to quit. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary or, for public health and social care terms, the Think Local Act Personal Care and Support Jargon Buster. # Allen Carr's in-person group seminar A session lasting between 4.5 and 6 hours with elements of cognitive behavioural therapy and a brief relaxation exercise. Participants are encouraged to carry on smoking as normal until they attend the session and to smoke as normal during scheduled smoking breaks (around every 45 to 60 minutes) until a final ritual cigarette at the end. After the session, regular texts remind participants that they can contact the provider if they have further questions. The price includes up to 2 shorter (around 3.5 hours) follow-up sessions if wanted. # Behavioural support Scheduled meetings (face to face or virtual) between someone who smokes and a counsellor trained to provide stop-smoking support. Behavioural support can be provided either individually or in a group. Discussions may include information, practical advice about goal setting, self-monitoring and dealing with the barriers to stopping smoking as well as encouragement. The support also includes anticipating and dealing with the challenges of stopping (see NICE's guideline on behaviour change: general approaches and the National Centre for Smoking Cessation and Training Training Standard). Support is typically offered weekly for at least the first 4 weeks of a quit attempt (that is, for 4 weeks after the quit date) or 4 weeks after discharge from hospital (where a quit attempt may have started before discharge), and normally given with stop-smoking pharmacotherapies. Behavioural support does not include Allen Carr's Easyway in-person group seminar. # Cessation Stopping the use of tobacco, smoked or smokeless. This includes stopping use of tobacco and moving on to pharmacotherapies (including nicotine replacement therapy) or nicotine-containing e‑cigarettes. # Closed institutions Environments where people are detained or stay for a long time and where smoking is not permitted. These include secure mental health units, immigration removal centres and custodial sites, as well as places like long-stay mental health units and military establishments. # Compensatory smoking Inhaling more deeply or smoking more of each cigarette to compensate for smoking fewer cigarettes. # E-cigarettes Also called electronic cigarettes or vaping devices. A product that can be used for the inhalation of vapour through a mouthpiece. E‑cigarettes can be disposable or refillable by means of a refill container and a tank, or can be rechargeable with single-use cartridges. Products may be used to consume nicotine or used without nicotine (see nicotine-containing e-cigarettes). Products that contain or could contain nicotine in the form of e‑liquid are covered under the European Union's 2014 Tobacco Products Directive and need to be notified to the Medicines and Healthcare products Regulatory Agency (MHRA). Other devices such as disposable e‑cigarettes that do not contain nicotine, and 0% nicotine e‑liquids, are regulated under the General Product Safety Regulations (2005; definition informed by the MHRA's e-cigarettes regulations for consumer products). E‑cigarettes are not currently (November 2021) licensed medicines but are regulated by the Tobacco and Related Products Regulations (2016). # Harm reduction Measures to reduce the illnesses and deaths caused by smoking tobacco among people who smoke and those around them. Some measures or products may reduce harm more than others. People who smoke and currently do not want, or are not ready, to stop in one go can reduce their harm by smoking less and abstaining from smoking temporarily. The benefits of harm reduction itself are uncertain, but it may mean people are more likely to stop smoking altogether in the future. # Medicinally licensed nicotine-containing products Nicotine-containing products that have been given marketing authorisation by the MHRA. At the time of publication (November 2021), nicotine replacement therapy products were the only type of medicinally licensed nicotine-containing product on the market. If any nicotine-containing e‑cigarette were licensed by the MHRA and made commercially available, it would be included in this definition. # Nicotine-containing products Products that contain nicotine but do not contain tobacco and so deliver nicotine without the harmful toxins found in tobacco. This currently includes nicotine replacement therapy, which has been medicinally licensed for smoking cessation by the MHRA (see nicotine replacement therapy), and nicotine-containing e-cigarettes. Currently there are no licensed nicotine-containing e‑cigarettes on the market. Nicotine-containing e‑cigarettes on general sale are regulated under the Tobacco and Related Products Regulations (2016) by the MHRA. For further details, see the MHRA website. # Nicotine-containing e-cigarettes Nicotine-containing e‑cigarettes are vaping devices filled with nicotine-containing e‑liquid. These devices must be notified to the MHRA and must meet the requirements of the European Union (2014) Tobacco Products Directive (definition informed by the MHRA's e-cigarettes regulations for consumer products). # Nicotine replacement therapy Products medicinally licensed for use as a stop smoking aid and for harm reduction, as outlined in the BNF. They include transdermal patches, gum, inhalation cartridges, sublingual tablets, lozenges, mouth spray and nasal spray. # Pharmacotherapies This covers medication licensed for smoking cessation such as varenicline or bupropion, as well as nicotine replacement therapy. In August 2022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. # Safety This refers to the incidence of minor and major side effects associated with nicotine-containing products. # Schools 'Schools' is used to refer to: maintained and independent primary, secondary and special schools city technology colleges and academies pupil referral units, secure training and local authority secure units further education colleges 'extended schools' where childcare or informal education is provided outside school hours. # Secondary care All publicly funded secondary and tertiary care facilities, including buildings, grounds and vehicles. It covers drug and alcohol services in secondary care; emergency care; inpatient, residential and long-term care for severe mental illness in hospitals, psychiatric and specialist units and secure hospitals; and planned specialist medical care or surgery. It also includes maternity care in hospitals, maternity units, outpatient clinics and in the community. # Self-help materials Any manual or structured programme, in written or digital format, that someone can use to try to stop smoking or reduce the amount they smoke. These can be used without the help of healthcare professionals, stop-smoking advisers or group support. They can be aimed at anyone who smokes, particular populations (for example, certain ages or ethnic groups), or may be tailored to individual need. # Smokefree Air that is free of tobacco smoke. E‑cigarettes are not covered by smokefree legislation. # Smokeless tobacco Any product containing tobacco that is placed in the mouth or nose and not burned and which is typically used in England by people of South Asian family origin. It does not include products that are sucked, like 'snus' or similar oral snuff products (as defined in the European Union 2014 Tobacco Products Directive). The types used vary across the country but they can be divided into 3 main categories, based on their ingredients (Stanfill et al. 2010): Tobacco with or without flavourants: misri India tobacco (powdered) and qimam (kiman). Tobacco with various alkaline modifiers: khaini, naswar (niswar, nass) and gul. Tobacco with slaked lime as an alkaline modifier and areca nut: gutkha, zarda, mawa, manipuri and betel quid (with tobacco). # South Asian family origin People with ancestral links to countries in southern Asia, including Bangladesh, India, Nepal, Pakistan or Sri Lanka. # Specialist tobacco cessation services Evidence-based services that offer support to help people stop smoking or using smokeless tobacco. In England, these are generally referred to as 'stop-smoking support or services' or 'smoking cessation services' because they normally focus on people who smoke tobacco. But a service might brand itself as a generic tobacco cessation or tobacco dependence service, to emphasise a focus on more than 1 form of tobacco. # Stop in one go The standard approach in most stop-smoking support. The person makes a commitment to stop smoking on or before a particular date (the quit date). This may or may not involve the use of pharmacotherapies or nicotine-containing e‑cigarettes before the quit date and for some time afterwards, depending on the person's needs. # Stop-smoking support Interventions and support to stop smoking, regardless of how services are commissioned or set up. # Telephone quitlines These provide proactive or reactive advice, encouragement, counselling and support by phone to anyone who smokes who wants to quit, or who has recently quit. # Temporary abstinence Stopping smoking with or without medication for a particular event or series of events, in a particular location, for specific time periods (for example, while at work, during long-haul flights or during a hospital stay), or for the foreseeable future. (The latter might include, for example, abstinence while serving a prison sentence or while detained in a secure mental health unit.) # Under-served groups Groups who may be less likely to benefit from an intervention because they have specific needs that the intervention does not address, or because they may face additional challenges in engaging with the intervention.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Health effects of e-cigarettes What are the short- and long-term health effects of e-cigarette use? Are there any specific health effects relating to use in pregnancy, or use by children and young people? For a short explanation of why the committee made the recommendation for research, see the rationale section on advice on nicotine-containing e-cigarettes . Full details of the evidence and the committee's discussion are in: evidence review K: cessation and harm-reduction treatments evidence review M: long-term health effects of e-cigarettes. Loading. Please wait. ## Nicotine replacement therapy and e-cigarettes and pregnancy Are nicotine replacement therapy or nicotine-containing e-cigarettes effective to help women stop smoking in pregnancy (and at what dose)? For a short explanation of why the committee made the recommendation for research, see the rationale section on nicotine replacement therapy (NRT) and other pharmacological support . Full details of the evidence and the committee's discussion are in evidence review J: nicotine replacement therapies and e-cigarettes in pregnancy: update. Loading. Please wait. ## Stop-smoking interventions for under-served groups How can effective and cost-effective interventions to support people to stop smoking be modified to improve engagement with and accessibility for under-served groups? How acceptable are these interventions to these groups? For a short explanation of why the committee made the recommendation for research, see the rationale section on commissioning and designing services . Full details of the evidence and the committee's discussion are in evidence review K: cessation and harm-reduction treatments. Loading. Please wait. ## Support for people with mental health conditions to stop smoking How can people with mental health conditions be supported effectively to stop smoking (at individual and system level)? What are the challenges and opportunities and how can they be addressed? For a short explanation of why the committee made the recommendation for research, see the rationale section on stop-smoking support in mental health services . Full details of the evidence and the committee's discussion are in evidence review O: tailored interventions for those with mental health conditions. Loading. Please wait. ## E-cigarettes and pregnancy What are the views and concerns of: pregnant women who smoke the healthcare professionals who care for them about the use of nicotine-containing e‑cigarettes during pregnancy? For a short explanation of why the committee made the recommendation for research, see the rationale section on nicotine replacement therapy and other pharmacological support . Full details of the evidence and the committee's discussion are in evidence review J: nicotine replacement therapies and e-cigarettes in pregnancy: update. Loading. Please wait. # Other recommendations for research ## E-cigarettes for harm reduction Are nicotine-containing e‑cigarettes effective and safe for harm reduction when used alongside tobacco products to cut down on smoking (dual-use approach)? For a short explanation of why the committee made the recommendation for research, see the rationale section on nicotine-containing e-cigarettes for harm reduction . Full details of the evidence and the committee's discussion are in evidence review K: cessation and harm-reduction treatments. Loading. Please wait. ## Use of e-cigarettes (amount and frequency) Does the effectiveness of nicotine-containing e‑cigarettes as an aid to stopping smoking vary according to the amount of nicotine they contain or the frequency of use? For a short explanation of why the committee made the recommendation for research, see the rationale section on advice on nicotine-containing e-cigarettes . Full details of the evidence and the committee's discussion are in evidence review K: cessation and harm-reduction treatments. Loading. Please wait. ## E-cigarette flavours Do the flavours used in nicotine-containing e‑cigarettes have an impact on their effectiveness as an aid to stopping smoking, and are there any adverse effects associated with them? For a short explanation of why the committee made the recommendation for research, see the rationale section on advice on nicotine-containing e-cigarettes . Full details of the evidence and the committee's discussion are in evidence review K: cessation and harm-reduction treatments. Loading. Please wait. ## E-cigarettes and established future smoking Is e‑cigarette use in children, young people and young adults who do not smoke associated with future established smoking? For a short explanation of why the committee made the recommendation for research, see the rationale section on adult-led interventions in schools . Full details of the evidence and the committee's discussion are in evidence review F and G: e-cigarettes and young people. Loading. Please wait. ## Factors that may influence the use of nicotine replacement therapy and e-cigarettes Which factors may prevent people who currently smoke tobacco from using other forms of nicotine such as NRT and nicotine-containing e‑cigarettes? Does this vary according to population group, particularly among under-served groups? For a short explanation of why the committee made the recommendation for research, see the rationale section on using stop-smoking interventions . Full details of the evidence and the committee's discussion are in evidence review L: barriers and facilitators to using e-cigarettes for cessation or harm reduction. Loading. Please wait. ## Relapse prevention Are NRT or nicotine-containing e‑cigarettes effective for preventing relapse after a successful quit attempt? For a short explanation of why the committee made the recommendation for research, see the rationale section on supporting people trying to stop smoking . Full details of the evidence and the committee's discussion are in evidence review N: smoking relapse prevention. Loading. Please wait. ## Relapse prevention after enforced, temporary quit How can people who have recently stopped or temporarily abstained from smoking in a smokefree inpatient or treatment environment be best supported after discharge to prevent relapse or to stop permanently? For a short explanation of why the committee made the recommendation for research, see the rationale section on supporting people trying to stop smoking . Full details of the evidence and the committee's discussion are in evidence review N: smoking relapse prevention. Loading. Please wait. ## Carbon monoxide monitoring What is the validity of different thresholds of carbon monoxide in exhaled breath as markers of quitting, based on diagnostic review and modelling? ## Allen Carr's Easyway For adults who want to stop smoking, what is the effectiveness and cost effectiveness of Allen Carr's Easyway programme delivered in formats other than in-person group seminars (for example online or using the self-help book) compared with other methods of smoking cessation? For specific groups who are at risk of health inequalities, for example pregnant women, people from lower socioeconomic backgrounds or people who do not speak English well: What is the differential effectiveness and cost-effectiveness of Allen Carr's Easyway (including the in-person group seminar and other formats)? What strategies or interventions are effective in minimising those differences? For a short explanation of why the committee made the recommendations for research, see the rationale section on stop-smoking interventions . Full details of the evidence and the committee's discussion are in evidence review P: effectiveness and cost-effectiveness of Allen Carr's Easyway. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the 2021 recommendations and how they might affect practice and services. They link to details of the evidence and a full description of the committee's discussion. # Adult-led interventions in schools Recommendations 1.6.3 and 1.6.4 ## Why the committee made the recommendations The committee wanted to discourage e‑cigarette use among young people and young adults who do not smoke because evidence shows that use of e‑cigarettes is linked with a higher chance of ever smoking later in life. The committee members agreed that ideas about smoking and what is normal can start from a young age so the recommendation should also apply to this age group. The committee agreed that school-based interventions could help to discourage e‑cigarette use among those who do not smoke. The committee noted the need to not inadvertently make e‑cigarettes desirable. They also emphasised that e‑cigarettes should not be confused with tobacco products, so talking about them separately is important. The committee agreed that more evidence is needed about whether e‑cigarette use is linked with habitual smoking (rather than experimental smoking) in the future, the factors that determine this link, and the levels of e‑cigarette use in people under 25 (see the recommendation for research on e-cigarettes and established future smoking). ## How the recommendations might affect practice Adding information about e‑cigarettes to existing curriculum-based interventions to stop people taking up smoking is a change to current practice, but it should have little resource impact. Return to recommendations # Stop-smoking interventions Recommendations 1.12.1 to 1.12.8 ## Why the committee made the recommendations The committee looked at a large amount of evidence assessing the relative effectiveness of several interventions, including medicinally licensed products (varenicline, bupropion and nicotine replacement therapy ) and nicotine-containing e‑cigarettes. They also looked at these interventions combined with each other. Most of the interventions or combinations of interventions were delivered with behavioural support. Most evidence investigated medicinally licensed products, with fewer studies about e‑cigarettes. The evidence found that these interventions were effective, and that some were likely to be more effective than others, especially in combination with behavioural support. The committee also agreed with the evidence that a combination of short- and long-acting NRT was effective as well. Based on the evidence of relative effectiveness and their expertise, the committee agreed that several individual products, as well as short-acting and long-acting NRT in combination, were likely to lead to people successfully stopping smoking when used alongside behavioural support. The committee agreed that people should first be told about all the available options so they can make their own choice. If people do want more information about which options are likely to work best, it is important that people providing stop-smoking support or advice can make this clear. The committee discussed very brief advice and using opportunities to tell people who smoke about the range of interventions available, along with having longer discussions about these options and providing more detailed advice. They agreed these align well with the principles of NHS England's making every contact count and NICE's making every contact count resources. The committee looked at the evidence for Allen Carr's Easyway to stop smoking in-person group seminars. This is an approach that uses cognitive behavioural therapy and relaxation methods without pharmacotherapy. It also includes a final ritual cigarette at the end of the seminar, regular follow-ups and optional shorter follow-up sessions. The evidence considered by the committee compared Allen Carr's Easyway in-person group seminar with 1-to-1 support provided by an NHS stop smoking service (which includes behavioural support and the use of medicinally licensed products) and with a remote stop smoking service (which included behavioural support and information about how to access medicinally licensed products). The committee agreed the evidence showed it was as good as other methods such as 1-to-1 support provided by local stop-smoking services, but there was not enough evidence to position Allen Carr's Easyway in-person group seminar within the hierarchy of effectiveness of interventions in recommendations 1.12.7 or 1.12.8. The committee noted that evidence suggests Allen Carr's Easyway in-person group seminar is cost effective and represents good value for money from an NHS and public sector perspective. They agreed that making it available through the NHS and local authorities alongside other interventions would broaden people's choice, and that the more choice people have the more likely they are to find the right intervention for them. They also agreed that some people are reluctant to use pharmacotherapy, and Allen Carr's Easyway would potentially increase the number of people attempting to stop smoking by offering an alternative to interventions that include pharmacotherapy. The committee discussed various ways of providing the seminar, including online, but noted that the evidence they saw was only for the in-person group seminar (although in 1 study an online follow up was offered). Therefore they were unable to generalise from this evidence to formats other than the in-person group seminar. The committee discussed the funding of studies of the intervention. One was funded by Allen Carr's Easyway, but the committee agreed that the methods used to conduct the study minimised any risk of bias associated with this. The committee discussed the potential effect of Allen Carr's Easyway on inequalities in health. They noted that the length of the seminar (4.5 to 6 hours) and any travel costs to attend the seminar might be difficult for some people, and that people who are housebound would not be able to attend an in-person group seminar at all. They also noted that the evidence did not include any analysis by age, family background, or pregnancy and so it was not clear whether its effectiveness differed in these groups. The committee were unaware whether the in-person group seminars were available in languages other than English, and agreed this was a potential barrier for some people. The evidence also showed that the quit rate was greater in people with higher education in the Allen Carr Easyway in-person group seminar arm. The committee discussed that commissioners would need to know and understand the needs of their local populations to be able to commission Allen Carr's Easyway in a way that would maximise access and use of the service. The committee agreed that more research on the effects of Allen Carr's Easyway in different population groups, and on the effectiveness of other ways to deliver the programme (for example the online and book versions) would be useful (see the recommendations for research on Allen Carr's Easyway). The committee decided not to recommend some combinations of interventions even though they were as effective as individual options. This was because, based on their experience, they had concerns over adherence rates, the difficulty of obtaining prescriptions for multiple interventions at once and a lack of information on contraindications that made these combinations less feasible than other options. In most of the evidence, the stop-smoking product (medicinally licensed products or nicotine-containing e‑cigarettes) was combined with some form of behavioural support. This meant that the results of the evidence depended on behavioural support being given alongside. The committee agreed that people providing stop-smoking support should offer behavioural support alongside any nicotine-containing products the person is using, irrespective of whether they are providing the product. This is to give people a better chance of stopping smoking. They also agreed that offering behavioural support to people using nicotine-containing e‑cigarettes would increase their chances of stopping smoking. In addition, the committee recognised the need for more evidence about what factors may prevent those who smoke from using other forms of nicotine, particularly among population groups with higher smoking prevalence. (See the recommendation for research on factors that may influence the use of nicotine replacement therapy and e-cigarettes.) ## How the recommendations might affect practice Conversations guided by each person's preference are good practice and should already be taking place. However, extra time may be needed for people providing stop-smoking support or advice to discuss the intervention options with people who want to stop smoking, especially for the additional advice on e‑cigarettes. If these recommendations lead people to quit successfully with fewer unsuccessful attempts, this may mean fewer appointments per person. Commissioning Allen Carr's Easyway in-person group seminar through the NHS or local authority would have resource implications for stop smoking services. But the intervention is cost effective and although the initial cost was higher than the comparator (Quit.ie or local stop smoking services group) this would be quickly offset (within 5 to 7 years) by the reduction in comorbidities and associated healthcare costs. The committee were also advised that the NHS or local authority is likely to be able to negotiate a discount for the intervention if enough people take up the offer. The committee noted that some people living in rural areas may need help with travel costs if they need to travel long distances to attend the in-person seminar. Return to recommendations # Advice on nicotine-containing e-cigarettes Recommendations 1.12.13 to 1.12.17 ## Why the committee made the recommendations Evidence showed that nicotine-containing e‑cigarettes can help people to stop smoking and are of similar effectiveness to other cessation options such as varenicline or long-acting and short-acting NRT. The extensive harms of smoking are well known, and the committee agreed it is unlikely that e‑cigarettes could cause similar levels of harm. But they also agreed that for people who do not smoke, it is unlikely that inhaling vapour from an e‑cigarette is as low risk as not doing so, although the extent of that risk is not yet known. They discussed the potential benefits and risks of using nicotine-containing e‑cigarettes to stop smoking. There was a small amount of evidence about short-term adverse events of e‑cigarettes that did not show that they caused any more adverse events than NRT, e‑cigarettes without nicotine or no treatment. The committee had low confidence in this evidence because studies were usually designed to investigate effectiveness and not adverse events, meaning they may not have been large enough to show an effect. There were only 2 studies about the long-term harms of using nicotine-containing e‑cigarettes, and the committee discussed the uncertainty of the evidence and their concerns with these studies. A call for evidence did not produce any additional evidence in this area. The committee agreed that there is insufficient evidence to tell whether e‑cigarettes cause long-term effects. E‑cigarettes are relatively new devices, and it is important to understand whether they cause any health harms or benefits aside from their potential to reduce smoking-related harm (see the recommendation for research on health effects of e-cigarettes). The committee recognised the need for evidence about what factors may influence use of e‑cigarettes. So they made recommendations for research relating to any possible impacts of the amount of nicotine and frequency of use, and flavourings. The committee discussed the outbreak of serious lung disease in the US in 2019, which US authorities identified was largely caused by vaping cannabis products containing vitamin E acetate. They also noted there has been a Medicines and Healthcare products Regulatory Agency (MHRA) Drug Safety Update highlighting serious lung injury with e‑cigarettes issued in January 2020 (E-cigarette use or vaping: reporting suspected adverse reactions, including lung injury). The committee discussed that the UK has well-established regulations for e‑cigarettes that restrict what they can contain. Experts from the MHRA described to the committee the monitoring process for both short- and long-term harms of using e‑cigarettes. Monitoring is ongoing and the evidence may change in the future, but the committee was not aware of any major concerns being identified. Accurate information relies on adverse events being reported, so the committee recommended that people providing stop-smoking support or advice should actively report any suspected adverse events and encourage people to report any that they experience. The committee used their knowledge and experience to supplement the very limited and uncertain evidence about harms. They agreed that because many of the harmful components of cigarettes are not present in e‑cigarettes, switching to nicotine-containing e‑cigarettes was likely to be significantly less harmful than continuing smoking. So, the committee agreed that people should be able to access them as part of the range of interventions they can choose to use (see the section on stop-smoking interventions). They also agreed that people should be given up-to-date information on what is known about e‑cigarettes to help them make an informed decision about whether to use them. The committee agreed that with the limited data on effects of longer-term use, people should only use e‑cigarettes for as long as they help prevent them going back to smoking. They also agreed that people should be discouraged from continuing to smoke when using e‑cigarettes, even if they are smoking less, because there is no information on whether this will reduce their harm from smoking. The committee discussed that it is more likely that people will not get enough nicotine to help them stop smoking, than get too much. They agreed that not getting enough nicotine is likely to increase the risk that the person will return to smoking, so they recommended that people should be encouraged to use as much as they need and told how to use the products effectively. ## How the recommendations might affect practice Extra time may be needed to discuss e‑cigarettes with people who are interested in using them. If these recommendations lead to more successful quit attempts, this may mean fewer appointments per person and substantial savings in downstream costs associated with smoking. Return to recommendations # Stop-smoking support in mental health services Recommendation 1.14.19 ## Why the committee made the recommendation The committee agreed the importance of stop-smoking support being available to all, and that people with mental health conditions should not be treated differently in this. However, because those with mental health conditions have a higher prevalence of smoking, and are less likely to access standard smoking cessation services and have lower quit rates, it is important to look at whether additional support could be appropriate. There was a small amount of evidence about tailored smoking cessation interventions for people with mental health conditions. The evidence of effectiveness identified was in populations with severe mental health conditions such as bipolar disorder, schizophrenia or post-traumatic stress disorder. However, the committee noted there was a lack of consensus of what constitutes a severe mental health condition. They heard from experts that people with other mental health conditions may need additional support as well. This applies both at an individual level and, for those in mental health settings, at a system level. The committee agreed that additional support should be offered to people with severe mental health conditions, and although it might be considered for other people with mental health conditions, there was insufficient evidence to make a wider recommendation. The committee noted that the recommended additional support would fit with current stop-smoking provision. Furthermore, the committee identified this as an important research gap that needs to be addressed to reduce health inequalities (see the recommendation for research on support for people with mental health conditions to stop smoking). ## How the recommendation might affect practice This potential additional support may need extra time and additional appointments. If these recommendations lead to more successful quit attempts, this may mean fewer appointments per person and substantial savings in downstream costs associated with smoking. Return to recommendations # Nicotine-containing e-cigarettes for harm reduction Recommendation for research 6 ## Why the committee made the recommendation for research No evidence was found on the use of e‑cigarettes specifically for harm reduction for people who do not want, or are not ready, to stop smoking in one go. So, the committee chose not to make recommendations on using e‑cigarettes for harm reduction. They did discuss that e‑cigarettes may be used in this way and that there may be substantial dual use; that is, when someone is both smoking and using e‑cigarettes. The committee agreed that more information is needed about the use of e‑cigarettes for those who may wish to reduce the amount they smoke. Return to the recommendation for research # Supporting people trying to stop smoking Recommendations 1.17.1 and 1.17.2 ## Why the committee made the recommendations The committee agreed that strategies to avoid relapsing are an important part of stop-smoking advice and support, and are likely to be most effective when introduced early in the process and regularly revisited. Evidence about NRT for preventing relapse was mixed. Although there was evidence that they may be effective in people who had recently quit, using a single type of fast-acting NRT did not reduce relapse with any certainty when people had stopped smoking for longer. The committee discussed this evidence and noted that in their experience, using NRT for longer can stop people relapsing to smoking, particularly if more than 1 type of NRT is used (usually combining patches with a fast-acting form of NRT). They discussed that only offering NRT for 12 weeks could cause people to relapse. Evidence showed that if people who have used varenicline and bupropion to stop smoking continue taking it for longer, this improves their chances of staying stopped. This included people diagnosed with serious mental illness. There were a small number of studies and they investigated different groups of people and used varenicline in different ways, so the committee had some uncertainty about the evidence. The committee reflected on the mixed findings from the evidence. They agreed that, because preventing relapse is so important for people who have been able to stop smoking, offering longer-term pharmacotherapy to help prevent relapse was reasonable. The committee noted that bupropion was not licensed for relapse prevention. The studies that evaluated bupropion for this indication had different dosing regimens, so the committee did not specify what dose or duration of bupropion was most effective for preventing relapse. The committee recognised the need for more evidence about which nicotine-containing products or combination of products are best at preventing relapse after a successful quit attempt (see the recommendations for research on relapse prevention and relapse prevention after enforced, temporary quit). ## How the recommendations might affect practice Stop-smoking advisers can use existing appointments to provide information about preventing relapse to people who want to stop smoking, so this is not expected to have a resource impact, though there may costs associated with prescribing additional pharmacotherapies. Return to recommendations # Reviewing the approach for people trying to stop smoking, cutting down or stopping temporarily Recommendations 1.17.6 and 1.17.7 ## Why the committee made the recommendations The committee discussed that it is important to review any stop-smoking or harm-reduction approach taken so that any problems can be addressed. They agreed that it can take someone multiple attempts to stop smoking for good. Encouraging people who have relapsed to smoking and talking to them about trying again may mean that they stay in touch with the service and are more likely to stop smoking in the long term. ## How the recommendations might affect practice Stop-smoking advisers can use existing appointments to discuss with people the approach they are taking and future attempts to stop or reduce harm from smoking, so this is not expected to have a resource impact. Return to recommendations # Identifying pregnant women who smoke and referring them for stop-smoking support Recommendations 1.18.1 to 1.18.3 ## Why the committee made the recommendations Stopping smoking in pregnancy is important for the health of both the woman and her baby. Existing recommended practice, based on NICE's previous guideline on stopping smoking in pregnancy and after childbirth, is to offer opt-out provision for pregnant women. The evidence about opt-out referral systems was mixed, but the most recent evidence showed that it resulted in higher self-reported quit rates and more engagement with stop-smoking support. Most current evidence uses carbon monoxide levels of 4 parts per million (ppm) as the cut-off for referral. Based on this and their expertise, the committee recommended that a carbon monoxide reading of 4 ppm or above would be an appropriate level to automatically refer women for stop-smoking support. This also aligns with the NHS Saving Babies' Lives Care Bundle. The evidence about women's views on opt-out referral showed that giving women information on carbon monoxide testing and the automatic referral was an important factor in whether they accepted the referral and took up the support. The committee discussed whether there was a specific need for a recommendation on giving information, because all clinical treatment pathways should ensure that people are fully informed and take an active part in their care. They agreed that a recommendation would be helpful in this case, because they considered opt-out treatment is not common in most areas of care. During development of this guideline, carbon monoxide monitoring was not being used because of COVID‑19 practice changes. The committee acknowledged that during the COVID‑19 pandemic referral decisions may need to be made without using carbon monoxide monitoring. ## How the recommendations might affect practice The recommendations reflect current widespread practice and so should have little resource impact. Return to recommendations # Nicotine replacement therapy and other pharmacological support Recommendations 1.20.6 to 1.20.8 and 1.20.10 ## Why the committee made the recommendations NICE's 2010 guideline on stopping smoking in pregnancy and after childbirth (replaced by this guideline) recommended nicotine replacement therapy (NRT) for pregnant women only if they are not able to stop smoking using a behavioural intervention without NRT, and once they have stopped smoking. New evidence showed that NRT may help women stop smoking in pregnancy when added to a behavioural intervention. The committee discussed that women may stop smoking temporarily during pregnancy and relapse afterwards. There was no evidence about continuing NRT after pregnancy to prevent this but, based on their expert opinion, the committee agreed it may be useful. Evidence showed that advice from healthcare professionals, particularly midwives, was valuable to pregnant women and contributed to their decisions about using NRT. The evidence also showed that consistent advice addressing the main concerns women tend to have about NRT during pregnancy (such as addictiveness, potential side effects and any pregnancy impacts) may help women to feel comfortable using NRT during and after pregnancy. There is little evidence about the effectiveness or safety of using nicotine-containing e‑cigarettes to help women stop smoking in pregnancy. Many of the studies in the effectiveness meta-analysis for nicotine replacement therapies were over 10 years old and most used doses of nicotine that would now be considered to be low. The committee therefore made recommendations for research to help understand what type and dose of NRT is most effective and the views and concerns of pregnant women and their healthcare professionals about using nicotine-containing e-cigarettes in pregnancy. Since the publication of this guideline, a National Institute for Health and Care Research trial on helping pregnant smokers quit has been published comparing e‑cigarettes and nicotine patches. NICE reviewed this trial with the help of topic experts (see the 2023 exceptional surveillance review). Although it provides some new data, there are still important gaps in the evidence - particularly for longer term outcomes. So NICE decided that more evidence on effectiveness and safety is still needed before it can update these recommendations. ## How the recommendations might affect practice The change in recommendations since NICE's previous guideline may increase prescriptions of NRT to pregnant women, and potentially increase how long it is prescribed for. If this leads to more cases of successful quitting, it will create considerable savings downstream. Return to recommendations # Incentives to stop smoking Recommendations 1.20.12 to 1.20.14 ## Why the committee made the recommendations Evidence showed that offering financial incentives to help pregnant women stop smoking was both effective and cost effective. Voucher incentives were acceptable to many pregnant women and healthcare providers. The committee noted that these are already being used in some areas. The committee discussed and agreed with the evidence that 'contingent rewards' (given only if biochemical tests prove the woman has stopped) were more effective than guaranteed payments given whether the woman has stopped or not. More evidence is needed to find out what value of incentive works best. Evidence from the UK showed that schemes in which around £400 could be gained in vouchers staggered over time (with reductions for each relapse made) were effective and cost effective, so the committee included this amount as a guide. Based on the evidence and their expertise, the committee agreed that incentive schemes that include both the pregnant woman and a significant other supporter could have a better chance of success. They also agreed that some staff may be unfamiliar with incentive schemes and would benefit from training to help deliver them. Although the guideline recommends that vouchers should be provided only to those with an abstinence validated by a biochemical method, the committee acknowledged that during the COVID‑19 pandemic carbon monoxide validation may not be being used. While this is the case, vouchers are recommended even if biochemical validation using carbon monoxide is not possible. ## How the recommendations might affect practice Incentive schemes are already used in some areas. Areas that do not already use them will need staff time to run them, and financial resources to award the vouchers. Training for people promoting and delivering the incentive schemes may need resources. Return to recommendations # Commissioning and designing services Recommendations 1.22.1 and 1.22.2 ## Why the committee made the recommendations The committee looked at a large amount of evidence assessing the relative effectiveness of interventions for stopping smoking (medicinally licensed products and nicotine-containing e‑cigarettes, alone or in combination). Most of the interventions or combinations of interventions were delivered with behavioural support. The committee agreed which interventions should be accessible (see the rationale and impact section for stop-smoking interventions). They agreed that the recommendation from NICE's 2018 guideline on stop-smoking interventions and services (replaced by this guideline) to make stop-smoking interventions available through local plans and approaches to health and wellbeing was still relevant, so they drew on that to make a new recommendation. The committee noted that not all medicinally licensed products are available in all stop-smoking services, and so local arrangements are in place to ensure that these are accessible when needed. Nicotine-containing e‑cigarettes are not licensed medicines so cannot currently be provided on prescription. However, there are ways of increasing their accessibility, for example by giving evidence-based advice about them and information on where people can access them. The committee were aware that some services use vouchers or starter pack schemes. Based on evidence and their experience of the use of NRT for preventing relapse, the committee recommended it for longer-term use (see the rationale and impact section for supporting people trying to stop smoking) and agreed this needed to be reflected in service specifications to make sure it was made available. The committee heard from experts that smoking prevalence is high in some population groups that may not be well served by existing stop-smoking provision (such as those with mental health conditions, or those who identify as LGBT+, or those with low income). And that although these groups may be motivated to stop smoking, they may experience additional challenges to successfully stopping (see the equality impact assessment). We did not find any evidence on how to tailor effective and cost-effective interventions to ensure that they are engaging and accessible for under-served groups, or how acceptable those interventions may be for those groups. The committee identified this as an important gap that needs to be addressed to reduce health inequalities (see the recommendation for research on stop-smoking interventions for under-served groups). ## How the recommendations might affect practice The committee noted that schemes are already in place in some areas to support starting the use of nicotine-containing e‑cigarettes for stopping smoking. NICE's 2013 guideline on smoking harm reduction already recommended that service specifications require providers of stop-smoking support to offer long-term NRT. Return to recommendations # Stop-smoking support in secondary care Recommendation 1.22.14 ## Why the committee made the recommendation The committee agreed that nicotine-containing products should be available for sale in secondary care settings to help people stop smoking and to support temporary abstinence for patients, staff and visitors because hospital grounds are covered by smokefree legislation. ## How the recommendation might affect practice Making the full range of effective options available for sale may be a change to current practice, but it is not expected to have a large impact on resources. Return to recommendations# Context In 2018, 14.7% of adults in the UK smoked cigarettes. Rates were higher than average for some groups, including those in routine and manual occupations, and those with mental health conditions. Although this is a decline of more than 5 percentage points since 2011, smoking is still the main cause of preventable illness and premature death in England (Office for National Statistics Adult smoking habits in the UK). In 2017/2018, an estimated 4% (489,300) of NHS hospital admissions in England, and an estimated 16% (77,800) of all deaths, were attributed to smoking (NHS Digital 2019 Statistics on smoking, England). Treating smoking-related illness is estimated to cost the NHS £2.6 billion a year and the wider cost to society is around £11 billion a year (NHS England Health matters: tobacco and alcohol CQUIN). In 1 in 5 local authorities, the specialist service has been replaced by an integrated lifestyle service (Action on Smoking and Health and Cancer Research UK's Stepping up: the response of stop smoking services in England to the COVID-19 pandemic). This guideline forms a single source for tobacco guidance that updates and replaces NICE's guidelines on: smoking: workplace interventions (PH5, 2007) smoking: preventing uptake in children and young people (PH14, 2008) smoking prevention in schools (PH23, 2010) smoking: stopping in pregnancy and after childbirth (PH26, 2010) smokeless tobacco: South Asian communities (PH39, 2012) smoking: harm reduction (PH45, 2013) smoking: acute, maternity and mental health services (PH48, 2013) stop-smoking interventions and services (NG92, 2018). This guideline includes recommendations on harm reduction, which was previously covered by PH45. In PH45, harm reduction included cutting down before stopping smoking, cutting down longer term, temporary abstinence, or stopping smoking altogether by switching to a medicinally licensed nicotine-containing product. In the current guideline, switching completely from smoking to any nicotine-containing product is considered to be stopping smoking rather than harm reduction. The approaches for harm reduction in this guideline should not detract from providing the highly cost-effective interventions to help people stop smoking altogether. Instead, recommendations on harm reduction are intended to support and extend the reach and impact of existing stop-smoking support. Although existing evidence is not clear about the health benefits of smoking reduction, people who reduce the amount they smoke are more likely to stop smoking eventually. This guideline was developed between 2019 and 2021. There has not been anything published to date on COVID‑19 that the committee considered to have an impact on this guideline. We have highlighted in the rationale sections any recommendations that are affected by temporary changes in practice because of COVID‑19. The committee further noted that some stop-smoking support may now be being delivered by phone or video rather than face to face, but this is not stopping the services from being delivered.	{'Recommendations on preventing uptake': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences.\n\nIn this guideline, we use the following terms for age groups:\n\nchildren: aged 5 to 11\n\nyoung people: aged 12 to 17\n\nyoung adults: aged 18 to 24\n\nadults: aged 18 and over.\n\nUnless otherwise stated, the recommendations on preventing uptake are for children and those aged 24 and under.\n\nAt the time of publication (November\xa02021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking.\n\nThese recommendations aim to prevent children, young people and young adults from taking up smoking. They cover anti-smoking mass-media and digital campaigns, measures to prevent tobacco being sold to and bought for children and young people, and prevention interventions in educational settings.\n\n# Organising and planning national, regional or local mass-media campaigns\n\nThese recommendations are for commissioners and organisers of mass-media campaigns.\n\nDevelop national, regional or local mass-media campaigns to prevent the uptake of smoking among young people under\xa018. Work in partnership with: the NHS, national, regional and local government and non-governmental organisations, children and young people, media professionals, healthcare professionals, public relations agencies and local anti-tobacco activists. \n\nIntegrate regional and local campaigns to prevent smoking in children and young people with any national communications strategy to tackle tobacco use. \n\nThink about targeting campaigns towards groups that epidemiological data identify as having higher than average or stagnant rates of smoking. Base the campaigns on research that identifies and helps to understand the target audiences. \n\nBase campaign messages on strategic research and qualitative before-and-after testing with the target audiences. Repeat the messages in various ways and regularly update them to keep the audience's attention. [2008, amended 2021]\n\nUse a range of media channels to get unpaid press coverage and generate as much publicity as possible. Reach specific audiences by:\n\nusing regional and local channels\n\nusing the full range of media used by children and young people. [2008, amended 2021]\n\nShare effective practice in campaigns to prevent smoking in children and young people, including effective local and regional media messages, locally, regionally and nationally. \n\nRun campaigns to prevent smoking in children and young people for 3\xa0to 5\xa0years. \n\nUse process and outcome measures to ensure campaigns are being delivered correctly and effectively. For recommendations on the principles of evaluation, see NICE's guideline on behaviour change: general approaches. \n\n# Campaign strategies to prevent uptake and denormalise tobacco use\n\nThese recommendations are for local authorities, trading standards bodies, organisers and planners of national, regional and local mass-media campaigns, and commissioners and planners.\n\nAssess whether an advocacy campaign is needed to support policy related to illegal tobacco sales. [2008, amended 2021]\n\nIf an advocacy campaign is needed, base it on good practice. Use a range of strategies to reduce the attractiveness of tobacco and contribute to changing society's attitude towards tobacco use, so that smoking is not considered the norm by any group. This could include:\n\ngenerating news by writing articles, commissioning newsworthy research and issuing press releases\n\nusing posters, brochures and other materials\n\nusing digital media. \n\nAs part of an advocacy campaign, provide a clear, published statement on how to deal with underage tobacco sales. \n\nDo not develop or deliver mass-media or access-restriction campaigns in conjunction with (or supported by) tobacco organisations. Actively discourage use of enforcement and related campaigns developed by tobacco organisations. \n\n# Helping retailers avoid illegal tobacco sales\n\nThese recommendations are for local authorities and trading standards bodies.\n\nProvide retailers with training and guidance on how to avoid illegal sales. This includes encouraging them to:\n\nask for proof of age from anyone who appears younger than\xa018 who attempts to buy cigarettes, and get it verified (examples of proof include a passport or driving licence, or cards bearing the nationally accredited 'PASS' hologram)\n\ninform Trading Standards of each tobacco sale refused on the grounds of age. \n\nMake it as difficult as possible for young people under\xa018 to get cigarettes and other tobacco products. In particular, exercise a statutory duty under the Children and Young Persons (Protection from Tobacco) Act (1991) to prevent underage sales by:\n\nprosecuting retailers who persistently break the law\n\nmaking test purchases each year, using local data to detect breaches in the law and auditing the breaches regularly to ensure consistent good practice across all local authorities. \n\nWork with other agencies to:\n\nidentify areas where underage tobacco sales are a particular problem\n\nimprove inspection and enforcement activities related to illegal tobacco sales. \n\nRun campaigns for retailers to publicise legislation prohibiting underage tobacco sales. These could include:\n\ndetails of possible fines that retailers can face\n\ndetails of where tobacco is being sold illegally\n\nsuccessful local prosecutions\n\nhealth information. \n\nEnsure efforts to reduce illegal tobacco sales by retailers are sustained. \n\n# Coordinated approach to school-based interventions\n\nThis recommendation is for schools, commissioners, local authorities, careers services or integrated youth support services, and local tobacco control alliances.\n\nEnsure smoking prevention interventions in schools and other educational establishments are:\n\npart of a local tobacco control strategy\n\nevidence-based\n\nlinked to the school or educational establishment's smokefree policy\n\nconsistent with regional and national tobacco control strategies\n\nintegrated into the curriculum. \n\nSee also NICE's guideline on behaviour change: general approaches.\n\n# Whole-school or organisation-wide smokefree policies\n\nThese recommendations are for everyone working in and with primary and secondary schools and further education colleges.\n\nDevelop a whole-school or organisation-wide smokefree policy in consultation with young people and staff:\n\nInclude smoking prevention activities (led by adults or young people).\n\nInclude staff training and development.\n\nTake account of children and young people's cultural, special educational or physical needs. (For example, by providing material in alternative formats such as pictures, large print, Braille, audio and video.) \n\nEnsure the policy forms part of the wider strategy on wellbeing, relationships education, relationships and sex education (RSE), health education, drug education and behaviour. \n\nApply the policy to everyone using the premises (grounds as well as buildings), for any purpose, at any time. Do not allow any areas in the grounds to be designated for smoking (with the exception of caretakers' homes, as specified by law). \n\nWidely publicise the policy and ensure it is easily accessible so that everyone using the premises is aware of its content. (This includes making a printed version available.) \n\nSee also NICE's guidelines on alcohol interventions in secondary and further education and social, emotional and mental wellbeing in primary and secondary education.\n\n# Adult-led interventions in schools\n\nThese recommendations are for everyone working in and with primary and secondary schools and further education colleges.\n\nIntegrate information about the health effects of tobacco use, as well as the legal, economic and social aspects of smoking, into the curriculum. For example, classroom discussions about tobacco could be relevant when teaching subjects such as biology, chemistry, citizenship, geography, mathematics and media studies. \n\nInclude accurate information about smoking in the curriculum, including its prevalence and its consequences. Tobacco use by adults and peers should be discussed and challenged. Aim to:\n\ndevelop decision-making skills through active learning techniques\n\ninclude strategies for enhancing self-esteem and resisting the pressure to smoke from the media, family members, peers and the tobacco industry. \n\nAs part of the curriculum on tobacco, alcohol and drug misuse, discourage children, young people and young adults who do not smoke from experimenting with or regularly using e-cigarettes. Talk about e‑cigarettes separately from tobacco products. \n\nWhen discussing e‑cigarettes, make it clear why children, young people and young adults who do not smoke should avoid e‑cigarettes to avoid inadvertently making them desirable. \n\nProvide additional 'booster' activities to support classroom education on tobacco until school leaving age. Activities might include school health fairs and guest speakers. \n\nEnsure smoking prevention interventions are delivered by teachers and higher-level teaching assistants who are both credible and competent in the subject, or by external experts. The latter should be trained to work with children and young people on tobacco issues. Interventions should be:\n\nentertaining, factual and interactive\n\ntailored to age and ability\n\nsensitive to family origin, culture and gender\n\nnon-judgemental. \n\nInvolve children and young people in schools in the design of interventions to prevent the uptake of smoking. \n\nEncourage parents and carers to become involved. For example, let them know about classwork or ask them to help with homework assignments. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on adult-led interventions in schools\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F and\xa0G: e-cigarettes and young people.\n\nLoading. Please wait.\n\n# Peer-led interventions in schools\n\nThis recommendation is for everyone working in and with secondary schools and further education colleges.\n\nConsider evidence-based, peer-led interventions aimed at preventing the uptake of smoking. They should:\n\nlink to relevant parts of the curriculum\n\nbe delivered both in class and informally, outside the classroom\n\nbe led by young people nominated by the students themselves (the peer leaders could be the same age or older)\n\nensure peer leaders receive support from adults who have the appropriate expertise during the course of the programme\n\nensure young people can consider and, if necessary, challenge peer and family norms on smoking, discuss the risks associated with it and the benefits of not smoking. [2010, amended 2021]\n\nSee also NICE's guideline on alcohol interventions in secondary and further education.", 'Recommendations on promoting quitting': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences.\n\nIn this guideline, we use the following terms for age groups:\n\nchildren: aged 5 to 11\n\nyoung people: aged 12 to 17\n\nyoung adults: aged 18 to 24\n\nadults: aged 18 and over.\n\nAt the time of publication (November\xa02021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking.\n\nThese recommendations promote options to help people stop smoking or using smokeless tobacco or, if they do not want or are not ready to stop in one go, to reduce their harm.\n\n# Using medicinally licensed nicotine-containing products\n\n## Raising awareness\n\nThese recommendations are for people working in public health, and others with tobacco control and providing advice about harm reduction as part of their remit.\n\nRaise public awareness of the harm caused by smoking and secondhand smoke. Make it clear that smoking causes a range of diseases and conditions including cancer, chronic obstructive pulmonary disease and cardiovascular disease. \n\nProvide information on how people who smoke can reduce the risk of illness and death (to themselves and others) by using 1\xa0or more medicinally licensed nicotine-containing products. Explain that they could be used as a partial or complete substitute for tobacco, either temporarily or in the long term. \n\nProvide the following information about nicotine:\n\nsmoking is highly addictive mainly because it delivers nicotine very quickly to the brain and this makes stopping smoking difficult\n\nmost smoking-related health problems are caused by other components in tobacco smoke, not by the nicotine\n\nnicotine levels in medicinally licensed nicotine-containing products are much lower than in tobacco, and the way these products deliver nicotine makes them less addictive than smoking. [2013, amended 2021]\n\nProvide the following information about the effectiveness and safety of medicinally licensed nicotine-containing products:\n\nany risks from using medicinally licensed nicotine-containing products are much lower than those of smoking; nicotine replacement therapy (NRT) products have been demonstrated in trials to be safe to use for at least 5\xa0years\n\nlifetime use of medicinally licensed nicotine-containing products is likely to be considerably less harmful than smoking. \n\nProvide information on using medicinally licensed nicotine-containing products, including:\n\nwhat forms they take\n\nhow to use them effectively when trying to stop or cut down smoking\n\nlong-term use to reduce the risk of relapsing\n\nwhere to get them\n\nthe cost compared with smoking. \n\nFor recommendations on what information to provide about nicotine-containing e‑cigarettes, see the section on advice on nicotine-containing e-cigarettes.\n\n## Point-of-sale promotion\n\nThese recommendations are for manufacturers and retailers of medicinally licensed nicotine-containing products, including tobacco retailers.\n\nEncourage people who smoke to consider stopping or, if they do not want or are not ready to stop in one go, to consider the harm-reduction approaches outlined in box\xa01. \n\n# Promoting stop-smoking support\n\n## Developers of communications strategies\n\nCoordinate communications strategies to support the delivery of stop-smoking support, telephone quitlines, school-based interventions, tobacco control policy changes and any other activities designed to help people to stop smoking. \n\nDevelop and deliver communications strategies about stopping smoking in partnership with the NHS, national, regional and local government and non-governmental organisations. The strategies should:\n\nUse the best available evidence of effectiveness, such as Cochrane reviews.\n\nBe developed and evaluated using audience research.\n\nUse 'why to' and 'how to' stop messages that are non-judgemental, empathetic and respectful. For example, use testimonials from people who smoke or used to smoke.\n\nInvolve community pharmacies in local campaigns and maintain links with other professional groups such as dentists, fire services and voluntary groups.\n\nEnsure campaigns are sufficiently extensive and sustained to have a reasonable chance of success.\n\nThink about targeting and tailoring campaigns towards groups that epidemiological data identify as having higher than average or stagnant rates of smoking, to address inequalities. [2018, amended 2021]\n\n## Schools\n\nMake information on local stop-smoking support easily available to staff and students. Include details on the type of help available and when, where and how to access the services. \n\n## Employers\n\nMake information on local stop-smoking support easily available at work. Include details on the type of help available and when, where and how to access the services. Publicise these interventions. \n\nBe responsive to individual needs and preferences of employees. If feasible, and if there is sufficient demand, provide on-site stop-smoking support. \n\nAllow staff to attend stop-smoking support during working hours without loss of pay. \n\nNegotiate a smokefree workplace policy with employees or their representatives. This should:\n\nState whether or not smoking breaks may be taken during working hours and, if so, where, how often and for how long.\n\nInclude a stop-smoking policy developed in collaboration with staff and their representatives.\n\nDirect people who wish to stop smoking to local stop-smoking support. \n\n## Employees and their representatives\n\nEncourage employers to provide advice, guidance and support to help employees who want to stop smoking. \n\n# Promoting support for people to stop using smokeless tobacco\n\nThese recommendations are for public sector, voluntary and community organisations, health and social care professionals and faith groups. They are particularly relevant to South Asian communities in areas of identified need.\n\nWork in partnership with existing community initiatives to raise awareness of local smokeless tobacco\xa0cessation services and how to access them. Ensure any material used to raise awareness of the services:\n\nUses the names that the smokeless tobacco products are known by locally, as well as the term 'smokeless tobacco'.\n\nGives information about the health risks associated with smokeless tobacco and the availability of services to help people quit.\n\nChallenges the perceived benefits – and the relative priority that users may place on these benefits (compared with the health risks). For example, some people think smokeless tobacco is an appropriate way to ease indigestion or relieve dental pain, or help freshen the breath.\n\nAddresses the needs of people whose first language is not English (by providing translations).\n\nAddresses a range of communication needs by providing material in alternative formats, for example pictures, large print, Braille, audio and video.\n\nIncludes information for specific South Asian subgroups (for example, older Bangladeshi women) who are known to have high rates of smokeless tobacco use.\n\nDiscusses the concept of addiction in a way that is sensitive to culture and religion (for example, it may be better to refer to users as having developed a 'habit', rather than being 'addicted').\n\nDoes not stigmatise users of smokeless tobacco products within their own community, or in the eyes of the general community. \n\nUse existing local South Asian information networks (including culturally specific TV and radio channels), and traditional sources of health advice within South Asian communities to provide information on smokeless tobacco. \n\nUse venues and events that members of local South Asian communities frequent to publicise, provide or consult on cessation services with them. (Examples include educational establishments and premises where prayer groups or cultural events are held.) \n\nRaise awareness among those who work with children and young people about smokeless tobacco use. This includes:\n\nproviding teachers with information on the harm that smokeless tobacco causes and that also challenges the perceived benefits – and the priority that users may place on these perceived benefits\n\nencouraging teachers to discuss with their students the reasons why people use smokeless tobacco; this could take place as part of drug education, or within any other relevant part of the curriculum. ", 'Recommendations on treating tobacco dependence': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences.\n\nIn this guideline, we use the following terms for age groups:\n\nchildren: aged 5 to 11\n\nyoung people: aged 12 to 17\n\nyoung adults: aged 18 to 24\n\nadults: aged 18 and over.\n\nUnless otherwise stated, the recommendations on treating tobacco dependence are for people over the age of 12 who want to stop smoking or reduce harm from smoking.\n\nAt the time of publication (November\xa02021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking.\n\nThese recommendations aim to help people aged 12\xa0or over (unless otherwise stated) to stop smoking or, if they do not want or are not ready to stop in one go, to reduce their harm from smoking. They cover interventions and services delivered in a range of settings, including NHS primary and secondary care, and emphasise the importance of targeting vulnerable groups who find giving up smoking hard or who smoke a lot. Pregnant women are mainly covered in the section on treating tobacco dependence in pregnant women.\n\n# Identifying and quantifying people's smoking\n\n## Identifying people who smoke\n\nThese recommendations are for health and social care professionals and those providing stop-smoking support or advice (for recommendations about pregnant women see the section on identifying pregnant women who smoke and referring them for stop-smoking support).\n\nAt every opportunity, ask people if they smoke or have recently stopped smoking. \n\nIf they smoke, advise them to stop smoking in a way that is sensitive to their preferences and needs, and advise them that stopping smoking in one go is the best approach. Explain how stop-smoking support can help. \n\nDiscuss any stop-smoking aids the person has used before, including personally purchased nicotine-containing products. \n\nOffer advice on using nicotine-containing products on general sale, including over-the-counter nicotine replacement therapy (NRT) and nicotine-containing e-cigarettes. \n\nIf someone does not want, or is not ready, to stop smoking in one go:\n\nfind out about the person's smoking behaviour and level of nicotine dependence by asking how many cigarettes they smoke – and how soon after waking\n\nmake sure they understand that stopping smoking reduces the risks of developing smoking-related illnesses or worsening conditions affected by smoking\n\nask them to think about adopting a harm-reduction approach (see the section on supporting people who do not want, or are not ready, to stop smoking in one go)\n\nencourage them to seek help to stop smoking completely in the future\n\nleave the offer of help open and offer support again the next time they are in contact. \n\nRecord smoking status and all actions, discussions and decisions related to advice, referrals or interventions about stopping smoking. \n\nAsk about their smoking status at the next available opportunity. \n\n## Identifying smoking among carers, family and other household members\n\nThese recommendations are for anyone who is responsible for providing health and support services (including stop-smoking support) to people using acute, maternity or mental health services.\n\nAt the earliest opportunity, ask if any of the following people smoke:\n\npartners of pregnant women\n\nparents or carers of people using acute or mental health services\n\nanyone else in the household. \n\nIf partners, parents, other household members and carers do not smoke, give them positive feedback if they are present. \n\nIf they do smoke:\n\nencourage them to stop if they are present, and refer them to a hospital or local stop-smoking support using local arrangements if they want to stop or cut down their smoking\n\nif they are not present, ask the person using services to suggest they contact stop-smoking support and provide contact details. \n\nDuring contact with partners, parents, other household members and carers of people using acute, maternity and mental health services:\n\nprovide clear advice about the danger of smoking and secondhand smoke, including to pregnant women and babies – before and after birth\n\nrecommend not smoking around the patient, pregnant woman, mother or baby (this includes not smoking in the house). \n\n# Stop-smoking interventions\n\nThese recommendations are for people providing stop-smoking support or advice. For training requirements see the National Centre for Smoking Cessation and Training (NCSCT) standard for training in smoking cessation treatments.\n\nFor recommendations on digital and mobile health interventions for stopping smoking, see NICE's guideline on behaviour change: digital and mobile health interventions.\n\nSee recommendation 1.14.23 for advice on people's use of prescribed medicines that are affected by smoking (or stopping smoking).\n\nTell people who smoke that a range of interventions is available to help them stop smoking. Explain how to access them and refer people to stop-smoking support if appropriate. \n\nEnsure the following are accessible to adults who smoke:\n\nbehavioural interventions:\n\n\n\nbehavioural support (individual and group)\n\nvery brief advice\n\n\n\nmedicinally licensed products:\n\n\n\nbupropion (see BNF information on bupropion hydrochloride)\n\nnicotine replacement therapy – short and long acting\n\nvarenicline (see NICE's technology appraisal guidance on varenicline for smoking cessation and the BNF information on varenicline)\n\n\n\nnicotine-containing e-cigarettes\n\nAllen Carr's Easyway in-person group seminar.In August 2022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. [2021, amended 2022]\n\nConsider NRT for young people aged 12\xa0and over who are smoking and dependent on tobacco. If this is prescribed, offer it with behavioural support. \n\nDo not offer varenicline or bupropion to people under\xa018.\xa0\n\nOffer behavioural support to people who smoke regardless of which option they choose to help them stop smoking, unless they have chosen the Allen Carr Easyway in-person group seminar. Explain how to access this support. [2021, amended 2022]\n\nDiscuss with people which options to use to stop smoking, taking into account:\n\ntheir preferences, health and social circumstances\n\nany medicines they are taking\n\nany contraindications and the potential for adverse effects\n\ntheir previous experience of stop-smoking aids.Also see the advice in the recommendations on medicinally licensed products, and the recommendations on nicotine-containing e-cigarettes. \n\nAdvise people (as appropriate for their age) that the following options, when combined with behavioural support, are more likely to result in them successfully stopping smoking:\n\nvarenicline (offered in line with NICE's technology appraisal guidance on varenicline for smoking cessation)\n\na combination of short-acting and long-acting NRT\n\nnicotine-containing e‑cigarettes.In August\xa02022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. \n\nAdvise people (as appropriate for their age) that the options that are less likely to result in them successfully stopping smoking, when combined with behavioural support, are:\n\nbupropion\n\nshort-acting NRT used without long-acting NRT\n\nlong-acting NRT used without short-acting NRT. \n\nFor adults, prescribe or provide bupropion, varenicline or NRT before they stop smoking:\n\nFor bupropion agree a quit date set within the first 2\xa0weeks of treatment, reassess the person shortly before the prescription ends.\n\nFor varenicline agree a quit date and start the treatment 1\xa0to\xa02\xa0weeks before this date, reassess the person shortly before the prescription ends.\n\nFor NRT agree a quit date and ensure the person has NRT ready to start the day before the quit date. In August\xa02022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. \n\nFor a short explanation of why the committee made the 2021 and 2022 recommendations and how they might affect practice, see the rationale and impact section on stop-smoking interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review L: barriers and facilitators to using e-cigarettes for cessation or harm reduction\n\nevidence review M: long-term health effects of e-cigarettes\n\nevidence review K: cessation and harm-reduction treatments\n\nevidence review P: effectiveness and cost-effectiveness of Allen Carr's Easyway.\n\nLoading. Please wait.\n\n## Advice on medicinally licensed products\n\nThese recommendations are for people providing stop-smoking support or advice.\n\nEmphasise that:\n\nmost smoking-related health problems are caused by other components in tobacco smoke, not by the nicotine\n\nany risks from using medicinally licensed nicotine-containing products or other stop-smoking pharmacotherapies are much lower than those of smoking. [2013, amended 2021]\n\nExplain how to use medicinally licensed nicotine-containing products correctly. This includes ensuring people know how to achieve a high enough dose to:\n\ncontrol cravings\n\nprevent compensatory smoking\n\nachieve their goals on stopping or reducing the amount they smoke. \n\nAdvise people using short-acting NRT to replace each cigarette with the product they are using, for example a lozenge or piece of gum. Ideally, they should use this before the usual time they would have had the cigarette, to allow for the slower nicotine release from these products. \n\n## Advice on nicotine-containing e-cigarettes\n\nThese recommendations are for people providing stop-smoking support or advice to adults.\n\nGive clear, consistent and up-to-date information about nicotine-containing e‑cigarettes to adults who are interested in using them to stop smoking (for example, see the NCSCT e-cigarette guide and Public Health England's information on e-cigarettes and vaping). \n\nAdvise adults how to use nicotine-containing e‑cigarettes. This includes explaining that:\n\ne‑cigarettes are not licensed medicines but are regulated by the Tobacco and Related Products Regulations (2016)\n\nthere is not enough evidence to know whether there are long-term harms from e‑cigarette use\n\nuse of e‑cigarettes is likely to be substantially less harmful than smoking\n\nany smoking is harmful, so people using e‑cigarettes should stop smoking tobacco completely. \n\nDiscuss:\n\nhow long the person intends to use nicotine-containing e‑cigarettes for\n\nusing them for long enough to prevent a return to smoking and\n\nhow to stop using them when they are ready to do so. \n\nAsk adults using nicotine-containing e‑cigarettes about any side effects or safety concerns that they may experience. Report these to the MHRA Yellow Card scheme, and let people know they can report side effects directly. \n\nExplain to adults who choose to use nicotine-containing e‑cigarettes the importance of getting enough nicotine to overcome withdrawal symptoms, and explain how to get enough nicotine. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on advice on nicotine-containing e-cigarettes\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review L: barriers and facilitators to using e-cigarettes for cessation or harm reduction\n\nevidence review M: long-term health effects of e-cigarettes\n\nevidence review K: cessation and harm-reduction treatments.\n\nLoading. Please wait.\n\n## Telephone quitlines\n\nEnsure publicly sponsored telephone stop-smoking quitlines offer a rapid, positive and authoritative response. If possible, give callers whose first language is not English access to information and support in their chosen language. \n\nEnsure all staff giving advice through stop-smoking quitlines receive stop-smoking training (at least in brief interventions to help people stop smoking). \n\nTrain staff who offer counselling through stop-smoking quitlines so that they meet the NCSCT Training Standard (individual behavioural counselling). Preferably, they should also have a relevant counselling qualification. Training should comply with the NCSCT Training Standard for training in smoking cessation treatments or its updates. [2008, amended 2018]\n\n# Support to stop smoking in primary care and community settings\n\nThis recommendation is for health and social care professionals in primary care and community settings. See recommendation 1.14.23 for advice on people's use of prescribed medicines that are affected by smoking (or stopping smoking).\n\nOther recommendations to support pregnant women to stop smoking are in the section on treating tobacco dependence in pregnant women.\n\nFor people who want to stop smoking:\n\ndiscuss with them how they can stop (NCSCT programmes explain how to do this)\n\nprovide stop-smoking interventions and advice; see the section on stop-smoking interventions\n\nif you are unable to provide stop-smoking interventions, refer them to local stop-smoking support, if available\n\nif they opt out of a referral to stop-smoking support, refer them to a professional who can offer pharmacotherapy and very brief advice. [2018, amended 2021]\n\n# Support to stop smoking in secondary care services\n\nThese recommendations are for health and social care professionals in all acute, maternity and mental health services (including both inpatient and community mental health services, health visitors and midwives). Other recommendations to support pregnant women to stop smoking are in the section on treating tobacco dependence in pregnant women.\n\n## Information on stopping smoking for those using acute, maternity and mental health services\n\nThese recommendations are about information and support before any secondary care admission.\n\nGive people information about the smokefree policy before their appointment, procedure or hospital stay. This should cover:\n\nthe short- and long-term health benefits of stopping smoking at any time; for example, stopping smoking at any time before surgery has no ill effects (although people may experience short-term withdrawal symptoms such as headaches or irritability from quitting), and people who stop in the 8\xa0weeks before surgery can benefit significantly\n\nthe risks of secondhand smoke\n\nthe fact that all buildings and grounds are smokefree so they must not smoke while admitted to, using or visiting these services (see the section on policy)\n\nthe types of support available to help them stop smoking completely or temporarily before, during and after an admission or appointment (see the sections on behavioural support in acute and mental health services and supporting people who have to stop smoking temporarily)\n\nabout the different pharmacotherapies that can help with stopping smoking and temporary abstinence, where to obtain them (including from GPs) and how to use them. [2013, amended 2021]\n\nBefore a planned or likely admission to an inpatient setting, work with the person to include how they will manage their smoking on admission or entry to the secondary care setting in their personal care plan. \n\nEncourage people being referred for elective surgery to stop smoking before their surgery. Refer them to local stop-smoking support. \n\nProvide information and take the opportunity to provide advice to visitors about the benefits of stopping smoking and how to contact local stop-smoking support. \n\n## Referring to behavioural support in acute, maternity and mental health services\n\nOffer and, if the person agrees, arrange for them to receive behavioural support to stop smoking during either their current outpatient visit or their inpatient stay. \n\nFor people using secondary care services in the community, staff trained to provide behavioural support to stop smoking should offer and provide support. Other staff should offer and, if accepted, arrange a referral to local stop-smoking support. \n\n## Behavioural support in acute and mental health services\n\nThese recommendations are for healthcare professionals, stop-smoking advisers and others trained to provide behavioural support to stop smoking. For pregnant women, see the section on providing support to stop smoking for pregnant women.\n\nDiscuss current and past smoking behaviour and develop a personal stop-smoking plan as part of a review of the person's health and wellbeing. \n\nProvide information about the different types of stop-smoking options and how to use them. [2013, amended 2021]\n\nProvide information about the types of behavioural support to stop smoking available. \n\nOffer and arrange or supply prescriptions of stop-smoking options (see the sections on stop-smoking interventions and stop-smoking pharmacotherapies in acute and mental health services). [2013, amended 2021]\n\nOffer to measure people's exhaled carbon monoxide level during each contact and use these measurements to motivate them to stop smoking and provide feedback on their progress. \n\nAlert the person's other healthcare providers and prescribers to changes in smoking behaviour because dosages of other medicines may need adjusting (see the section on drug dosages for people who have stopped smoking). \n\nFor people who smoke who are admitted to secondary care, as well as following the recommendations in this section:\n\nProvide immediate support if necessary, otherwise within 24\xa0hours of admission.\n\nProvide support (on site) as often and for as long as needed during admission.\n\nOffer weekly sessions, preferably face to face, for at least 4\xa0weeks after discharge. If it is not possible to provide this support after discharge, arrange a referral to local stop-smoking support. \n\nFor people who smoke who are receiving secondary care services in the community or at outpatient clinics (including preoperative assessments) follow the recommendations in this section and:\n\nProvide immediate support at the outpatient site.\n\nOffer weekly sessions, preferably face to face, for at least 4\xa0weeks after the date they stopped smoking. Arrange a referral to local stop-smoking support if the person prefers. \n\n## Stop-smoking pharmacotherapies in acute and mental health services\n\nFor pregnant women, see recommendations on nicotine replacement therapy and other pharmacological support in the pregnancy section.\n\nAlso see the recommendations on smoking in the physical health section of NICE's guideline on psychosis and schizophrenia in adults.\n\nIf stop-smoking pharmacotherapy is accepted, make sure it is provided immediately. \n\nAdvise people to remove nicotine replacement therapy patches 24\xa0hours before microvascular reconstructive surgery and surgery using vasopressin injections. \n\nWhen people are discharged from hospital, ensure they have enough stop-smoking pharmacotherapy to last at least 1\xa0week or until their next contact with stop-smoking support. \n\nTell them about local policies on indoor and outdoor use of nicotine-containing e-cigarettes. [2013, amended 2021]\n\nSee also the section on stop-smoking interventions.\n\n## Stop-smoking support in mental health services\n\nFor people with severe mental health conditions who may need additional support to stop smoking, offer:\n\ndelivery by a specialist adviser with mental health expertise\n\nsupport that is tailored in duration and intensity to the person's needs. \n\nSee also the section on stop-smoking interventions.\n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on stop-smoking support in mental health services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: tailored interventions for those with mental health conditions.\n\nLoading. Please wait.\n\n## Supporting people who have to stop smoking temporarily\n\nThese recommendations are for health and social care professionals, stop-smoking advisers and voluntary and community organisations.\n\nFor those who need to abstain temporarily to use acute and mental health services:\n\ntell them about the different types of medicinally licensed nicotine-containing products and how to use them and\n\nencourage the use of medicinally licensed nicotine-containing products to help them abstain and, if possible, prescribe them. \n\nProvide behavioural support alongside medicinally licensed nicotine-containing products to maintain abstinence from smoking while in secondary care. \n\nOffer behavioural support to people who want or need to abstain from smoking temporarily in all settings, including closed institutions for example. Support could include:\n\none-to-one or group sessions by specialist services\n\ndiscussing why it is important to reduce the harm caused by smoking (to others as well as themselves)\n\nencouraging people to consider other times or situations when they could stop. \n\n## Medicine dosages for people who have stopped smoking\n\nThese recommendations are for people who prescribe stop-smoking pharmacotherapies, and for pharmacists, and health and social care professionals in acute, maternity and mental health services (including both inpatient and community mental health services).\n\nMonitor people's use of prescribed medicines that are affected by smoking (or stopping smoking) for efficacy and adverse effects. Adjust the dosage as appropriate. Medicines that are affected include: clozapine, olanzapine, theophylline and warfarin. Refer to specific information for individual medicines, such as in the BNF or summaries of product characteristics in the electronic medicines compendium. [2013, amended 2021]\n\nDiscuss with people who use secondary care and their carers that it might be possible to reduce the dose of some prescribed medicines when they stop smoking. Also advise them to seek medical advice if they notice any side effects from changing the amount they smoke. \n\n## Making stop-smoking options available in hospital\n\nThese recommendations are for hospital pharmacists and managers.\n\nEnsure hospital pharmacies stock the medicinally licensed products recommended in the section on stop-smoking interventions for patients and staff. \n\nEnsure people using secondary care have access to stop-smoking pharmacotherapies at all times. \n\nSee also recommendation 1.22.14.\n\n## Supporting staff in secondary care and closed institutions to stop smoking\n\nThese recommendations are for providers of secondary care and stop-smoking support, and managers of closed institutions and other services where smoking is not permitted.\n\nAdvise all staff who smoke to stop. Ensure systems are in place for staff who smoke to receive advice and guidance on how to stop in one go. \n\nEncourage staff to use stop-smoking support to stop or cut down the amount they smoke. Provide contact details for community support if preferred. \n\nSee also the section on stop-smoking interventions and the NCSCT's service and delivery guidance 2014.\n\n## Supporting staff in secondary care and closed institutions to reduce their harm from smoking and comply with smokefree policies\n\nThese recommendations are for providers of secondary care, and managers of closed institutions and other services where smoking is not permitted.\n\nFor staff in secondary care and closed institutions who do not want, or are not ready, to stop smoking in one go:\n\nAsk them if they would like to think about reducing the harm from smoking (see box\xa01).\n\nAdvise them to use medicinally licensed nicotine-containing products to help them not to smoke immediately before and during working hours. Advise them where to get them. \n\nOffer and provide behavioural support to help staff in secondary care and closed institutions not to smoke during working hours. \n\n# Supporting people who do not want, or are not ready, to stop smoking in one go to reduce their harm from smoking\n\nThese recommendations are for providers of stop-smoking support and other specially trained professionals.\n\n## Choosing a harm-reduction approach\n\nAdvise people that stopping smoking in one go is the best approach. \n\nIf someone does not want, or is not ready, to stop smoking in one go, ask if they would like to think about reducing the harm from smoking. If they agree, help them to identify why they smoke, their smoking triggers and their smoking behaviour. Use this information to work through the approaches outlined in box\xa01. \n\nSuggest which approaches to stopping smoking might be most suitable, based on the person's smoking behaviour, previous attempts to stop and their health and social circumstances. Briefly discuss the merits of each approach to help them choose. \n\nCutting down before stopping smoking\n\nwith the help of 1\xa0or more medicinally licensed nicotine-containing products (the products may be used as long as needed to prevent relapse to previous levels of smoking)\n\nwithout using medicinally licensed nicotine-containing products.\n\nSmoking reduction\n\nwith the help of 1\xa0or more medicinally licensed nicotine-containing products (the products may be used as long as needed to prevent relapse to previous levels of smoking)\n\nwithout using medicinally licensed nicotine-containing products.\n\nTemporarily not smoking\n\nwith the help of 1\xa0or more medicinally licensed nicotine-containing products\n\nwithout using medicinally licensed nicotine-containing products.\n\n[2013, amended 2021]\n\n## Medicinally licensed nicotine-containing products for harm reduction\n\nThese recommendations are for health and social care professionals, stop-smoking advisers and voluntary and community organisations.\n\nReassure people who smoke that medicinally licensed nicotine-containing products are a safe, effective way to reduce the amount they smoke or to cut down before stopping. Also:\n\nadvise them that these products can be used as a complete or partial substitute for tobacco, either in the short or long term\n\nexplain that using these products also helps avoid compensatory smoking and increases their chances of stopping in the longer term\n\nreassure them that it is better to use these products and reduce the amount they smoke than to continue smoking at their current level. \n\nAdvise people that medicinally licensed nicotine-containing products can be used for as long as they help stop them going back to previous levels of smoking (see box\xa01). [2013, amended 2021]\n\nIf possible, supply or prescribe medicinally licensed nicotine-containing products. Otherwise, encourage people to ask their GP or pharmacist for them, or tell them where they can buy the products themselves. \n\nIf more intensive support is needed, refer to stop-smoking support. \n\n## Behavioural support for harm reduction\n\nThese recommendations are for stop-smoking advisers and those trained to provide behavioural support to help people stop smoking, including telephone quitlines and internet support sites.\n\nUse the information gathered about smoking behaviour (see the section on identifying and quantifying people's smoking) to help people set goals and discuss reduction strategies. This may include:\n\nincreasing the time interval between cigarettes\n\ndelaying the first cigarette of the day\n\nchoosing periods during the day, or specific occasions, when they will not smoke. \n\nHelp people who are cutting down before stopping smoking to set a specific quit date. Normally this quit date should be within 6\xa0weeks of them starting behavioural support, although the sooner the better. Help them to develop a schedule detailing how much they aim to cut down (and when) in the lead up to that date. \n\nHelp people who are aiming to reduce the amount they smoke (but not intending to stop) to set a date when they will have achieved their goal. Help them to develop a schedule for this or to identify specific periods of time (or specific events) when they will not smoke. \n\nTell people who are not prepared to stop smoking that the health benefits from reducing the amount they smoke are unclear. But advise them that if they reduce their smoking now, they are more likely to stop smoking in the future. Explain that this is particularly true if they use medicinally licensed nicotine-containing products to help reduce the amount they smoke. \n\nIf necessary, advise people how to use medicinally licensed nicotine-containing products effectively. \n\n## Harm-reduction self-help materials\n\nProvide self-help materials in a range of formats and languages, tailored to meet the needs of groups in which smoking is widespread and many people are dependent on tobacco, for example, those listed as being at high risk of harm in the section on commissioning and designing services. [2013, amended 2021]\n\nSelf-help materials for people who smoke should include advice about the areas covered in the section on choosing a harm-reduction approach, as well as details of where to find more help and support. Use social media websites to publicise self-help materials. \n\n## Manufacturer information supplied with medicinally licensed nicotine-containing products\n\nProvide consumers with clear, accurate information on the health risks of any medicinally licensed nicotine-containing product, compared with continuing to smoke and not smoking. Include details on long-term use. \n\nProvide simple, clear instructions on how to use medicinally licensed nicotine-containing products to support the harm-reduction approaches outlined in box\xa01. \n\nThink about providing information on the outer packaging as well as in the enclosed leaflet for medicinally licensed nicotine-containing products. \n\nPackage medicinally licensed nicotine-containing products in a way that makes it as easy as possible for people to take the recommended dose for the right amount of time. \n\n# Stopping use of smokeless tobacco\n\n## Identifying people who use smokeless tobacco and offering referral\n\nThese recommendations are for GPs, dentists, pharmacists and other healthcare professionals, particularly those providing services for South Asian communities.\n\nAsk people if they use smokeless tobacco, using the names that the various products are known by locally. If necessary, use visual aids to show them what the products look like. (This may be necessary if the person does not speak English well or does not understand the terms being used.) Record the outcome in the person's notes. \n\nIf someone uses smokeless tobacco, ensure they are aware of the health risks (for example, the risk of cardiovascular disease, oropharyngeal cancers and periodontal disease). Use a brief intervention to advise them to stop. \n\nRefer people who use smokeless tobacco who want to quit to local specialist tobacco cessation services (see the section on stop-smoking interventions). This includes services specifically for South Asian groups, where they are available. \n\nRecord the person's response to any attempts to encourage or help them to stop using smokeless tobacco in their notes (as well as recording whether they smoke). \n\n## Providing support to stop using smokeless tobacco\n\nThese recommendations are for people providing support or advice as part of a comprehensive specialist tobacco cessation service.\n\nUse the local names when referring to smokeless tobacco products. [2012, amended 2021]\n\nProvide advice on how to quit to people who use smokeless tobacco (or recommend that they get advice to help them quit). [2012, amended 2021]\n\nOffer people who use smokeless tobacco help to prevent a relapse after an attempt to stop. If possible, check the success of the attempt by using a cotinine test (saliva examination). Monitor for any possible increase in tobacco smoking or use of areca nut. [2012, amended 2021]\n\nAdvise people on how to cope with the potential adverse effects of quitting smokeless tobacco. This may include, for example, referring people for help to cope with oral pain, as well as providing general support to cope with withdrawal symptoms. [2012, amended 2021]\n\nCheck whether smokeless tobacco users also smoke tobacco and, if that is the case, provide help to quit them both. [2012, amended 2021]\n\n## Developing services for people using smokeless tobacco\n\nThese recommendations are for people who commission, plan and run services to help people stop using tobacco.\n\nAs part of the local joint strategic needs assessment, gather information on where, when and how often smokeless tobacco cessation services are promoted and provided to local South Asian communities – and by whom. Aim to get an overview of the services on offer. \n\nConsult with local voluntary and community organisations that work with, or alongside, South Asian communities to understand their specific issues and needs in relation to smokeless tobacco (see the section on working with local South Asian communities). \n\nCollect and analyse data on the use of smokeless tobacco among local South Asian communities. For example, collect data from local South Asian voluntary and community organisations, dental health professionals and primary and secondary care services. This data should provide information on:\n\nprevalence and incidence of smokeless tobacco use and detail on the people who use it (for example, their age, family origin, gender, language, religion, disability status and socioeconomic status)\n\npeople who use smokeless tobacco and do not use cessation services\n\ntypes of smokeless tobacco used\n\nperceived level of health risk associated with these products\n\ncircumstances in which these products are used locally\n\nproportion and demographics of people who both smoke and use smokeless tobacco products. \n\nWhen collecting and analysing information on smokeless tobacco, use consistent terminology to describe the products. Note any local variation in the terminology used by retailers and consumers. \n\nThink about working with neighbouring local authorities to analyse routinely collected data from a wider geographical area on the health problems associated with smokeless tobacco among local South Asian communities. In particular, collect and analyse data on the rate of oropharyngeal cancers. Note any demographic patterns. Data could be gathered from local cancer registers, Hospital Episode Statistics, joint strategic needs assessments and local cancer networks. \n\nCollect information from tobacco cessation services on the number of South Asian people who have recently sought help to give up smoking or smokeless tobacco. Depending on the level of detail available, data should be broken down demographically (for example, by age, family origin, gender, religion and socioeconomic status). \n\nThese recommendations are for public sector, voluntary and community organisations, health and social care professionals and faith groups.\n\nWork with local South Asian communities to plan, design, coordinate, implement and publicise activities to help them stop using smokeless tobacco:\n\nDevelop relationships and build trust between relevant organisations, communities and people by involving them in all aspects of planning.\n\nTake account of existing and past activities to address smokeless tobacco use and other health issues among these communities.\n\nAlso see NICE's guideline on community engagement: improving health and wellbeing and reducing health inequalities. \n\nWork with local South Asian communities to understand how to make smokeless tobacco cessation services more accessible. For example, if smokeless tobacco cessation services are provided within existing mainstream stop-smoking support, find out what would make it easier for South Asian people to use the service. \n\nThese recommendations are for directors of public health and those responsible for commissioning and managing tobacco cessation services.\n\nIf local needs assessment shows that it is necessary, commission a range of services to help South Asian people stop using smokeless tobacco. Services should be in line with any existing local agreements or local enhanced service arrangements. \n\nProvide services for South Asian users of smokeless tobacco either within existing stop-smoking support or, for example, as:\n\nPart of services offered within a range of healthcare and community settings (for example, GP or dental surgeries, community pharmacies and community centres – see the section on identifying people who use smokeless tobacco and offering referral).\n\nA stand-alone service tailored to local needs (see the section on providing support to stop using smokeless tobacco). This might cater for specific groups such as South Asian women, speakers of a specific language or people who use a certain type of smokeless tobacco product. (The latter type of service could be named after the product, for example, it could be called a 'gutkha' cessation service.) \n\nEnsure local smokeless tobacco cessation services are coordinated and integrated with other tobacco control, prevention and cessation activities, as part of a comprehensive local tobacco control strategy. The services (and activities to promote them) should also be coordinated with, or linked to, national stop-smoking initiatives and other related national initiatives (for example, dental health campaigns). \n\nEnsure smokeless tobacco cessation services are part of a wider approach to addressing the health needs facing South Asian communities. They should be planned in partnership with relevant local voluntary and community organisations and user groups, and in consultation with local South Asian communities. \n\nEnsure smokeless tobacco cessation services take into account the fact that some people who use smokeless tobacco products also smoke. \n\nEnsure smokeless tobacco cessation services take into account the needs of people:\n\nfrom different local South Asian communities (for example, by using staff with relevant language skills or translators, or by providing translated materials or resources in a non-written format)\n\nwho may be particularly concerned about confidentiality\n\nwho may not realise smokeless tobacco is harmful\n\nwho may not know help is available\n\nwho may find it difficult to use existing local services because of their social circumstances, gender, language, culture or lifestyle. \n\nRegularly monitor and evaluate all local smokeless tobacco cessation services (and activities to promote them). Ensure they are effective and acceptable to service users. If necessary, adjust services to meet local need more effectively. The following outcomes should be reported:\n\nnumber of quit attempts\n\npercentage of successful quit attempts at 4\xa0weeks\n\npercentage of quit attempts leading to an adverse or unintended consequence (such as someone switching to, or increasing, their use of smoked tobacco or areca nut-only products). \n\n# Adherence and relapse prevention\n\nThese recommendations are for people providing stop-smoking support or advice.\n\n## Supporting people trying to stop smoking\n\nDiscuss ways of preventing a relapse to smoking. This could include talking about coping strategies and practical ways of making it easier to prevent a relapse to smoking. Do this at an early stage and at each contact. \n\nOffer the opportunity for a further course of varenicline, NRT or bupropion to prevent a relapse to smoking.In November\xa02021, this was an off-label use of bupropion. See NICE's information on prescribing medicines. In August\xa02022, varenicline was unavailable in the UK. See the MHRA alert on varenicline. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on supporting people trying to stop smoking\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: smoking relapse prevention.\n\nLoading. Please wait.\n\n## Supporting people cutting down or stopping temporarily\n\nIf people who set out to reduce the amount they smoke or to stop temporarily have been successful, assess how motivated they are to:\n\nmaintain that level\n\nreduce the amount they smoke even more\n\nstop completely. \n\nAt appropriate intervals, measure people's exhaled breath for carbon monoxide to gauge their progress and help motivate them to stop smoking. Ask them whether daily activities, for example climbing the stairs or walking uphill, have become easier. Use this feedback to prompt discussion about the benefits of cutting down and, if appropriate, to encourage them to cut down even more or stop completely. \n\nOffer medicinally licensed nicotine-containing products, as needed, to help prevent a relapse among people who have reduced the amount they smoke. [2013, amended 2021]\n\n## Reviewing the approach for people trying to stop smoking, cutting down or stopping temporarily\n\nFor people attempting to stop smoking and those reducing their harm, offer follow‑up appointments and review the approach taken at each contact. \n\nEncourage people who have not achieved their quitting or harm-reduction goals to try again. Remind them that various interventions are available to help them and discuss which option to use next. See the sections on stop-smoking interventions and on supporting people who do not want, or are not ready, to stop smoking in one go to reduce their harm from smoking. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on reviewing the approach\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: smoking relapse prevention.\n\nLoading. Please wait.", 'Recommendations on treating tobacco dependence in pregnant women': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences.\n\nAt the time of publication (November\xa02021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking.\n\nThese recommendations aim to help women stop smoking during pregnancy and in the first year after childbirth.\n\nOther recommendations relevant to pregnant women are in the section on support to stop smoking in secondary care services.\n\n# Identifying pregnant women who smoke and referring them for stop-smoking support\n\nThese recommendations are for healthcare professionals providing maternity care.\n\nProvide routine carbon monoxide testing at the first antenatal appointment and at the 36-week appointment to assess every pregnant woman's exposure to tobacco smoke. Provide carbon monoxide testing at all other antenatal appointments if the pregnant woman:\n\nsmokes or\n\nis quitting or\n\nused to smoke or\n\ntested with 4\xa0parts per million (ppm) or above at the first antenatal appointment. \n\nProvide an opt-out referral to receive stop-smoking support for all pregnant women who:\n\nsay they smoke or have stopped smoking in the past 2\xa0weeks or\n\nhave a carbon monoxide reading of 4\xa0ppm or above or\n\nhave previously been provided with an opt-out referral but have not yet engaged with stop-smoking support. See also the section on identifying smoking among carers, family and other household members. \n\nExplain to the woman:\n\nthat it is normal practice to refer all pregnant women who smoke or have recently quit\n\nthat the carbon monoxide test will allow her to see a physical measure of her smoking and exposure to other people's smoking\n\nwhat her carbon monoxide reading means, taking into consideration the time since she last smoked and the number of cigarettes smoked (and when) on the day of the test. \n\nIf the pregnant woman does not smoke but has a carbon monoxide level of 3\xa0ppm or more, help her to identify the source of carbon monoxide and reduce it. (Other sources include household or other secondhand smoke, heating appliances or traffic emissions.) \n\nIf the pregnant woman has a high carbon monoxide reading (more than 10\xa0ppm) but says she does not smoke:\n\nadvise her about possible carbon monoxide poisoning\n\nask her to contact the Gas Emergency Line (0800\xa0111\xa0999) for gas safety advice\n\nphrase any further questions about smoking sensitively to encourage a frank discussion. \n\nRecord carbon monoxide level and any feedback given in the pregnant woman's antenatal records. If her antenatal records are not available locally, use local protocols to record this information. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on identifying pregnant women who smoke and referring them for stop-smoking support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: opt-out stop-smoking support.\n\nLoading. Please wait.\n\n# Following up women who have been referred for stop smoking support\n\nThese recommendations are for people providing stop-smoking support or advice.\n\nContact all pregnant women who have been referred for help. Discuss smoking and pregnancy and the issues they face, using an impartial, person-centred approach. Invite them to use the service. If necessary (and resources permit), make at least 3\xa0contacts using different methods. Advise the maternity booking midwife of the outcome. \n\nTry to see pregnant women who cannot be contacted by other methods. This could happen during a routine antenatal care visit (for example, when they attend for a scan). \n\nProvide information about the risks of smoking to an unborn child and the benefits of stopping for both mother and baby. \n\nAddress any factors that prevent pregnant women from using stop-smoking support. This could include:\n\na lack of confidence in their ability to quit\n\nlack of knowledge about the services on offer\n\ndifficulty accessing them\n\nlack of suitable childcare\n\nfear of failure and concerns about being stigmatised. \n\nIf pregnant women are reluctant to attend the stop-smoking service, think about providing structured self-help materials or giving details of telephone quitlines or NHS online stop-smoking support. Also think about offering to visit them at home, or at another venue, if it is difficult for them to attend specialist services. \n\nAddress any concerns pregnant women and their partners or family may have about stopping smoking and offer personalised information, advice and support on how to stop. \n\nSend information on smoking and pregnancy to women who opt out during the initial telephone call. This should include details on how to get help to quit at a later date. \n\n# Providing support to stop smoking\n\nThese recommendations are for people providing stop-smoking support or advice.\n\nProvide the pregnant woman with intensive and ongoing support (brief interventions alone are unlikely to be sufficient) throughout pregnancy and beyond. This includes regularly monitoring her smoking status using carbon monoxide tests. Use carbon monoxide measurements to encourage her to quit and as a way to provide positive feedback once a quit attempt has been made. \n\nBiochemically validate that the pregnant woman has quit on the date she set and 4\xa0weeks after. If possible, use urine or saliva cotinine tests, as these are more accurate than carbon monoxide tests. (They can detect exposure over the past few days rather than hours.) \n\nWhen carrying out tests, check whether the pregnant woman is using nicotine replacement therapy (NRT) as this may raise her cotinine levels. Take into account that no measure can be 100% accurate. Some people may smoke so infrequently – or inhale so little – that their intake cannot reliably be distinguished from that from passive smoking. \n\nIf the pregnant woman stopped smoking in the 2\xa0weeks before her maternity booking appointment, continue to provide support in line with the recommendations above and stop-smoking support practice protocols. \n\nEstablish links with contraceptive services, fertility clinics and antenatal and postnatal services so that everyone working in those organisations knows about local stop-smoking support. Ensure they understand what these services offer and how to refer people to them. \n\nFor pregnant women taking prescribed medicines, also see the section on medicine dosages for people who have stopped smoking.\n\n## Nicotine replacement therapy and other pharmacological support\n\nConsider NRT alongside behavioural support to help women stop smoking in pregnancy (see BNF information on NRT). \n\nConsider NRT at the earliest opportunity in pregnancy and continue to provide it after pregnancy if the woman needs it to prevent a relapse to smoking, including if the pregnancy does not continue (see BNF information on NRT). \n\nGive pregnant women clear and consistent information about NRT. Explain:\n\nthat it may help them stop smoking and reduce their cravings\n\nhow to use NRT correctly, including how to get a high enough dose of nicotine to control cravings, prevent compensatory smoking and stop successfully. \n\nAdvise pregnant women who are using nicotine patches to remove them before going to bed. \n\nEmphasise to pregnant women that:\n\nmost smoking-related health problems are caused by other components in tobacco smoke, not by the nicotine\n\nany risks from using NRT are much lower than those of smoking\n\nnicotine levels in NRT are much lower than in tobacco, and the way these products deliver nicotine makes them considerably less addictive than smoking. \n\nDo not offer varenicline or bupropion to pregnant or breastfeeding women. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on nicotine replacement therapy and other pharmacological support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: nicotine replacement therapy and e-cigarettes in pregnancy: update.\n\nLoading. Please wait.\n\n## Incentives to stop smoking\n\nThese recommendations are for providers of stop-smoking support.\n\nIn addition to NRT and behavioural support, offer voucher incentives to support women to stop smoking during pregnancy, as follows:\n\nrefer women to an incentive scheme at the first maternity booking appointment or at the next available opportunity\n\nprovide vouchers only for abstinence validated using a biochemical method, such as a carbon monoxide test with a reading of less than 4\xa0ppm\n\nstagger incentives until at least the end of pregnancy (incentives totalling around £400 have been shown to be effective)\n\ndo not exclude women who have relapsed or those whose pregnancy does not continue from continuing to take part in the scheme and try again\n\nensure vouchers cannot be used to buy products that could be harmful during pregnancy (for example, alcohol and cigarettes). \n\nConsider providing voucher incentives jointly to the pregnant woman and to a friend or family member that she has chosen to support her during her quit attempt. \n\nEnsure staff are trained to promote and deliver incentive schemes to pregnant women to stop smoking. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on incentives to stop smoking\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: incentives during pregnancy.\n\nLoading. Please wait.\n\n## Enabling all pregnant women to access stop-smoking support\n\nThese recommendations are to help providers of stop-smoking support reach all pregnant women, including those whose circumstances may make it more difficult to use services (for example, because of cultural or sociodemographic factors, age or language).\n\nInvolve pregnant women who find it difficult to use or access existing stop-smoking support in the planning and development of services. \n\nCollaborate with the family nurse partnership and other outreach schemes to identify additional opportunities for providing intensive and ongoing support to pregnant women to stop smoking. (Note: family nurses make frequent home visits.) \n\nWork in partnership with agencies that support pregnant women who have complex social and emotional needs. This includes substance misuse services, youth and teenage pregnancy support and mental health services. \n\n## Helping partners and others in the household who smoke\n\nThese recommendations are for providers of stop-smoking support. See also the section on identifying smoking among carers, family and other household members.\n\nOffer pregnant women's partners who smoke help to stop. Use an intervention that comprises 3\xa0or more elements and multiple contacts. Discuss with them which options to use – and in which order, taking into account:\n\ntheir preferences\n\ncontraindications and the potential for adverse effects from stop-smoking pharmacotherapies\n\nthe likelihood that they will follow the course of treatment\n\ntheir previous experience of stop-smoking aids\n\ndo not favour one course of treatment over another; together, choose the one that seems most likely to succeed taking into account the above. ", 'Recommendations on policy, commissioning and training': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read alongside NICE's guidelines on patient experience in adult NHS services and babies, children and young people's experience of healthcare, which have guidance on giving information to people and discussing their views and preferences.\n\nIn this guideline, we use the following terms for age groups:\n\nchildren: aged 5 to 11\n\nyoung people: aged 12 to 17\n\nyoung adults: aged 18 to 24\n\nadults: aged 18 and over.\n\nAt the time of publication (November\xa02021), no nicotine-containing e-cigarettes were licensed as a medicine for stopping smoking by the Medicines and Healthcare products Regulatory Agency (MHRA) and commercially available in the UK market. All nicotine-containing e‑cigarettes in the UK that are not licensed as a medicine by the MHRA are regulated by the Tobacco and Related Products Regulations (2016), and cannot be marketed by the manufacturer for use for stopping smoking.\n\nThese recommendations are for people with responsibility for developing smokefree policy, and for commissioning and training services.\n\n# Policy\n\nDevelop a policy for smokefree grounds in collaboration with secondary care staff and people who use secondary care services, including services in the community, or their representatives. The policy should:\n\nset out a clear timeframe to establish or reinstate smokefree grounds\n\nidentify the roles and responsibilities of staff\n\nban staff from supervising or helping people to take smoking breaks\n\nidentify the resources needed to support the policy\n\nban the sale of tobacco products\n\nbe periodically reviewed and updated, in line with all other organisational policies. \n\nEnsure smokefree implementation plans include:\n\nsupport for staff and people who use secondary care services to stop smoking completely or temporarily\n\ntraining for staff (see the section on training for healthcare staff)\n\nremoving shelters or other designated outdoor smoking areas\n\nstaff, contractor and volunteer contracts that do not allow smoking during work hours or when recognisable as an employee (for example, when in uniform, wearing identification, or handling hospital business)\n\nhow secondary care staff can work with people who use services and carers to protect themselves from tobacco smoke when they visit people's homes. (In accordance with smokefree legislation, employers must take action to reduce the risk to the health and safety of their employees from secondhand smoke to as low a level as is reasonably practicable.) \n\nEnsure policies, procedures and resources are in place to:\n\nhelp comply with, and resolve immediately, any breaches of smokefree policies, including a process for staff to report incidents\n\nsupport staff to encourage others to comply with the smokefree policy\n\nwork with people who use services, carers, visitors and staff to overcome any problems that may result from smoking restrictions (supported by 'personal care plans' as covered in the section on information on stopping smoking for those using acute, maternity and mental health services). \n\nEnsure all staff are aware of the smokefree policy and comply with it. \n\n## Communicating the smokefree policy\n\nDevelop, deliver and maintain a communications strategy on local smokefree policy requirements. This could include newsletters, pamphlets, posters and signage (smokefree signs for vehicles or areas that are enclosed or substantially enclosed must comply with regulations under the Health and Safety at Work etc Act 1974). Include information for people who use secondary care services, their parents or carers, staff and visitors, and the wider local population. Also include:\n\nclear, consistent messages about the need to keep buildings and grounds smokefree\n\npositive messages about the health benefits of a smokefree environment\n\nthe fact that health and social care professionals have a duty to provide a safe, healthy environment for staff and people who use or visit secondary care services\n\ninformation about stop-smoking support and how to access services, including support to temporarily stop, for staff and people who use secondary care services\n\nthe fact that staff are not allowed to smoke at any time during working hours or when recognisable as an employee, contractor or volunteer (for example, when in uniform, wearing identification, or handling hospital business). \n\n## Closed institutions\n\nInclude management of smoking in the care plan of people in closed institutions who smoke. \n\nDevelop a policy to ensure effective stop-smoking interventions are provided and promoted in prisons, military establishments and long-stay health centres, such as mental healthcare units. Use Department of Health and Social Care guidance to develop the policy. \n\nSee also the sections on employers, support to stop smoking in secondary care services and supporting people who do not want, or are not ready, to stop smoking in one go to reduce their harm from smoking.\n\n## Ensuring local tobacco control strategies include secondary care\n\nThese recommendations are for people with responsibility for planning, commissioning and running tobacco control strategies.\n\nEnsure the joint strategic needs assessment:\n\ntakes into account the impact of smoking on local communities\n\nidentifies expected numbers of particular groups of people who are at very high risk of tobacco-related harm (for example, those listed as being at high risk of harm in the section on commissioning and designing services)\n\nidentifies the proportion of people at very high risk reached by services and the numbers who successfully stop smoking. \n\nMake it clear in the local tobacco control strategy that people working in secondary care should:\n\ncommunicate key messages about tobacco-related harm to everyone who uses services\n\ndevelop policies and support to help people stop smoking\n\nidentify people who want to stop smoking and, if appropriate, refer them to a stop-smoking adviser\n\nimplement a comprehensive smokefree policy that includes the grounds of the establishment. \n\nDevelop a local stop-smoking care pathway and referral procedure to ensure there is continuity of care between primary, community and secondary care. \n\n# Commissioning and designing services\n\nThese recommendations are for directors and senior managers in settings where stop-smoking support is needed, and commissioners, providers and managers of stop-smoking support.\n\nUse integrated care systems plans, health and wellbeing strategies, and other relevant local strategies and plans to make the range of interventions in the section on stop-smoking interventions accessible to adults who smoke. \n\nEnsure service specifications require providers of stop-smoking support to offer nicotine replacement therapy (NRT) for as long as needed to help prevent a relapse to smoking. \n\nUse the government's local tobacco control profiles to estimate smoking prevalence among the local population. \n\nPrioritise groups at high risk of tobacco-related harm. These may include:\n\npeople with mental health conditions (for example, see NICE's guideline on depression in adults)\n\npeople who misuse substances (for example, see NICE's guideline on coexisting severe mental illness and substance misuse: community health and social care services)\n\npeople with health conditions caused or made worse by smoking (for example, see NICE's guidelines on cardiovascular disease: identifying and supporting people most at risk of dying early, type 1 diabetes in adults, asthma and chronic obstructive pulmonary disease)\n\npeople with a smoking-related illness (see NICE's guideline on lung cancer)\n\npopulations with a high prevalence of smoking-related morbidity or a particularly high susceptibility to harm\n\ncommunities or groups with particularly high smoking prevalence (such as manual workers, travellers and LGBT+ people)\n\npeople with a low socioeconomic status\n\npregnant women who smoke. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on commissioning and designing services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review N: smoking relapse prevention\n\nevidence review K: cessation and harm-reduction treatments.\n\nLoading. Please wait.\n\n## Providing stop-smoking support to employers\n\nOffer support to employers who want to help their employees to stop smoking. If appropriate and feasible, provide support on the employer's premises. \n\nIf initial demand exceeds the resources available, focus on the following:\n\nsmall and medium-sized enterprises\n\nenterprises with a high proportion of employees on low pay\n\nenterprises with a high proportion of employees at high risk of tobacco-related harm. \n\n## Harm reduction within stop-smoking support\n\nEnsure investment in harm-reduction approaches does not detract from, but supports and extends the reach and impact of, existing stop-smoking support. \n\nDevelop stop-smoking referral and treatment pathways to ensure a range of approaches and interventions is available to support people who opt for a harm-reduction approach (see box\xa01). \n\nEnsure service specifications require providers of stop-smoking support to offer medicinally licensed nicotine-containing products on a long-term basis to help people maintain a lower level of smoking. [2013, amended 2021]\n\n## Stop-smoking support in secondary care\n\nEnsure all secondary care buildings and grounds are smokefree. \n\nEnsure the NHS standard contract and local authority contract includes smokefree strategies. \n\nEnsure all hospitals have on-site stop-smoking support. \n\nEnsure stop-smoking medicinally licensed products are included in secondary care formularies. \n\nInclude NICE-recommended nicotine-containing products as options for sale in secondary care settings (for example, in hospital shops). \n\nEnsure secondary care service specifications and service-level agreements require:\n\nall staff to be trained to give advice on stopping smoking and to make a referral to behavioural support\n\nrelevant staff to undertake regular continuing professional development in how to provide behavioural support to stop smoking. \n\nMonitor and audit the implementation and impact of recommendations for secondary care services. This may include recording:\n\nindividual smoking status (including for pregnant women at the time of giving birth)\n\nnumber of referrals\n\nuptake of interventions\n\nprescribing of stop-smoking pharmacotherapies\n\n‑week quit rates\n\nstaff training. Ensure the needs of higher-risk groups identified in the joint strategic needs assessment are being met (see the section on ensuring local tobacco control strategies include secondary care). \n\nEnsure secondary care providers have enough resources to maintain a smokefree policy. \n\nEnsure secondary care pathways cover the following actions:\n\nidentifying people who smoke\n\nproviding advice on likely smoking-related complications\n\nproviding advice on how to stop smoking\n\nproactively referring people to stop-smoking support. \n\nSecondary care directors and managers leading on stop-smoking support should assign a clinical or medical director to lead on stop-smoking support for people who use, or work in, secondary care services. As well as implementing the recommendations in this guideline on providing and commissioning stop-smoking support in secondary care, the designated lead should ensure:\n\nthe organisation has an annual improvement programme for stop-smoking support given to people who use, or work in, secondary care services\n\nstop-smoking support (for patients and staff) is promoted and communicated effectively (see the section on communicating the smokefree policy) to start a cultural change within the organisation\n\nthe quality of stop-smoking support continues to improve\n\nperformance monitoring and feedback on outcomes is provided to all staff. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on stop-smoking support in secondary care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: cessation and harm-reduction treatments.\n\nLoading. Please wait.\n\n## Referral systems for people who smoke\n\nEnsure there are systems for consistently recording and maintaining records of smoking status. All patient records should:\n\nprovide a prompt for action (including referral to stop-smoking support)\n\nbe stored for easy access and audit. \n\nMake sure there is a robust system (preferably electronic) to support continuity of care between secondary care and local stop-smoking support for people moving in and out of secondary care. \n\n## Monitoring stop-smoking services by commissioners and managers\n\nSet targets for stop-smoking services, including the number of people using the service and the proportion who successfully stop smoking. Performance targets should include:\n\ntreating at least 5% of the estimated local population who smoke each year\n\nachieving a stop-smoking rate of at least 35% at 4\xa0weeks, based on everyone who starts treatment and defining success as not having smoked (confirmed by carbon monoxide monitoring of exhaled breath) in the fourth week after the quit date. \n\nCheck self-reported smoking abstinence using a carbon monoxide test. Define success as the person having less than 10\xa0parts per million (ppm) of carbon monoxide in their exhaled breath at 4\xa0weeks after the quit date. This does not imply that treatment should stop at 4\xa0weeks. \n\nMonitor performance data for stop-smoking services routinely and independently. Make the results publicly available. \n\nAudit exceptional results (for example, 4‑week smoking quit rates lower than 35% or above 70%). Use the audit to determine the reasons for unusual performance as well as to identify good practice and ensure it is being followed. \n\nAssess the performance of providers that support people who want to reduce the harm from smoking. Additional measures could include:\n\nnumbers attending the services (for comparison with the numbers attending before harm-reduction options were offered)\n\nclassifying the harm-reduction approaches used (see box\xa01)\n\ncharacteristics of people using the service (such as demographic data, cigarette usage, level of dependency and previous attempts to stop)\n\ntype and amount of medicinally licensed nicotine-containing products supplied or prescribed, and over-the-counter sales of these products\n\nnumber of people setting a quit date. \n\n# Training\n\n## Training to prevent uptake of smoking\n\nThis recommendation is for those with responsibility for improving the health and wellbeing of children, young people and young adults who attend school.\n\nWork in partnership with those involved in smoking prevention and stop-smoking activities to design, deliver, monitor and evaluate smoking prevention training and interventions. Partners could include:\n\nnational and local education agencies\n\ntraining agencies\n\nlocal authorities\n\ntobacco control alliances\n\nschool nursing service\n\nvoluntary sector organisations\n\nlocal health improvement services\n\nproviders of stop-smoking support\n\nuniversities. \n\nSee also NICE's guidelines on behaviour change: general approaches and alcohol interventions in secondary and further education.\n\n## Training on stopping smoking\n\nTrain all frontline healthcare staff to offer very brief advice on how to stop smoking in accordance with the section on support to stop smoking in primary care and community settings. Also train them to make referrals, if necessary and possible, to local stop-smoking support. Frontline secondary care staff should also be trained to refer people for behavioural support. [2013, amended 2018]\n\nProvide additional, specialised training on providing stop-smoking support for those working with specific groups, for example people with mental health conditions and pregnant women who smoke. [2008, amended 2018]\n\nEncourage and train healthcare professionals to ask people about smoking and to advise them of the dangers of exposure to secondhand smoke. [2008, amended 2018]\n\nEnsure staff working in closed institutions recognise that some people see smoking as an integral part of their lives. Also ensure staff recognise the issues arising from being forced to stop, as opposed to doing this voluntarily. \n\nEnsure staff recognise how the closed environment may restrict the techniques and coping mechanisms that people would normally use to stop smoking or reduce the amount they smoke. Provide the support needed for their circumstances. This includes prescribing or supplying medicinally licensed nicotine-containing products. \n\nEnsure staff understand that if someone reduces the amount they smoke, or stops completely, this can affect psychotropic and some other medications (see the summaries of product characteristics for individual drugs in the electronic medicines compendium for further details). Ensure arrangements are in place to adjust their medication accordingly. See the section on medicine dosages for people who have stopped smoking. \n\nDo not allow staff with health and social care or custodial responsibilities to smoke during working hours in locations where the people in their care are not allowed to smoke. \n\nEnsure all midwives are trained to assess and record people's smoking status and their readiness to quit. They should also:\n\nknow about the health risks of smoking and the benefits of quitting\n\nunderstand why it can be difficult to stop\n\nknow about the treatments that can help people to quit, including nicotine replacement therapy\n\nknow how to refer people who smoke to local services for treatment. See the National Centre for Smoking Cessation and Training's (NCSCT) module on very brief advice on smoking for pregnant women. [2010, amended 2021]\n\nEnsure all healthcare and other professionals who work with pregnant women are trained in the same skills to support women to stop smoking, and to the same standard, as midwives. This includes:\n\nGPs, practice nurses\n\nhealth visitors\n\nobstetricians\n\npaediatricians\n\nsonographers\n\nmidwives (including young people's lead midwives)\n\nfamily nurses\n\nthose working in fertility clinics, dental facilities and community pharmacies\n\nthose working in youth and teenage pregnancy services, children's centres, social services and voluntary and community organisations. \n\nEnsure that all healthcare and other professionals who work with pregnant women (see recommendation\xa01.23.10):\n\nunderstand the impact that smoking can have on a woman and her unborn child\n\nunderstand the dangers of exposing a pregnant woman and her unborn child – and other children – to secondhand smoke. \n\nTrain all midwives who deliver intensive stop-smoking interventions (one-to-one or group support) to the same standard as stop-smoking advisers. The minimum standard for these interventions is set by the NCSCT. Also provide additional, specialised training and offer them ongoing support and training updates. See the NCSCT's specialty module on pregnancy and the postpartum period. \n\nEnsure that midwives and specialist stop-smoking advisers who work with pregnant women:\n\nknow how to ask them questions in a way that encourages them to be open about their smoking\n\nalways recommend quitting rather than cutting down\n\nhave received accredited training in the use of carbon monoxide monitors. \n\nEnsure training for health, dental health and allied professionals (for example, community pharmacists) covers:\n\nthe fact that smokeless tobacco may be used locally – and the need to keep abreast of statistics on local prevalence\n\nthe reasons why, and how, members of the South Asian community use smokeless tobacco (including the cultural context for its use)\n\nthe health risks associated with smokeless tobacco\n\nthe fact that some people of South Asian family origin may be less used to a preventive approach to health than the general population\n\nthe local names used for smokeless tobacco products, while emphasising the need to use the term 'smokeless tobacco' as well when talking to users about them. \n\nEnsure training helps professionals to:\n\nrecognise the signs of smokeless tobacco use\n\nknow how to ask someone, in a sensitive and culturally aware manner, whether they use smokeless tobacco\n\nprovide information in a culturally sensitive way on the harm smokeless tobacco causes (this includes being able to challenge any perceived benefits – and the relative priority that users may place on these benefits)\n\ndeliver a brief intervention and refer people to tobacco cessation services if they want to quit. ", 'Terms used in this guideline': "This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary or, for public health and social care terms, the Think Local Act Personal Care and Support Jargon Buster.\n\n# Allen Carr's in-person group seminar\n\nA session lasting between 4.5 and 6\xa0hours with elements of cognitive behavioural therapy and a brief relaxation exercise. Participants are encouraged to carry on smoking as normal until they attend the session and to smoke as normal during scheduled smoking breaks (around every 45 to 60\xa0minutes) until a final ritual cigarette at the end. After the session, regular texts remind participants that they can contact the provider if they have further questions. The price includes up to 2 shorter (around 3.5\xa0hours) follow-up sessions if wanted.\n\n# Behavioural support\n\nScheduled meetings (face to face or virtual) between someone who smokes and a counsellor trained to provide stop-smoking support. Behavioural support can be provided either individually or in a group. Discussions may include information, practical advice about goal setting, self-monitoring and dealing with the barriers to stopping smoking as well as encouragement. The support also includes anticipating and dealing with the challenges of stopping (see NICE's guideline on behaviour change: general approaches and the National Centre for Smoking Cessation and Training [NCSCT] Training Standard). Support is typically offered weekly for at least the first 4\xa0weeks of a quit attempt (that is, for 4\xa0weeks after the quit date) or 4\xa0weeks after discharge from hospital (where a quit attempt may have started before discharge), and normally given with stop-smoking pharmacotherapies. Behavioural support does not include Allen Carr's Easyway in-person group seminar.\n\n# Cessation\n\nStopping the use of tobacco, smoked or smokeless. This includes stopping use of tobacco and moving on to pharmacotherapies (including nicotine replacement therapy) or nicotine-containing e‑cigarettes.\n\n# Closed institutions\n\nEnvironments where people are detained or stay for a long time and where smoking is not permitted. These include secure mental health units, immigration removal centres and custodial sites, as well as places like long-stay mental health units and military establishments.\n\n# Compensatory smoking\n\nInhaling more deeply or smoking more of each cigarette to compensate for smoking fewer cigarettes.\n\n# E-cigarettes\n\nAlso called electronic cigarettes or vaping devices. A product that can be used for the inhalation of vapour through a mouthpiece. E‑cigarettes can be disposable or refillable by means of a refill container and a tank, or can be rechargeable with single-use cartridges. Products may be used to consume nicotine or used without nicotine (see nicotine-containing e-cigarettes).\n\nProducts that contain or could contain nicotine in the form of e‑liquid are covered under the European Union's 2014 Tobacco Products Directive and need to be notified to the Medicines and Healthcare products Regulatory Agency (MHRA). Other devices such as disposable e‑cigarettes that do not contain nicotine, and 0% nicotine e‑liquids, are regulated under the General Product Safety Regulations (2005; definition informed by the MHRA's e-cigarettes regulations for consumer products). E‑cigarettes are not currently (November\xa02021) licensed medicines but are regulated by the Tobacco and Related Products Regulations (2016).\n\n# Harm reduction\n\nMeasures to reduce the illnesses and deaths caused by smoking tobacco among people who smoke and those around them. Some measures or products may reduce harm more than others. People who smoke and currently do not want, or are not ready, to stop in one go can reduce their harm by smoking less and abstaining from smoking temporarily. The benefits of harm reduction itself are uncertain, but it may mean people are more likely to stop smoking altogether in the future.\n\n# Medicinally licensed nicotine-containing products\n\nNicotine-containing products that have been given marketing authorisation by the MHRA. At the time of publication (November\xa02021), nicotine replacement therapy products were the only type of medicinally licensed nicotine-containing product on the market. If any nicotine-containing e‑cigarette were licensed by the MHRA and made commercially available, it would be included in this definition.\n\n# Nicotine-containing products\n\nProducts that contain nicotine but do not contain tobacco and so deliver nicotine without the harmful toxins found in tobacco. This currently includes nicotine replacement therapy, which has been medicinally licensed for smoking cessation by the MHRA (see nicotine replacement therapy), and nicotine-containing e-cigarettes. Currently there are no licensed nicotine-containing e‑cigarettes on the market. Nicotine-containing e‑cigarettes on general sale are regulated under the Tobacco and Related Products Regulations (2016) by the MHRA. For further details, see the MHRA website.\n\n# Nicotine-containing e-cigarettes\n\nNicotine-containing e‑cigarettes are vaping devices filled with nicotine-containing e‑liquid. These devices must be notified to the MHRA and must meet the requirements of the European Union (2014) Tobacco Products Directive (definition informed by the MHRA's e-cigarettes regulations for consumer products).\n\n# Nicotine replacement therapy\n\nProducts medicinally licensed for use as a stop smoking aid and for harm reduction, as outlined in the BNF. They include transdermal patches, gum, inhalation cartridges, sublingual tablets, lozenges, mouth spray and nasal spray.\n\n# Pharmacotherapies\n\nThis covers medication licensed for smoking cessation such as varenicline or bupropion, as well as nicotine replacement therapy. In August\xa02022, varenicline was unavailable in the UK. See the MHRA alert on varenicline.\n\n# Safety\n\nThis refers to the incidence of minor and major side effects associated with nicotine-containing products.\n\n# Schools\n\n'Schools' is used to refer to:\n\nmaintained and independent primary, secondary and special schools\n\ncity technology colleges and academies\n\npupil referral units, secure training and local authority secure units\n\nfurther education colleges\n\n'extended schools' where childcare or informal education is provided outside school hours.\n\n# Secondary care\n\nAll publicly funded secondary and tertiary care facilities, including buildings, grounds and vehicles. It covers drug and alcohol services in secondary care; emergency care; inpatient, residential and long-term care for severe mental illness in hospitals, psychiatric and specialist units and secure hospitals; and planned specialist medical care or surgery. It also includes maternity care in hospitals, maternity units, outpatient clinics and in the community.\n\n# Self-help materials\n\nAny manual or structured programme, in written or digital format, that someone can use to try to stop smoking or reduce the amount they smoke. These can be used without the help of healthcare professionals, stop-smoking advisers or group support. They can be aimed at anyone who smokes, particular populations (for example, certain ages or ethnic groups), or may be tailored to individual need.\n\n# Smokefree\n\nAir that is free of tobacco smoke. E‑cigarettes are not covered by smokefree legislation.\n\n# Smokeless tobacco\n\nAny product containing tobacco that is placed in the mouth or nose and not burned and which is typically used in England by people of South Asian family origin. It does not include products that are sucked, like 'snus' or similar oral snuff products (as defined in the European Union 2014 Tobacco Products Directive).\n\nThe types used vary across the country but they can be divided into 3\xa0main categories, based on their ingredients (Stanfill et\xa0al.\xa02010):\n\nTobacco with or without flavourants: misri India tobacco (powdered) and qimam (kiman).\n\nTobacco with various alkaline modifiers: khaini, naswar (niswar, nass) and gul.\n\nTobacco with slaked lime as an alkaline modifier and areca nut: gutkha, zarda, mawa, manipuri and betel quid (with tobacco).\n\n# South Asian family origin\n\nPeople with ancestral links to countries in southern Asia, including Bangladesh, India, Nepal, Pakistan or Sri Lanka.\n\n# Specialist tobacco cessation services\n\nEvidence-based services that offer support to help people stop smoking or using smokeless tobacco. In England, these are generally referred to as 'stop-smoking support or services' or 'smoking cessation services' because they normally focus on people who smoke tobacco. But a service might brand itself as a generic tobacco cessation or tobacco dependence service, to emphasise a focus on more than 1\xa0form of tobacco.\n\n# Stop in one go\n\nThe standard approach in most stop-smoking support. The person makes a commitment to stop smoking on or before a particular date (the quit date). This may or may not involve the use of pharmacotherapies or nicotine-containing e‑cigarettes before the quit date and for some time afterwards, depending on the person's needs.\n\n# Stop-smoking support\n\nInterventions and support to stop smoking, regardless of how services are commissioned or set up.\n\n# Telephone quitlines\n\nThese provide proactive or reactive advice, encouragement, counselling and support by phone to anyone who smokes who wants to quit, or who has recently quit.\n\n# Temporary abstinence\n\nStopping smoking with or without medication for a particular event or series of events, in a particular location, for specific time periods (for example, while at work, during long-haul flights or during a hospital stay), or for the foreseeable future. (The latter might include, for example, abstinence while serving a prison sentence or while detained in a secure mental health unit.)\n\n# Under-served groups\n\nGroups who may be less likely to benefit from an intervention because they have specific needs that the intervention does not address, or because they may face additional challenges in engaging with the intervention.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Health effects of e-cigarettes\n\nWhat are the short- and long-term health effects of e-cigarette use? Are there any specific health effects relating to use in pregnancy, or use by children and young people? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on advice on nicotine-containing e-cigarettes\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review K: cessation and harm-reduction treatments\n\nevidence review M: long-term health effects of e-cigarettes.\n\nLoading. Please wait.\n\n## Nicotine replacement therapy and e-cigarettes and pregnancy\n\nAre nicotine replacement therapy or nicotine-containing e-cigarettes effective to help women stop smoking in pregnancy (and at what dose)? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on nicotine replacement therapy (NRT) and other pharmacological support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: nicotine replacement therapies and e-cigarettes in pregnancy: update.\n\nLoading. Please wait.\n\n## Stop-smoking interventions for under-served groups\n\nHow can effective and cost-effective interventions to support people to stop smoking be modified to improve engagement with and accessibility for under-served groups? How acceptable are these interventions to these groups? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on commissioning and designing services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: cessation and harm-reduction treatments.\n\nLoading. Please wait.\n\n## Support for people with mental health conditions to stop smoking\n\nHow can people with mental health conditions be supported effectively to stop smoking (at individual and system level)? What are the challenges and opportunities and how can they be addressed? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on stop-smoking support in mental health services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: tailored interventions for those with mental health conditions.\n\nLoading. Please wait.\n\n## E-cigarettes and pregnancy\n\nWhat are the views and concerns of:\n\npregnant women who smoke\n\nthe healthcare professionals who care for them\n\nabout the use of nicotine-containing e‑cigarettes during pregnancy? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on nicotine replacement therapy and other pharmacological support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: nicotine replacement therapies and e-cigarettes in pregnancy: update.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## E-cigarettes for harm reduction\n\nAre nicotine-containing e‑cigarettes effective and safe for harm reduction when used alongside tobacco products to cut down on smoking (dual-use approach)? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on nicotine-containing e-cigarettes for harm reduction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: cessation and harm-reduction treatments.\n\nLoading. Please wait.\n\n## Use of e-cigarettes (amount and frequency)\n\nDoes the effectiveness of nicotine-containing e‑cigarettes as an aid to stopping smoking vary according to the amount of nicotine they contain or the frequency of use? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on advice on nicotine-containing e-cigarettes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: cessation and harm-reduction treatments.\n\nLoading. Please wait.\n\n## E-cigarette flavours\n\nDo the flavours used in nicotine-containing e‑cigarettes have an impact on their effectiveness as an aid to stopping smoking, and are there any adverse effects associated with them? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on advice on nicotine-containing e-cigarettes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: cessation and harm-reduction treatments.\n\nLoading. Please wait.\n\n## E-cigarettes and established future smoking\n\nIs e‑cigarette use in children, young people and young adults who do not smoke associated with future established smoking? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on adult-led interventions in schools\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F and\xa0G: e-cigarettes and young people.\n\nLoading. Please wait.\n\n## Factors that may influence the use of nicotine replacement therapy and e-cigarettes\n\nWhich factors may prevent people who currently smoke tobacco from using other forms of nicotine such as NRT and nicotine-containing e‑cigarettes? Does this vary according to population group, particularly among under-served groups? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on using stop-smoking interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: barriers and facilitators to using e-cigarettes for cessation or harm reduction.\n\nLoading. Please wait.\n\n## Relapse prevention\n\nAre NRT or nicotine-containing e‑cigarettes effective for preventing relapse after a successful quit attempt? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on supporting people trying to stop smoking\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: smoking relapse prevention.\n\nLoading. Please wait.\n\n## Relapse prevention after enforced, temporary quit\n\nHow can people who have recently stopped or temporarily abstained from smoking in a smokefree inpatient or treatment environment be best supported after discharge to prevent relapse or to stop permanently? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on supporting people trying to stop smoking\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: smoking relapse prevention.\n\nLoading. Please wait.\n\n## Carbon monoxide monitoring\n\nWhat is the validity of different thresholds of carbon monoxide in exhaled breath as markers of quitting, based on diagnostic review and modelling? \n\n## Allen Carr's Easyway\n\nFor adults who want to stop smoking, what is the effectiveness and cost effectiveness of Allen Carr's Easyway programme delivered in formats other than in-person group seminars (for example online or using the self-help book) compared with other methods of smoking cessation? \n\nFor specific groups who are at risk of health inequalities, for example pregnant women, people from lower socioeconomic backgrounds or people who do not speak English well:\n\nWhat is the differential effectiveness and cost-effectiveness of Allen Carr's Easyway (including the in-person group seminar and other formats)?\n\nWhat strategies or interventions are effective in minimising those differences? \n\nFor a short explanation of why the committee made the recommendations for research, see the rationale section on stop-smoking interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review P: effectiveness and cost-effectiveness of Allen Carr's Easyway.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the 2021 recommendations and how they might affect practice and services. They link to details of the evidence and a full description of the committee's discussion.\n\n# Adult-led interventions in schools\n\nRecommendations 1.6.3 and 1.6.4\n\n## Why the committee made the recommendations\n\nThe committee wanted to discourage e‑cigarette use among young people and young adults who do not smoke because evidence shows that use of e‑cigarettes is linked with a higher chance of ever smoking later in life. The committee members agreed that ideas about smoking and what is normal can start from a young age so the recommendation should also apply to this age group.\n\nThe committee agreed that school-based interventions could help to discourage e‑cigarette use among those who do not smoke.\n\nThe committee noted the need to not inadvertently make e‑cigarettes desirable. They also emphasised that e‑cigarettes should not be confused with tobacco products, so talking about them separately is important.\n\nThe committee agreed that more evidence is needed about whether e‑cigarette use is linked with habitual smoking (rather than experimental smoking) in the future, the factors that determine this link, and the levels of e‑cigarette use in people under\xa025 (see the recommendation for research\xa0on e-cigarettes and established future smoking).\n\n## How the recommendations might affect practice\n\nAdding information about e‑cigarettes to existing curriculum-based interventions to stop people taking up smoking is a change to current practice, but it should have little resource impact.\n\nReturn to recommendations\n\n# Stop-smoking interventions\n\nRecommendations 1.12.1 to 1.12.8\n\n## Why the committee made the recommendations\n\nThe committee looked at a large amount of evidence assessing the relative effectiveness of several interventions, including medicinally licensed products (varenicline, bupropion and nicotine replacement therapy [NRT]) and nicotine-containing e‑cigarettes. They also looked at these interventions combined with each other. Most of the interventions or combinations of interventions were delivered with behavioural support. Most evidence investigated medicinally licensed products, with fewer studies about e‑cigarettes.\n\nThe evidence found that these interventions were effective, and that some were likely to be more effective than others, especially in combination with behavioural support. The committee also agreed with the evidence that a combination of short- and long-acting NRT was effective as well.\n\nBased on the evidence of relative effectiveness and their expertise, the committee agreed that several individual products, as well as short-acting and long-acting NRT in combination, were likely to lead to people successfully stopping smoking when used alongside behavioural support. The committee agreed that people should first be told about all the available options so they can make their own choice. If people do want more information about which options are likely to work best, it is important that people providing stop-smoking support or advice can make this clear. The committee discussed very brief advice and using opportunities to tell people who smoke about the range of interventions available, along with having longer discussions about these options and providing more detailed advice. They agreed these align well with the principles of NHS England's making every contact count and NICE's making every contact count resources.\n\nThe committee looked at the evidence for Allen Carr's Easyway to stop smoking in-person group seminars. This is an approach that uses cognitive behavioural therapy and relaxation methods without pharmacotherapy. It also includes a final ritual cigarette at the end of the seminar, regular follow-ups and optional shorter follow-up sessions.\n\nThe evidence considered by the committee compared Allen Carr's Easyway in-person group seminar with 1-to-1 support provided by an NHS stop smoking service (which includes behavioural support and the use of medicinally licensed products) and with a remote stop smoking service (which included behavioural support and information about how to access medicinally licensed products). The committee agreed the evidence showed it was as good as other methods such as 1-to-1 support provided by local stop-smoking services, but there was not enough evidence to position Allen Carr's Easyway in-person group seminar within the hierarchy of effectiveness of interventions in recommendations 1.12.7 or 1.12.8.\n\nThe committee noted that evidence suggests Allen Carr's Easyway in-person group seminar is cost effective and represents good value for money from an NHS and public sector perspective. They agreed that making it available through the NHS and local authorities alongside other interventions would broaden people's choice, and that the more choice people have the more likely they are to find the right intervention for them. They also agreed that some people are reluctant to use pharmacotherapy, and Allen Carr's Easyway would potentially increase the number of people attempting to stop smoking by offering an alternative to interventions that include pharmacotherapy.\n\nThe committee discussed various ways of providing the seminar, including online, but noted that the evidence they saw was only for the in-person group seminar (although in 1 study an online follow up was offered). Therefore they were unable to generalise from this evidence to formats other than the in-person group seminar.\n\nThe committee discussed the funding of studies of the intervention. One was funded by Allen Carr's Easyway, but the committee agreed that the methods used to conduct the study minimised any risk of bias associated with this.\n\nThe committee discussed the potential effect of Allen Carr's Easyway on inequalities in health. They noted that the length of the seminar (4.5 to 6 hours) and any travel costs to attend the seminar might be difficult for some people, and that people who are housebound would not be able to attend an in-person group seminar at all. They also noted that the evidence did not include any analysis by age, family background, or pregnancy and so it was not clear whether its effectiveness differed in these groups. The committee were unaware whether the in-person group seminars were available in languages other than English, and agreed this was a potential barrier for some people. The evidence also showed that the quit rate was greater in people with higher education in the Allen Carr Easyway in-person group seminar arm. The committee discussed that commissioners would need to know and understand the needs of their local populations to be able to commission Allen Carr's Easyway in a way that would maximise access and use of the service.\n\nThe committee agreed that more research on the effects of Allen Carr's Easyway in different population groups, and on the effectiveness of other ways to deliver the programme (for example the online and book versions) would be useful (see the recommendations for research on Allen Carr's Easyway).\n\nThe committee decided not to recommend some combinations of interventions even though they were as effective as individual options. This was because, based on their experience, they had concerns over adherence rates, the difficulty of obtaining prescriptions for multiple interventions at once and a lack of information on contraindications that made these combinations less feasible than other options.\n\nIn most of the evidence, the stop-smoking product (medicinally licensed products or nicotine-containing e‑cigarettes) was combined with some form of behavioural support. This meant that the results of the evidence depended on behavioural support being given alongside. The committee agreed that people providing stop-smoking support should offer behavioural support alongside any nicotine-containing products the person is using, irrespective of whether they are providing the product. This is to give people a better chance of stopping smoking. They also agreed that offering behavioural support to people using nicotine-containing e‑cigarettes would increase their chances of stopping smoking.\n\nIn addition, the committee recognised the need for more evidence about what factors may prevent those who smoke from using other forms of nicotine, particularly among population groups with higher smoking prevalence. (See the recommendation for research on factors that may influence the use of nicotine replacement therapy and e-cigarettes.)\n\n## How the recommendations might affect practice\n\nConversations guided by each person's preference are good practice and should already be taking place. However, extra time may be needed for people providing stop-smoking support or advice to discuss the intervention options with people who want to stop smoking, especially for the additional advice on e‑cigarettes. If these recommendations lead people to quit successfully with fewer unsuccessful attempts, this may mean fewer appointments per person.\n\nCommissioning Allen Carr's Easyway in-person group seminar through the NHS or local authority would have resource implications for stop smoking services. But the intervention is cost effective and although the initial cost was higher than the comparator (Quit.ie or local stop smoking services group) this would be quickly offset (within 5 to 7 years) by the reduction in comorbidities and associated healthcare costs. The committee were also advised that the NHS or local authority is likely to be able to negotiate a discount for the intervention if enough people take up the offer.\n\nThe committee noted that some people living in rural areas may need help with travel costs if they need to travel long distances to attend the in-person seminar.\n\nReturn to recommendations\n\n# Advice on nicotine-containing e-cigarettes\n\nRecommendations 1.12.13 to 1.12.17\n\n## Why the committee made the recommendations\n\nEvidence showed that nicotine-containing e‑cigarettes can help people to stop smoking and are of similar effectiveness to other cessation options such as varenicline or long-acting and short-acting NRT.\n\nThe extensive harms of smoking are well known, and the committee agreed it is unlikely that e‑cigarettes could cause similar levels of harm. But they also agreed that for people who do not smoke, it is unlikely that inhaling vapour from an e‑cigarette is as low risk as not doing so, although the extent of that risk is not yet known. They discussed the potential benefits and risks of using nicotine-containing e‑cigarettes to stop smoking.\n\nThere was a small amount of evidence about short-term adverse events of e‑cigarettes that did not show that they caused any more adverse events than NRT, e‑cigarettes without nicotine or no treatment. The committee had low confidence in this evidence because studies were usually designed to investigate effectiveness and not adverse events, meaning they may not have been large enough to show an effect.\n\nThere were only 2\xa0studies about the long-term harms of using nicotine-containing e‑cigarettes, and the committee discussed the uncertainty of the evidence and their concerns with these studies. A call for evidence did not produce any additional evidence in this area.\n\nThe committee agreed that there is insufficient evidence to tell whether e‑cigarettes cause long-term effects. E‑cigarettes are relatively new devices, and it is important to understand whether they cause any health harms or benefits aside from their potential to reduce smoking-related harm (see the recommendation for research\xa0on health effects of e-cigarettes).\n\nThe committee recognised the need for evidence about what factors may influence use of e‑cigarettes. So they made recommendations for research relating to any possible impacts of the amount of nicotine and frequency of use, and flavourings.\n\nThe committee discussed the outbreak of serious lung disease in the US in 2019, which US authorities identified was largely caused by vaping cannabis products containing vitamin\xa0E acetate. They also noted there has been a Medicines and Healthcare products Regulatory Agency (MHRA) Drug Safety Update highlighting serious lung injury with e‑cigarettes issued in January 2020 (E-cigarette use or vaping: reporting suspected adverse reactions, including lung injury). The committee discussed that the UK has well-established regulations for e‑cigarettes that restrict what they can contain.\n\nExperts from the MHRA described to the committee the monitoring process for both short- and long-term harms of using e‑cigarettes. Monitoring is ongoing and the evidence may change in the future, but the committee was not aware of any major concerns being identified. Accurate information relies on adverse events being reported, so the committee recommended that people providing stop-smoking support or advice should actively report any suspected adverse events and encourage people to report any that they experience.\n\nThe committee used their knowledge and experience to supplement the very limited and uncertain evidence about harms. They agreed that because many of the harmful components of cigarettes are not present in e‑cigarettes, switching to nicotine-containing e‑cigarettes was likely to be significantly less harmful than continuing smoking. So, the committee agreed that people should be able to access them as part of the range of interventions they can choose to use (see the section on stop-smoking interventions). They also agreed that people should be given up-to-date information on what is known about e‑cigarettes to help them make an informed decision about whether to use them.\n\nThe committee agreed that with the limited data on effects of longer-term use, people should only use e‑cigarettes for as long as they help prevent them going back to smoking. They also agreed that people should be discouraged from continuing to smoke when using e‑cigarettes, even if they are smoking less, because there is no information on whether this will reduce their harm from smoking.\n\nThe committee discussed that it is more likely that people will not get enough nicotine to help them stop smoking, than get too much. They agreed that not getting enough nicotine is likely to increase the risk that the person will return to smoking, so they recommended that people should be encouraged to use as much as they need and told how to use the products effectively.\n\n## How the recommendations might affect practice\n\nExtra time may be needed to discuss e‑cigarettes with people who are interested in using them. If these recommendations lead to more successful quit attempts, this may mean fewer appointments per person and substantial savings in downstream costs associated with smoking.\n\nReturn to recommendations\n\n# Stop-smoking support in mental health services\n\nRecommendation 1.14.19\n\n## Why the committee made the recommendation\n\nThe committee agreed the importance of stop-smoking support being available to all, and that people with mental health conditions should not be treated differently in this. However, because those with mental health conditions have a higher prevalence of smoking, and are less likely to access standard smoking cessation services and have lower quit rates, it is important to look at whether additional support could be appropriate.\n\nThere was a small amount of evidence about tailored smoking cessation interventions for people with mental health conditions. The evidence of effectiveness identified was in populations with severe mental health conditions such as bipolar disorder, schizophrenia or post-traumatic stress disorder. However, the committee noted there was a lack of consensus of what constitutes a severe mental health condition. They heard from experts that people with other mental health conditions may need additional support as well. This applies both at an individual level and, for those in mental health settings, at a system level. The committee agreed that additional support should be offered to people with severe mental health conditions, and although it might be considered for other people with mental health conditions, there was insufficient evidence to make a wider recommendation. The committee noted that the recommended additional support would fit with current stop-smoking provision. Furthermore, the committee identified this as an important research gap that needs to be addressed to reduce health inequalities (see the recommendation for research on support for people with mental health conditions to stop smoking).\n\n## How the recommendation might affect practice\n\nThis potential additional support may need extra time and additional appointments. If these recommendations lead to more successful quit attempts, this may mean fewer appointments per person and substantial savings in downstream costs associated with smoking.\n\nReturn to recommendations\n\n# Nicotine-containing e-cigarettes for harm reduction\n\nRecommendation for research 6\n\n## Why the committee made the recommendation for research\n\nNo evidence was found on the use of e‑cigarettes specifically for harm reduction for people who do not want, or are not ready, to stop smoking in one go. So, the committee chose not to make recommendations on using e‑cigarettes for harm reduction. They did discuss that e‑cigarettes may be used in this way and that there may be substantial dual use; that is, when someone is both smoking and using e‑cigarettes.\n\nThe committee agreed that more information is needed about the use of e‑cigarettes for those who may wish to reduce the amount they smoke.\n\nReturn to the recommendation for research\n\n# Supporting people trying to stop smoking\n\nRecommendations 1.17.1 and 1.17.2\n\n## Why the committee made the recommendations\n\nThe committee agreed that strategies to avoid relapsing are an important part of stop-smoking advice and support, and are likely to be most effective when introduced early in the process and regularly revisited.\n\nEvidence about NRT for preventing relapse was mixed. Although there was evidence that they may be effective in people who had recently quit, using a single type of fast-acting NRT did not reduce relapse with any certainty when people had stopped smoking for longer. The committee discussed this evidence and noted that in their experience, using NRT for longer can stop people relapsing to smoking, particularly if more than 1\xa0type of NRT is used (usually combining patches with a fast-acting form of NRT). They discussed that only offering NRT for 12\xa0weeks could cause people to relapse.\n\nEvidence showed that if people who have used varenicline and bupropion to stop smoking continue taking it for longer, this improves their chances of staying stopped. This included people diagnosed with serious mental illness. There were a small number of studies and they investigated different groups of people and used varenicline in different ways, so the committee had some uncertainty about the evidence.\n\nThe committee reflected on the mixed findings from the evidence. They agreed that, because preventing relapse is so important for people who have been able to stop smoking, offering longer-term pharmacotherapy to help prevent relapse was reasonable. The committee noted that bupropion was not licensed for relapse prevention. The studies that evaluated bupropion for this indication had different dosing regimens, so the committee did not specify what dose or duration of bupropion was most effective for preventing relapse.\n\nThe committee recognised the need for more evidence about which nicotine-containing products or combination of products are best at preventing relapse after a successful quit attempt (see the recommendations for research on relapse prevention and relapse prevention after enforced, temporary quit).\n\n## How the recommendations might affect practice\n\nStop-smoking advisers can use existing appointments to provide information about preventing relapse to people who want to stop smoking, so this is not expected to have a resource impact, though there may costs associated with prescribing additional pharmacotherapies.\n\nReturn to recommendations\n\n# Reviewing the approach for people trying to stop smoking, cutting down or stopping temporarily\n\nRecommendations 1.17.6 and 1.17.7\n\n## Why the committee made the recommendations\n\nThe committee discussed that it is important to review any stop-smoking or harm-reduction approach taken so that any problems can be addressed. They agreed that it can take someone multiple attempts to stop smoking for good. Encouraging people who have relapsed to smoking and talking to them about trying again may mean that they stay in touch with the service and are more likely to stop smoking in the long term.\n\n## How the recommendations might affect practice\n\nStop-smoking advisers can use existing appointments to discuss with people the approach they are taking and future attempts to stop or reduce harm from smoking, so this is not expected to have a resource impact.\n\nReturn to recommendations\n\n# Identifying pregnant women who smoke and referring them for stop-smoking support\n\nRecommendations 1.18.1 to 1.18.3\n\n## Why the committee made the recommendations\n\nStopping smoking in pregnancy is important for the health of both the woman and her baby.\n\nExisting recommended practice, based on NICE's previous guideline on stopping smoking in pregnancy and after childbirth, is to offer opt-out provision for pregnant women. The evidence about opt-out referral systems was mixed, but the most recent evidence showed that it resulted in higher self-reported quit rates and more engagement with stop-smoking support.\n\nMost current evidence uses carbon monoxide levels of 4\xa0parts per million (ppm) as the cut-off for referral. Based on this and their expertise, the committee recommended that a carbon monoxide reading of 4\xa0ppm or above would be an appropriate level to automatically refer women for stop-smoking support. This also aligns with the NHS Saving Babies' Lives Care Bundle.\n\nThe evidence about women's views on opt-out referral showed that giving women information on carbon monoxide testing and the automatic referral was an important factor in whether they accepted the referral and took up the support. The committee discussed whether there was a specific need for a recommendation on giving information, because all clinical treatment pathways should ensure that people are fully informed and take an active part in their care. They agreed that a recommendation would be helpful in this case, because they considered opt-out treatment is not common in most areas of care.\n\nDuring development of this guideline, carbon monoxide monitoring was not being used because of COVID‑19 practice changes. The committee acknowledged that during the COVID‑19 pandemic referral decisions may need to be made without using carbon monoxide monitoring.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current widespread practice and so should have little resource impact.\n\nReturn to recommendations\n\n# Nicotine replacement therapy and other pharmacological support\n\nRecommendations 1.20.6 to 1.20.8 and 1.20.10\n\n## Why the committee made the recommendations\n\nNICE's 2010 guideline on stopping smoking in pregnancy and after childbirth (replaced by this guideline) recommended nicotine replacement therapy (NRT) for pregnant women only if they are not able to stop smoking using a behavioural intervention without NRT, and once they have stopped smoking. New evidence showed that NRT may help women stop smoking in pregnancy when added to a behavioural intervention.\n\nThe committee discussed that women may stop smoking temporarily during pregnancy and relapse afterwards. There was no evidence about continuing NRT after pregnancy to prevent this but, based on their expert opinion, the committee agreed it may be useful.\n\nEvidence showed that advice from healthcare professionals, particularly midwives, was valuable to pregnant women and contributed to their decisions about using NRT. The evidence also showed that consistent advice addressing the main concerns women tend to have about NRT during pregnancy (such as addictiveness, potential side effects and any pregnancy impacts) may help women to feel comfortable using NRT during and after pregnancy.\n\nThere is little evidence about the effectiveness or safety of using nicotine-containing e‑cigarettes to help women stop smoking in pregnancy. Many of the studies in the effectiveness meta-analysis for nicotine replacement therapies were over 10\xa0years old and most used doses of nicotine that would now be considered to be low. The committee therefore made recommendations for research to help understand what type and dose of NRT is most effective and the views and concerns of pregnant women and their healthcare professionals about using nicotine-containing e-cigarettes in pregnancy.\n\nSince the publication of this guideline, a National Institute for Health and Care Research trial on helping pregnant smokers quit has been published comparing e‑cigarettes and nicotine patches. NICE reviewed this trial with the help of topic experts (see the 2023 exceptional surveillance review). Although it provides some new data, there are still important gaps in the evidence - particularly for longer term outcomes. So NICE decided that more evidence on effectiveness and safety is still needed before it can update these recommendations.\n\n## How the recommendations might affect practice\n\nThe change in recommendations since NICE's previous guideline may increase prescriptions of NRT to pregnant women, and potentially increase how long it is prescribed for. If this leads to more cases of successful quitting, it will create considerable savings downstream.\n\nReturn to recommendations\n\n# Incentives to stop smoking\n\nRecommendations 1.20.12 to 1.20.14\n\n## Why the committee made the recommendations\n\nEvidence showed that offering financial incentives to help pregnant women stop smoking was both effective and cost effective. Voucher incentives were acceptable to many pregnant women and healthcare providers. The committee noted that these are already being used in some areas.\n\nThe committee discussed and agreed with the evidence that 'contingent rewards' (given only if biochemical tests prove the woman has stopped) were more effective than guaranteed payments given whether the woman has stopped or not.\n\nMore evidence is needed to find out what value of incentive works best. Evidence from the UK showed that schemes in which around £400 could be gained in vouchers staggered over time (with reductions for each relapse made) were effective and cost effective, so the committee included this amount as a guide.\n\nBased on the evidence and their expertise, the committee agreed that incentive schemes that include both the pregnant woman and a significant other supporter could have a better chance of success.\n\nThey also agreed that some staff may be unfamiliar with incentive schemes and would benefit from training to help deliver them.\n\nAlthough the guideline recommends that vouchers should be provided only to those with an abstinence validated by a biochemical method, the committee acknowledged that during the COVID‑19 pandemic carbon monoxide validation may not be being used. While this is the case, vouchers are recommended even if biochemical validation using carbon monoxide is not possible.\n\n## How the recommendations might affect practice\n\nIncentive schemes are already used in some areas. Areas that do not already use them will need staff time to run them, and financial resources to award the vouchers. Training for people promoting and delivering the incentive schemes may need resources.\n\nReturn to recommendations\n\n# Commissioning and designing services\n\nRecommendations 1.22.1 and 1.22.2\n\n## Why the committee made the recommendations\n\nThe committee looked at a large amount of evidence assessing the relative effectiveness of interventions for stopping smoking (medicinally licensed products and nicotine-containing e‑cigarettes, alone or in combination). Most of the interventions or combinations of interventions were delivered with behavioural support. The committee agreed which interventions should be accessible (see the rationale and impact section for stop-smoking interventions). They agreed that the recommendation from NICE's 2018 guideline on stop-smoking interventions and services (replaced by this guideline) to make stop-smoking interventions available through local plans and approaches to health and wellbeing was still relevant, so they drew on that to make a new recommendation.\n\nThe committee noted that not all medicinally licensed products are available in all stop-smoking services, and so local arrangements are in place to ensure that these are accessible when needed. Nicotine-containing e‑cigarettes are not licensed medicines so cannot currently be provided on prescription. However, there are ways of increasing their accessibility, for example by giving evidence-based advice about them and information on where people can access them. The committee were aware that some services use vouchers or starter pack schemes.\n\nBased on evidence and their experience of the use of NRT for preventing relapse, the committee recommended it for longer-term use (see the rationale and impact section for supporting people trying to stop smoking) and agreed this needed to be reflected in service specifications to make sure it was made available.\n\nThe committee heard from experts that smoking prevalence is high in some population groups that may not be well served by existing stop-smoking provision (such as those with mental health conditions, or those who identify as LGBT+, or those with low income). And that although these groups may be motivated to stop smoking, they may experience additional challenges to successfully stopping (see the equality impact assessment).\n\nWe did not find any evidence on how to tailor effective and cost-effective interventions to ensure that they are engaging and accessible for under-served groups, or how acceptable those interventions may be for those groups. The committee identified this as an important gap that needs to be addressed to reduce health inequalities (see the recommendation for research on stop-smoking interventions for under-served groups).\n\n## How the recommendations might affect practice\n\nThe committee noted that schemes are already in place in some areas to support starting the use of nicotine-containing e‑cigarettes for stopping smoking.\n\nNICE's 2013 guideline on smoking harm reduction already recommended that service specifications require providers of stop-smoking support to offer long-term NRT.\n\nReturn to recommendations\n\n# Stop-smoking support in secondary care\n\nRecommendation 1.22.14\n\n## Why the committee made the recommendation\n\nThe committee agreed that nicotine-containing products should be available for sale in secondary care settings to help people stop smoking and to support temporary abstinence for patients, staff and visitors because hospital grounds are covered by smokefree legislation.\n\n## How the recommendation might affect practice\n\nMaking the full range of effective options available for sale may be a change to current practice, but it is not expected to have a large impact on resources.\n\nReturn to recommendations", 'Context': "In 2018, 14.7% of adults in the UK smoked cigarettes. Rates were higher than average for some groups, including those in routine and manual occupations, and those with mental health conditions. Although this is a decline of more than 5\xa0percentage points since 2011, smoking is still the main cause of preventable illness and premature death in England (Office for National Statistics Adult smoking habits in the UK). In 2017/2018, an estimated 4% (489,300) of NHS hospital admissions in England, and an estimated 16% (77,800) of all deaths, were attributed to smoking (NHS Digital 2019 Statistics on smoking, England).\n\nTreating smoking-related illness is estimated to cost the NHS £2.6\xa0billion a year and the wider cost to society is around £11\xa0billion a year (NHS England Health matters: tobacco and alcohol CQUIN).\n\nIn 1\xa0in 5\xa0local authorities, the specialist service has been replaced by an integrated lifestyle service (Action on Smoking and Health and Cancer Research UK's Stepping up: the response of stop smoking services in England to the COVID-19 pandemic).\n\nThis guideline forms a single source for tobacco guidance that updates and replaces NICE's guidelines on:\n\nsmoking: workplace interventions (PH5, 2007)\n\nsmoking: preventing uptake in children and young people (PH14, 2008)\n\nsmoking prevention in schools (PH23, 2010)\n\nsmoking: stopping in pregnancy and after childbirth (PH26, 2010)\n\nsmokeless tobacco: South Asian communities (PH39, 2012)\n\nsmoking: harm reduction (PH45, 2013)\n\nsmoking: acute, maternity and mental health services (PH48, 2013)\n\nstop-smoking interventions and services (NG92, 2018).\n\nThis guideline includes recommendations on harm reduction, which was previously covered by PH45. In PH45, harm reduction included cutting down before stopping smoking, cutting down longer term, temporary abstinence, or stopping smoking altogether by switching to a medicinally licensed nicotine-containing product. In the current guideline, switching completely from smoking to any nicotine-containing product is considered to be stopping smoking rather than harm reduction.\n\nThe approaches for harm reduction in this guideline should not detract from providing the highly cost-effective interventions to help people stop smoking altogether. Instead, recommendations on harm reduction are intended to support and extend the reach and impact of existing stop-smoking support. Although existing evidence is not clear about the health benefits of smoking reduction, people who reduce the amount they smoke are more likely to stop smoking eventually.\n\nThis guideline was developed between 2019 and 2021. There has not been anything published to date on COVID‑19 that the committee considered to have an impact on this guideline. We have highlighted in the rationale sections any recommendations that are affected by temporary changes in practice because of COVID‑19. The committee further noted that some stop-smoking support may now be being delivered by phone or video rather than face to face, but this is not stopping the services from being delivered."}	https://www.nice.org.uk/guidance/ng209	This guideline covers support to stop smoking for everyone aged 12 and over, and help to reduce people's harm from smoking if they are not ready to stop in one go. It also covers ways to prevent children, young people and young adults aged 24 and under from taking up smoking. The guideline brings together and updates all NICE's previous guidelines on using tobacco, including smokeless tobacco. It covers nicotine replacement therapy and e-cigarettes to help people stop smoking or reduce their harm from smoking. It does not cover using tobacco products such as ‘heat not burn’ tobacco.
16ae85b0c878e0458c66deb1a5e33e29f78aa12e	nice	Disabled children and young people up to 25 with severe complex needs: integrated service delivery and organisation across health, social care and education	Disabled children and young people up to 25 with severe complex needs: integrated service delivery and organisation across health, social care and education This guideline covers support for disabled children and young people with severe complex needs, from birth to 25 years. It aims to encourage education, health and social care services to work together and provide more coordinated support to children and young people, and their families and carers. # Recommendations on support for all disabled children and young people with severe complex needs People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. These recommendations cover the support that all disabled children and young people with severe complex needs should receive. There are also recommendations in this guideline on: specialist support, covering palliative care, communication aids, environmental adaptations and accessibility, travel training and employment service organisation, including working culture, training, integrated working, and commissioning. The government's special educational needs and disability (SEND) code of practice is the primary guidance for processes around SEND. This NICE guideline makes recommendations on how existing legislation and statutory guidance should be put into practice. When there is evidence that existing legislation and statutory guidance is not being implemented, the guideline recommendations reiterate this and provide further guidance to help with implementation. # Principles for working with children, young people and their families ## Key principles Education, health and social care practitioners should always: put the views, life goals and ambitions and preferences of the disabled child or young person with severe complex needs at the centre of planning and decision making take the views of parents and carers into account take account of the cultural background of the child or young person and their parents and carers. For children and young people who are not able to actively participate in planning or decision making, education, health and social care practitioners should take into account the views of the people who know them best. Do not assume that all children and young people with a particular diagnosis need the same support. ## Involving children and young people and their families Ensure that all children and young people are involved in discussions and decisions about their education, health and social care support. Get each child or young person's input in the way that is most effective and accessible for them. For example: invite them to attend in-person or virtual meetings (or parts of meetings) where their views should be represented short 'about me' presentations photo diaries video or voice recordings. Keep a record of how the child or young person participated in discussions and decisions, and what contribution they made. Find out which members of the child or young person's family should be involved, in the context of their current individual family circumstances (for example, when a family member other than a parent has parental responsibility). Review this if their family circumstances change. Work closely with children, young people and their families and carers to: get to know them better, to understand their needs draw on the expertise they have from their lived experience and associated needs build a positive working relationship with them, to better understand their views, life goals and ambitions. Encourage and support children and young people to give their views on their health, care, education and support, and express what they want and need. Take account of the communication needs of children and young people. If needed, consider getting support from a specialist to help them participate in discussions and decisions and express their views. Encourage parents and carers to think about how their child can give their own views and be involved in decisions. Ask them what services can do to support their child in communicating their views. Regularly check that children and young people and their families and carers are satisfied with how they are involved in decisions about their support. If they are not satisfied, look for ways to address their concerns. Learn about the approaches families and carers use (now or previously) when caring for their child. If they are beneficial, continue using them in the same context. Avoid using those that have not worked well in the past. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles for working with children, young people and their families . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review B: involving children and young people evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. ## Communication formats and providing information Take care to use empathetic, supportive language when communicating with families and carers, because they may be anxious and perceive judgemental attitudes from practitioners. Provide information in a spirit of partnership with families and carers. Avoid being directive (unless the family and carers prefer this), and take their experience and perspective into account when providing information. Be sensitive to and address the feelings of children, young people and their families and carers when providing information. Help them to understand and reflect on information, and direct them to sources of statutory and independent support if needed. Enable children and young people to communicate their views in a way that is appropriate for their age, developmental level and communication abilities. Find out what communication formats and media the child or young person prefers (for example, children who are non-verbal might use alternative and augmentative communication). Communicate with them using their preferred format. Ensure the format allows them to use any inclusive terminology that is relevant to them. Be aware that a child or young person may prefer different communication formats for different purposes. Ask children and young people and their families and carers if they have an up-to-date communication passport. Record children and young people's communication preferences in a format that can be shared, so that they do not have to repeat this information. Establish the most effective way of communicating with families and carers, for example providing information in different languages or involving an interpreter. Be aware that parents or carers may have communication preferences and needs of their own, and that these may affect their ability to take part in discussions and understand information about their child's support. Education, health and social care services should give children, young people and their families and carers up-to-date, accessible information and advice about: the process and purpose of assessment and diagnosis the education, health and social care support they are receiving any delays or changes in the above what other support they are entitled to the meetings they will be involved in and how to contribute their views the roles of the practitioners and services that are currently supporting them, and any services or practitioners that they have been referred to for future support what to expect from services relevant policies and processes how to raise a concern about their support and how to provide feedback to encourage service development (for example via parent carer forums). Education, health and social care services should direct children, young people and their families and carers to sources of support and advice, including: SEND Information, Advice and Support services specialist national or local support groups local carer support groups (for example parent carer forums) peer support groups their SEND Local Offer. SEND Information, Advice and Support services should help children, young people and their families and carers understand what support is available for them, based on their specific needs. Ask children and young people and their families and carers what they expect from services. If their expectations cannot be met, explain why and explore alternatives. For more guidance on communicating and discussing complex information, identifying preferred communication formats, cultural sensitivity in communication, and tailoring information to individuals, see the: NICE guideline on babies, children and young people's experience of healthcare NICE guideline on patient experience in adult NHS services (in particular recommendation 1.5.14). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communication formats and providing information . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review B: involving children and young people evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. ## Preparing for and running meetings with children and young people Ask children and young people and their families and carers how they would like to be involved in practitioner-led review meetings about them. Before discussions and meetings, practitioners should help children and young people prepare by: providing them with information (in accessible formats) and support to help them and their parents and carers take part, and checking that they understand this information encouraging their parents and carers to discuss the meeting with them in advance providing support for their parents or carers before the meeting if they need help completing any documents checking that meetings are physically accessible, and that they can afford to get there. Before meetings, the chair should find out: what is important to the child or young person their age, communication abilities and circumstances (see recommendation 1.1.16). Use this information when planning meetings, to ensure that the child or young person can meaningfully participate (see the recommendations on information sharing and privacy). When planning meeting agendas: prioritise the child or young person's wishes, aspirations and goals, in addition to the statutory content and include any other relevant issues that parents, carers and education, health and social care practitioners need to cover. As far as possible (based on practitioners' contracted working hours), consider the child or young person's preferences when planning meetings, to help them participate and understand what is happening. For example: Ask them when and where they would like to have the meeting: consider scheduling it at a time of day when they are not usually tired and/or consider scheduling meetings outside of school time when possible, so they do not miss lessons or feel excluded and/or consider having the meeting in a place where they feel comfortable and do not have to travel too far and/or consider virtual meetings. Consider showing them the meeting room and asking them where they would like to sit. Consider if they are anxious in groups of people or do not want to discuss a sensitive topic in front of everyone. Arrange a separate meeting so they can get their views across (for example, a one-to-one meeting with a practitioner they trust, or a videoconference). Consider making adjustments to the meeting format and schedule (for example providing breaks during long meetings). Take into account family circumstances. Ensure that, at each meeting: there will be education, health and social care practitioners who know the child or young person and are involved in their support key additional relevant people are able to attend (for example, a college representative for a review on transition from school to college). Take account of the child or young person's right to privacy: hold meetings in places with as much privacy as possible tell them who will be at the meeting, and why -nly invite the key education, health and social care practitioners who are needed at the meeting, to avoid large groups of practitioners that may be intimidating for some children and young people. Consider using person-centred planning tools (for example, Planning Alternative Tomorrows with Hope ) to help structure and conduct meetings. Communicate with the child or young person at meetings using their preferred format, and any basic rules that help them to feel comfortable. The chair should remind everyone at the meeting what the child or young person's communication preferences are before the meeting starts. Give children and young people plenty of time to take in information and express their views in discussions and meetings. Do not rush them. When providing information in discussions and meetings, check that children and young people understand it and how it applies to them. Agree clear actions (at meetings, and in other discussions between practitioners and the child or young person and their family and carers). For actions that will directly affect the child or young person: record them in an action log, in a format that the child or young person and their family and carers can understand share the log with the child or young person and everyone involved in their care review the log regularly to ensure the actions are being done. Practitioners should consider recording meetings (written, audio or video; in line with local policies on information governance and consent), so the child or young person and their family and carers can review them again later. If a practitioner cannot attend a meeting, decide whether it needs to be rescheduled. Take into account: the problems caused by delaying the meeting the risk of the meeting not being productive if it goes ahead without all the relevant practitioners the risk of causing discomfort or distress to the child or young person if there are people at the meeting that they do not know the consequences for the family and carers (such as parents having to rearrange time off from work). If a practitioner cannot attend an interagency team meeting, or any meeting with the child or young person, they should: tell the person who arranged the meeting in advance send a fully briefed delegate to represent them, or provide a written update or report request details of any relevant actions and follow these up review the meeting minutes and action log when available. Ask the child or young person if they would like to involve any siblings or friends in meetings (to share their views on the child or young person's strengths and interests). If they would like to do this: ask the child or young person to invite the sibling or friend if the sibling or friend agrees to attend the meeting, contact them to explain how they can be involved involve the parents and carers of the child or young person and their sibling or friend as necessary at each stage of this process. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preparing for and running meetings with children and young people . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review B: involving children and young people evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. ## Using a consistent approach Education, health and social care services should work together to make the way they interact with each child and young person more consistent. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on using a consistent approach . Full details of the evidence and the committee's discussion are in evidence review M: views and experiences of service providers. Loading. Please wait. ## Decision making These recommendations should be read alongside guidance on Deprivation of Liberty Safeguards and Liberty Protection Safeguards. Provide children and young people and their families and carers with information to help them play a part in shared decision making. When a child is unable to respond with intentional communication, think about whether their preferences could be identified in another way (for example through observation, play, or their behaviour). When a child can express a view, but their view does not align with the views of their parents, support the child and parent to understand each other's perspective and try to get agreement. If this is not possible, work impartially and separately with them and with their parents. If disagreements cannot be resolved and the child or young person is under 16: remember that the child or young person's needs are paramount take the views of the parents into account remember that children and young people under 16 can give their own consent if it is clear that they fully understand what is involved. If disagreements cannot be resolved and the young person is over 16, consider the young person's views first. You must uphold their decision if they have capacity to make it. If you think a young person aged 16 or over lacks capacity to make a particular decision about their support and education, you must: follow the requirements of the Mental Capacity Act 2005 and its statutory code of practice ensure that the young person is as involved as possible in the decisions made on their behalf. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on decision making . Full details of the evidence and the committee's discussion are in: evidence review B: involving children and young people evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. ## Information sharing and privacy Ask children and young people and their parents and carers about information sharing as early as possible, to avoid them having to repeat information to different practitioners. Ask for and record informed consent to share information when needed with other practitioners and services. Ask if there is any information they do not want to be shared, and discuss the implications of not sharing this information. Ask who they would prefer to discuss sensitive information with. Explain what information will be shared without their consent, for example in relation to safeguarding. Practitioners should follow and stay up to date with their organisation's policy on consent. Practitioners must stay up to date with the relevant legislation and statutory guidance. Once you know the child or young person's preferences, share all agreed information with all services involved in supporting them. Make sure that all services involved have access to all agreed information about the child or young person. When specialised care plans (such as behaviour management plans) have been agreed for a child or young person, share these plans (and any updates) with them and their parents and carers, and with all relevant practitioners. Check the information sharing preferences of children and young people and their families and carers at least annually (for example, check at each education, health and care plan review). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information sharing and privacy . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. # Identifying needs and involving other services Be aware that disabled children and young people may have emotional and mental health needs that can be obscured by their severe complex needs. ## When needs are first identified in health services These recommendations should be read alongside Section 23 in the Children and Families Act 2014. If you think a child or young person may have complex health needs or disabilities, think about whether they are likely to also have special educational needs and social care needs. If a child or young person is likely to have complex health needs or disabilities and is also likely to have special educational and social care needs: discuss this with them and their parents and carers before notifying the local authority, and if possible get their agreement on when to do this advise them and their parents and carers about any voluntary organisations that can provide advice or assistance, and any educational support that is available before they start or return to school direct them and their parents and carers to their special educational needs and disability (SEND) Local Offer and SEND Information, Advice and Support services after getting consent, find out which education and social care services need to be involved and contact them at the first opportunity. ## When needs are first identified in education services If you think a child or young person may have a special educational need, think more broadly about their circumstances and decide whether they need to be referred to other services. For example: Do they have specific needs that can be addressed with clear actions and solutions, or are they likely to need broader support? Could there be an underlying health condition, and do health services need to be involved? Could they have unmet social care needs, and do social care services need to be involved? If a child or young person is likely to have special educational needs and is also likely to have complex health and social care needs: discuss this with them and their parents and carers advise them and their parents and carers about any support organisations in their SEND Local Offer that can provide advice or assistance, and any educational support that is available before they start or return to school direct them and their parents and carers to SEND Information, Advice and Support services after getting consent, find out which health and social care services need to be involved and contact them at the first opportunity. ## Referral to social care services All disabled children are defined as 'in need' and entitled to an assessment of need under Section 17 of the Children Act 1989. However, some social care support for families may be available without an assessment. These recommendations should be read alongside the duties on reasonable adjustments in the Equality Act 2010. When making a referral for a social care assessment for family support: include a detailed description of the reasons for making the referral, including the emerging health and social care needs (as discussed with the child or young person and their parents and carers) and include any reasons the family might need help to access healthcare services (for example, families on low income who cannot afford to get to appointments) and discuss the potential outcomes of the referral (including an assessment of need) with the child or young person and their family. Be aware that parents and carers may be anxious about involving social care services. Find out what they know about social care (particularly family support services), and: explain areas they do not understand address any misconceptions explain the difference between safeguarding, child protection social care, and broader family support services. If you identify a concern, refer in line with local safeguarding policy. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying needs and involving other services . Full details of the evidence and the committee's discussion are in: evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. # Education, health and care needs assessment These recommendations should be read alongside NHS England guidance on Care, Education and Treatment Reviews and chapter 9 of the special educational needs and disability (SEND) code of practice. ## Requesting a needs assessment If you think a child or young person may have a special educational need, explain to them and their families and carers: who can request an education, health and care (EHC) needs assessment how to request an EHC needs assessment the criteria the local authority will use to decide whether to carry out an EHC needs assessment what the assessment involves how to get help with this process (for example, from support groups) how to make an appeal, if the local authority does not think an EHC needs assessment is needed. Local authorities should explain to education, health and care practitioners that EHC needs assessments should be requested based on a child or young person's needs, and not on other factors such as potential availability of funding. Do not exclude children and young people from EHC needs assessments based solely on whether or not they have a particular diagnosis, or no diagnosis at all. Practitioners should support children or young people and their families during the EHC needs assessment, so that families do not have to manage the process themselves. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on requesting a needs assessment . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. ## Supporting children, young people and their families during a needs assessment When carrying out an EHC needs assessment, local authorities should explain to the child or young person and their families and carers: the possible outcomes of the EHC needs assessment process the purpose of the EHC plan and what it can help with how they can be involved in the process and how their views will be incorporated which services will be involved in the process how long it should take to get an EHC plan (no more than 20 weeks after their initial request) what will happen if an EHC plan is not issued how to contact SEND Information, Advice and Support services. If an EHC plan will not be produced in the statutory timeframe, local authorities should update children, young people and their families and carers on the reasons for this and provide information on current progress. While children and young people and their families and carers are waiting for an EHC needs assessment, explain what services are available and might be appropriate, and the criteria for accessing them. Direct children, young people and their families and carers to SEND Information, Advice and Support services for information about the criteria for funding and support. Give families and carers help, time and opportunities to express their views and explain what support they think their child needs. Record this information during the assessment process. Education, health and social care services should start working together before an EHC plan is issued, to ensure that: the child or young person gets the interim assessments they need, and interim support as soon as a need is identified the transition from interim support to EHC plan is as simple as possible. While children and young people and their families and carers are waiting for the EHC needs assessment process to finish, provide support based on their identified needs. For example: healthcare professionals should work with local teams to identify what interim assessments and support can be provided practitioners should explain what support is available as part of the SEND Local Offer (such as short breaks) education practitioners should provide special educational provision, based on what is currently understood about the strengths and needs of the child or young person. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting children, young people and their families during a needs assessment . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. ## Carrying out the needs assessment During the EHC needs assessment process: take into account the child or young person's age, level of understanding, communication needs and specific circumstances contact any practitioners who have relevant or specialist knowledge about the needs of the child or young person, but who are not part of the interagency team, to better define the child or young person's needs identify emerging needs and make referrals as these needs are identified, without waiting for the assessment process to finish. Use all information available (including information from other practitioners or services) for assessments of children and young people. ## Timescales for completing a needs assessment and producing an EHC plan These recommendations should be read alongside paragraphs 9.41 to 9.44 of the SEND code of practice. When conducting EHC needs assessments, local authorities, services and practitioners must work to the timescales specified in the Children and Families Act 2014 and SEND Regulations 2014. In particular: when an EHC needs assessment is requested, local authorities must decide whether the assessment is needed within 6 weeks when a local authority requests information as part of an EHC needs assessment, services and practitioners must respond within 6 weeks if the local authority decides that an EHC plan is not needed, they must inform the child or young person and their parents within 16 weeks of the initial assessment request if the local authority decides that an EHC plan is needed, they must complete the needs assessment and produce a finalised EHC plan within 20 weeks of the initial assessment request. ## If parents or carers decline any assessments If parents or carers decline any assessments: think about why they are declining and take account of any cultural or communication challenges discuss their reasons for declining and address any concerns they have explain how they can request an assessment in future, and encourage them to get in touch if they change their minds think about whether this may cause a safeguarding issue, and follow local safeguarding processes. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on carrying out the needs assessment, timescales for the assessment and when parents or carers decline an assessment . Full details of the evidence and the committee's discussion are in: evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. # Education, health and care plans These recommendations should be read alongside requirements on draft education, health and care (EHC) plans in Section 38 of the Children and Families Act 2014, Regulation 13 of the Special educational needs and disability (SEND) Regulations 2014 and chapter 9 of the SEND code of practice. ## Agreeing on outcomes for the plan Encourage all disabled children and young people with severe complex needs to express their life goals, ambitions and aspirations, and explore their strengths, abilities and interests with them. Focus on all of these when agreeing outcomes for the EHC plan. Take the views of parents and carers into account throughout the assessment, production and review of EHC plans (see the recommendations on principles for working with children, young people and their families). When writing the agreed outcomes in EHC plans: make them SMART (specific, measurable, attainable, relevant and timely) consider using the 'outcome sandwich' (specify the timeframe, the skill to be developed, and what this skill would help the person to do). Base your expectations for a child or young person on their own life goals and ambitions, rather than on their condition or needs. Query with other practitioners if you think their expectations for a child or young person are too low. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on agreeing on outcomes for the EHC plan . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. ## Providing information and advice for the plan Practitioners within the same organisation should read the information and advice produced for the EHC plan by their colleagues, to ensure they can support all the proposed outcomes through their own work with the child or young person. Local authorities should consider providing the proposed outcomes for each child or young person to education, health and care services. Services should specify how they will support these outcomes when contributing their advice and information to the EHC plan. Record the views of children and young people in EHC plans. Make it clear which parts of the plan contain their contributions. When local authorities write EHC plans: they should use the information provided by practitioners to describe the special educational, therapy, medical, health and social care needs of children and young people in sections B, C and D of the plan they should distinguish between what practical and therapeutic support is needed to educate or train the child or young person and what health and medical support they need to stay well. Commissioners should use the information in sections F, G and H of the EHC plan to commission the services the child or young person needs. When contributing information and advice for EHC plans, practitioners should (within their own area of expertise) specify the special education, health and social care support that will help children and young people to achieve the outcomes in the plan, including: the type of support they need how often they need this support the level of expertise required to provide the support who is responsible for providing the support (see the recommendations about competency in delegated clinical tasks). Local authorities and health commissioners should ensure that EHC plans: are based on up-to-date information are informed by information and advice contributed by practitioners who have the right expertise and knowledge of the child or young person. Preserve the child or young person's voice when recording their views: use their preferred communication format use their own words, or the equivalent in a different format if they do not communicate verbally (for example, symbols or other alternative or augmentative communication, drawings, photo collages, or like/dislike lists) do not rewrite what they have said. Local authorities should write the outcomes and support provision sections of the plan in language that is understandable to the child or young person and their families and carers. For guidance on providing information in different formats, see: the section on providing information in the NICE guideline on babies, children and young people's experience of healthcare recommendation 1.5.13 in the NICE guideline on patient experience in adult NHS services. During the planning process, check with the child or young person and their family and carers and: make sure that they understand the plan outcomes, and what these will mean in practice make sure that the plan makes sense to them and they agree with it check if they have any concerns if they have a concern that cannot be addressed as part of the EHC planning process, explain and record the reasons why.It may be difficult to do this for some children and young people. However, you should still involve them as far as possible. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on providing advice and information for the EHC plan . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review B: involving children and young people evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. ## Reviewing progress and needs, and coordinating with EHC plan reviews Education, health and social care practitioners should review the child or young person's progress and needs at regular intervals, to: check if their needs or circumstances have changed ensure that outcomes remain realistic and focused on helping them reach their full potential. Conduct a professional assessment if: the child or young person's needs change significantly (for example, if they develop new health problems or there is a change in their existing conditions) or their circumstances change significantly. Share the results of the professional assessment with the local authority so that they can decide whether: the EHC plan is still fit for purpose or any provisions in the existing EHC plan should be changed (without a full EHC plan review or reassessment) or to conduct a reassessment of the EHC plan. Consider coordinating the EHC plan annual reviews and social care reviews. Do not reduce the support specified in the EHC plan just because a child or young person shows improvements in particular areas or is able to do new things, because they may rely on the support they get to do this. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reviewing progress and needs, and coordinating with EHC plan reviews . Full details of the evidence and the committee's discussion are in: evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. ## Funding Local authority commissioners and their partners should provide sufficient funding to enable all support listed in the EHC plan that they are responsible for to be provided. When requests for additional resources are refused: the people who make this decision should explain the reasons for not providing this support to the practitioners involved the practitioners should discuss this with the child or young person and their family and carers, and explain potential courses of action. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on funding . Full details of the evidence and the committee's discussion are in evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. ## If children, young people and their families decline an EHC plan If parents or carers decline an EHC plan: discuss their reasons for this address any concerns they have, taking account of any assumptions or cultural beliefs discuss the potential implications of deciding not to have an EHC plan explain how they can request an EHC needs assessment in future, and encourage them to get in touch if they change their minds agree what ongoing support will continue to be provided think about whether this may cause a safeguarding issue, and follow local safeguarding processes. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on if children, young people and their families decline an EHC plan . Full details of the evidence and the committee's discussion are in evidence review M: views and experiences of service providers. Loading. Please wait. # Personal budgets and direct payments These recommendations should be read alongside government guidance on children and young people's continuing care; NHS England guidance on continuing healthcare and government guidance for local authorities and clinical commissioning groups on the delivery of direct payments and personal health budgets. Local authorities and health services should inform disabled children and young people with severe complex needs and their families and carers about personal budgets (including personal health budgets) and direct payments, covering: if they are eligible, and if so how to apply what they can use the money for. Local authorities and health commissioners should continue to ensure services coordinate even if they have been commissioned using direct payments. For example, if the family commission health and care support for a child or young person, the local authority and health commissioners should ensure that those providers still have access to health and care advice directly from statutory providers. Be aware that personal budgets are mandatory for people aged 18 and over who have a care and support plan (although the person can decide whether or not to receive their budget as a direct payment), in line with the Care Act 2014. For children, young people and families and carers who are receiving direct payments, local authorities should assess the full cost of providing the services proposed in the needs assessment. For more guidance on personal budgets and direct payments for young people aged 18 and over, see the section on personal budgets and direct payments in the NICE guideline on people's experience in adult social care services. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on personal budgets and direct payments . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. # Supporting parents and carers Direct families and carers to sources of practical support (including the special educational needs and disability Information Advice and Support services) and emotional support, to help them come to terms with their child's needs and diagnosis (or lack of diagnosis). Consider using a person-centred planning approach, to help include parents and carers in care planning. Ask families and carers how much they want to be involved in making decisions about care planning, because different families will want different levels of involvement. Be aware that families may change their minds over time about the level of involvement they want. The interagency team should consider providing information about the emotional and practical support options available to help parents plan for what will happen when they cannot care for their child (for example, if they are too unwell, or after their death). Support options could include voluntary and community support, advocacy, or seeking independent legal advice. ## Training for parents and carers Education, health and social care services should consider: jointly developing training for parents and carers co-producing this training with parents and carers. In training for parents and carers, consider covering: helping them to understand and meet their child's needs helping them effectively support their child's preferred method of communication how the different services work and what support to expect for their child what they can do if they think they are not receiving the support they are entitled to how to advocate for their child. Ensure that the training is appropriate to the needs of families. Ensure that the practitioners leading the training have the appropriate knowledge and skills (for example, a consultant might not be needed if the training is not going into detail on medical needs). Consider using different teaching styles as needed, so the training is useful for all parents and carers. Consider providing opportunities for parents and carers to discuss their experiences with each other during the training (for example, with group activities or by setting time aside for free discussion), because this will help them to learn from each other and develop support networks. Do not restrict training to a single point in time (for example, at diagnosis). Let parents and carers take up training when they are ready for it, at different points in the child or young person's life. Regularly ask parents if they want to take up training (for example, at review meetings). Consider making training sessions more accessible to parents and carers by: providing flexibility on training session times, locations and formats scheduling training at times when the child or young person has pre-arranged care (for example, when they are at school) taking account of childcare arrangements for the family's other children. Review the effectiveness of training (for example, by asking for feedback from parents and carers), to ensure it meets its objectives and the needs of parents and carers. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting parents and carers, and training . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review D: supporting families and carers evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. # Social participation Ideally, social activities would be accessible to all children, so that children with and without disabilities could participate together. However, there is evidence that disabled children and young people with severe complex needs often do not have access to any social activities. So, although there are other ways to improve social participation for the wider population of disabled children and young people, these recommendations focus on improving social participation for disabled children and young people with severe complex needs. Be aware that social participation: is as important as care and education for maintaining and improving the quality of life of disabled children and young people with severe complex needs is more difficult for children and young people who are not in education or work may justify a young person with progressive or fluctuating illness in attending school or college, even if their attendance may be interrupted. Local authorities should consider developing and funding group activities (for example, sports or theatre) as part of their short break services. When developing these activities, they should work with other organisations (including voluntary and community organisations). When local authorities are planning group social activities as part of short break services, they should: ensure there is a range of options to accommodate different behavioural, mobility, learning and communication needs, and different cultural backgrounds and family circumstances think about access for those living in rural areas think about what equipment will be needed to make activities accessible. For statutory requirements on short breaks, see the Department for Education guidance on short breaks for disabled children. Education, health and social care services should adapt activities, communication formats, the physical environment and participation methods as needed to meet the needs of the children and young people who are attending. Interagency teams should plan support to help children and young people to participate in social activities. This could involve: helping them make friends and access local community facilities helping them use the internet and social media to maintain their friendships and meet new people safely helping them to volunteer in the community. Use short breaks for the benefit of the child or young person (for example, by running group social activities), as well as a break for families. Health services should work with education and social care services to address children and young people's health needs flexibly, so they can join in with education and social activities alongside other children and young people. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on social participation . Full details of the evidence and the committee's discussion are in: evidence review F: supporting participation in education and social activities evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. # Transition from children's to adults' services These recommendations should be read alongside the special educational needs and disability (SEND) code of practice (chapter 8 and paragraphs 9.151 to 9.152), and supporting legislation. Local authorities must ensure that preparation for adulthood is covered at education, health and care (EHC) plan reviews from year 9 onwards, in line with the SEND Regulations 2014. When working with young people, interagency teams should: focus on the young person's goals for adulthood, instead of just treating health problems or providing short-term support help the young person and their parental deputy to prepare for adult life and maximise their independence. Do not assume that young people will have a clear plan for adulthood at the start of transition planning. Help them to understand the different options, and give them and their families enough information to make informed decisions. For young people who lack capacity to plan for adulthood, work with the people who know them best (including their parents and carers), using best interests decision making in line with the Mental Capacity Act. Healthcare professionals should find out what services are available locally, and involve them as needed to help with the transition. In addition to statutory transition points, education, health and social care services should work with the young person and their family and carers to coordinate the age of non-statutory transitions to adults' services, to ensure a consistent approach across sectors. Interagency teams should work together to plan the transition between children's and adults' services for each young person. Each practitioner should read the sections of the plan produced by other practitioners, to make sure the plan works as a whole. In transition reviews, make short-term goals (such as staying away from home overnight) as well as long-term goals (such as living independently). Do not assume that all young people will go on to further education. For young adults aged 18 to 25 who are not in education, health and social care practitioners should ensure that their ongoing needs are met in line with Department for Education's SEND guidance on 19- to 25-year-olds' entitlement to EHC plans. Plan well in advance of the transition to adults' services to prepare young people for alternatives to education (for example, look at supported internships and community adult social care support). As early as possible and by the time young people are approaching adulthood, explain to them and their parents: how their rights will change how the level of parental involvement and decision making may change how parents can register to act as a deputy if their child lacks mental capacity. When a young person is transferring from children's to adults' services, the named worker should: -versee and coordinate transition hand over their responsibilities as named worker to someone in adults' services, and give this person's contact details to the young person and their family. During transition, give young people and their families and carers information about: the purpose and potential outcomes of the adult needs assessment the timing of appointments and when decisions will be made which services will be involved in their care during and after transition what happens to their support if their EHC plan stops. For more guidance on transition, see the NICE guideline on transition from children's to adults' services for young people using health or social care services, in particular the sections on: person-centred approaches (recommendation 1.1.4) named workers involving young people in their transition planning involving parents and carers in transition planning support from the named worker before transition planning and developing transition services involving young people and their carers in service design (recommendation 1.1.1) nominating senior executives and managers to develop and implement transition strategies (recommendation 1.5.1). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on transition from children's to adult services . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review G: promoting and maintaining inclusion, independence and wellbeing evidence review J: planning and managing transition from children's to adults' services evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait.# Recommendations on specialist support for disabled children and young people with particular needs People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. These recommendations cover specialist support on palliative care, communication aids, environmental adaptations and accessibility, travel training and employment. There are also recommendations in this guideline on: general support for all disabled children and young people with severe complex needs service organisation, including working culture, training, integrated working and commissioning. The government's special educational needs and disability (SEND) code of practice is the primary guidance for processes around SEND. This NICE guideline makes recommendations on how existing legislation and statutory guidance should be put into practice. When there is evidence that existing legislation and statutory guidance is not being implemented, the guideline recommendations reiterate this and provide further guidance to help with implementation. # Palliative care and end of life care These recommendations should be read alongside government guidance on children and young people's continuing care, particularly for those who require fast-track assessment because of the nature of their needs (such as a palliative care need). Before making a palliative or end of life care plan, find out if the child or young person has already documented their wishes (for example, in an advance care plan). When making a palliative or end of life care plan for a disabled child or young person with severe complex needs, healthcare professionals should: tell the education and social care practitioners who are supporting the child or young person request a review of the education, health and care (EHC) plan (if they have one). The interagency team should explain what support options are available and find out what further support family and carers need at each stage of the palliative and end of life care process. Let the child or young person choose which support and activities to continue with. Keep providing these in parallel with the palliative care plan and end of life support. When reviewing the EHC plan and other support the child or young person receives, be flexible, and focus on: maintaining things that the child or young person views as important, such as social activities and contact with friends (this includes seeing friends at school or college) addressing new problems or needs that have developed since palliative or end of life care started (for example, new health problems). When a child or young person's needs change and new support is agreed, implement this as soon as possible, without waiting for the EHC plan to be finalised. Education and social care practitioners should continue to be involved. They should adjust the support they provide in line with the palliative or end of life care plan. Interagency teams should arrange regular joint reviews of the palliative or end of life care plan, with the frequency of review based on how rapidly the child or young person's needs are changing. Health services should consider providing training for education and social care practitioners, to help them understand how palliative and end of life care and parallel planning work. This training should be delivered by the most relevant healthcare professionals with experience in providing palliative and end of life care for children and young people. For more guidance on end of life care, see the NICE guideline on end of life care for infants, children and young people with life-limiting conditions. In particular, see the sections on: general principles and decision making advance care planning care of the child or young person who is approaching the end of life preferred place of care and place of death. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on palliative care and end of life care . Full details of the evidence and the committee's discussion are in evidence review E: palliative and end of life care. Loading. Please wait. # Communication aids When conducting assessments for communication aids: think about how these would work across multiple settings (for example, if the child or young person can use the communication aid at school and at home) if possible, provide equipment to the child or young person rather than to a service they use (such as their school), so they can use the equipment wherever they go include the child or young person and their families and carers in the assessment process. When a child or young person has been provided with a communication aid, education, health and social care services should: provide information to staff, and train them to support the child or young person and to make best use of the communication aid (the local augmentative and alternative communication service can provide this training, working with the specialised service as needed) ensure that staff know how to get support if the device is damaged or no longer fit for purpose agree who is responsible for maintaining, servicing and insuring the communication aid provide support during transition (for example, when the child or young person finishes education), so that they can continue using the communication aid in new environments and with new staff provide a paper-based backup for children and young people who are using powered systems, for when the powered system breaks or is not appropriate work with specialist services to ensure that the child or young person can use their communication aid in all settings (home, school and others) arrange reviews for the communication aid, to ensure it continues to meet the needs of the child or young person. Services should also provide all this information, support and training to families and carers. Education, health and social care practitioners should tell children and young people who use augmentative and alternative communication and their families and carers about any support and mentoring groups that could help them with communication and social interaction. Education, health and social care services should tell their staff about the eligibility criteria for augmentative and alternative communication services (both local services and NHS England specialised services). Education, health and social care practitioners should refer disabled children and young people with severe complex needs to specialised augmentative and alternative communication services if they meet the eligibility criteria. For specialised services, education, health and social care services should follow the referral process and eligibility criteria specified in the NHS England guidance for commissioning augmentative and alternative communication services and equipment. Do not add requirements for referrals to be made by specific practitioners (such as occupational therapists), because this will cause delays. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communication aids . Full details of the evidence and the committee's discussion are in evidence review I: suitability and accessibility of environments. Loading. Please wait. # Environmental adaptations When environmental adaptations may be needed for disabled children and young people with severe complex needs, education, health and social care services should: provide information on how to get assessments for adaptations support families through the process of assessment. When conducting assessments for environmental adaptations: think about how these would work across multiple settings (for example, whether the child or young person can use a switch at school and at home) if possible, provide equipment to the child or young person rather than to a service they use (such as their school), so they can use the equipment wherever they go include the child or young person and their families and carers in the assessment process. When an environmental adaptation has been made for a child or young person, education, health and social care services should: provide information and train staff on how to use the adaptation agree who is responsible for maintaining, repairing, servicing and insuring the adaptation. Education, health and social care services should train children and young people and their families and carers to use environmental adaptations they are provided with, and check that they are competent to do so. Education, health and social care services should tell children and young people and their families and carers how to get a review and reassessment of their environmental adaptations when their needs change. Education, health and social care practitioners should tell children and young people who use environmental adaptations and their families and carers about any support and mentoring groups that could help them with environmental accessibility and social interaction. When families move, education, health and social care services and practitioners from the old area and the new area should work together to ensure that they can access necessary equipment during and after the move. This involves: checking who owns the equipment, and if the child or young person can take it with them or if they will need replacements in the new area agreeing what assessments are needed in the new area keeping children and young people and their families up to date during and after the move. Education, health and social care services should tell their staff about environmental control services, so that staff know to refer children and young people who meet the eligibility criteria. Education, health and social care practitioners should refer children and young people to specialist environmental control services if they meet the eligibility criteria. Education, health and social care services should follow the referral process and eligibility criteria specified in the NHS England service specifications for environmental control services. Do not add requirements for referrals to be made by specific practitioners (such as occupational therapists), because this will cause delays. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on environmental adaptations . Full details of the evidence and the committee's discussion are in evidence review I: suitability and accessibility of environments. Loading. Please wait. ## Environmental accessibility Be aware that there is existing best practice and statutory guidance on environmental accessibility (for example, the Royal College of Occupational Therapists' guide to planning and delivering home adaptations, and UK building regulations on access to and use of buildings). Examples of environmental accessibility adaptations include: disabled access for children and young people who use mobility aids and devices space to use and to store environmental control equipment suitable toilets lighting and acoustic adaptations, to avoid distractions or distress. Education, health and social care providers should conduct regular accessibility assessments (at least annually) of their services, looking at the physical environment (including sensory aspects and whether the environment is child or young person friendly) and staff behaviours and knowledge of disability and accessibility. Charities and support organisations can provide advice on what changes are needed (for example, see the National Autistic Society accreditation scheme). Education services should make the results of these accessibility assessments publicly available. Health and social care services should consider making the results of these accessibility assessments publicly available. Interagency teams should make sure that the results of the accessibility assessments are available for key public places that the child or young person needs to access (in line with their education, health and care plan). For example: after-school clubs (if they are not held at the school) short break services community facilities. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on environmental accessibility . Full details of the evidence and the committee's discussion are in evidence review I: suitability and accessibility of environments. Loading. Please wait. # Travel training Local authorities should help disabled children and young people with severe complex needs to use transport (to help them get anywhere they need to go, not just to school). They should consider providing a training framework to achieve this. Local authorities could develop their own training programmes as part of this framework, or use existing ones (such as ASDAN's module on using transport). Local authorities should ensure that services implement the training framework. Travel training could cover: assessing the child or young person's mobility skills and identifying problems they will have with using public transport assessing and managing risks route planning using assistance services for booking tickets mobility and traffic awareness having someone accompany the child or young person until they are used to the route travelling with parents and carers, for children and young people who will not be able to travel on their own how communication aids can help, if the child or young person uses them how to safely ask for help when something goes wrong. Local authorities should provide parents, carers and relevant professionals (such as teachers) with information to help them better support children and young people who are using public transport (for example, independent travel training, availability of concessionary fares). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on travel training . Full details of the evidence and the committee's discussion are in evidence review I: suitability and accessibility of environments. Loading. Please wait. # Employment Education providers should ensure that independent careers information, advice and guidance is provided using the Gatsby benchmarks, to help disabled young people with severe complex needs think about their employment options. For more information on the Gatsby benchmarks, see the Department for Education's statutory guidance on careers guidance. Local authorities and commissioners should ensure that supported internship programmes are available in their local area for young people, to help them develop job searching and employability skills, and to support them into employment. When commissioning employment support services for young people, local authorities should include a requirement in the service specification to provide a lead employment practitioner (for example, a job coach) for each young person who is going to undertake a supported internship. This practitioner should have expertise in helping young people with disabilities to find work, and the authority to coordinate work and direct the interagency team on issues related to employment. When commissioning employment support services for young people, local authorities should consider including a requirement in the service specification to provide a lead employment practitioner (for example, a job coach) for each young person who has employment as an outcome in their education, health and care (EHC) plan. Education, health and social care practitioners should start discussing employment as a future option from the start of transition planning (by year 9, age 13 or 14, but ideally earlier than this). Follow this up with more specific discussions, and direct the young person and their family and carers to relevant sources of information. Education, health and social care practitioners should consider making a vocational profile with young people who are considering employment, to identify their skills and what they want to do in the future. Do this well in advance of the move into post‑16 education. Education, health and social care practitioners should work together when planning employment support and consider that young people may need to be involved in: travel training, to help them prepare for a work commute developing communication passports or communication plans to support them at work identifying any environmental adaptations or equipment that they will need for work planning their personal care needs at work planning support if they are anxious about starting work training for employers, to help them communicate with and support the young person with their work. Supported internship providers should help disabled young people to find work by: creating links with local employers, so they can identify job opportunities, address employer misconceptions about disabled young people, and explain what on-the-job support the interagency team can provide contacting relevant support groups. Following a supported internship, and before ceasing the EHC plan, the current provider should work with the prospective employer to plan next steps for the young person after the internship ends: agree what changes will happen, and when agree who the young person can go to for help look for ways the young person can use their experience from the internship in their job. Local authorities should include information about support workers and job coaches in their special educational needs and disability (SEND) Local Offer, so that young people, their families and prospective employers know what help and resources are available. Funding for support workers and job coaches is available through the Department for Work and Pensions' Access to Work scheme. Encourage employers to train and appoint workplace buddies (who are not their line manager) for disabled young people. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on employment . Full details of the evidence and the committee's discussion are in evidence review H: preparation for employment. Loading. Please wait.# Recommendations on service organisation, integration and commissioning People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. These recommendations cover service organisation, including working culture, training, integrated working and commissioning. There are also recommendations in this guideline on: general support for all disabled children and young people with severe complex needs specialist support, covering palliative care, communication aids, environmental adaptations and accessibility, travel training, and employment. The government's special educational needs and disability (SEND) code of practice is the primary guidance for processes around SEND. This NICE guideline makes recommendations on how existing legislation and statutory guidance should be put into practice. When there is evidence that existing legislation and statutory guidance is not being implemented, the guideline recommendations reiterate this and provide further guidance to help with implementation. # All education, health and social care practitioners ## Working culture Education, health and social care practitioners should collaborate to develop a positive working culture and: take time to develop positive relationships with each other treat everyone involved in the care of the disabled child or young person with severe complex needs as equals encourage open discussion be sensitive and constructive when challenging someone else's professional opinion. ## Organising handovers If the key practitioners involved need to change, organise a handover to avoid disruptions in care. Tell the child or young person and their family about the change and update any new practitioners on the child or young person's history. ## Learning about other practitioners and services Education, health and social care practitioners should learn about the responsibilities of other people and services involved in supporting the child or young person. They should use this knowledge to provide more wide-ranging and coordinated support and information (outside their own specialty) to the child or young person and their family and carers, and to reduce the number of different people the family have to contact. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on all education, health and social care practitioners . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers. Loading. Please wait. # Education, health and social care services These recommendations also apply to local authorities when they provide services. ## Working culture Education, health and social care services and managers should ensure that practitioners have dedicated time for team and relationship building. For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on working culture . Full details of the evidence and the committee's discussion are in evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. ## Key working support These recommendations should be read alongside paragraph 2.21 of the special educational needs and disability (SEND) code of practice. The level of key working support for disabled children and young people with severe complex needs should: be flexible be tailored to individual needs take account of their family circumstances. Senior managers in education, health and social care services should work together to ensure that: each disabled child and young person with severe complex needs has a practitioner providing them with key working support these practitioners have the training, time and resources needed to provide this support, taking into account their other commitments. Managers should ensure that interagency team members understand what key working support involves. The practitioner who is assigned to provide key working support should: become part of the interagency team be someone the child or young person is comfortable with get to know the child or young person well and understand their needs be identified based on the child or young person's individual needs and preferences (for example, if they mainly have healthcare needs then a healthcare practitioner would be best). Provide children and young people and their families with contact details for the practitioner providing them with key working support. Interagency teams should work with managers to assign a practitioner to provide key working support for each child and young person. Practitioners providing key working support should: coordinate meetings, timings and records between the different services involved, and with the child or young person and their family and carers (this should not be left to parents or carers to arrange themselves) keep other practitioners updated with changes in the child or young person's care (for example, by sharing hospital letters with their school) help the child or young person and their family and carers to navigate services be available for discussions between reviews and meetings if the child or young person has questions or needs more support. If the practitioner who provides key working support needs to change, managers should: work with the interagency team to assign a new practitioner (chosen based on the child or young person's needs and preferences, and not just because they do the same job as the old practitioner) -rganise a handover ensure the new practitioner is updated on the child or young person's history, preferences, goals and ambitions ensure the handover is supported to ensure continuity of care ensure that everyone involved is told about the change (the child or young person, their family and carers, and all relevant education, health and social care practitioners). Practitioners who provide key working support should support families when they move area (in particular, to help families who move area regularly), by: identifying practitioners in their new area to share relevant information with, to ensure continuity of care and support giving a copy of this information to the child or young person and their family and carers telling practitioners in their old area that the family are moving telling practitioners who are responsible for providing environmental equipment that the family are moving. Managers should have a contingency plan for how to maintain consistency if the practitioner providing key working support leaves. Education, health and social care services should have governance and information sharing arrangements in place to ensure that practitioners providing key working support can work effectively with all the different organisations involved. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on key working support . Full details of the evidence and the committee's discussion are in: evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers evidence review N: commissioning, practice and service delivery models. Loading. Please wait. ## Making processes easier to understand Education, health and social care services should consider looking for ways to make what they do and how they work together more transparent to children and young people. For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on making processes easier to understand . Full details of the evidence and the committee's discussion are in evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. ## Training for practitioners Education, health and social care services should consider training practitioners to understand the roles of other people and services involved in the care of children and young people. Education, health and social care services should work with local authorities to provide training for education practitioners on how to include and support disabled children and young people with severe complex needs in mainstream education. Education, health and social care services should provide training for practitioners to help them recognise: social, emotional and mental health needs internalising symptoms (such as anxiety and depression). Education, health and social care services should work together to develop joint training for all practitioners on: working with disabled children and young people with severe complex needs taking their views into account, and supporting them to achieve their life goals how to adapt communication for children and young people who communicate differently use of communication aids. Education, health and social care services should consider running training workshops for practitioners from all 3 sectors, covering needs that are present in all settings (for example, safe eating and drinking, personal care and language development). Education, health and social care services should provide practitioners with opportunities to observe practitioners from different sectors working with the child or young person. Education, health and social care services should work with each other to agree consistent messages and ensure that their staff understand: how their contributions affect education, health and care (EHC) needs assessments how the contributions of individual staff fit together to show what support the child or young person needs how their contributions will affect the EHC plan outcomes that will be agreed for the child or young person. When developing awareness training programmes, involve children and young people and parents and carers in: deciding what to cover in the training deciding how to structure and evaluate it delivering the training (if appropriate). Education, health and social care services should consider providing short-term observational placements for practitioners from other sectors (as part of induction and then annually). Design these placements to help practitioners learn about children and young people's needs in different contexts, and to understand how other services work to meet those needs. Services that provide short-term observational placements should ensure that interagency teams have a process for providing these placements. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on training for practitioners . Full details of the evidence and the committee's discussion are in: evidence review D: supporting families and carers evidence review K: barriers and facilitators of joined-up care evidence review L: enabling professionals to meet the needs of children and young people evidence review M: views and experiences of service providers. Loading. Please wait. ## Delegated clinical tasks When training support workers to undertake delegated clinical tasks, registered healthcare professionals should follow guidance on training and competency from the Care Quality Commission, the General Medical Council, the Nursing and Midwifery Council, the Health and Care Professions Council, and the professional organisations that align to these. In particular, registered healthcare professionals should: -nly train support workers to carry out delegated clinical tasks if these workers are employed and insured for these tasks, and accountable for their professional conduct after delivering training, actively assess the competency of support workers to carry out delegated clinical tasks at the required standard ensure that ongoing clinical supervision arrangements are in place for support workers. For support workers who have been delegated clinical tasks by healthcare practitioners, health and social care employers should follow guidance on training and competency from the Care Quality Commission, the General Medical Council, the Nursing and Midwifery Council, the Health and Care Professions Council, and the professional organisations that align to these. In particular, health and social care employers should: ensure support workers are competent to carry out these tasks ensure the type of delegated work they are expected to carry out is specified in their job descriptions put indemnity insurance in place for delegated clinical tasks ensure that training providers or other suitable organisations will provide ongoing supervision of support workers when a clinical competency must be assured to be at a required standard agree a joint incident investigation policy with relevant education, health and social care partner organisations (using the framework set out in the NHS Quality Board Position Statement on Quality in Integrated Care Systems), covering: reporting of incidents who will lead investigations when a collaborative investigation is needed. For parents and family members who have been delegated clinical tasks, healthcare practitioners should follow guidance from the Care Quality Commission, the General Medical Council, the Nursing and Midwifery Council, the Health and Care Professions Council and the professional organisations that align to these. In particular, practitioners should: train parents and family members to undertake delegated clinical tasks and use any equipment needed to undertake these tasks after training, actively assess the competence of parents and family members to carry out delegated clinical tasks at the required standard provide parents and family members with ongoing clinical support from an agreed named contact set up a process for parents and family members to report problems or to request further training. ## Feedback Education, health and social care services should periodically jointly request feedback from children and young people and their families and carers on how well they have worked together with the other services involved in their care and support. Services should periodically jointly request feedback from children and young people and their families and carers on how well they worked together with them. Services should have processes in place for addressing the feedback of young people and their families and carers, if they are not satisfied with the support they have received. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on delegated clinical tasks and feedback . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. # Interagency teams ## Organising interagency teams Education, health and social care services should: -rganise all the practitioners working with the child or young person into an interagency team ensure that interagency teams include practitioners with the skills and experience to address all of the child or young person's needs (from birth to 25 years). Education, health and social care services should develop procedures for resolving disagreements that arise within interagency teams. ## Meeting needs in all settings Interagency teams should ensure that the child or young person's needs are met in all settings (for example, if they communicate differently, make sure they have support at home and in school). ## Sharing knowledge within the team Interagency team members should share their experiences of supporting the disabled child or young person within the team, so they can learn from each other and gain a broader understanding of the needs of the child or young person. In interagency team meetings, members should share specialist knowledge and sources of support with practitioners outside of their speciality. This could include: changes in clinical practice, legislation or statutory guidance particular caring techniques professional networks -ther organisations that can provide support (such as patient organisations). For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on interagency teams . Full details of the evidence and the committee's discussion are in: evidence review G: promoting and maintaining inclusion, independence and wellbeing evidence review K: barriers and facilitators of joined-up care evidence review L: enabling professionals to meet the needs of children and young people. Loading. Please wait. # Local authorities and health commissioners When commissioning education, health and social care services for disabled children and young people with severe complex needs: focus on early intervention and multi-agency involvement to identify, assess and address needs -nly make long-distance placements if options to provide care and support close to home and within their community are not suitable for their needs and outcomes specify outcomes in contracts, and avoid contracts that only describe what services should be provided think about how each service will fit in and work with other services, and how commissioning changes in one service may affect other services and the ability to provide integrated education, health and social care support. Local authorities and health commissioners should plan how funding and services will be organised across education, health and social care for young people once they turn 18 or transition to adult services, to ensure continuity of support to meet their needs and outcomes. Do not restrict access to services based solely on: what support people have previously received whether or not they have a particular diagnosis, or no diagnosis at all (unless there is a medical reason for these restrictions). Do not deprioritise children and young people who are having an education, health and care (EHC) needs assessment solely to meet organisational targets, or because statutory deadlines have been missed. ## Making referral and joint working easier Commissioners, local authorities and service providers should make referral and joint working easier by: establishing clear processes and criteria for referring children and young people, both within services and between different services making information about these processes easily available, so practitioners know how and when to make a referral. ## Involving children, young people, parents and carers in planning services When commissioning education, health and social care services, commissioners should: check with disabled children and young people with severe complex needs and their parents and carers, to ensure services meet the needs of the local population involve disabled children and young people and their parents and carers in planning services work with children, young people and their parents and carers to ensure their participation is effective and their role in planning is clear focus on outcomes and personalised services. Involve disabled children and young people in the review of existing services, by asking for their feedback on how services are working. Commission services based on the needs of children and young people, rather than expecting them to just use the services that already exist. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on local authorities and health commissioners . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs evidence review K: barriers and facilitators of joined-up care evidence review M: views and experiences of service providers evidence review N: commissioning, practice and service delivery models. Loading. Please wait. ## Coordinating EHC plan process changes with local services Local authorities should consider notifying services and commissioners before making changes to their processes for producing EHC plans (for example, changes in the plan format or the information they require from practitioners). Local authorities should consider involving services and commissioners with these changes, if they can do this without delaying support or assessments for children and young people. ## Training Local authorities should provide training on EHC plans and related processes for education, health and social care practitioners, covering: an explanation of the EHC needs assessment process and how an EHC plan is developed guidance on filling in templates and contributing advice and information to support an EHC plan. Local authorities should provide training on how to write EHC plans for practitioners in their special educational needs and disability (SEND) team. ## Short breaks Local authorities must provide a range of short breaks for disabled children and young people with severe complex needs, in line with the Breaks for Carers of Disabled Children Regulations 2011. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on coordinating EHC plan process changes with local services, training and short breaks . Full details of the evidence and the committee's discussion are in: evidence review D: supporting families and carers evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. ## What to include in the SEND Local Offer Local authorities should include the following in their SEND Local Offer: a comprehensive explanation of their EHC needs assessment process, which: includes any eligibility criteria makes it clear that EHC needs assessments should be requested based on a child or young person's needs, and not on other factors (such as potential availability of funding) details of what services are available, and the roles of the different services and practitioners a list of support groups for disabled children and young people who use assistive technologies details of the leisure activities (including social activities) and related support available to disabled children and young people details of the employment support they offer disabled young people. Tell all children, young people and their families that they can give feedback on the SEND Local Offer, in line with the Children and Families Act 2014 and the SEND Regulations 2014. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on what to include in the SEND Local Offer . Full details of the evidence and the committee's discussion are in: evidence review A: views and experiences of service users evidence review F: supporting participation in education and social activities evidence review H: preparation for employment evidence review I: suitability and accessibility of environments evidence review K: barriers and facilitators of joined-up care. Loading. Please wait. # Improving how local authorities, commissioners and services work together Integrated care systems and local authorities should develop a joint commissioning framework to use when commissioning services across education, health and social care. Commissioners should specify in their contract requirements that education, health and social care services should work together in an integrated way to support disabled children and young people with severe complex needs. Senior managers in education, health and social care services should have formal processes in place to support interagency team working (see the recommendations on decision making and information sharing and privacy). Education, health and social care providers should make arrangements or agreements setting out how they will work together in an integrated way to support disabled children and young people with severe complex needs. Healthcare professionals should check that children and young people with severe complex needs and a learning disability or autism are included on a locally maintained dynamic support register. Health commissioners should ensure that education and social care services: know about the dynamic support register are consulted regularly to ensure the register is maintained effectively. For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on improving how local authorities, commissioners and services work together . Full details of the evidence and the committee's discussion are in: evidence review G: promoting and maintaining inclusion, independence and wellbeing evidence review N: commissioning, practice and service delivery models. Loading. Please wait.# Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. # Augmentative and alternative communication (AAC) services Services that help people with significant communication impairment. For more information, including eligibility criteria, see the NHS England service specification for specialised AAC services. # Awareness training programmes Any training programme that is: for parents and carers or for practitioners, but is focused on helping them work more effectively with the child, young person and their family or carers. # Communication aid Anything that helps a person communicate more effectively. Communication aids include paper-based systems (for example, letter or word boards), signing, and computer equipment. # Disabled children and young people with severe complex needs Disabled children and young people from birth to 25 years who: need coordinated education, health and social care support because of their severe and complex needs and are eligible for an education, health and care plan, in line with the Children and Families Act 2014. Some recommendations in this guideline may be difficult or impossible to implement for babies or very young children. However, it is also difficult to give useful age cut-offs for particular recommendations. Children develop at different rates, and their development rate will be affected by their specific disabilities and health conditions. Any age cut-offs risk mistakenly excluding and disadvantaging some children. If a particular recommendation is not appropriate for a baby or young child, it is still important to involve them as far as possible in discussions and decisions about their care and support. For more information, see: recommendation 1.1.47 NICE's guideline on babies, children and young people's experience of healthcare. # End of life care In this guideline, end of life care includes the care and support given in the final days, weeks and months of life, and the planning and preparation for this. # Environmental adaptations Building adaptations designed to make homes, schools and other buildings (such as short break settings) accessible to disabled children and young people. Adaptations include minor changes (such as fitting grab handles or levelling door thresholds) and major changes (such as specially adapted bathrooms or fitting ceiling track hoists). # Environmental control services Services that help people with complex physical disabilities use electronic devices (for example, the TV), if they cannot use the standard controls. For more information, see the NHS England service specification for environmental control services. # Interagency team The existing team of key education, health and social care practitioners who are working together with the family to support the child or young person. # Local authorities This includes individual and combined local authorities. # Named worker This refers to the named worker as defined in the NICE guideline on transition from children's to adults' services. # Palliative care An approach to care covering physical, emotional, social and spiritual support. Palliative care focuses on improving the quality of life for the child or young person and supporting their family members or carers, and includes managing distressing symptoms, providing respite care, and support with death and bereavement. # Parallel planning Planning for end of life care while taking account of the often unpredictable course of life‑limiting conditions. It involves making multiple plans for care, and using the one that best fits the child or young person's circumstances at the time. # Parents and carers This includes anyone with parental responsibility for disabled children and young people with severe complex needs, including corporate parents. # Special educational needs and disability (SEND) Local Offer This explains what support services are available in the local area for children and young people with special educational needs or disabilities, and their families. Every local authority is responsible for writing a SEND Local Offer and making it publicly available. # Special educational need These are defined in the SEND code of practice: 'A pupil has SEN where their learning difficulty or disability calls for special educational provision, namely provision different from or additional to that normally available to pupils of the same age'. # Supported internships A study programme designed for young people who are aged 16 to 24 and who have an education, health and care plan. It provides them with the extra support they need to find employment. The internship includes support from a job coach. Supported internships are primarily based with an employer, and are normally designed to lead to a job when they finish. Because of this, a supported internship is usually the final year of education for a young person. For more information, see the guidance on supported internships from the Department for Education. # Support workers (section 1.13 on employment) See the Department for Work and Pensions' Access to Work Scheme. # Support workers (section 1.15 on education, health and social care services) Anyone other than a family member who has been delegated clinical tasks (including teachers, teaching assistants and other staff in education or care settings).# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Assistive technology How effective is assistive technology in enabling disabled children and young people with severe complex needs to express their views to education, health, and social care services? For a short explanation of why the committee made the recommendation for research, see the rationale section on communication aids . Full details of the evidence and the committee's discussion are in evidence review G: promoting and maintaining inclusion, independence and wellbeing. Loading. Please wait. ## Environmental adaptations What are the most effective environmental adaptations to ensure the suitability and accessibility of the settings where disabled children and young people with severe complex needs receive education, health and social care support? For a short explanation of why the committee made the recommendation for research, see the rationale section on environmental accessibility . Full details of the evidence and the committee's discussion are in evidence review I: suitability and accessibility of environments. Loading. Please wait. ## Dedicated key workers What is the effectiveness of dedicated key workers for delivering joined-up services to meet the education, health and social care needs of disabled children and young people with severe complex needs? For a short explanation of why the committee made the recommendation for research, see the rationale section on key working support . Full details of the evidence and the committee's discussion are in evidence review N: commissioning, practice and service delivery models. Loading. Please wait. ## Care close to home What are the most effective commissioning, practice and service delivery models to deliver joined-up services to meet the education, health and social care needs of disabled children and young people with severe complex needs while enabling them to stay close to home? For a short explanation of why the committee made the recommendation for research, see the rationale section on local authorities and health commissioners . Full details of the evidence and the committee's discussion are in evidence review N: commissioning, practice and service delivery models. Loading. Please wait. ## Short break services What components of short break services are most effective for disabled children and young people with severe complex needs and their families and carers? For a short explanation of why the committee made the recommendation for research, see the rationale section on coordinating education, health and care (EHC) plan process changes with local services, training and short breaks . Full details of the evidence and the committee's discussion are in evidence review D: supporting families and carers. Loading. Please wait. # Other recommendations for research ## Telehealth and virtual platforms What is the effectiveness of telehealth and virtual platforms for communicating with disabled children and young people with severe complex needs and providing education, health and social care interventions? For a short explanation of why the committee made the recommendation for research, see the rationale section on principles for working with children, young people and their families . Full details of the evidence and the committee's discussion are in evidence review B: involving children and young people. Loading. Please wait. ## Joint commissioning arrangements What are the most effective joint commissioning arrangements for disabled children and young people with severe complex needs? For a short explanation of why the committee made the recommendation for research, see the rationale section on local authorities and health commissioners . Full details of the evidence and the committee's discussion are in evidence review N: commissioning, practice and service delivery models. Loading. Please wait.# Rationale and impact for recommendations on supporting all disabled children and young people with severe complex needs These sections briefly explain why the committee made the recommendations and how they might affect practice and services. # Principles for working with children, young people and their families Recommendations 1.1.1 to 1.1.12 ## Why the committee made the recommendations There was moderate-quality qualitative evidence that: service providers do not always use a person-centred approach, and do not adequately capture the child or young person's perspective the potential of children and young people may be underestimated, while good education, health and care (EHC) plans should recognise their aspirations and think about long-term options. The committee's understanding of the special educational needs and disability (SEND) code of practice is that it highlights the importance of supporting children and young people to achieve their ambitions. Based on the committee's experience, cultural backgrounds and preferences can impact on the views, life goals and ambitions of individuals, and so this should be taken into consideration to provide truly person-centred care. There was moderate- and high-quality evidence that parents and carers felt positive when given the chance to provide their views, and that they felt negative when their views were ignored. In the committee's experience, children and young people with the most complex needs may not be able to actively participate in planning or decision making. In this situation, taking into account the views of the people who know the child or young person best will help to ensure that the child or young person's perspective is fully represented. Support needs are individual to each child or young person, and not everyone with the same diagnosis will need the same support. In the committee's experience, this is sometimes overlooked, and they made a recommendation to remind practitioners of this point. The Children and Families Act 2014 requires arrangements to be made to provide the information and support that is necessary to enable children, young people and parents to participate in decisions. There was moderate-quality qualitative evidence that disabled children and young people and their families and carers value a person-centred approach. Despite this, in the committee's experience, children and young people are often not invited to participate in meetings where decisions are made about their support and are not actively included if they do attend. In the committee's experience not all children and young people want to, or are able to, attend meetings. However, it is still important to get their input in other ways to facilitate their participation in decisions. Keeping a record of how children and young people participate, and their contributions, can help to keep practitioners accountable. The qualitative evidence highlighted multiple benefits from involving children and young people in their care and support: there was low-quality evidence that this made them feel more positive there was moderate-quality evidence that it made them show more confidence there was moderate-quality evidence that their involvement gives practitioners a more accurate understanding of their needs, goals and ambitions. In the committee's experience, it is important to find out which family members need to be involved (for example, in situations of family breakdown). They made a recommendation to cover this, so that practitioners do not make assumptions about family roles and structure. There was moderate-quality qualitative evidence that drawing on the experience and expertise of families and carers would improve knowledge of the child or young person's needs. This is important, because there was also qualitative evidence of negative consequences when the child or young person's needs are not well understood. Moderate-quality qualitative evidence showed that it is important to focus on the views of the children or young person, because these can differ from the views of their parents. This can be difficult to do. In the committee's experience, disabled children and young people with severe complex needs may need specialist support to participate, and their parents and carers need encouragement and support to help their child express their views. In the committee's experience, and in light of the moderate-quality qualitative evidence previously discussed, it is important to regularly ask children and young people and their families and carers if they are satisfied with how they have been involved in decisions about their support, so that involvement is beneficial and not just tokenistic. And when children and young people are not satisfied with their involvement, it is equally important to find ways to address their concerns. The committee were not able to specify a time frame for doing this because it would depend on the services and support being received. There was moderate-quality qualitative evidence that children and young people wanted practitioners to use the same approaches that their families and carers had been using to care for them at home. The committee agreed that this consistency was important if the approaches used have been beneficial. They also agreed that it was important to avoid practices that had been used in the past by families and found not to work well. There was no evidence on the effectiveness of telehealth or virtual platforms for supporting disabled children and young people with severe complex needs. Therefore, the committee made a recommendation for research in this area. ## How the recommendations might affect practice Practitioners will need more time, for example for discussions with children and young people and their families and carers to get their views. However, if practitioners spend more time getting these views, families are likely to have fewer queries, complaints and problems, resulting in time savings later on. Return to recommendations # Communication formats and providing information Recommendations 1.1.13 to 1.1.27 ## Why the committee made the recommendations There was low-quality qualitative evidence that children and young people and their families and carers appreciated when practitioners adapted their communication styles to suit the topic of conversation, and moderate-quality qualitative evidence that non-judgemental and non-directive communication was valued. Based on their experience, the committee agreed that practitioners do not always deal with sensitive conversations effectively and that it was important to prompt practitioners to be empathetic and supportive. This style of communication will help to address the family's feelings and help them to process the information they receive. Low-quality qualitative evidence also showed that a flexible approach to communication was important, taking into account the child or young person's age, developmental level and communication skills. Although this evidence was low quality, the committee were confident that having a flexible approach was necessary to enable children and young people to express their views. Local authorities also have a duty under the Children and Families Act 2014 to have regard to the views of disabled children and young people and those with special educational needs. In the committee's experience, finding the child or young person's preferred communication formats is particularly important, because this group is more likely to communicate differently and to use communication aids. Some children and young people have a communication passport. In the committee's experience, practitioners can use this to learn about a child or young person's communication preferences without having to ask the family to repeat information they have already provided. There was moderate-quality qualitative evidence that language barriers made it difficult for parents to find out about available services, and that more support was needed to help them understand and access support that was available. In the committee's experience parents and carers may also have disabilities or other problems that make it more difficult for them to communicate with practitioners and understand information. There was qualitative evidence on communication formats and providing information: there was low-quality evidence that children and young people and their families and carers needed more information and advice there was moderate-quality evidence that the advice they received was limited there was high-quality evidence that the advice they received was often based on outdated information. The committee agreed that it is important to provide enough up-to-date information, support and advice to allow people to make more informed decisions. Based on the qualitative evidence and their experience, they highlighted areas where children and young people and their families and carers commonly wanted more information. The recommendation on directing children and young people and their families and carers to sources of support and advice is based on: the Children and Families Act 2014, which requires local authorities to make arrangements for providing advice and information about matters relating to special educational needs and disability available to children and young people with special educational needs or disabilities and their parents. the SEND code of practice, which mentions SEND Information, Advice and Support services as an option for providing this information The SEND Regulations 2014, which specify what information must be included in the SEND Local Offer, and include information about forums for parents and carers and support groups moderate-quality qualitative evidence that children and young people benefited from speaking to peers who had experience with the education, health and care system. In the committee's experience, practitioners providing information on peer support groups would have a professional duty of care to make sure that any sources of support they provide are quality-assured. Moderate-quality qualitative evidence indicated that children and young people did not receive the level of support or involvement that they had expected from services. The committee agreed that practitioners needed to find out what expectations people had, in order to provide the support they wanted (if possible) and help them to understand what services can do. When it is not possible to meet people's expectations, it is also important to explain the reasons for this and explore alternatives. ## How the recommendations might affect practice Practitioners might need more time to communicate with children and young people (depending on their preferred communication format) and their families and carers, and to find out about their expectations. This could mean that some more time is required for preparation, and consultation times are longer, which could create a resource impact for services. However, if practitioners spend more time helping children and young people to communicate and understand what services can do, they are likely to have fewer queries, complaints and problems, resulting in time savings later on from practitioners not having to address these. Training may be needed if the preferred communication method requires specialist knowledge. Services across education, health and social care will have to establish processes to share information and to allow more coordinated and joined-up working. Interagency training may also be needed, to ensure that practitioners understand relevant policies and processes and the role of other practitioners and services. Return to recommendations # Preparing for and running meetings with children and young people Recommendations 1.1.28 to 1.1.43 ## Why the committee made the recommendations Moderate-quality qualitative evidence indicated that parents and carers had differing views about involving children and young people in decisions about their care. Some parents and carers felt that participation was inappropriate for their child because of their age, or the nature of their special educational need or disability. Other parents and carers thought it was important to fully involve their child. The Children and Families Act 2014 requires local authorities to provide the information and support necessary to enable children, young people and parents to participate in decisions. As some of these decisions would take place during practitioner-led review meetings, the committee felt strongly that children and young people should be present at these meetings. However, given the concerns of parents and carers and the qualitative evidence that meetings can be intimidating for children and young people, they agreed it would be better to ask them how they would like to be involved. Low-quality qualitative evidence showed that children and young people are better able to communicate their views if they are given help to understand their options and prepare for meetings. In the committee's experience, if parents and carers discuss meetings with their child in advance, they can prepare in a more relaxed home environment. This also allows parents and carers to better understand their child's views in advance of the meeting. These recommendations align with the sections of the Children and Families Act 2014 that cover providing the information and support necessary to enable children, young people and parents to participate in decisions. In addition, the committee's understanding of the SEND code of practice is that it recommends including time to prepare for discussions and meetings. The committee also recommended helping parents and carers to complete documents before meetings because in their experience this can be difficult and confusing, and meetings may be dominated by completing paperwork if this has not been done in advance. In the committee's experience the physical accessibility and cost of attending meetings can cause problems for children and young people and their parents and carers, so practitioners need to check this in advance. In the committee's experience, children or young people are more likely to be motivated to participate in meetings if the issues being discussed are ones that are important to them. Therefore, it is important to get this information ahead of meetings. It is also crucially important that children and young people are able to meaningfully participate in decisions about their care and support, and this is one way to achieve this. Qualitative evidence showed that children and young people had various levels of ability that affected their level of involvement and understanding. The committee agreed it was important to establish the age, communication ability and circumstances of the child or young person in advance of meetings, to ensure that they can meaningfully participate. There was moderate-quality qualitative evidence that: children and young people want practitioners to make more effort to respect their privacy children and young people may be able to better communicate their views in smaller meetings or one-on-one attending meetings can be intimidating for children and young people. Based on this evidence, and their own experience, the committee highlighted ways that the structure and content of meetings could be improved (for example, having meetings in a place where the child or young person feels comfortable). The committee were confident that these recommendations would enable children and young people to participate more effectively in meetings and understand what is happening – both of which are key to their involvement in making informed decisions. In response to moderate-quality qualitative evidence that practitioners do not always take a person-centred approach to meetings, the committee recommended considering the use of person-centred planning tools. In their experience, these tools help ensure that planning is based on information from the child or young person about their needs, wishes and what is important to them. This stops practitioners from making generic assumptions and taking prejudiced attitudes towards the child or young person as a result of their condition. These tools also focus on developing a plan to deliver the outcomes desired by the child or young person. Using a person-centred approach is specified in the SEND code of practice as a way to ensure that children, young people and parents are involved in all aspects of planning and decision making in the EHC needs assessment and planning process. In the committee's experience, disabled children and young people with severe complex needs may need more time to process information and communicate their views. They may also give very brief answers to questions, and may need encouragement and additional time to expand on these. To ensure that they can meaningfully participate in meetings, the committee believed that children and young people needed adequate time to express their views and take in information, and practitioners needed to check that they have understood the information they are given. Children and young people also need to be supported to communicate using their preferred method. Identifying their preferred communication method is particularly important, because this group is more likely to communicate differently and to use communication aids. In the committee's experience, children, young people and their families and carers benefit if meetings are recorded, because this gives them more time to process information. There was moderate-quality qualitative evidence highlighting the importance of respecting children and young people's rights to privacy, and that attending meetings with large numbers of professionals can be intimidating. Therefore, the committee made recommendations to reflect this. There was moderate-quality qualitative evidence that agreeing actions in front of other practitioners and parents improved accountability and made it more likely that practitioners would follow through on agreed actions. The committee's understanding of the Children and Families Act 2014 is that it requires education and training provision to be integrated with health and social care provision. However, moderate-quality qualitative evidence showed that practitioners are often not collaborating effectively and either do not attend interagency meetings or do not prepare for meetings in advance. In the committee's experience, it is crucial that practitioners who know the child or young person and are involved in their support make all reasonable efforts to attend meetings. These practitioners need to come from all services involved, in order for the support provided to be fully integrated. However, the committee acknowledged that this may not always be possible. They used their experience to highlight: factors to consider when deciding whether to go ahead with a meeting if a relevant practitioner cannot attend ways to reduce the impact if the meeting does go ahead without a relevant practitioner. The committee believe that siblings and friends have a different perspective to the practitioners caring for a disabled child or young person with severe complex needs. This different perspective can improve the practitioners' understanding of the child or young person, and can demonstrate strengths and interests that the practitioners have not observed. This enables a broader view of what the child or young person is capable of, so practitioners can make better judgements about their future abilities and adjust outcomes accordingly. Based on this, the committee agreed that children and young people should have the opportunity to invite siblings or friends to share their views. ## How the recommendations might affect practice Practitioners might need more time to plan how to involve children and young people in discussions and meetings. Meetings may also need to be longer, with more breaks, potentially taking more time. However, this should result in children and young people being able to more effectively participate and engage in discussions and decisions about their care and support, saving time later on by leaving fewer problems to deal with. Engagement with care will positively impact their care and outcomes and will outweigh any additional costs. In addition, if care is not person-centred, children and young people may end up with support that does not meet their needs. This may cost services much more further down the line. Holding review meetings outside of a school day might result in health and social care practitioners working alternative hours, and schools will need to negotiate patterns of annual directed time flexibly, including allowing teachers to use their planning, preparation and assessment time if meetings have to be held outside of the school day. Services that want to record meetings may have to buy equipment to do this. However, the recommendations allow them to use written records instead if needed. Return to recommendations # Using a consistent approach Recommendation 1.1.44 ## Why the committee made the recommendation There was moderate-quality qualitative evidence that using a consistent approach when interacting with children and young people was beneficial, in terms of making services more predictable across education, health and social care. This aligned with the experience of the committee that interacting in a consistent way helps children and young people know what to expect and feel safer and more confident in their interactions with services, so they made a recommendation in support of this. ## How the recommendation might affect practice Services across education, health and social care services will have to share knowledge about the child or young person's preferences, such as method of communication, the way they like to be addressed, how they express agreement or disagreement, and positive behaviour support, so that all practitioners can use this information consistently. Return to recommendation # Decision making Recommendations 1.1.45 to 1.1.50 ## Why the committee made the recommendations There was moderate-quality qualitative evidence that parents did not always feel comfortable making decisions about their child's care, because they sometimes lacked the knowledge and expertise to do so. The committee believe it is very important for children and young people and their parents and carers to be involved in decision making as much as they are able to, so they made a recommendation in support of this. This recommendation also aligns with the Children and Families Act 2014. In some situations, children will be unable to respond with intentional communication. The committee wanted to ensure that practitioners still tried to identify their preferences in these situations, to ensure their care and support is appropriate and to meet the requirement in the Children and Families Act 2014 to have regard to the views of disabled children and young people and those with special educational needs. The SEND code of practice states that the views of parents must not be used as a proxy for the views of the young person. However, the committee agreed that this is not consistently done in practice. In particular, members of the committee who had been through this process themselves as young people explained that they were sometimes ignored, with practitioners assuming they did not understand and primarily addressing their parents. The SEND code of practice briefly covers what to do when there are disagreements between parents and their children. There is also other relevant legislation and guidance on consent (such as the Mental Capacity Act and guidance from professional governance organisations). However, the committee are aware that practitioners need more guidance, as issues around decision making are complicated and practitioners are not always well informed in this area. The committee made recommendations to help practitioners when disagreements between parents and children or young people cannot be resolved, or when there are capacity issues. ## How the recommendations might affect practice The guidance in this area will make practice more consistent. Practitioners might need more time to communicate with children and young people, provide them with information, and help them formulate their views. Additional time may also be needed for getting the views of parents and carers, resolving disagreements and reaching shared decisions. However, if practitioners spend more time helping children and young people to communicate, they are likely to be more engaged with the process and have fewer queries, complaints and problems, resulting in time savings later on. Return to recommendations # Information sharing and privacy Recommendations 1.1.51 to 1.1.57 ## Why the committee made the recommendations There was moderate- and high-quality qualitative evidence that: services do not always share information with each other, and when they do share it is not always done well because they do not understand what other services need to know children and young people and their families and carers have to repeat the same information to different services, and find this exhausting and difficult (particularly when repeating sensitive or distressing information) it is important to respect children and young people's right to privacy and right to be involved in decisions not all services could access online electronic patient records, and that practitioners believed that being able to access these records would improve joint working, information sharing, and identification of severe complex needs in disabled children and young people. The committee agreed that information sharing does not always happen effectively and that concerns about confidentiality, privacy, consent and security can have an impact. They therefore made recommendations to promote effective information sharing and address the concerns highlighted by the evidence. The committee noted that while individual services have electronic patient record systems, there is no interagency record system across education, health and social care. This kind of system could be very useful, but it would be very expensive to develop and there would be data protection issues to consider. Therefore, the committee agreed that they could not make a recommendation in support of a shared electronic patient record system. Instead, they recommended that services work actively to ensure that other services can access relevant information when needed. One specific area of information sharing highlighted by moderate-quality qualitative evidence was the development and sharing of behaviour management plans. The committee did not make a recommendation specifically on behaviour management plans, because not all disabled children and young people with severe complex needs will need a behaviour management plan. However, they agreed that when any specialised care plans have been made, these should be shared with the child or young person and their parents and carers, and all practitioners working with them. This will improve practitioner knowledge and understanding of the child or young person's needs. ## How the recommendations might affect practice Practitioners might need a little more time to find out about the information sharing preferences of children and young people and their families. Services across education, health and social care may need to establish processes to share those preferences more effectively, if they have not already done so. Effective information sharing will ensure that children and young people and their families and carers do not have to repeat the same information to multiple practitioners, which can be distressing. Ineffective information sharing may lead to children and young people being provided with support that does not meet their needs and result in low satisfaction and complaints. This may cost services much more further down the line. Return to recommendations # Identifying needs and involving other services Recommendations 1.2.1 to 1.2.8 ## Why the committee made the recommendations There were only a few small studies in this area. Most of these studies focused on children and young people with autism, were very low quality, and reported on waiting times only. The committee did not feel the evidence could be generalised to the much wider population covered by the guideline and subsequently made recommendations based on their knowledge and experience. In the committee's experience, emotional and mental health needs can go unrecognised and undiagnosed, because they are often obscured by the other needs of disabled children and young people with severe complex needs. In the committee's experience severe complex needs and disabilities are normally first identified by health services. If the child is under compulsory school age, section 23 of the Children and Families Act 2014 requires health services to: tell their parents give the parents the chance to discuss their opinion tell the parents about any voluntary organisations that can provide advice or assistance tell the appropriate local authority about the child. This requirement only applies to children under compulsory school age, but the committee agreed to cover all children and young people in the recommendation because this process is helpful whatever age special educational needs are identified. In line with their understanding of the SEND code of practice and the requirements of the Children and Families Act 2014, the committee also recommended directing families to SEND Information, Advice and Support services and the SEND Local Offer for their area. In the committee's experience this is not always done, and can result in parents independently sourcing inaccurate information. To ensure that children and young people receive the support they need, the committee agreed on the importance of linking health services up with education and social care services as soon as possible. They highlighted that appropriate consent to share data is needed for this. Sometimes severe complex needs and disabilities are first identified by education services. In line with the recommendations for health services, the committee made recommendations for education services on involving health and social care services and starting discussions with children and young people and their families and carers. They also recommended informing parents and carers about support organisations in the SEND Local Offer, and directing them to SEND Information, Advice and Support services, in line with their understanding of the SEND code of practice and Children and Families Act 2014. Based on their experience, the committee made a recommendation on referrals for social care assessment for family support. The reasons for these referrals are often unclear, particularly around the emerging needs, and this can delay social care involvement and provision of support for the child or young person. The committee felt strongly that such preventable delays need to be avoided and were confident that including the reasons for the referral (including the emerging needs) would resolve this. They also agreed it was important to include any barriers to engaging with healthcare services in the referral to social care service, because in their experience families on low income may not be able to afford to travel to attend all health appointments, or be able to afford the equipment needed to attend appointments remotely. Including such barriers in the referral should result in potential solutions to this issue being explored. Low-quality qualitative evidence showed that families can be reluctant to engage with social care services because of fear and perceived stigma. The committee agreed that families can be confused by the difference between child protection social services and family support services, and made a recommendation to address this. In the committee's experience, disabled children and young people are at increased risk of vulnerability, abuse and neglect. However, it is often incorrectly assumed that if the child or young person has a social worker from a disabled children's team, then this individual will pick up any safeguarding issues and there is less of a need to report concerns. The committee were confident that making a recommendation on the action needed if a safeguarding concern is identified would correct this misunderstanding. ## How the recommendations might affect practice Professionals might need more time to assess the needs a child or young person may have, and to share these with other services. They might also need more time to explain the education, health and care needs assessment process to children and young people and their families and carers. However, if practitioners spend more time on this, there will likely be fewer queries, complaints and problems, resulting in time savings later on. If practitioners spend more time thinking about what support children and young people need from other services, services may start communicating with each other sooner and there may be fewer delays in making referrals. Practitioners may also make a small number of extra referrals to other services, because they have better knowledge of other agencies that can support the child or young person and their family and carers. Return to recommendations # Requesting a needs assessment Recommendations 1.3.1 to 1.3.4 ## Why the committee made the recommendations There was low-quality qualitative evidence that families and carers often felt that children and young people had to reach a crisis point before an EHC plan was considered necessary. The committee were confident that encouraging services to explain the process to families when special educational needs are first suspected should help to prevent children and young people reaching a crisis point. While the SEND code of practice already contains this information, the committee agreed that it would be more accessible if individual practitioners could provide it. There was low-quality qualitative evidence that some practitioners felt like they were pressured to not apply for EHC plans because of a lack of funding, even though this would be a breach of the legislation. In the committee's experience this risk should be reduced if local authorities explain that an EHC needs assessment should be requested based on a child or young person's needs. There was low- and moderate-quality qualitative evidence that access to services sometimes depends on the child or young person receiving a particular diagnosis. This excludes some disabled children and young people from support, because they can have severe complex needs but not have a specific, diagnosable health problem. While the committee's understanding of the SEND code of practice is that it allows local authorities to develop criteria to help decide if an EHC needs assessment is needed, they must be prepared to depart from these criteria if there is a compelling reason to do so. The SEND code of practice also specifies that '…local authorities must not apply a "blanket" policy to particular groups of children or certain types of need…'. There was moderate-quality qualitative evidence that parents felt a need to constantly fight for the support their children needed, as support was not always provided if they did not arrange and manage things themselves. The committee agreed that families should not be responsible for managing processes (in particular, they should not have to manage the EHC needs assessment and EHC plan process themselves), and that practitioners should support families with this. ## How the recommendations might affect practice Practitioners may need more time to explain the EHC needs assessment process and support families through this. However, if practitioners spend more time on this, families will likely have fewer queries, complaints and problems, resulting in time savings later on. It should also help prevent children and young people from getting to a crisis point, which is detrimental to their quality of life and costly to address. More disabled children and young people with severe complex needs may be able to access services earlier if they are not excluded for not having a specific diagnosis. Similarly, if parents and carers have a better understanding of the EHC needs assessment process, they may be more likely to request an assessment and more children and young people may be accessing services. Return to recommendations # Supporting children, young people and their families during a needs assessment Recommendations 1.3.5 to 1.3.11 ## Why the committee made the recommendations There was moderate-quality qualitative evidence that children and young people and their families and carers did not understand the EHC needs assessment process. They also experienced a lack of transparency around how decisions about EHC needs assessment were made, the timings of reviews, and the processes for appeals and complaints. Explaining the process to people helps them to participate and reduces uncertainty. The 20‑week period specified in the recommendation for the EHC plan process is taken from the SEND Regulations 2014. In the committee's experience, many EHC plans are not produced within the statutory timeframe and children, young people and their parents and carers have to seek updates and information about progress. The committee made a recommendation to address this issue. There was moderate- and high-quality qualitative evidence that: children and young people and their families and carers do not receive the level of support or input that they had expected from services they feel frustrated because it is not clear how resources are allocated children and young people, families and carers, and service providers felt that the level of support provided did not always reflect the needs of the child or young person, and that more assertive people were more likely to get the support they wanted. Based on this evidence, the committee made recommendations to ensure that children and young people and their families and carers are better informed about what services are available while they are waiting for a needs assessment. The committee also noted, based on their experience, that children and young people and their families and carers are not always asked for their views as part of the EHC needs assessment. This is required by the Children and Families Act 2014 and the SEND Regulations 2014, so the committee made recommendations to support this. There was moderate-quality qualitative evidence that children and young people, their families and carers, and service providers all felt there was a lack of urgency about providing support until the child or young person reached a crisis point. Similarly, all these groups also felt that the crisis point could be avoided if support was provided earlier. This evidence aligned with the committee's experience, and they believed a lack of resources, issues with prioritisation, use of threshold criteria for accessing support, and statutory obligations all affected the situation. In response to this, the committee made a recommendation for services to work together before an EHC plan is issued to provide interim support and a simpler transition from interim support to the EHC plan, to keep people from reaching a crisis point. The EHC needs assessment process can take several weeks to complete. In addition, some services (such as schools) will conduct their own additional assessments, and there was high-quality qualitative evidence that this causes delays to the implementation of EHC plans. The committee agreed that support from education, health and social care was still needed during this process. These recommendations are in line with the committee's understanding of the SEND code of practice, which states 'where particular services are assessed as being needed…, their provision should be delivered in line with the relevant statutory guidance and should not be delayed until the EHC plan is complete'. ## How the recommendations might affect practice Practitioners may need more time to explain the EHC needs assessment process. However, if practitioners spend more time on this, families will likely have fewer queries, complaints and problems, resulting in time savings later on. It should also help prevent children and young people from getting to a crisis point, which is detrimental to their quality of life and costly to address. Professionals may need slightly more time to explain what services are available and the criteria for accessing them. Services may need to work together to provide interagency training for education, health and social care practitioners on other services and their roles and responsibilities, to ensure practitioners can provide clear and relevant information. Providing this support to children and young people and their families is part of person-centred care. It may help children and young people in making decisions, and ensure that they get support that meets their needs. This prevents scarce resources from being wasted. It ultimately results in better choices, care and outcomes for disabled children and young people with severe complex needs. Commissioners will have to set up commissioning frameworks (or use existing frameworks), to reinforce a more coordinated approach to EHC needs assessments. This coordinated approach may mean holding more interagency team meetings and more effective communication between education, health and social care services. However, it will mean services and practitioners are able to work together more effectively to provide the support that is needed by children and young people. Return to recommendations # Carrying out the needs assessment, timescales for the assessment, and when parents or carers decline an assessment Recommendations 1.3.12 to 1.3.15 ## Why the committee made the recommendations The committee agreed it was important to make recommendations on the EHC needs assessment process, to make it more streamlined. In the committee's experience, children and young people need a more personalised plan that is specific to their age, level of understanding, communication needs, and circumstances. This was supported by moderate-quality qualitative evidence that the involvement and understanding of the child or young person was dependent on their level of ability. There was moderate-quality qualitative evidence that some practitioners felt they did not have the chance to contribute relevant information they had about a child or young person to assessments led by other services. The committee considered it was very important that specialist knowledge about the needs of the child or young person from practitioners outside of the interagency team is included in the EHC needs assessment in order to fully assess a child or young person's needs. There was low-quality qualitative evidence that early identification of needs and referral can be helpful in securing support for children and young people. To make sure that services are ready to provide support when it is needed, the committee felt strongly that practitioners and services need to make referrals as needs are identified, without waiting for the assessment process to finish. They were confident that doing this would help children and young people get the support they need sooner. There was low-quality qualitative evidence that children and young people and their families and carers felt that the process of getting an EHC plan took too long, and needed a lot of effort on their part. Moderate-quality qualitative evidence showed service providers thought there was a lack of transparency about how decisions on EHC plans were made, timescales for review, and processes for appeals or complaints. The Children and Families Act 2014 and the SEND Regulations 2014 set out timescales for each stage of the process for EHC needs assessments and EHC plans, so the committee could not make different recommendations on this. However, they did highlight the time limits from the legislation, as the evidence and their own experience suggest that these time limits are not always adhered to. In the committee's experience, there are circumstances when parents or carers decline assessments. This was reflected by moderate-quality qualitative evidence that parents and carers felt disillusioned with statutory provisions and thought there was little point in requesting help, so opted out of the process. The committee agreed that the reasons for declining assessments were varied, so this should be discussed with parents or carers to ensure that the best possible support can be provided for the child or young person. They also thought it was important to ensure parents and carers understood how to request an assessment in future (because their circumstances and views may change), and for professionals to consider whether declining an assessment may cause a safeguarding issue. The committee were confident that making this recommendation was necessary to ensure appropriate support could be given to parents and carers. ## How the recommendations might affect practice Services will need to work in a more coordinated way, for example by ensuring a consistent approach when carrying out assessments, or by holding more meetings with each other. Commissioners across education, health and social care will have to set up or reinforce commissioning frameworks, to encourage a more coordinated approach to EHC needs assessments. Making referrals as needs are identified (without waiting for the assessment process to finish) may result in earlier referrals and quicker turnover between services. The recommendation on timescales for completing a needs assessment and producing an EHC plan helps spread awareness of existing statutory guidance and may reduce variation in practice. Return to recommendations # Agreeing on outcomes for the EHC plan Recommendations 1.4.1 to 1.4.5 ## Why the committee made the recommendations There was moderate-quality qualitative evidence that practitioners can have low expectations of disabled children and young people with severe complex needs and may underestimate their potential. This reflected the committee's experience that many children and young people have not had the chance to consider their aspirations for employment, independence, relationships and community involvement. This can lead to restricted goals and ambitions, and an EHC plan that does not reflect the genuine strengths, abilities and interests of the child or young person. The committee therefore highlighted ways to address this in the recommendations. The committee's understanding of the SEND code of practice and legislation in the Children and Families Act 2014 is that parents and carers must be consulted throughout the EHC plan process. However, moderate-quality qualitative evidence suggested that sometimes this is limited and only done in a tokenistic way. Based on this, the committee emphasised the need to take the views of parents and carers into account throughout the process. There was moderate-quality quantitative evidence that a lack of specific, measurable, attainable, relevant and timely (SMART) outcomes in EHC plans made it unclear what support will be needed, and who is responsible for providing it. The committee's understanding of the SEND code of practice was that it recommends that SMART outcomes should be used, but in the committees' experience this is not always done. The committee recommended that practitioners consider using the outcome sandwich, because in their experience it is a helpful tool that can help practitioners to develop meaningful outcomes. ## How the recommendations might affect practice The recommendations reflect effective practice, but are currently implemented to varying degrees by different services and will involve a change of practice for some providers. Longer consultations or additional follow-up may be needed to fully discuss the outcomes for EHC plans with children and young people and their parents and carers. Spending sufficient time deciding on outcomes for the EHC plan will help practitioners to provide person-centred care. It ensures children and young people are engaged with the process and that EHC plans align with their aspirations. If not done correctly, it can lead to restricted goals and ambitions, poor engagement, and ultimately lower quality of life and general wellbeing. A good process for developing outcomes will help children and young people with making decisions, ensures that they get support that meets their needs, and ensures that scarce resources are not wasted. Return to recommendations # Providing information and advice for the EHC plan Recommendations 1.4.6 to 1.4.15 ## Why the committee made the recommendations Currently, individual services contribute information and advice for EHC plans without knowing what the proposed outcomes are for the children and young people. This can lead to inconsistencies between the information and advice provided by different practitioners and services, and an EHC plan that is not practical to implement. These problems often lead to the statutory 20-week timeframe for producing an EHC plan being missed. Therefore, the committee felt strongly that recommendations were needed to address this issue. Based on their experience, the committee were confident that sharing the proposed outcomes with services would allow services to specify how they would help to achieve these outcomes when contributing advice and information. This would result in EHC plans that made sense and would support the agreed outcomes for each disabled child or young person with severe complex needs. Although recording the views of children and young people in EHC plans is mandatory, moderate-quality qualitative evidence indicated that this is not always done accurately or in enough detail. Practitioners often paraphrase the words of children and young people, and this can lead to inaccuracies. Advice and information contributed by different services needs to be put in specific sections of the EHC plan when written by local authorities, so that commissioners can see which services need to be provided from which budget lines. In the committee's experience this is often done poorly, with a lack of distinction between what practical and therapeutic support is needed to educate or train the child or young person and what health and medical support they need to stay well. The committee were confident that including this information correctly in EHC plans would resolve these issues so that children and young people are provided with the support they need. Moderate-quality qualitative evidence indicated that children and young people, their families and carers, and service providers thought that EHC plans were not clear on who is responsible for providing the support specified in the plan. Therefore, the committee recommended specifying the support needed to help children and young people achieve the outcomes in their EHC plans. Moderate-quality qualitative evidence indicated that service providers lacked the expertise and knowledge needed to complete EHC plans. In addition, the committee's experience was that EHC plans are often based on old information and therefore do not fulfil their purpose. Preparing good-quality EHC plans is crucial to ensuring that disabled children and young people with severe complex needs get the support they need. To address this, the committee made recommendations for local authorities (who are ultimately responsible for the EHC plan process) and health commissioners, to ensure plans are brought up to the correct standard. Moderate-quality qualitative evidence showed that children and young people's views are not always captured accurately, and that it is important to make sure views are not rewritten in a way that changes the meaning. Based on their experience, the committee recommended ways in which the child or young person's voice could be preserved when recording their views. Moderate-quality qualitative evidence identified that it can be difficult for children and young people and their families and carers to understand the complicated terminology used in EHC plans. The evidence further highlighted that using accessible language would make it easier for children and young people to get involved, and improve accountability by ensuring everyone knows who is responsible for each part of the plan. The committee noted that certain sections of the plan would need to be written in technical language (for example information about health), but recommended that the outcomes and support provision sections should be written in clear language that can be understood by the child or young person and their families and carers. This aligns with the committee's understanding of the SEND code of practice, which states that 'EHC plans should be clear, concise, understandable and accessible to parents, children, young people, providers and practitioners'. As part of ensuring that children and young people understand and agree with the plan, the committee recommended that practitioners check it with them during the planning process. Moderate-quality qualitative evidence indicated that parents and carers felt more positive about the EHC process when their involvement was clearly valued and they had the chance to make amendments to the EHC plan. Parents and carers have valuable experience from caring for their child, including an understanding of their child's needs, so their contributions to the plan are useful. In addition, explaining how their concerns have been addressed in the plan is a simple way of showing how their involvement is valued. ## How the recommendations might affect practice The recommendations reflect effective practice, and legislation and statutory guidance, but are currently implemented to varying degrees across education, health and social care. EHC plans are crucial, as they identify the educational, health and social care needs of disabled children and young people with severe complex needs and specify what support must be put in place to help achieve the desired outcomes. Local authorities may need to change their practice to provide services with the proposed outcomes for children and young people. However, this would help services to provide more consistent information and advice, reduce the time needed to resolve inconsistencies, and lead to an EHC plan that is practical to implement. This will have a positive effect on the care and support received by children and young people and on their ability to achieve the desired outcomes. It should also make it easier to produce EHC plans within the statutory 20-week timeframe. Some providers may need to change their practice, and more staff time may be needed for follow-up and discussions of EHC plans with children and young people and their families and carers. Checking the draft plan with children, young people and their families will ensure that they understand the content of the plan and support that must be put in place to help them. This will help them to engage with the process and will make it more likely that the agreed care and support will be effective. All of this will positively impact their care and outcomes. Return to recommendations # Reviewing progress and needs, and coordinating with EHC plan reviews Recommendations 1.4.16 to 1.4.20 ## Why the committee made the recommendations In the committee's experience, the needs and circumstances of disabled children and young people with severe complex needs can change frequently. Therefore, the committee highlighted that professional reviews need to be regular. They could not specify exact timings as this would vary for different people. They also provided detail about when to conduct a professional assessment, to ensure that any change in needs is captured. The local authority is responsible for making decisions about whether an EHC plan is still fit for purpose, whether any changes to the plan are needed, and whether to conduct a reassessment. To help local authorities with these decisions and ensure they have the latest information, the committee recommended that the results of any professional assessments conducted by individual services are shared with local authorities. There was low-quality qualitative evidence that parents and carers spend a lot of time and effort contacting and coordinating between services, because services do not talk to each other. The committee looked at ways this could be addressed for the different reviews children and young people have. One possibility is the approach used for looked-after children and young people, who have coordinated EHC plan annual reviews and social care reviews with aligned review periods. The committee agreed that doing this for all children and young people would be helpful and make things simpler for families. Low-quality qualitative evidence indicated that children and young people and their families and carers were concerned that their support would be reduced if they acknowledged improvements or talked about the child or young person's strengths in the EHC plan. The committee agreed that this can be a problem in practice. They were confident that the level of support specified in the EHC plan should only be reduced if the child or young person no longer needs it, otherwise there was a risk that the improvements may not be maintained. ## How the recommendations might affect practice The recommendations on review and reassessment of EHC plans reinforce statutory requirements and current practice, so should represent no change in practice for services. The recommendation to reduce the level of support only if the child or young person no longer needs it may mean a change in practice for some services. However, this will prevent avoidable crises that are caused by services reducing the level of support too early. Return to recommendations # Funding Recommendations 1.4.21 and 1.4.22 ## Why the committee made the recommendations There was moderate-quality qualitative evidence in this area, based on the views of practitioners. They reported a decrease in funding that has reduced availability of services and prevents them from providing person-centred, joined-up care. In response, the committee highlighted that under section 42 of the Children and Families Act 2014, local authorities and health commissioners have a duty to secure or arrange (respectively) the provision specified in EHC plans. They therefore recommended that sufficient funding should be provided to enable the support in EHC plans to be provided. There was also moderate-quality qualitative evidence that practitioners' requests for additional funding to support a child or young person can be refused without a reason being provided. This causes frustration, stops practitioners from providing clear information to children and young people and their families and carers, and can make it difficult to appeal the decision. Therefore, the committee recommended making the reasons for refusing additional resources clear to both practitioners and families. ## How the recommendations might affect practice The recommendations repeat legislation and statutory guidance, so there is no change in the resource impact on services. More funding may be needed in areas where local arrangements are not compliant with legislation and statutory guidance. Practitioners may need more time to explain why requests for additional resources have been refused, and to explain potential courses of action. It is difficult to say if this will have an impact on the appeals process. There may be more appeals because families understand the process better, or there may be fewer appeals because the reasons for not providing additional resources are clearer. Return to recommendations # If children, young people and their families decline an EHC plan Recommendation 1.4.23 ## Why the committee made the recommendation In the committee's experience, there are circumstances when parents or carers can decline an EHC plan. For example, if they are unhappy with the school named in the plan. The committee highlighted that in these circumstances, it is important to still engage with parents and carers, so that their children do not become lost to services and miss out on support. ## How the recommendation might affect practice Practitioners may need more time for discussions with parents or carers who decline an EHC plan. However, this rarely happens, so the overall time impact will be small. Return to recommendation # Personal budgets and direct payments Recommendations 1.5.1 to 1.5.5 ## Why the committee made the recommendations There was moderate-quality qualitative evidence that: personal budgets and direct payments can increase flexibility and give families greater choice about which services they use, but that they can also create additional responsibility for the family families were unclear about whether they were entitled to a personal budget or direct payment, or how useful these were families were unsure what they could use the funds for, whether personal budgets and direct payments improved their child's access to services, or whether either option would be applicable to their individual circumstances parents were not always sure if they were able or willing to take on the responsibility of a personal budget or direct payments, and they questioned whether they had sufficient knowledge to make care decisions parents were uncertain if choosing a personal budget or direct payments would affect how professionals were involved in their support. The Special Educational Needs (Personal Budgets) Regulations 2014 requires local authorities to provide parents and young people with information on personal budgets, if the child or young person has an EHC plan or will be issued with one. Based on the evidence, the committee supplemented this statutory requirement with a recommendation on specific information that local authorities should provide on personal budgets and direct payments. In the committee's experience, when services are commissioned through direct payments and families become the commissioners of care, there can be a loss of coordination between support purchased through direct payments and statutory support provided directly through health and social care providers. Given the emphasis in the legislation and the SEND code of practice on services working together, the committee used their experience to recommend that local authorities and health commissioners continue to ensure services coordinate even if they have been commissioned using direct payments. Personal budgets are mandatory for people aged 18 and over if they have a care and support plan, but they can choose whether or not to receive this budget as a direct payment. The committee agreed it was important to make people aware of this, as the difference between personal budgets and direct payments is not well understood. There was moderate-quality qualitative evidence that families were concerned that personal budgets and direct payments would lead to uneven provision, shortages in provision and a reduction in services. Families did not want to be disadvantaged, and were concerned about having to prioritise within the constraints of a limited budget. They were also concerned that the budget may not be equivalent to the level of funding that is already available. In the committee's experience, direct payments are sometimes only large enough to cover the service itself but not any related costs. As a consequence, activities that the child or young person enjoyed previously may no longer be affordable, which could impact on their quality of life and ability to achieve the outcomes in their EHC plan. The committee were confident that if local authorities assessed the full cost of providing the services proposed in the needs assessment, this would help to address this problem. ## How the recommendations might affect practice Practitioners may need more time to advise children and young people and their families about personal budgets (including personal health budgets) and direct payments. As a result of this advice, there may be a change in the uptake of personal budgets and direct payments. For families receiving direct payments, health and education services are already required to assess the full cost of providing services proposed in the needs assessment. However, this may represent a change in practice for social care. Services may be encouraged to think differently about the approach to funding and provision, and consider including support costs (for example, transport costs or variable costs of accessing different provision) in direct payments. Local authorities and health commissioners will need to apply the same frameworks and processes they use to ensure the quality of directly commissioned statutory support to the support commissioned by families through direct payments. This could include frameworks and processes on training and competency, information sharing, monitoring and review. Doing this will ensure that all services supporting children and young people will receive the information needed to provide effective advice and support. Return to recommendations # Supporting parents and carers, and training Recommendations 1.6.1 to 1.6.12 ## Why the committee made the recommendations There was evidence that parent training provided numerous benefits to parents and carers, improving their: communication ability and confidence to meet the needs of their child range of social contacts, providing them with social, emotional and practical support. However, the evidence varied between very low to high quality. Important differences were seen when the outcomes were measured on some scales, but not on others, indicating uncertainty in the results. Therefore, the committee interpreted the results with caution and used the evidence to recommend general elements of the interventions rather than recommending any specific intervention. They also supplemented the evidence with their own knowledge and experience. In the committee's experience, families often report a desire to have been directed to services that can provide emotional and practical support to enable them to come to terms with their child's diagnosis. There was very-low- to low-quality evidence that person-centred planning approaches were beneficial in helping to include parents and carers in care planning, so the committee recommended that these were considered. Moderate-quality qualitative evidence, supported by the committee's experience, showed that different families and carers want different levels of involvement in decision making. Some families want to be regularly involved in making decisions, whereas some prefer to be guided by professional advice. In addition, in the committee's experience, families change their minds about the level of involvement they want over time. Moderate-quality qualitative evidence showed that parents felt that they coordinated most of the services for their child and were worried about what would happen if they could no longer do this. To ensure parents are prepared, the committee recommended that practitioners should consider providing information about available emotional and practical support options. There was very-low- to high-quality evidence that training for parents and carers was beneficial, and low-quality qualitative evidence showed that families needed more support to provide care for a disabled child or young person with severe complex needs. Therefore, the committee recommended that services consider working together to co-produce training with parents and carers. The committee also identified areas that this training could cover, based on the evidence. In the committee's experience, there is variation in the level of training that each family needs. Some families will want more in-depth training straight away, and others will not. The committee felt strongly that training needs to be appropriate to the needs of families, so that families are able to learn at the level that will be most beneficial to them. The committee felt equally strongly that practitioners who lead the training need to have skills that are appropriate for the content of the training, so that people are not going beyond their skillsets, because this could make the training ineffective. In addition, the committee agreed that people all learn differently, so using different teaching styles in training would be sensible. Some of the parent training interventions in the evidence were conducted in group format, and provided parents and carers with an opportunity to engage with each other and share experiences. The committee agreed that providing such opportunities would likely have a positive impact on parents and carers by helping them to learn from each other and develop support networks. The committee have seen that not all families are ready to start training immediately (for example, if they have just received a diagnosis). Some families need more time, and the committee were confident that training would be more effective if families were able to start the training when they were ready. More flexible options around training delivery (including session times, locations and formats) would make training sessions more accessible to parents and carers. Flexibility is particularly important for parents and carers of disabled children and young people, because their substantial caring responsibilities make it difficult to find time for the training. ## How the recommendations might affect practice Practitioners may need more time to include and support parents and carers (for example, by directing them to sources of support and including them in care planning). However, all local areas should already have processes for doing this, so there should be no significant impact. Parent and carer training is currently available and there are examples of good practice across the country. However, practice is variable, and the recommendations may result in additional costs for some services. For example, training content may need to be slightly modified, and group activities may need to be included to provide opportunities for parents and carers to discuss their experiences. Currently, services commission parent and carer training in isolation, or with only 2 services working together. There might be costs associated with setting up the framework for a collaborative approach if services choose to do this, for example, more meetings and communication between services may be needed. However, collaborative working will make the training approach coordinated, cut out duplication of effort and result in efficiencies and cost savings to the organisations involved. It will also make practice more consistent. Most importantly, supporting parents and carers may avoid a breakdown in care, preventing crises and expensive care placements. Return to recommendations # Social participation Recommendations 1.7.1 to 1.7.7 ## Why the committee made the recommendations In the committee's experience, social inclusion is as important as care and education for improving the quality of life of disabled children and young people with severe complex needs, but this may be more difficult for children and young people who are not in education or work. So the committee made recommendations to raise awareness of this. There was very-low-quality evidence from 1 study that an adapted fitness programme increased positive social interactions for disabled children and young people with severe complex needs during group activities. The committee recommended considering adapted group activities (such as theatre) because some children and young people may prefer these to sports, and the committee agreed that children and young people are likely to have positive social interactions in other group activities as well. The committee agreed that the adaptations included in the fitness programme were an important part of the intervention and, therefore, recommended that providers adapt activities as needed. Local authorities have a duty to provide short break services, but they will need to collaborate with voluntary and community organisations to provide a wide range of meaningful activities as part of these services. Moderate-quality qualitative evidence highlighted that short breaks provide benefits for children and young people, but also that services may only provide limited opportunities for activities, so the committee made a recommendation to address this. Local authorities will need to think about options for people living in rural areas, to prevent inequalities in access to these social activities. The committee used their experience to make recommendations on ways services and practitioners could help children and young people to participate in social activities. This aligns with the committee's understanding of the SEND code of practice – that social inclusion should be included as a preparation for adulthood outcome in all EHC plans and reviews from year 9 onwards. The examples given are important areas of social participation that most people take for granted, but that disabled children and young people with severe complex needs may need assistance to get involved in. There was some limited quantitative evidence that collaboration between health and education services can improve the ability of disabled children and young people with severe complex needs to communicate in classrooms. The main limitations with this evidence were that it was from only 1 study, and there were issues with the study design. However, this evidence was consistent with high-quality qualitative evidence that education practitioners valued the opportunity to learn from health professionals. The committee were confident that this collaboration is important to ensure that: unaddressed health needs do not get in the way of social participation the way that health needs are addressed is not itself a barrier to social participation (for example, healthcare appointments are not scheduled during activities that children and young people want to participate in). The committee agreed that similar benefits could be seen in other settings if health and social care services collaborated. ## How the recommendations might affect practice Local authorities have a duty to provide short break services, and the recommended group activities would fall under this category of service. Because local authorities already have to fund these services, there should be no resource impact. However, the type of short break services provided may change. Short breaks are integral to any support package. They allow young people with disabilities and severe complex needs to meet friends, take part in activities, develop independence, and improve their quality of life. More children and young people may be able to attend education settings or community activities. There may be a higher cost to services, but there will be improvements in the quality of life and wellbeing of disabled children and young people with severe complex needs. Because there is already a legal duty to make reasonable adjustments, which would include the adaptations specified in the recommendation, there should be no change in practice or resource impact to making these adaptations. Services will need to set up or use existing frameworks for a collaborative approach for commissioning and providing activities that can help improve social participation. Services may need to hold more joint and coordinated meetings to allow them to work together more closely on supporting social participation. Return to recommendations # Transition from children's to adults' services Recommendations 1.8.1 to 1.8.14 ## Why the committee made the recommendations Regulations 20(6) and 21(6) in the SEND Regulations 2014 require local authorities to ensure that preparation for adulthood is covered in EHC plan reviews from year 9 onwards. However, moderate-quality qualitative evidence indicated that preparation and decision making for adulthood is insufficient and left too late. The committee made recommendations to emphasise these regulations. There was low- and very-low-quality quantitative evidence that participation and inclusion were improved when a young adult team approach was used to help with transition from children's to adults' services. There were important limitations to this evidence. In particular, the evidence came from only 1 study, and there were issues with potential bias. However, this quantitative evidence was consistent with moderate-quality qualitative evidence that practitioners valued a child- or young-person-centred approach that encouraged a multidisciplinary team working around the child or young person to identify and meet their needs. The SEND code of practice states that high aspirations are crucial to the success of the child or young person and that discussions should focus on their strengths, capabilities and the outcomes they want to achieve. However, in the committee's experience, some practitioners are not following this approach and are instead focusing on short-term support that can more easily be achieved. So they agreed it was important to promote a focus on goals for adulthood and maximising independence. The committee's understanding of the SEND code of practice is that local authorities should ensure there are pathways into employment, independent living and participation in society, and that they must work with children, young people and families to develop coordinated approaches to securing better outcomes for adult life. However, in the committee's experience, because most of the work on preparing for adulthood is done in educational settings, the focus is often on staying in education. In addition, there was qualitative evidence that young people need more support to understand their options and reach their full potential. The committee wanted to ensure that young people understood all their options and had time to prepare for them, so made recommendations to address this. In the committee's experience, the transition from paediatrics to adult health services can cause problems, as not many adult services provide the same 'wrap round' services as paediatrics. This can be a major source of concern for families, because paediatricians tend to coordinate care for the young person, and this coordination is then lost when the young person transfers to adult services. The committee agreed that for effective transition planning, healthcare professionals should find out what local services are available and involve them as needed to help with the transition. The qualitative evidence highlighted various problems with preparations for adulthood: there was low-quality evidence that education, health and social care services used different age thresholds for transition to adult services there was low- to moderate-quality evidence that the process lacked coordination, and caused uncertainty and stress for young people there was moderate-quality evidence that preparation is insufficient and left too late. In the committee's experience, the variation between services in the ages used for non-statutory transitions creates gaps in the services that young people can access. This is significantly detrimental to the care and support young people receive and potentially exposes them to harm, so the committee were confident that a consistent approach was needed. The committee felt strongly that services needed to work together to better coordinate transition, and needed to read the sections of the plan produced by other practitioners. If this was not done, they were confident that it would lead to a plan that is not practical to implement. They also recommended areas that young people and their families and carers should be given information about, so that they know what to expect and experience less uncertainty and stress. In the committee's experience, practitioners do not always focus on long-term goals throughout the transition process. Planning and goals for adult life are only raised near the point of transition, which can make them seem overwhelming and unachievable for young people and their families. It is important to include short-term goals, to break down the long-term goals into manageable steps and help young people see how they can progress. Not all young people with severe complex needs will continue in education. The committee directed practitioners to relevant guidance to ensure that the needs of these people are still met. There was moderate-quality qualitative evidence that having the same named worker throughout the process helped maintain consistency and a positive relationship between young people and services (named workers are recommended by the NICE guideline on transition from children's to adults' services). It would not be possible to have the same named worker before and after transition, so the committee made a recommendation on handing over these responsibilities to maintain consistency and continuity of care. Moderate-quality qualitative evidence showed that parents felt shut out once their child reached adulthood, so the committee recommended that parents and young people are given information to help them prepare for the change. There was evidence relevant to other parts of the process: limited, low-quality quantitative evidence that involving managers and parents in steering groups reduced levels of unmet needs and improved parents' satisfaction low- to high-quality qualitative evidence that young people and their parents and carers felt more positive when they were involved, and that the input of young people leads to a more accurate understanding of their needs low- to moderate-quality quantitative evidence that parents were more satisfied with services when they had a transition worker. These areas are covered in the NICE guideline on transition from children's to adults' services. Because of this, the committee did not make new recommendations in these areas. ## How the recommendations might affect practice The recommendations reflect current practice and existing NICE guidance, and align with legislation and statutory guidance. However, more practitioner time might still be needed to meaningfully involve children and young people in transition planning. And education, health and social care practitioners might need to hold more joint and coordinated meetings, for example, to ensure that young people understood all their options, and to plan and set goals. Early planning will ensure that there is plenty of time to achieve the outcomes specified and that everything is not left to the final review, by which time it is too late to do any developmental work. Transition planning done in the right way will result in more efficient person-centred processes. It may potentially result in better long-term outcomes, with goals being achieved and overall savings to the services. It can also have important economic consequences, if young people are able to find employment or volunteer work. There is variation in how far children and young people are involved in transition planning, and in the effectiveness of transition between children's and adults' health services. The recommendations should make practice more consistent. There may be a greater uptake of certain services, such as supported internships. Return to recommendations# Rationale and impact for recommendations on specialist support for disabled children and young people with particular needs These sections briefly explain why the committee made the recommendations and how they might affect practice and services. # Palliative care and end of life care Recommendations 1.9.1 to 1.9.10 ## Why the committee made the recommendations It was not possible to determine which aspects of practice and service delivery models improved outcomes, based on the limited, very-low-quality quantitative evidence available. So the committee made recommendations based on their knowledge and experience. Health services will be the first to know when a child or young person needs a palliative or end of life care plan. It is important to find out if the child or young person has already documented their wishes (for example, in an advance care plan) before sharing information with other services. In the committee's experience, other services are not always notified, and this can cause interruptions to the support provided to the child or young person. Health services should also consider providing training for other services, to help them understand how to best meet the changing needs of children and young people with palliative or end of life care plans. The committee felt strongly that all services should continue to be involved. They were confident that doing this would improve planning, provide stable and consistent support, and give children and young people flexibility in which activities they want to continue. In their experience, there is a widespread belief that when children enter an end of life care process, they do not need much support beyond that offered by health services. This can lead to things that are important to the child or young person, such as community participation and maintaining social relationships, being overlooked. There was moderate-quality qualitative evidence that education, health and care (EHC) plans are not always viewed as live documents that need reviewing and updating. However, the committee's understanding of the special educational needs and disability (SEND) code of practice is that EHC plans should be reviewed when there are significant changes in need, and the need for palliative or end of life care is a clear example of this. Changes in support need to be implemented as soon as possible because of the time pressures associated with end of life care. Similarly, regular reviews of the palliative or end of life care plans are needed, as the child or young person's needs can change frequently. The committee were not able to be more specific about the frequency of reviews because this would depend on individual circumstances. It is important to consider the support needs of the child or young person's family, because these can be overlooked during palliative and end of life care, and families may not feel able to seek support in this situation if practitioners do not offer it. ## How the recommendations might affect practice It may be a change in practice for some services to continue social care and education support at the end of life. Services may need to work in a more coordinated way and be more explicit about the roles and responsibilities of different professionals. Services will have to consider how support might need to change for a child or young person who has an end of life care plan. As a result, they may request more reviews of EHC plans. Services will also need to consider how to provide interagency training, to ensure that practitioners can provide better palliative and end of life support to children and young people and their families and carers. Return to recommendations # Communication aids Recommendations 1.10.1 to 1.10.6 ## Why the committee made the recommendations There was very-low-quality evidence that assistive technology may increase interpersonal interactions, participation and inclusion. There were issues with the quality of the evidence (for example, there was only 1 study and it was not conducted in the UK) and at follow up, not all of the participants had received the recommended assistive technology. This evidence was from a service that made recommendations on assistive technology but did not fund or provide this technology. Therefore, the committee agreed that a greater benefit may have been expected if the technology was provided. There are existing augmentative and alternative communication services (local services, and NHS England specialised services) that provide support for people with communication needs. However, in the committee's experience, the specialised services are not well known and so are underused. This experience is consistent with moderate-quality qualitative evidence that practitioners and other staff lack the necessary skills and knowledge to work effectively to meet the needs of children and young people. It is important that staff know about the eligibility criteria for both local and specialised augmentative and alternative communication services, so that lack of knowledge is not a barrier to children and young people receiving support. The committee were aware that referrals are usually made by occupational therapists and speech and language therapists. However, the services accept referrals from other education, health and social care practitioners, so it is important that services do not cause delays by putting extra restrictions on who can make a referral. Moderate-quality qualitative evidence highlighted that more training and multi-agency work is needed to communicate effectively with disabled children and young people. The committee also felt strongly that there needs to be agreement about who will maintain, service and insure communication aids, so that people know how to get support if equipment is damaged. In the committee's experience, these issues are often not resolved effectively, which means the equipment does not get used and children and young people's needs are not met. The committee were confident that making the responsibilities around these areas more explicit would resolve this issue. In the committee's experience, it is also important to provide a paper-based backup for children and young people using powered communication aids, so that they can continue to communicate if the equipment breaks down. There was moderate-quality qualitative evidence that using a consistent approach was beneficial for children and young people, as it is more predictable and helps them to generalise across different settings. As part of this, the committee encouraged services to think about how equipment can be used in multiple settings and across transitions, and how the child or young person and their families and carers can be involved in the assessment process. They also agreed that education, health and care services would need to coordinate with specialist services, to ensure that the child or young person can use their communication aid in all settings and get the most value out of their communication aid. There was moderate-quality qualitative evidence that children and young people and their families and carers need more information and support to understand the services available to them, to help them make decisions and access services. To address this, the committee made a recommendation about providing information on support groups for children and young people who use assistive technologies. The SEND Regulations 2014 also specify that the SEND Local Offer must include information about available support groups. There was a lack of evidence on whether assistive technology enabled disabled children and young people with severe complex needs to express their views. Because getting their views is central to the EHC needs assessment process and ensures that services and resources are allocated appropriately, the committee made a research recommendation on this. ## How the recommendations might affect practice In some areas, specialised augmentative and alternative communication services are underused. The recommendations may lead to an increase in referrals to these services. However, the specialised services are already funded by NHS England, so this will not lead to an increase in costs for local education, health and care services. The availability of training on communication aids is variable, so providing training might represent a change in practice for some services. And practitioners may need to spend more time showing children and young people and their families and carers how to use communication aids. The amount of time required will vary depending on the complexity of the equipment and the number of people that need to be trained to use it. Training practitioners to use the equipment properly will ensure that the often costly equipment that has been assessed and prescribed will be used, and used correctly. It will improve outcomes, such as independence. It will also mitigate against the risk that only 1 practitioner knows how to use the equipment, so if they stop working with the child or young person, the equipment stops being used, potentially resulting in a deterioration of the child or young person's health and wellbeing. There are established frameworks in place for maintaining, servicing and insuring communication aids, for example those provided by NHS England specialised augmentative and alternative communication services. This particular recommendation is only highlighting that responsibilities around these areas should be stated more explicitly. Return to recommendations # Environmental adaptations Recommendations 1.11.1 to 1.11.10 ## Why the committee made the recommendations In the committee's experience, families often need support with the assessments needed to get environmental adaptations, and with the reassessments needed to ensure these adaptations are still appropriate when the child or young person's needs change. There was very-low-quality evidence that assistive technology may increase interpersonal interactions, participation and inclusion. There were issues with the quality of the evidence (for example, there was only 1 study and it was not conducted in the UK) and at follow up, not all of the participants had received the recommended assistive technology. This evidence was from a service that made recommendations on assistive technology but did not fund or provide this technology. Therefore, the committee agreed that a greater benefit may have been expected if the technology was provided. The committee have seen that services do not always think about how environmental adaptation equipment will be used across multiple settings. Often, equipment is provided to a specific service rather than the child or young person, preventing them from using it in other places. The recommendation on this is supported by moderate-quality qualitative evidence, which showed that children and young people benefited from a consistent approach as it is more predictable and helps them to generalise across different settings. In the committee's experience, training would also be useful for children and young people who are using environmental adaptations, as well as for their families. This is particularly important because there would be safety concerns if environmental adaptations are not used correctly, so the committee made recommendations on training staff and families in how to use environmental adaptations. The committee also felt strongly that there needs to be agreement about who will maintain, repair, service and insure the equipment, and that it is important that people know how to get support if it is damaged. In the committee's experience, these issues are often not resolved effectively, which means the equipment does not get used and children and young people's needs are not met. The committee were confident that making the responsibilities around these areas more explicit would resolve this issue. There was moderate-quality qualitative evidence that children and young people and their families and carers need more information and support to understand the services available to them, to help them make decisions and access services. To address this, the committee made a recommendation about providing information on support groups for children and young people who use environmental adaptations. The SEND Regulations 2014 also specifies that the SEND Local Offer must include information about support groups. Based on the committee's experience, children and young people with environmental adaptation equipment can have difficulties when they move area, as it is not always possible to take equipment with them. This often has a negative impact on their quality of life, so the committee made recommendations to address this. There are existing environmental control services that provide support for people with physical disabilities and multi-sensory impairments that restrict their ability to independently operate standard controls. However, in the committee's experience these specialist services are not well known and so are underused. This experience is consistent with moderate-quality qualitative evidence that practitioners and other staff lack the necessary skills and knowledge to work effectively to meet the needs of children and young people. It is important that staff are made aware of environmental control services, so that lack of knowledge is not a barrier to children and young people receiving support, and so that they refer children and young people if they meet the eligibility criteria. The committee were aware that referrals are usually made by occupational therapists. However, the services accept referrals from other education, health and social care practitioners, so it is important that services do not cause delays by putting extra restrictions on who can make a referral. ## How the recommendations might affect practice In some areas, specialised environmental control services are underused. The recommendations may lead to an increase in referrals to these services. However, the specialist services are already funded by NHS England, so this will not lead to an increase in costs for local education, health and care services. The availability of training on environmental adaptations is variable, so providing training might represent a change in practice for some services. And practitioners will need to spend more time showing children and young people and their families and carers how to use these adaptations. The amount of time required will vary depending on the complexity of the equipment and the number of people that need to be trained to use it. Training practitioners to use the equipment properly will ensure that the often costly equipment that has been assessed and prescribed will be used, and used correctly. It will improve outcomes, such as independence. It will also mitigate against the risk that only 1 practitioner knows how to use the equipment, so if they stop working with the child or young person, the equipment stops being used, potentially resulting in a deterioration of the child or young person's health and wellbeing. There may also be fewer injuries if children and young people know how to use the equipment correctly. There are established frameworks in place for maintaining, servicing and insuring environmental equipment, for example frameworks provided by the environmental control services. This particular recommendation is only highlighting that responsibilities around these areas should be stated more explicitly. Return to recommendations # Environmental accessibility Recommendations 1.11.11 to 1.11.15 ## Why the committee made the recommendations There was no comparative evidence in this area. However, there is best practice and statutory guidance on environmental accessibility that the committee referred to. The Department for Education already requires regular assessment of the accessibility of education environments, but in the committee's experience this statute is not well known and is poorly understood. The committee agreed that health and social care services should also conduct annual assessments, to ensure that children and young people can access the full range of services they need and prevent barriers to access. In the committee's experience, the results of accessibility assessments provide important information to help children and young people and their families and carers make decisions about which services to use. It is a statutory requirement for education providers to make their accessibility assessments publicly available, but the committee agreed that it could also be helpful for health and social care services to make this information publicly available because it would help families with decision making. Staff knowledge of disability and accessibility should also be assessed because, in order for environments to be fully accessible, staff need to be committed to this ideal and to making reasonable adjustments; physical adaptations alone are not enough. Accessibility assessments should be available for key public places that disabled children and young people need to access, to ensure they can access the provision specified in their EHC plans and to allow them to participate and feel included (for example, in after-school clubs that are not held at their school). Publicly funded organisations have a statutory duty to make reasonable adaptations to promote accessibility, but in the committee's experience some community organisations might not be aware of this duty or have sufficient knowledge about the required adaptations. Therefore, the committee agreed that interagency teams should ensure accessibility assessments are available. There was no comparative evidence available on the effectiveness of adaptations to physical or sensory environments. Therefore, the committee recommended further research in this area. ## How the recommendations might affect practice Annual assessments of accessibility at a service level represent a change in practice for health and social care services. However, health and social care practitioners do already conduct accessibility assessments for individuals, to comply with legislation on access for disabled people. Overall this recommendation should not be a substantial change in practice. There may be some additional resources associated with setting accessibility assessments up and coordinating at a service level. Assessing staff knowledge of disability and accessibility as part of annual accessibility assessments should already be a part of any properly conducted assessment. However, this may represent a change in practice for underperforming services, which will have to improve their annual assessments. Return to recommendations # Travel training Recommendations 1.12.1 to 1.12.4 ## Why the committee made the recommendations There was some very-low-quality evidence that travel training increased independent public transport use by disabled children and young people with severe complex needs. The evidence was focused on travel to and from school, but the committee agreed it is important that training helps children and young people to go anywhere they need to, in order to increase independence and participation. The recommendation is not limited to public transport, because in the committee's experience there will be some children and young people who cannot use public transport. For this group, being able to use other forms of transport (such as powered wheelchairs, taxis, or adapted cars that they can drive themselves) will significantly improve independence. The committee were confident that the same travel training process would apply, and there was no plausible reason the training would not work equally as well for these additional scenarios. Based on their experience, the committee agreed that local authorities should consider providing a training framework to support travel training for all disabled children and young people with severe complex needs. This was because local authorities sometimes commission third party organisations to provide the training. The committee agreed that an organisation needed to have overall responsibility for implementing travel training to ensure that it happens. They were confident that local authorities were the appropriate organisation to direct the recommendation to. The topics that travel training could cover were based on topics covered in the study the committee reviewed, and on their knowledge and experience of some of the challenges and risks children and young people face when travelling independently. Providing information to parents, carers and relevant professionals was a key component of the travel training in the evidence, so the committee recommended that local authorities should do this. The study on travel training also included providing disability awareness training for staff as part of the intervention. The committee agreed with this, as it would help disabled children and young people with severe complex needs to independently use public transport. However, as providers of public transport already have a statutory duty under the Equality Act 2010 to provide disability awareness training to their staff, the committee did not make recommendations on this. ## How the recommendations might affect practice Local authorities must make transport arrangements when needed to allow school-age children and young people to attend school. Travel training is one of the ways local authorities can do this for disabled children and young people with severe complex needs. Help with travel to education and training for young people aged over 16 is covered by the Department for Education's statutory guidance on post-16 transport to education and training for local authorities. Local authorities are required to produce a transport policy statement, setting out any transport or other arrangements that they think are needed to allow young people to access education (this includes young people aged under 25 with EHC plans). Travel training is one of the arrangements that local authorities can use to help young people use public transport independently. Although there are other options, and there is no requirement for local authorities to provide travel training, in the committee's experience many of them do for this group. For disabled young people with severe complex needs who are no longer in education, there is no requirement for local authorities to provide help with travel. In addition, the EHC plans for these children and young people will have ceased, removing a potential source of funding. However, the committee's view was that there is only a very small number of disabled young people who would actually use travel training when they are aged over 16 and not in education. So although there might be some additional costs to implement this recommendation, it would not have a significant resource impact. Travel training is not consistently available in all areas, so there will be a change in practice for local authorities that do not have a training framework. However, most EHC plans will already specify a need for travel training, either because independent travel is listed as an outcome in its own right or because it is a means to achieve another outcome (for example, employment). The recommendation is unlikely to have significant resource implications because the committee's understanding of the SEND code of practice is that local authorities should provide enough funding for all the provisions agreed in EHC plans. Return to recommendations # Employment Recommendations 1.13.1 to 1.13.11 ## Why the committee made the recommendations The evidence on joint-working practices to prepare disabled children and young people for employment ranged from very low to low quality. Concerns included a risk of bias, the small number of studies, and the fact that the studies were not conducted in the UK. Therefore, the committee supplemented the evidence with their own knowledge and experience. In the committee's experience, there is variation in the assistance provided to guide children, young people and their families and carers through employment options in the SEND Local Offer and the information is not always easy to understand. To improve consistency, the committee recommended using the Gatsby benchmarks, which are also recommended in statutory guidance from the Department for Education. There was no evidence on supported internships. However, there was evidence that follow-on support increased independence in disabled young people with severe complex needs. The components of follow-on support in this study and supported internships in the UK are similar, so the committee used this evidence to make recommendations on supported internships. In addition, the SEND code of practice focuses on preparing for adulthood outcomes (which includes employment) in EHC plans from year 9 onwards. However, young people with severe complex needs have a very low chance of progressing to employment without assistance. The committee were aware of evaluations of supported internship programmes that have been undertaken by the Department for Education and UK Government. These evaluations concluded that supported internships are effective at helping young people with severe complex needs into employment. Therefore, the committee were confident that supported internships should be made available. There was very-low-quality evidence that a named responsible practitioner improved young people's ability and confidence in meeting workplace expectations. This supported the committee's experience. They were confident that an essential component of supported internships is a lead employment practitioner with expertise related to helping young people with disabilities to find work. This lead practitioner provides one-to-one support to the young person, to coach them on the workplace skills and processes they will need to understand. Without this support, the committee agreed that employment outcomes would be much less likely to be successful. The committee also agreed that the same benefit was likely to be seen for young people with employment as an outcome in their EHC plan but who were not undertaking a supported internship. To support implementation of this, they recommended that providing a lead employment practitioner should be a requirement in service specifications for employment support services. In the committee's experience, the lead employment practitioner would usually be a job coach. However, as there are other practitioners that could carry out this role, the committee did not limit it in the recommendation. There are existing professionals who are trained to perform the role of lead employment practitioner. However, many people who are not trained are still providing such employment support. It is essential to have someone trained in employment support because the severe complex needs of this group of young people mean that additional and bespoke support is needed to help them find work. There was moderate-quality qualitative evidence that preparations for adulthood are insufficient, inconsistent and left too late. In the committee's experience, families and young people are left to research employment options at the point when the young person is looking for a job. Preparing for adulthood early on would lead to better outcomes, so the committee made recommendations to support this. The committee agreed that vocational profiles can help young people to find the type of work they would be good at. In the committee's experience, it is important for practitioners from all services to work together and consider what employment support the young person may need, to prevent barriers to young people effectively participating in employment support. The committee were confident that practitioners should do this so that the responsibility does not fall on the young person and their family or carers. Based on their experience, the committee recommended actions that supported internship providers can take to help young people move into paid employment or volunteer work when their supported internship ends. This is because this group will have additional hurdles to overcome compared with non-disabled people who are competing for the same jobs. Doing this will support employers to make reasonable adjustments around recruitment. The committee agreed that young people and their families are not always aware of the support available from support workers and job coaches, and so recommended local authorities signpost to these services in the SEND Local Offer. It is a requirement of the SEND Regulations 2014 that the SEND Local Offer contains information about all services available in that local area. In the committee's experience, mentors and workplace buddies are a useful source of support for young people, and make the start of their job go more smoothly for both the young person and the employer. It is important that workplace buddies are not the young person's line manager because the young person has to be able to share their anxieties with their buddy, so they can receive effective support before this results in a performance issue. ## How the recommendations might affect practice Commissioners are already required to make suitable arrangements for disabled young people who are eligible to access supported internships, where these are provided as part of the post‑16 SEND Local Offer. The recommendations on this should make practice more consistent and effective, but may represent a change in practice for underperforming services or poorly served areas. More practitioners will need to be trained to provide employment support for young people, so that every young person who is undertaking a supported internship can be provided with a lead employment practitioner. Further practitioners will need to be trained if local authorities also decide to provide a lead employment practitioner to those young people who have employment as an outcome in their EHC plan. However, because this is an outcome in the EHC plan, funding already exists to enable this training to happen. Therefore, there will not be a significant resource implication. Return to recommendations# Rationale and impact for recommendations on working culture, training, service organisation, integration and commissioning These sections briefly explain why the committee made the recommendations and how they might affect practice and services. # All education, health and social care practitioners Recommendations 1.14.1 to 1.14.3 ## Why the committee made the recommendations There was moderate-quality qualitative evidence on the experience of practitioners from different services working together: there can be negative relationships between professionals, leading to disagreements practitioners agreed it was important to put aside their differences, to work together for the good of the child or young person mutual respect and viewing other practitioners as equal partners made it easier to voice opinions and challenge each other, which was seen to improve joint working practitioners valued each other's skills and knowledge, and wanted opportunities to learn from each other and build their expertise working relationships improved when practitioners worked together frequently or for extended periods, and when they had the opportunity to meet face-to-face. To address this evidence, the committee made a recommendation on collaborating to develop a positive working culture. Moderate-quality qualitative evidence also showed that using a consistent approach when interacting with children and young people was beneficial. It made services more predictable for children and young people, and made things easier for them to understand when dealing with a new service. The recommendation on arranging handovers will help to improve consistency and reduce the need for children, young people and their families and carers to repeat information. There was limited quantitative evidence that having a local assessment team reduced waiting times for assessment. However, there was only 1 study in this area, focusing on children and young people with autism. It was very low quality, and reported on waiting times only. Because of these problems with the evidence, local assessment teams were not recommended. The committee did agree that practitioners would be better able to coordinate with each other and provide information to children and young people if they understood the responsibilities of other practitioners and services involved in supporting the education, health and care needs of the child or young person. The need for more coordinated support was highlighted by moderate-quality qualitative evidence that service providers value the different skill sets and knowledge of others and opportunities to learn from each other and build expertise. In the committee's experience, service providers already gain an understanding of the responsibilities of other people and services in an ad hoc way; the recommendations would simply encourage a proactive approach. ## How the recommendations might affect services The recommendations reinforce principles of good practice and should not represent a change for most services. However, some underperforming services may have to implement more effective practices, for example around arranging handovers. Services will also have to develop interagency training for practitioners on other services and their roles and responsibilities. Extra practitioner time might be needed to provide more wide-ranging and coordinated support. However, if practitioners are better trained on the roles and responsibilities of other services, this may lead to more efficient and timely delivery of care, with less duplication. Return to recommendations # Working culture Recommendation 1.15.1 ## Why the committee made the recommendation There was moderate-quality qualitative evidence that joint working improved when practitioners had shared values and priorities. From their experience, the committee agreed there is difficulty in practitioners from different services building effective teams and relationships with each other without having dedicated time for this and support from managers. ## How the recommendation might affect services Services will need to give practitioners dedicated time for team and relationship building. Return to recommendation # Key working support Recommendations 1.15.2 to 1.15.12 ## Why the committee made the recommendations There was no evidence comparing services that did and did not have key workers, so the committee made a research recommendation about the effectiveness of dedicated key workers. However, moderate-quality qualitative evidence showed that key workers are seen as important by families and practitioners, for being able to better understand the child or young person's needs, and for being able to coordinate services. Moderate-quality qualitative evidence also highlighted that having a single person for families to contact would simplify processes and be beneficial to joint working. The committee's understanding of the special educational needs and disability (SEND) code of practice is that it recommends that local authorities should adopt a key working approach, to provide a single point of regular and consistent contact, and help ensure holistic provision and coordination of services and support. However, in the committee's experience this is not happening consistently and there is variation in understanding of what key working may involve. The committee were confident that providing effective key working support to everyone who needs it requires flexibility in the support that is provided, tailoring of the support to individual needs and consideration of family circumstances. Very-low-quality qualitative evidence highlighted that families are less accepting of key workers who have not had much involvement with the family. To address this, the committee made a recommendation on how to choose a key worker who could actively engage and work well with the family. Low- and moderate-quality qualitative evidence also showed that: children, young people and their families spent a considerable amount of time chasing and coordinating services, conducting administrative work and arranging meetings more information and support is needed to help children, young people and their families to understand and access services there is a lack of communication between services. The committee made a recommendation on the responsibilities of the practitioner providing key working support, to address the problems identified in the evidence. These responsibilities align with the committee's understanding of the key working functions set out in the SEND code of practice. Based on their experience, the committee were confident that key working support can only be effective if senior managers support practitioners, ensuring they have the training, time and resources needed and understand what key working support involves. Without involvement from senior managers, there is inconsistent provision. Some children and young people miss out on key working support, and others do not receive good-quality support. In the committee's experience, information sharing and governance arrangements are needed to ensure that key working support functions can be delivered across different services. Moderate-quality qualitative evidence showed that the continuity of key workers is important for consistency (particularly during transition to adult services), and that children and young people felt negatively when key worker support ended prematurely. Staff turnover is inevitable, so it is important that good handover and contingency plans are in place to maintain consistency and minimise the impact of changes on children and young people. In the committee's experience, some families do not have a permanently fixed location and move frequently. This can cause difficulties with effective coordination of care and support and timely transfer of information. The committee made recommendations on the actions needed when families move to a new area, to prevent inequalities in access. ## How the recommendations might affect services The committee's understanding of the SEND code of practice is that it recommends a key working approach (paragraph 2.21). However, this has never been fully implemented, and practitioners providing key working support do not have enough allocated time to provide all these functions. Because the recommendations on key working support are in line with the committee's understanding of the SEND code of practice, there should not be a significant resource impact. However, practice is variable, and the implementation of these recommendations might require additional resources for services with suboptimal practices. Services will need to make changes to enable key working approaches. They will also need to ensure caseloads are manageable and practitioners have dedicated resources to deliver effective key working. A dedicated key worker role would be preferred, with a separate job description and role specification, rather than key working functions being allocated to members of the team on top of their existing roles. However, there was no evidence of effectiveness or cost effectiveness to justify a specific key worker post. Using a key working approach will ensure a single point of regular and consistent contact to help ensure holistic provision and coordination of services and support. It will reduce the burden on families to coordinate care, meaning they no longer have to spend as much time away from their other commitments, including care for siblings and time off work, which should increase their ability to manage at home, avoiding the cost of expensive care placements. Because of the current lack of key working support, there are routine reports of communication and coordination failures (that is, different services not working well with each other), leading to inefficient processes, missed meetings and poor information provision. Using a key working approach will counteract this and ensure coordinated and seamless care, joined-up outcomes, and a reduction in complaints. There is no bespoke training for practitioners who will be providing key working support. The essential skills needed involve project management, negotiation, and communication, and usually involve component-based training. Return to recommendations # Making processes easier to understand Recommendation 1.15.13 ## Why the committee made the recommendation Moderate-quality qualitative evidence highlighted that there is a lack of transparency about how decisions are made on education, health and care (EHC) plans, the timescales for reviews, and the processes for appeals or complaints. Although the evidence was only about the EHC plan process, the committee agreed, based on their experience, that having increased transparency about what services do and how they work together would improve the child or young person's understanding of how to navigate the system. It would also increase their confidence in the care and support they are receiving and empower them to be more assertive about their needs. So the committee agreed services should consider doing this. ## How the recommendation might affect services Making processes more consistent and transparent may mean more practitioner time is needed, to improve coordination and joined-up working, and for learning about the roles and responsibilities of other practitioners. Return to recommendation # Training for practitioners Recommendations 1.15.14 to 1.15.23 ## Why the committee made the recommendations The committee used themes from the qualitative evidence to make recommendations on training for education, health and social care services. Moderate-quality evidence showed that joint working was negatively affected when practitioners did not understand the roles, responsibilities and expectations of other practitioners or services. Based on their experience, the committee agreed that training could help. Moderate-quality evidence showed that education providers need support and training to help them integrate disabled children and young people with severe complex needs into mainstream education. High-quality evidence showed that practitioners do not always understand the social, emotional and mental health needs of disabled children and young people with severe complex needs. When these needs are not recognised and addressed, it can be more difficult for children and young people to get EHC plans. The committee agreed that training was needed to help practitioners recognise these needs. Moderate-quality qualitative evidence showed that: services often do not adequately capture the child or young person's perspective on what support they need there is a lack of available training in how to adapt communication and make better use of communication aids for children and young people with communication difficulties; multi-agency work is needed to improve this. The committee were confident that children, young people and parents and carers need to be involved in developing awareness training programmes that are for them or that help practitioners work more effectively with them, to ensure that training is targeted and relevant. This was supported by moderate-quality qualitative evidence that parents and carers felt positive when given the opportunity to provide their views, and praised practitioners who valued their expertise but maintained appropriate boundaries. In the committee's experience, the development of training programmes did not always involve children, young people or parents and carers. There was very-low-quality quantitative evidence that practitioners were better able to meet the needs of disabled children and young people after gaining experience working in other settings. Although this experience was referred to as a secondment in the evidence, the committee agreed that the intervention more closely resembled short-term observational placements, and made recommendations in support of these. This was supported by moderate-quality qualitative evidence that service providers value the different skill sets and knowledge of practitioners from other sectors and opportunities to learn from each other and build expertise. Regular contact among professionals was valued as a way to improve relationships and effective team working. Low-quality evidence also suggested that sharing staff across multiple settings improved knowledge of the child or young person. ## How the recommendations might affect services Currently, while training is provided within each sector about support needs presenting across settings (for example, safe eating and drinking, and personal care), this training is not run jointly. Doing so would be a change in practice. Services will have to develop interagency training for practitioners, but this will reduce conflicting advice, encourage all 3 sectors to work together more efficiently, cut out duplication, and potentially reduce training costs to individual services. Funds to provide the training already exist. Services will only need to reprioritise and reorganise their existing training budgets to deliver this. Joint training will enable practitioners to get insight into other professional perspectives, which should ultimately improve the support provided to disabled children and young people with severe complex needs. Other recommended training already exists (for example, training on the EHC needs assessment process, and recognising social, emotional and mental health needs). However, it is not available everywhere, and the recommendations may represent a change in practice for some services. This training could be provided in various low-cost ways, for example remotely, as pre-recorded sessions. The benefits of these training programmes could be substantial. For example, training to recognise social, emotional and mental health needs should result in those needs being identified sooner, so that earlier, less intensive interventions can be provided. It should also help prevent children and young people from reaching a crisis point that significantly affects their quality of life and is more costly to address. Providing short-term placements so practitioners can gain experience in a different sector is not widespread current practice. However, it is unlikely to have significant resource implications because employers already have funds set aside for training their workforce, and some of these funds could be used to fund the placements. Children, young people and parents and carers are not always involved in the development of awareness training programmes, so this recommendation may represent a change in practice for some services. There may be some additional resources required, such as extra practitioner time, to help them get involved. Return to recommendations # Delegated clinical tasks and feedback Recommendations 1.15.24 to 1.15.29 ## Why the committee made the recommendations There was moderate-quality qualitative evidence from both families and service providers that professionals and staff lacked the necessary skills and knowledge to meet the needs of disabled children and young people with severe complex needs. In moderate-quality qualitative evidence, families who were delivering interventions reported anxiety about not having enough time to discuss these interventions with professionals and staff and make sure they were doing them properly. The committee directed people to guidance from the relevant professional governance organisations because they provide advice on training and competency in delegated clinical tasks. Separate guidance was made for support workers and parents and family members, to reflect variances in the training, competency and support needs of these groups. The committee were confident it was important that children, young people and their families and carers are asked for feedback because they may have different perspectives from practitioners and it is important to get this input to ensure they are getting effective care and support. Processes should be in place for addressing this feedback, so that improvements can be made. ## How the recommendations might affect services The recommendations in this area make other guidance more explicit. There are wide variations in practice across the country about how this guidance is understood and implemented, including some poor practice. The recommendations should make practice less variable. They may also prevent a breakdown in interagency working and prevent critical incidents that could have a detrimental effect on children and young people and substantial financial implications for services. Return to recommendations # Interagency teams Recommendations 1.16.1 to 1.16.5 ## Why the committee made the recommendations There was very-low-quality quantitative evidence that when practitioners work together as part of an interagency team, rather than working individually, children and young people benefit through increased participation, inclusion and educational achievement. Despite the low quality of the evidence, the committee were confident that working together in a coordinated way across education, health and social care services would improve care and support for children and young people. It is also important to ensure that interagency teams have the right practitioners, with the skills and experience to meet all of the child or young person's needs. Moderate-quality qualitative evidence reflected that a lack of skills, knowledge and training among practitioners was preventing them from working effectively to meet the needs of children and young people. In the committee's experience, working relationships between practitioners improve when there is an opportunity to air and resolve disputes. The committee agreed that most services have existing procedures and policies to do this internally, but procedures for resolving interagency disagreements were needed to facilitate the joint integrated working emphasised by this guideline and the legislation. There was evidence of an important benefit of a collaborative life skills programme involving an active partnership of parents, teachers and school clinicians in increasing the participation and inclusion, and educational achievement or attainment in disabled children and young people with severe complex needs. This evidence was very low quality so the committee did not recommend this specific intervention. However, they agreed on the importance of collaborative working across education, health and social care services to ensure that the child or young person's needs are accounted for in all settings. Moderate- and high-quality qualitative evidence highlighted practitioners need more training to meet the needs of disabled children and young people with severe complex needs. However, there was limited evidence about what the content of this training should be. In the committee's experience, learning from other practitioners in the interagency team can be a useful way of finding out about the child or young person's needs and possible approaches for meeting those needs. This was consistent with low-quality qualitative evidence that sharing information increases understanding of the child or young person and their needs. There was also moderate-quality qualitative evidence that practitioners value the skills and knowledge of others, and want opportunities to learn from each other and build expertise. There was limited evidence, based on the experiences of a traumatic brain injury consulting team, that workshops, inter-professional education and ongoing supervision improved the team's ability to meet the needs of children and young people. However, this approach was not recommended because the evidence was limited in terms of both quality and the population it covered, and it did not report how effective the consulting team were at supporting other practitioners. In the committee's experience, individual members of the interagency team often have a wealth of specialist knowledge and information that can be used to improve the care and support provided to disabled children and young people with severe complex needs. The committee felt strongly that this knowledge and information should be shared between members of the interagency team and were confident that doing so would mean they can provide more comprehensive care and support and meet the child or young person's needs more effectively. Based on their experience, they suggested areas of specialist knowledge that could be shared. Moderate-quality qualitative evidence showed that there can be negative relationships between professionals, leading to disagreements. In the committee's experience, interagency teams need the opportunity to air and resolve disputes to improve working relationships guided by policies and procedures that have been created for resolving interagency disagreements. ## How the recommendations might affect services There will already be a team of education, health and social care practitioners who are working together with the family to support the child or young person. The recommendation on interagency teams is about formally organising this, so it reinforces current practice. It may mean that interagency teams include a more comprehensive range of practitioners, with the skills and experience to address all the needs of the child or young person. The recommendations imply greater sharing of knowledge within existing interagency team meetings. Teams that do not do this will have to set dedicated time at team meetings to discuss changes in practice, legislation or statutory guidance. Interagency teams already have ways of resolving disagreements between different practitioners. Some resources might be needed to agree and formalise these practices. Return to recommendations # Local authorities and health commissioners Recommendations 1.17.1 to 1.17.8 ## Why the committee made the recommendations The committee agreed that early intervention and multi-agency involvement will help to identify, assess and address the needs of disabled children and young people with severe complex needs and prevent them reaching crisis point. This was supported by moderate-quality qualitative evidence reporting that services can be slow to provide support until children and young people reach crisis points. Some disabled children and young people with severe complex needs are cared for in specialist residential placements that may be some distance from their home. The committee agreed that, for some children and young people, this may be the most effective option, because it is difficult to meet their support needs any other way. However, in the committee's experience, long-distance placements are also made for some children and young people because there are no local services available to provide the care they need, or because they do not meet the eligibility criteria for local services. The committee were confident that providing care within their community would be beneficial for children, young people and their families and carers, improving their quality of life and maintaining their family and social relationships. The committee therefore agreed, based on their experience, to recommend exploring all local options before using long-distance placements. They also made a research recommendation to establish the most effective commissioning, practice and service delivery models for enabling children and young people to stay close to home. In the committee's experience, it is widespread practice for services to be commissioned and developed based on replicating existing services rather than based on services that meet the needs of the population. This approach does not necessarily consider what the outcomes of such services should be. Specifying outcomes in contracts would lead to services that are better equipped to meet the needs of disabled children and young people with severe complex needs. In the committee's experience, services often work in isolation and do not consider the effect that changes in service structure or processes may have on other services involved in the care of disabled children and young people. This can cause delays and gaps in service provision. There was moderate-quality qualitative evidence that the services provided often do not meet the needs of children and young people, because of a lack of funding and resources. This is a particular problem for young people over 16. There was also moderate-quality qualitative evidence that decisions on transition are left too late, further affecting young people. In the committee's experience, working together to plan how services will be funded and organised once young people turn 18 or transfer into adult services would ensure continuity of support and lead to more effective use of limited resources. There may be health reasons to limit some specialised services based on diagnosis. However, in general the committee felt strongly that, in line with their understanding of the SEND code of practice, support should be provided based on needs rather than diagnosis. This was supported by moderate-quality qualitative evidence from both families and practitioners suggesting that this would minimise gaps in service provision. In the committee's experience, services sometimes deprioritise children and young people on their waiting lists to meet organisational and statutory targets. If the statutory deadline for producing the EHC plan has been missed for a child, they may then be forced to wait even longer, as services prioritise meeting the deadline for other children or young people. Although this allows organisations to meet more statutory deadlines overall, in practice it penalises some children and young people for no practical reason and may exacerbate their needs. The committee were confident that a recommendation was needed to discourage this. There was low-quality qualitative evidence of a lack of clear pathways for referral between services. This aligned with the experience of the committee, who felt strongly that the processes for referral needed to be more effective. They were confident that doing this will help practitioners provide effective and coordinated care and support to disabled children and young people with severe complex needs. They made recommendations on how to do this. There was some evidence involving parents in steering committees and advisory groups could improve their quality of life. There was also moderate-quality qualitative evidence that using a more flexible approach would be beneficial. A flexible approach is when services work to meet the individual needs of the child or young person, rather than fitting the child or young person within existing rigid service models. Moderate-quality qualitative evidence reported families feeling disillusioned with statutory provisions and seeing little point in requesting help, leading to occasions when they opted out of seeking support. The committee agreed that getting the views of service users on the effectiveness of services could potentially improve statutory provisions and subsequently reduce the disillusionment about current services. This is in line with the committee's understanding of the SEND code of practice, which specifies that children and young people with special educational needs and disabilities and their parents must be engaged in commissioning decisions, so that users' experiences, ambitions and expectations can shape decisions on the services provided. The committee's understanding of the SEND code of practice was also that children and young people with special educational needs and disabilities and their parents must be consulted when reviewing educational and training provision and social care provision. The committee's understanding of the SEND code of practice is that services should be commissioned based on the needs of people in that area. However, in their experience the committee has seen the opposite happening, with people being expected to just use services that already exist. The committee made a recommendation to discourage this. There was some evidence that dedicated funding for services, joint budgets and having a designated service manager improved parents' satisfaction and quality of life. However, this evidence was very limited and was specifically related to the provision of key workers. There was also insufficient information in the studies on the exact funding and commissioning arrangements. Therefore, the committee recommended further research into the most effective joint commissioning arrangements for disabled children and young people with severe complex needs. ## How the recommendations might affect services The recommendations reinforce existing legislation and statutory guidance and would only represent a change in practice for services that are not compliant with these. Coordinated and joint-working practices are not consistent. Commissioners will have to set up or use existing commissioning frameworks to reinforce joint working and to ensure that children, young people, parents and carers are involved in planning services. In practice, this will mean more practitioner time, more meetings and more communication between education, health and social care services. Education, health, and social care services working together in an integrated way will deliver better, more joined-up, holistic services to children and young people with disabilities and severe complex needs to keep them supported within their families and local communities. This will lead to early identification of needs (before they reach a crisis), and reduce the need for expensive, often extended, hospital stays. This may also prevent expensive out-of-area placements. Ultimately, integrated ways of working achieve better outcomes for children and young people with severe complex needs, for example maintaining independence, improving health outcomes and quality of life, and general wellbeing. This would also improve educational outcomes by getting the right support for engaging in learning earlier. Return to recommendations # Coordinating EHC plan process changes with local services, training and short breaks Recommendations 1.17.9 to 1.17.13 ## Why the committee made the recommendations There was high-quality qualitative evidence that the paperwork and processes of EHC plans are revised without service providers being given any notice or consultation. The committee agreed that this is a source of inefficiency and frustration, and made recommendations to involve services and commissioners more closely in the process. There was moderate-quality qualitative evidence that both service providers and families have trouble understanding the EHC plan process. Services are concerned about their lack of training and knowledge on how to support the development of EHC plans, which potentially leads to discrepancies and a lack of consistency. Local authorities are responsible for the EHC process, so the committee recommended that they provide training on this for practitioners. Producing good-quality EHC plans is crucial to ensuring that disabled children and young people with severe complex needs get the support that they need. In the committee's experience, short breaks help parents and carers with the delivery of care by providing respite. This was supported by moderate-quality qualitative evidence. Although the Breaks for Carers of Disabled Children Regulations 2011 requires local authorities to provide short break services, in the committee's experience the range of options can be constrained by the resources currently available in their area. The committee were confident that the most successful and valuable short breaks are those provided in consultation with parents or carers, and tailored to their specific needs. Therefore, they highlighted the requirement in the regulations that a range of short breaks must be provided. There is no evidence on the effectiveness of short breaks. So it is not clear which aspects of short breaks are most effective or why children and young people and their families and carers prefer some short breaks over others. The committee agreed that a research recommendation was needed to determine which components of short break services are most effective. ## How the recommendations might affect services Local authorities will have to spend more time explaining EHC plan process changes to education, health and social care services. If practitioners understand the process better, this will lead to production of better EHC plans, and ultimately more efficient delivery of services, increased transparency, and more timely care. Training on the EHC needs assessment process already exists within most services. This training could be provided in various low-cost ways, for example remotely, as pre-recorded sessions. Such training will reduce conflicting advice and encourage all 3 sectors to work together more efficiently, minimising duplication. Recommendations on short breaks reiterate the duty under the Breaks for Carers of Disabled Children Regulations 2011. Return to recommendations # What to include in the SEND Local Offer Recommendations 1.17.14 and 1.17.15 ## Why the committee made the recommendations In the committee's experience, not everyone knows that the SEND Local Offer provides information about the services and support that are available for disabled children and young people and their families. To prevent inequality in access, they made recommendations about what should be included in the SEND Local Offer. The SEND Regulations 2014 specify what information must be included in the SEND Local Offer. A variety of themes from the qualitative evidence highlighted areas where information provision was poor or lacking. The committee used these themes to make recommendations highlighting what local authorities should include in their SEND Local Offer, that were consistent with the regulations and guidance in the SEND code of practice. The committee mentioned eligibility criteria used in the EHC needs assessment process in response to low-quality qualitative evidence. This showed that families thought their child had to reach a crisis point before an EHC plan was considered necessary. In response to low-quality qualitative evidence that practitioners felt pressure not to apply for an EHC plan because of funding issues, the committee recommended explaining the criteria for an EHC needs assessment. There was qualitative evidence that children and young people and their families and carers need more information to understand and access available services. Assistive technology is highlighted because there were specific concerns in the qualitative evidence about the lack of training and knowledge of staff in this area. The committee agreed, based on their experience, that details of social activities should be included. This is because social inclusion is as important as care and education for improving the quality of life of disabled children and young people. Providing details of support to assist with preparation for adulthood and independent living in the SEND Local Offer is a requirement of the SEND Regulations 2014. The SEND code of practice provides guidance on what information about employment should be provided. In the committee's experience, employment may be a daunting prospect for disabled children and young people, but this can be improved when local authorities make the available services clear. In line with the Children and Families Act 2014 and SEND Regulations 2014, local authorities must involve children, young people and their parents in planning and reviewing the content of the SEND Local Offer, which gives families the opportunity to say what services they think are needed and raise issues if they are not happy with what is available. ## How the recommendations might affect services The information local authorities include in their SEND Local Offers varies, and the recommendations will help reduce this variation. Local authorities that do not currently provide this information may need to spend more time and resources collecting it and including it in the SEND Local Offer. Return to recommendations # Improving how local authorities, commissioners and services work together Recommendations 1.18.1 to 1.18.6 ## Why the committee made the recommendations There is a joint commissioning duty in the Children and Families Act 2014, between clinical commissioning groups and local authorities. However, this is only happening in parts of the system. There is no universally established framework at an organisational level to enable joint working across all 3 sectors. Many of the recommendations in this guideline emphasise the need for joint working, but the ability of services to implement these would be limited without a framework being established at an organisational level. The committee noted that the commissioning duty of clinical commissioning groups is being absorbed by integrated care systems and therefore the same duty should apply to the relationship between integrated care systems and local authorities, so they recommended developing a joint commissioning framework. In the committee's view, interagency team working will only be effective if there is a formal commitment, setting out how providers and services should work together in an integrated way. The committee were confident that effective interagency team working is of central importance to improving support for disabled children and young people with severe complex needs, and so made recommendations on how to achieve this. Based on their experience, they agreed that the mechanisms to achieve effective integrated working would be for commissioners to specify how services should work together in contract requirements; for senior managers in all services to have processes in place to support interagency team working; and for providers to have agreements setting out how they will work together. Clinical commissioning groups are required to develop and maintain dynamic support registers. However, education and social care services are often not aware of these registers. Dynamic support registers are a useful source of information on children and young people who are likely to need additional support. In turn, this should make it easier to recognise early signs that might lead to a crisis, and enable extra support to prevent unnecessary hospitalisation. ## How the recommendations might affect services Integrated care systems are replacing clinical commissioning groups and may need to work collaboratively with local authorities where they are not already doing so, which potentially could have some resource implications. Joint commissioning of services is currently only being done for particular provisions, for example some patient advice and support services, some bespoke packages for post‑16s, and some short breaks. Developing a joint commissioning framework would be a change in practice. Given the integral part local authorities play in the identification, assessment and care pathways for children and young people with disabilities and severe complex needs, joint working (facilitated by a joint commissioning framework) is essential to bring meaningful improvements in the care of these children and young people. A joint commissioning framework across education, health and social care will enable collaborative working, coordination, consistency and efficiencies for all parties involved. It will enable holistic care and a less fragmented experience. It will also allow practitioners to deliver person-centred care that addresses their needs across the 3 sectors, and ultimately, it will result in better care and support for the person. For example, better joined-up working will lead to early identification of needs (before they reach a crisis). This may prevent expensive out-of-area placements and prolonged hospital stays. It will improve health outcomes because the right care can be started early, avoiding the delays in care that exacerbate problems. This would also improve educational outcomes by getting the right support for engaging in learning earlier. Education, health and social care services will have to make their processes more joined-up and coordinated. They may need more joint and collaborative meetings. Commissioners will need to establish frameworks for collaborative and cooperative working. Dynamic support registers are an existing requirement, so there should not be a significant resource implication from this recommendation. There may need to be a change in practice in areas where these are not being used. Return to recommendations# Context It is important that education, health and social care services work together to effectively meet the changing needs of disabled children and young people with severe complex needs. But there are a variety of challenges to doing so. The lives of disabled children and young people with severe complex needs can be improved by education, health and social care services that: are joined-up are tailored to the needs of the individual child or young person involve children and young people in decisions about their education, health and social care involve families and carers in decisions about their child's education, health and social care incorporate support for families and carers. This guideline focuses on delivering integrated education, health and social care services. It is designed to help local authorities, health commissioners, and education, health and social care providers and practitioners to implement the special educational needs and disability (SEND) code of practice in order to improve outcomes for this group of children and young people and their families and carers. The guideline covers disabled children and young people with severe complex needs who: need coordinated education, health and social care support because of their severe and complex needs and are eligible for an education, health and care plan, in line with the Children and Families Act 2014. The guideline does not make recommendations specific to particular disabilities or health conditions. The guideline includes recommendations on: involving children, young people and their families in their care communication and providing information planning and running meetings with children and young people identifying needs education, health and care (EHC) needs assessment and EHC plans support and training for parents and carers social participation transition palliative and end of life care environmental adaptations employment working culture training for practitioners service organisation joint working and integrated support joint commissioning.	{'Recommendations on support for all disabled children and young people with severe complex needs': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThese recommendations cover the support that all disabled children and young people with severe complex needs should receive. There are also recommendations in this guideline on:\n\nspecialist support, covering palliative care, communication aids, environmental adaptations and accessibility, travel training and employment\n\nservice organisation, including working culture, training, integrated working, and commissioning.\n\nThe government's special educational needs and disability (SEND) code of practice is the primary guidance for processes around SEND.\n\nThis NICE guideline makes recommendations on how existing legislation and statutory guidance should be put into practice. When there is evidence that existing legislation and statutory guidance is not being implemented, the guideline recommendations reiterate this and provide further guidance to help with implementation.\n\n# Principles for working with children, young people and their families\n\n## Key principles\n\nEducation, health and social care practitioners should always:\n\nput the views, life goals and ambitions and preferences of the disabled child or young person with severe complex needs at the centre of planning and decision making\n\ntake the views of parents and carers into account\n\ntake account of the cultural background of the child or young person and their parents and carers.\n\nFor children and young people who are not able to actively participate in planning or decision making, education, health and social care practitioners should take into account the views of the people who know them best.\n\nDo not assume that all children and young people with a particular diagnosis need the same support.\n\n## Involving children and young people and their families\n\nEnsure that all children and young people are involved in discussions and decisions about their education, health and social care support. Get each child or young person's input in the way that is most effective and accessible for them. For example:\n\ninvite them to attend in-person or virtual meetings (or parts of meetings) where their views should be represented\n\nshort 'about me' presentations\n\nphoto diaries\n\nvideo or voice recordings.\n\nKeep a record of how the child or young person participated in discussions and decisions, and what contribution they made.\n\nFind out which members of the child or young person's family should be involved, in the context of their current individual family circumstances (for example, when a family member other than a parent has parental responsibility). Review this if their family circumstances change.\n\nWork closely with children, young people and their families and carers to:\n\nget to know them better, to understand their needs\n\ndraw on the expertise they have from their lived experience and associated needs\n\nbuild a positive working relationship with them, to better understand their views, life goals and ambitions.\n\nEncourage and support children and young people to give their views on their health, care, education and support, and express what they want and need.\n\nTake account of the communication needs of children and young people. If needed, consider getting support from a specialist to help them participate in discussions and decisions and express their views.\n\nEncourage parents and carers to think about how their child can give their own views and be involved in decisions. Ask them what services can do to support their child in communicating their views.\n\nRegularly check that children and young people and their families and carers are satisfied with how they are involved in decisions about their support. If they are not satisfied, look for ways to address their concerns.\n\nLearn about the approaches families and carers use (now or previously) when caring for their child. If they are beneficial, continue using them in the same context. Avoid using those that have not worked well in the past.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles for working with children, young people and their families\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review B: involving children and young people\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Communication formats and providing information\n\nTake care to use empathetic, supportive language when communicating with families and carers, because they may be anxious and perceive judgemental attitudes from practitioners.\n\nProvide information in a spirit of partnership with families and carers. Avoid being directive (unless the family and carers prefer this), and take their experience and perspective into account when providing information.\n\nBe sensitive to and address the feelings of children, young people and their families and carers when providing information. Help them to understand and reflect on information, and direct them to sources of statutory and independent support if needed.\n\nEnable children and young people to communicate their views in a way that is appropriate for their age, developmental level and communication abilities.\n\nFind out what communication formats and media the child or young person prefers (for example, children who are non-verbal might use alternative and augmentative communication). Communicate with them using their preferred format. Ensure the format allows them to use any inclusive terminology that is relevant to them.\n\nBe aware that a child or young person may prefer different communication formats for different purposes.\n\nAsk children and young people and their families and carers if they have an up-to-date communication passport.\n\nRecord children and young people's communication preferences in a format that can be shared, so that they do not have to repeat this information.\n\nEstablish the most effective way of communicating with families and carers, for example providing information in different languages or involving an interpreter.\n\nBe aware that parents or carers may have communication preferences and needs of their own, and that these may affect their ability to take part in discussions and understand information about their child's support.\n\nEducation, health and social care services should give children, young people and their families and carers up-to-date, accessible information and advice about:\n\nthe process and purpose of assessment and diagnosis\n\nthe education, health and social care support they are receiving\n\nany delays or changes in the above\n\nwhat other support they are entitled to\n\nthe meetings they will be involved in and how to contribute their views\n\nthe roles of the practitioners and services that are currently supporting them, and any services or practitioners that they have been referred to for future support\n\nwhat to expect from services\n\nrelevant policies and processes\n\nhow to raise a concern about their support and how to provide feedback to encourage service development (for example via parent carer forums).\n\nEducation, health and social care services should direct children, young people and their families and carers to sources of support and advice, including:\n\nSEND Information, Advice and Support services\n\nspecialist national or local support groups\n\nlocal carer support groups (for example parent carer forums)\n\npeer support groups\n\ntheir SEND Local Offer.\n\nSEND Information, Advice and Support services should help children, young people and their families and carers understand what support is available for them, based on their specific needs.\n\nAsk children and young people and their families and carers what they expect from services. If their expectations cannot be met, explain why and explore alternatives.\n\nFor more guidance on communicating and discussing complex information, identifying preferred communication formats, cultural sensitivity in communication, and tailoring information to individuals, see the:\n\nNICE guideline on babies, children and young people's experience of healthcare\n\nNICE guideline on patient experience in adult NHS services (in particular recommendation 1.5.14).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communication formats and providing information\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review B: involving children and young people\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Preparing for and running meetings with children and young people\n\nAsk children and young people and their families and carers how they would like to be involved in practitioner-led review meetings about them.\n\nBefore discussions and meetings, practitioners should help children and young people prepare by:\n\nproviding them with information (in accessible formats) and support to help them and their parents and carers take part, and checking that they understand this information\n\nencouraging their parents and carers to discuss the meeting with them in advance\n\nproviding support for their parents or carers before the meeting if they need help completing any documents\n\nchecking that meetings are physically accessible, and that they can afford to get there.\n\nBefore meetings, the chair should find out:\n\nwhat is important to the child or young person\n\ntheir age, communication abilities and circumstances (see recommendation 1.1.16). Use this information when planning meetings, to ensure that the child or young person can meaningfully participate (see the recommendations on information sharing and privacy).\n\nWhen planning meeting agendas:\n\nprioritise the child or young person's wishes, aspirations and goals, in addition to the statutory content and\n\ninclude any other relevant issues that parents, carers and education, health and social care practitioners need to cover.\n\nAs far as possible (based on practitioners' contracted working hours), consider the child or young person's preferences when planning meetings, to help them participate and understand what is happening. For example:\n\nAsk them when and where they would like to have the meeting:\n\n\n\nconsider scheduling it at a time of day when they are not usually tired and/or\n\nconsider scheduling meetings outside of school time when possible, so they do not miss lessons or feel excluded and/or\n\nconsider having the meeting in a place where they feel comfortable and do not have to travel too far and/or\n\nconsider virtual meetings.\n\n\n\nConsider showing them the meeting room and asking them where they would like to sit.\n\nConsider if they are anxious in groups of people or do not want to discuss a sensitive topic in front of everyone. Arrange a separate meeting so they can get their views across (for example, a one-to-one meeting with a practitioner they trust, or a videoconference).\n\nConsider making adjustments to the meeting format and schedule (for example providing breaks during long meetings).\n\nTake into account family circumstances.\n\nEnsure that, at each meeting:\n\nthere will be education, health and social care practitioners who know the child or young person and are involved in their support\n\nkey additional relevant people are able to attend (for example, a college representative for a review on transition from school to college).\n\nTake account of the child or young person's right to privacy:\n\nhold meetings in places with as much privacy as possible\n\ntell them who will be at the meeting, and why\n\nonly invite the key education, health and social care practitioners who are needed at the meeting, to avoid large groups of practitioners that may be intimidating for some children and young people.\n\nConsider using person-centred planning tools (for example, Planning Alternative Tomorrows with Hope [PATH]) to help structure and conduct meetings.\n\nCommunicate with the child or young person at meetings using their preferred format, and any basic rules that help them to feel comfortable. The chair should remind everyone at the meeting what the child or young person's communication preferences are before the meeting starts.\n\nGive children and young people plenty of time to take in information and express their views in discussions and meetings. Do not rush them.\n\nWhen providing information in discussions and meetings, check that children and young people understand it and how it applies to them.\n\nAgree clear actions (at meetings, and in other discussions between practitioners and the child or young person and their family and carers). For actions that will directly affect the child or young person:\n\nrecord them in an action log, in a format that the child or young person and their family and carers can understand\n\nshare the log with the child or young person and everyone involved in their care\n\nreview the log regularly to ensure the actions are being done.\n\nPractitioners should consider recording meetings (written, audio or video; in line with local policies on information governance and consent), so the child or young person and their family and carers can review them again later.\n\nIf a practitioner cannot attend a meeting, decide whether it needs to be rescheduled. Take into account:\n\nthe problems caused by delaying the meeting\n\nthe risk of the meeting not being productive if it goes ahead without all the relevant practitioners\n\nthe risk of causing discomfort or distress to the child or young person if there are people at the meeting that they do not know\n\nthe consequences for the family and carers (such as parents having to rearrange time off from work).\n\nIf a practitioner cannot attend an interagency team meeting, or any meeting with the child or young person, they should:\n\ntell the person who arranged the meeting in advance\n\nsend a fully briefed delegate to represent them, or provide a written update or report\n\nrequest details of any relevant actions and follow these up\n\nreview the meeting minutes and action log when available.\n\nAsk the child or young person if they would like to involve any siblings or friends in meetings (to share their views on the child or young person's strengths and interests). If they would like to do this:\n\nask the child or young person to invite the sibling or friend\n\nif the sibling or friend agrees to attend the meeting, contact them to explain how they can be involved\n\ninvolve the parents and carers of the child or young person and their sibling or friend as necessary at each stage of this process.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preparing for and running meetings with children and young people\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review B: involving children and young people\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Using a consistent approach\n\nEducation, health and social care services should work together to make the way they interact with each child and young person more consistent.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on using a consistent approach\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Decision making\n\nThese recommendations should be read alongside guidance on Deprivation of Liberty Safeguards and Liberty Protection Safeguards.\n\nProvide children and young people and their families and carers with information to help them play a part in shared decision making.\n\nWhen a child is unable to respond with intentional communication, think about whether their preferences could be identified in another way (for example through observation, play, or their behaviour).\n\nWhen a child can express a view, but their view does not align with the views of their parents, support the child and parent to understand each other's perspective and try to get agreement. If this is not possible, work impartially and separately with them and with their parents.\n\nIf disagreements cannot be resolved and the child or young person is under\xa016:\n\nremember that the child or young person's needs are paramount\n\ntake the views of the parents into account\n\nremember that children and young people under\xa016 can give their own consent if it is clear that they fully understand what is involved.\n\nIf disagreements cannot be resolved and the young person is over\xa016, consider the young person's views first. You must uphold their decision if they have capacity to make it.\n\nIf you think a young person aged\xa016 or over lacks capacity to make a particular decision about their support and education, you must:\n\nfollow the requirements of the Mental Capacity Act 2005 and its statutory code of practice\n\nensure that the young person is as involved as possible in the decisions made on their behalf.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on decision making\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B: involving children and young people\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n## Information sharing and privacy\n\nAsk children and young people and their parents and carers about information sharing as early as possible, to avoid them having to repeat information to different practitioners.\n\nAsk for and record informed consent to share information when needed with other practitioners and services.\n\nAsk if there is any information they do not want to be shared, and discuss the implications of not sharing this information.\n\nAsk who they would prefer to discuss sensitive information with.\n\nExplain what information will be shared without their consent, for example in relation to safeguarding.\n\nPractitioners should follow and stay up to date with their organisation's policy on consent.\n\nPractitioners must stay up to date with the relevant legislation and statutory guidance.\n\nOnce you know the child or young person's preferences, share all agreed information with all services involved in supporting them.\n\nMake sure that all services involved have access to all agreed information about the child or young person.\n\nWhen specialised care plans (such as behaviour management plans) have been agreed for a child or young person, share these plans (and any updates) with them and their parents and carers, and with all relevant practitioners.\n\nCheck the information sharing preferences of children and young people and their families and carers at least annually (for example, check at each education, health and care plan review).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information sharing and privacy\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n# Identifying needs and involving other services\n\nBe aware that disabled children and young people may have emotional and mental health needs that can be obscured by their severe complex needs.\n\n## When needs are first identified in health services\n\nThese recommendations should be read alongside Section 23 in the Children and Families Act 2014.\n\nIf you think a child or young person may have complex health needs or disabilities, think about whether they are likely to also have special educational needs and social care needs.\n\nIf a child or young person is likely to have complex health needs or disabilities and is also likely to have special educational and social care needs:\n\ndiscuss this with them and their parents and carers before notifying the local authority, and if possible get their agreement on when to do this\n\nadvise them and their parents and carers about any voluntary organisations that can provide advice or assistance, and any educational support that is available before they start or return to school\n\ndirect them and their parents and carers to their special educational needs and disability (SEND) Local Offer and SEND Information, Advice and Support services\n\nafter getting consent, find out which education and social care services need to be involved and contact them at the first opportunity.\n\n## When needs are first identified in education services\n\nIf you think a child or young person may have a special educational need, think more broadly about their circumstances and decide whether they need to be referred to other services. For example:\n\nDo they have specific needs that can be addressed with clear actions and solutions, or are they likely to need broader support?\n\nCould there be an underlying health condition, and do health services need to be involved?\n\nCould they have unmet social care needs, and do social care services need to be involved?\n\nIf a child or young person is likely to have special educational needs and is also likely to have complex health and social care needs:\n\ndiscuss this with them and their parents and carers\n\nadvise them and their parents and carers about any support organisations in their SEND Local Offer that can provide advice or assistance, and any educational support that is available before they start or return to school\n\ndirect them and their parents and carers to SEND Information, Advice and Support services\n\nafter getting consent, find out which health and social care services need to be involved and contact them at the first opportunity.\n\n## Referral to social care services\n\nAll disabled children are defined as 'in need' and entitled to an assessment of need under Section 17 of the Children Act 1989. However, some social care support for families may be available without an assessment. These recommendations should be read alongside the duties on reasonable adjustments in the Equality Act 2010.\n\nWhen making a referral for a social care assessment for family support:\n\ninclude a detailed description of the reasons for making the referral, including the emerging health and social care needs (as discussed with the child or young person and their parents and carers) and\n\ninclude any reasons the family might need help to access healthcare services (for example, families on low income who cannot afford to get to appointments) and\n\ndiscuss the potential outcomes of the referral (including an assessment of need) with the child or young person and their family.\n\nBe aware that parents and carers may be anxious about involving social care services. Find out what they know about social care (particularly family support services), and:\n\nexplain areas they do not understand\n\naddress any misconceptions\n\nexplain the difference between safeguarding, child protection social care, and broader family support services.\n\nIf you identify a concern, refer in line with local safeguarding policy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying needs and involving other services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n# Education, health and care needs assessment\n\nThese recommendations should be read alongside NHS England guidance on Care, Education and Treatment Reviews and chapter 9 of the special educational needs and disability (SEND) code of practice.\n\n## Requesting a needs assessment\n\nIf you think a child or young person may have a special educational need, explain to them and their families and carers:\n\nwho can request an education, health and care (EHC) needs assessment\n\nhow to request an EHC needs assessment\n\nthe criteria the local authority will use to decide whether to carry out an EHC needs assessment\n\nwhat the assessment involves\n\nhow to get help with this process (for example, from support groups)\n\nhow to make an appeal, if the local authority does not think an EHC needs assessment is needed.\n\nLocal authorities should explain to education, health and care practitioners that EHC needs assessments should be requested based on a child or young person's needs, and not on other factors such as potential availability of funding.\n\nDo not exclude children and young people from EHC needs assessments based solely on whether or not they have a particular diagnosis, or no diagnosis at all.\n\nPractitioners should support children or young people and their families during the EHC needs assessment, so that families do not have to manage the process themselves.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on requesting a needs assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Supporting children, young people and their families during a needs assessment\n\nWhen carrying out an EHC needs assessment, local authorities should explain to the child or young person and their families and carers:\n\nthe possible outcomes of the EHC needs assessment process\n\nthe purpose of the EHC plan and what it can help with\n\nhow they can be involved in the process and how their views will be incorporated\n\nwhich services will be involved in the process\n\nhow long it should take to get an EHC plan (no more than 20\xa0weeks after their initial request)\n\nwhat will happen if an EHC plan is not issued\n\nhow to contact SEND Information, Advice and Support services.\n\nIf an EHC plan will not be produced in the statutory timeframe, local authorities should update children, young people and their families and carers on the reasons for this and provide information on current progress.\n\nWhile children and young people and their families and carers are waiting for an EHC needs assessment, explain what services are available and might be appropriate, and the criteria for accessing them.\n\nDirect children, young people and their families and carers to SEND Information, Advice and Support services for information about the criteria for funding and support.\n\nGive families and carers help, time and opportunities to express their views and explain what support they think their child needs. Record this information during the assessment process.\n\nEducation, health and social care services should start working together before an EHC plan is issued, to ensure that:\n\nthe child or young person gets the interim assessments they need, and interim support as soon as a need is identified\n\nthe transition from interim support to EHC plan is as simple as possible.\n\nWhile children and young people and their families and carers are waiting for the EHC needs assessment process to finish, provide support based on their identified needs. For example:\n\nhealthcare professionals should work with local teams to identify what interim assessments and support can be provided\n\npractitioners should explain what support is available as part of the SEND Local Offer (such as short breaks)\n\neducation practitioners should provide special educational provision, based on what is currently understood about the strengths and needs of the child or young person.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting children, young people and their families during a needs assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Carrying out the needs assessment\n\nDuring the EHC needs assessment process:\n\ntake into account the child or young person's age, level of understanding, communication needs and specific circumstances\n\ncontact any practitioners who have relevant or specialist knowledge about the needs of the child or young person, but who are not part of the interagency team, to better define the child or young person's needs\n\nidentify emerging needs and make referrals as these needs are identified, without waiting for the assessment process to finish.\n\nUse all information available (including information from other practitioners or services) for assessments of children and young people.\n\n## Timescales for completing a needs assessment and producing an EHC plan\n\nThese recommendations should be read alongside paragraphs 9.41 to 9.44 of the SEND code of practice.\n\nWhen conducting EHC needs assessments, local authorities, services and practitioners must work to the timescales specified in the Children and Families Act 2014 and SEND Regulations 2014. In particular:\n\nwhen an EHC needs assessment is requested, local authorities must decide whether the assessment is needed within 6\xa0weeks\n\nwhen a local authority requests information as part of an EHC needs assessment, services and practitioners must respond within 6\xa0weeks\n\nif the local authority decides that an EHC plan is not needed, they must inform the child or young person and their parents within 16\xa0weeks of the initial assessment request\n\nif the local authority decides that an EHC plan is needed, they must complete the needs assessment and produce a finalised EHC plan within 20\xa0weeks of the initial assessment request.\n\n## If parents or carers decline any assessments\n\nIf parents or carers decline any assessments:\n\nthink about why they are declining and take account of any cultural or communication challenges\n\ndiscuss their reasons for declining and address any concerns they have\n\nexplain how they can request an assessment in future, and encourage them to get in touch if they change their minds\n\nthink about whether this may cause a safeguarding issue, and follow local safeguarding processes.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on carrying out the needs assessment, timescales for the assessment and when parents or carers decline an assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n# Education, health and care plans\n\nThese recommendations should be read alongside requirements on draft education, health and care (EHC) plans in Section 38 of the Children and Families Act 2014, Regulation 13 of the Special educational needs and disability (SEND) Regulations 2014 and chapter 9 of the SEND code of practice.\n\n## Agreeing on outcomes for the plan\n\nEncourage all disabled children and young people with severe complex needs to express their life goals, ambitions and aspirations, and explore their strengths, abilities and interests with them. Focus on all of these when agreeing outcomes for the EHC plan.\n\nTake the views of parents and carers into account throughout the assessment, production and review of EHC plans (see the recommendations on principles for working with children, young people and their families).\n\nWhen writing the agreed outcomes in EHC plans:\n\nmake them SMART (specific, measurable, attainable, relevant and timely)\n\nconsider using the 'outcome sandwich' (specify the timeframe, the skill to be developed, and what this skill would help the person to do).\n\nBase your expectations for a child or young person on their own life goals and ambitions, rather than on their condition or needs.\n\nQuery with other practitioners if you think their expectations for a child or young person are too low.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on agreeing on outcomes for the EHC plan\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Providing information and advice for the plan\n\nPractitioners within the same organisation should read the information and advice produced for the EHC plan by their colleagues, to ensure they can support all the proposed outcomes through their own work with the child or young person.\n\nLocal authorities should consider providing the proposed outcomes for each child or young person to education, health and care services. Services should specify how they will support these outcomes when contributing their advice and information to the EHC plan.\n\nRecord the views of children and young people in EHC plans. Make it clear which parts of the plan contain their contributions.\n\nWhen local authorities write EHC plans:\n\nthey should use the information provided by practitioners to describe the special educational, therapy, medical, health and social care needs of children and young people in sections\xa0B, C and D of the plan\n\nthey should distinguish between what practical and therapeutic support is needed to educate or train the child or young person and what health and medical support they need to stay well.\n\nCommissioners should use the information in sections\xa0F, G and H of the EHC plan to commission the services the child or young person needs.\n\nWhen contributing information and advice for EHC plans, practitioners should (within their own area of expertise) specify the special education, health and social care support that will help children and young people to achieve the outcomes in the plan, including:\n\nthe type of support they need\n\nhow often they need this support\n\nthe level of expertise required to provide the support\n\nwho is responsible for providing the support (see the recommendations about competency in delegated clinical tasks).\n\nLocal authorities and health commissioners should ensure that EHC plans:\n\nare based on up-to-date information\n\nare informed by information and advice contributed by practitioners who have the right expertise and knowledge of the child or young person.\n\nPreserve the child or young person's voice when recording their views:\n\nuse their preferred communication format\n\nuse their own words, or the equivalent in a different format if they do not communicate verbally (for example, symbols or other alternative or augmentative communication, drawings, photo collages, or like/dislike lists)\n\ndo not rewrite what they have said.\n\nLocal authorities should write the outcomes and support provision sections of the plan in language that is understandable to the child or young person and their families and carers. For guidance on providing information in different formats, see:\n\nthe section on providing information in the NICE guideline on babies, children and young people's experience of healthcare\n\nrecommendation 1.5.13 in the NICE guideline on patient experience in adult NHS services.\n\nDuring the planning process, check with the child or young person and their family and carers and:\n\nmake sure that they understand the plan outcomes, and what these will mean in practice\n\nmake sure that the plan makes sense to them and they agree with it\n\ncheck if they have any concerns\n\nif they have a concern that cannot be addressed as part of the EHC planning process, explain and record the reasons why.It may be difficult to do this for some children and young people. However, you should still involve them as far as possible.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on providing advice and information for the EHC plan\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review B: involving children and young people\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Reviewing progress and needs, and coordinating with EHC plan reviews\n\nEducation, health and social care practitioners should review the child or young person's progress and needs at regular intervals, to:\n\ncheck if their needs or circumstances have changed\n\nensure that outcomes remain realistic and focused on helping them reach their full potential.\n\nConduct a professional assessment if:\n\nthe child or young person's needs change significantly (for example, if they develop new health problems or there is a change in their existing conditions) or\n\ntheir circumstances change significantly.\n\nShare the results of the professional assessment with the local authority so that they can decide whether:\n\nthe EHC plan is still fit for purpose or\n\nany provisions in the existing EHC plan should be changed (without a full EHC plan review or reassessment) or\n\nto conduct a reassessment of the EHC plan.\n\nConsider coordinating the EHC plan annual reviews and social care reviews.\n\nDo not reduce the support specified in the EHC plan just because a child or young person shows improvements in particular areas or is able to do new things, because they may rely on the support they get to do this.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reviewing progress and needs, and coordinating with EHC plan reviews\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Funding\n\nLocal authority commissioners and their partners should provide sufficient funding to enable all support listed in the EHC plan that they are responsible for to be provided.\n\nWhen requests for additional resources are refused:\n\nthe people who make this decision should explain the reasons for not providing this support to the practitioners involved\n\nthe practitioners should discuss this with the child or young person and their family and carers, and explain potential courses of action.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on funding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n## If children, young people and their families decline an EHC plan\n\nIf parents or carers decline an EHC plan:\n\ndiscuss their reasons for this\n\naddress any concerns they have, taking account of any assumptions or cultural beliefs\n\ndiscuss the potential implications of deciding not to have an EHC plan\n\nexplain how they can request an EHC needs assessment in future, and encourage them to get in touch if they change their minds\n\nagree what ongoing support will continue to be provided\n\nthink about whether this may cause a safeguarding issue, and follow local safeguarding processes.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on if children, young people and their families decline an EHC plan\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: views and experiences of service providers.\n\nLoading. Please wait.\n\n# Personal budgets and direct payments\n\nThese recommendations should be read alongside government guidance on children and young people's continuing care; NHS England guidance on continuing healthcare and government guidance for local authorities and clinical commissioning groups on the delivery of direct payments and personal health budgets.\n\nLocal authorities and health services should inform disabled children and young people with severe complex needs and their families and carers about personal budgets (including personal health budgets) and direct payments, covering:\n\nif they are eligible, and if so how to apply\n\nwhat they can use the money for.\n\nLocal authorities and health commissioners should continue to ensure services coordinate even if they have been commissioned using direct payments. For example, if the family commission health and care support for a child or young person, the local authority and health commissioners should ensure that those providers still have access to health and care advice directly from statutory providers.\n\nBe aware that personal budgets are mandatory for people aged\xa018 and over who have a care and support plan (although the person can decide whether or not to receive their budget as a direct payment), in line with the Care Act\xa02014.\n\nFor children, young people and families and carers who are receiving direct payments, local authorities should assess the full cost of providing the services proposed in the needs assessment.\n\nFor more guidance on personal budgets and direct payments for young people aged\xa018 and over, see the section on personal budgets and direct payments in the NICE guideline on people's experience in adult social care services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on personal budgets and direct payments\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n# Supporting parents and carers\n\nDirect families and carers to sources of practical support (including the special educational needs and disability [SEND] Information Advice and Support services) and emotional support, to help them come to terms with their child's needs and diagnosis (or lack of diagnosis).\n\nConsider using a person-centred planning approach, to help include parents and carers in care planning.\n\nAsk families and carers how much they want to be involved in making decisions about care planning, because different families will want different levels of involvement. Be aware that families may change their minds over time about the level of involvement they want.\n\nThe interagency team should consider providing information about the emotional and practical support options available to help parents plan for what will happen when they cannot care for their child (for example, if they are too unwell, or after their death). Support options could include voluntary and community support, advocacy, or seeking independent legal advice.\n\n## Training for parents and carers\n\nEducation, health and social care services should consider:\n\njointly developing training for parents and carers\n\nco-producing this training with parents and carers.\n\nIn training for parents and carers, consider covering:\n\nhelping them to understand and meet their child's needs\n\nhelping them effectively support their child's preferred method of communication\n\nhow the different services work and what support to expect for their child\n\nwhat they can do if they think they are not receiving the support they are entitled to\n\nhow to advocate for their child.\n\nEnsure that the training is appropriate to the needs of families. Ensure that the practitioners leading the training have the appropriate knowledge and skills (for example, a consultant might not be needed if the training is not going into detail on medical needs).\n\nConsider using different teaching styles as needed, so the training is useful for all parents and carers.\n\nConsider providing opportunities for parents and carers to discuss their experiences with each other during the training (for example, with group activities or by setting time aside for free discussion), because this will help them to learn from each other and develop support networks.\n\nDo not restrict training to a single point in time (for example, at diagnosis). Let parents and carers take up training when they are ready for it, at different points in the child or young person's life. Regularly ask parents if they want to take up training (for example, at review meetings).\n\nConsider making training sessions more accessible to parents and carers by:\n\nproviding flexibility on training session times, locations and formats\n\nscheduling training at times when the child or young person has pre-arranged care (for example, when they are at school)\n\ntaking account of childcare arrangements for the family's other children.\n\nReview the effectiveness of training (for example, by asking for feedback from parents and carers), to ensure it meets its objectives and the needs of parents and carers.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting parents and carers, and training\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review D: supporting families and carers\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n# Social participation\n\nIdeally, social activities would be accessible to all children, so that children with and without disabilities could participate together. However, there is evidence that disabled children and young people with severe complex needs often do not have access to any social activities. So, although there are other ways to improve social participation for the wider population of disabled children and young people, these recommendations focus on improving social participation for disabled children and young people with severe complex needs.\n\nBe aware that social participation:\n\nis as important as care and education for maintaining and improving the quality of life of disabled children and young people with severe complex needs\n\nis more difficult for children and young people who are not in education or work\n\nmay justify a young person with progressive or fluctuating illness in attending school or college, even if their attendance may be interrupted.\n\nLocal authorities should consider developing and funding group activities (for example, sports or theatre) as part of their short break services. When developing these activities, they should work with other organisations (including voluntary and community organisations).\n\nWhen local authorities are planning group social activities as part of short break services, they should:\n\nensure there is a range of options to accommodate different behavioural, mobility, learning and communication needs, and different cultural backgrounds and family circumstances\n\nthink about access for those living in rural areas\n\nthink about what equipment will be needed to make activities accessible. For statutory requirements on short breaks, see the Department for Education guidance on short breaks for disabled children.\n\nEducation, health and social care services should adapt activities, communication formats, the physical environment and participation methods as needed to meet the needs of the children and young people who are attending.\n\nInteragency teams should plan support to help children and young people to participate in social activities. This could involve:\n\nhelping them make friends and access local community facilities\n\nhelping them use the internet and social media to maintain their friendships and meet new people safely\n\nhelping them to volunteer in the community.\n\nUse short breaks for the benefit of the child or young person (for example, by running group social activities), as well as a break for families.\n\nHealth services should work with education and social care services to address children and young people's health needs flexibly, so they can join in with education and social activities alongside other children and young people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on social participation\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review F: supporting participation in education and social activities\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n# Transition from children's to adults' services\n\nThese recommendations should be read alongside the special educational needs and disability (SEND) code of practice (chapter\xa08 and paragraphs\xa09.151 to\xa09.152), and supporting legislation.\n\nLocal authorities must ensure that preparation for adulthood is covered at education, health and care (EHC) plan reviews from year\xa09 onwards, in line with the SEND Regulations\xa02014.\n\nWhen working with young people, interagency teams should:\n\nfocus on the young person's goals for adulthood, instead of just treating health problems or providing short-term support\n\nhelp the young person and their parental deputy to prepare for adult life and maximise their independence.\n\nDo not assume that young people will have a clear plan for adulthood at the start of transition planning. Help them to understand the different options, and give them and their families enough information to make informed decisions.\n\nFor young people who lack capacity to plan for adulthood, work with the people who know them best (including their parents and carers), using best interests decision making in line with the Mental Capacity Act.\n\nHealthcare professionals should find out what services are available locally, and involve them as needed to help with the transition.\n\nIn addition to statutory transition points, education, health and social care services should work with the young person and their family and carers to coordinate the age of non-statutory transitions to adults' services, to ensure a consistent approach across sectors.\n\nInteragency teams should work together to plan the transition between children's and adults' services for each young person. Each practitioner should read the sections of the plan produced by other practitioners, to make sure the plan works as a whole.\n\nIn transition reviews, make short-term goals (such as staying away from home overnight) as well as long-term goals (such as living independently).\n\nDo not assume that all young people will go on to further education. For young adults aged 18 to 25 who are not in education, health and social care practitioners should ensure that their ongoing needs are met in line with Department for Education's SEND guidance on 19- to 25-year-olds' entitlement to EHC plans.\n\nPlan well in advance of the transition to adults' services to prepare young people for alternatives to education (for example, look at supported internships and community adult social care support).\n\nAs early as possible and by the time young people are approaching adulthood, explain to them and their parents:\n\nhow their rights will change\n\nhow the level of parental involvement and decision making may change\n\nhow parents can register to act as a deputy if their child lacks mental capacity.\n\nWhen a young person is transferring from children's to adults' services, the named worker should:\n\noversee and coordinate transition\n\nhand over their responsibilities as named worker to someone in adults' services, and give this person's contact details to the young person and their family.\n\nDuring transition, give young people and their families and carers information about:\n\nthe purpose and potential outcomes of the adult needs assessment\n\nthe timing of appointments and when decisions will be made\n\nwhich services will be involved in their care during and after transition\n\nwhat happens to their support if their EHC plan stops.\n\nFor more guidance on transition, see the NICE guideline on transition from children's to adults' services for young people using health or social care services, in particular the sections on:\n\nperson-centred approaches (recommendation 1.1.4)\n\nnamed workers\n\ninvolving young people in their transition planning\n\ninvolving parents and carers in transition planning\n\nsupport from the named worker before transition\n\nplanning and developing transition services\n\ninvolving young people and their carers in service design (recommendation 1.1.1)\n\nnominating senior executives and managers to develop and implement transition strategies (recommendation 1.5.1).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on transition from children's to adult services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review G: promoting and maintaining inclusion, independence and wellbeing\n\nevidence review J: planning and managing transition from children's to adults' services\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.", 'Recommendations on specialist support for disabled children and young people with particular needs': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThese recommendations cover specialist support on palliative care, communication aids, environmental adaptations and accessibility, travel training and employment. There are also recommendations in this guideline on:\n\ngeneral support for all disabled children and young people with severe complex needs\n\nservice organisation, including working culture, training, integrated working and commissioning.\n\nThe government's special educational needs and disability (SEND) code of practice is the primary guidance for processes around SEND.\n\nThis NICE guideline makes recommendations on how existing legislation and statutory guidance should be put into practice. When there is evidence that existing legislation and statutory guidance is not being implemented, the guideline recommendations reiterate this and provide further guidance to help with implementation.\n\n# Palliative care and end of life care\n\nThese recommendations should be read alongside government guidance on children and young people's continuing care, particularly for those who require fast-track assessment because of the nature of their needs (such as a palliative care need).\n\nBefore making a palliative or end of life care plan, find out if the child or young person has already documented their wishes (for example, in an advance care plan).\n\nWhen making a palliative or end of life care plan for a disabled child or young person with severe complex needs, healthcare professionals should:\n\ntell the education and social care practitioners who are supporting the child or young person\n\nrequest a review of the education, health and care (EHC) plan (if they have one).\n\nThe interagency team should explain what support options are available and find out what further support family and carers need at each stage of the palliative and end of life care process.\n\nLet the child or young person choose which support and activities to continue with. Keep providing these in parallel with the palliative care plan and end of life support.\n\nWhen reviewing the EHC plan and other support the child or young person receives, be flexible, and focus on:\n\nmaintaining things that the child or young person views as important, such as social activities and contact with friends (this includes seeing friends at school or college)\n\naddressing new problems or needs that have developed since palliative or end of life care started (for example, new health problems).\n\nWhen a child or young person's needs change and new support is agreed, implement this as soon as possible, without waiting for the EHC plan to be finalised.\n\nEducation and social care practitioners should continue to be involved. They should adjust the support they provide in line with the palliative or end of life care plan.\n\nInteragency teams should arrange regular joint reviews of the palliative or end of life care plan, with the frequency of review based on how rapidly the child or young person's needs are changing.\n\nHealth services should consider providing training for education and social care practitioners, to help them understand how palliative and end of life care and parallel planning work. This training should be delivered by the most relevant healthcare professionals with experience in providing palliative and end of life care for children and young people.\n\nFor more guidance on end of life care, see the NICE guideline on end of life care for infants, children and young people with life-limiting conditions. In particular, see the sections on:\n\ngeneral principles and decision making\n\nadvance care planning\n\ncare of the child or young person who is approaching the end of life\n\npreferred place of care and place of death.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on palliative care and end of life care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: palliative and end of life care.\n\nLoading. Please wait.\n\n# Communication aids\n\nWhen conducting assessments for communication aids:\n\nthink about how these would work across multiple settings (for example, if the child or young person can use the communication aid at school and at home)\n\nif possible, provide equipment to the child or young person rather than to a service they use (such as their school), so they can use the equipment wherever they go\n\ninclude the child or young person and their families and carers in the assessment process.\n\nWhen a child or young person has been provided with a communication aid, education, health and social care services should:\n\nprovide information to staff, and train them to support the child or young person and to make best use of the communication aid (the local augmentative and alternative communication service can provide this training, working with the specialised service as needed)\n\nensure that staff know how to get support if the device is damaged or no longer fit for purpose\n\nagree who is responsible for maintaining, servicing and insuring the communication aid\n\nprovide support during transition (for example, when the child or young person finishes education), so that they can continue using the communication aid in new environments and with new staff\n\nprovide a paper-based backup for children and young people who are using powered systems, for when the powered system breaks or is not appropriate\n\nwork with specialist services to ensure that the child or young person can use their communication aid in all settings (home, school and others)\n\narrange reviews for the communication aid, to ensure it continues to meet the needs of the child or young person. Services should also provide all this information, support and training to families and carers.\n\nEducation, health and social care practitioners should tell children and young people who use augmentative and alternative communication and their families and carers about any support and mentoring groups that could help them with communication and social interaction.\n\nEducation, health and social care services should tell their staff about the eligibility criteria for augmentative and alternative communication services (both local services and NHS England specialised services).\n\nEducation, health and social care practitioners should refer disabled children and young people with severe complex needs to specialised augmentative and alternative communication services if they meet the eligibility criteria.\n\nFor specialised services, education, health and social care services should follow the referral process and eligibility criteria specified in the NHS England guidance for commissioning augmentative and alternative communication services and equipment. Do not add requirements for referrals to be made by specific practitioners (such as occupational therapists), because this will cause delays.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communication aids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: suitability and accessibility of environments.\n\nLoading. Please wait.\n\n# Environmental adaptations\n\nWhen environmental adaptations may be needed for disabled children and young people with severe complex needs, education, health and social care services should:\n\nprovide information on how to get assessments for adaptations\n\nsupport families through the process of assessment.\n\nWhen conducting assessments for environmental adaptations:\n\nthink about how these would work across multiple settings (for example, whether the child or young person can use a switch at school and at home)\n\nif possible, provide equipment to the child or young person rather than to a service they use (such as their school), so they can use the equipment wherever they go\n\ninclude the child or young person and their families and carers in the assessment process.\n\nWhen an environmental adaptation has been made for a child or young person, education, health and social care services should:\n\nprovide information and train staff on how to use the adaptation\n\nagree who is responsible for maintaining, repairing, servicing and insuring the adaptation.\n\nEducation, health and social care services should train children and young people and their families and carers to use environmental adaptations they are provided with, and check that they are competent to do so.\n\nEducation, health and social care services should tell children and young people and their families and carers how to get a review and reassessment of their environmental adaptations when their needs change.\n\nEducation, health and social care practitioners should tell children and young people who use environmental adaptations and their families and carers about any support and mentoring groups that could help them with environmental accessibility and social interaction.\n\nWhen families move, education, health and social care services and practitioners from the old area and the new area should work together to ensure that they can access necessary equipment during and after the move. This involves:\n\nchecking who owns the equipment, and if the child or young person can take it with them or if they will need replacements in the new area\n\nagreeing what assessments are needed in the new area\n\nkeeping children and young people and their families up to date during and after the move.\n\nEducation, health and social care services should tell their staff about environmental control services, so that staff know to refer children and young people who meet the eligibility criteria.\n\nEducation, health and social care practitioners should refer children and young people to specialist environmental control services if they meet the eligibility criteria.\n\nEducation, health and social care services should follow the referral process and eligibility criteria specified in the NHS England service specifications for environmental control services. Do not add requirements for referrals to be made by specific practitioners (such as occupational therapists), because this will cause delays.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on environmental adaptations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: suitability and accessibility of environments.\n\nLoading. Please wait.\n\n## Environmental accessibility\n\nBe aware that there is existing best practice and statutory guidance on environmental accessibility (for example, the Royal College of Occupational Therapists' guide to planning and delivering home adaptations, and UK building regulations on access to and use of buildings). Examples of environmental accessibility adaptations include:\n\ndisabled access for children and young people who use mobility aids and devices\n\nspace to use and to store environmental control equipment\n\nsuitable toilets\n\nlighting and acoustic adaptations, to avoid distractions or distress.\n\nEducation, health and social care providers should conduct regular accessibility assessments (at least annually) of their services, looking at the physical environment (including sensory aspects and whether the environment is child or young person friendly) and staff behaviours and knowledge of disability and accessibility. Charities and support organisations can provide advice on what changes are needed (for example, see the National Autistic Society accreditation scheme).\n\nEducation services should make the results of these accessibility assessments publicly available.\n\nHealth and social care services should consider making the results of these accessibility assessments publicly available.\n\nInteragency teams should make sure that the results of the accessibility assessments are available for key public places that the child or young person needs to access (in line with their education, health and care [EHC] plan). For example:\n\nafter-school clubs (if they are not held at the school)\n\nshort break services\n\ncommunity facilities.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on environmental accessibility\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: suitability and accessibility of environments.\n\nLoading. Please wait.\n\n# Travel training\n\nLocal authorities should help disabled children and young people with severe complex needs to use transport (to help them get anywhere they need to go, not just to school). They should consider providing a training framework to achieve this. Local authorities could develop their own training programmes as part of this framework, or use existing ones (such as ASDAN's module on using transport).\n\nLocal authorities should ensure that services implement the training framework.\n\nTravel training could cover:\n\nassessing the child or young person's mobility skills and identifying problems they will have with using public transport\n\nassessing and managing risks\n\nroute planning\n\nusing assistance services for booking tickets\n\nmobility and traffic awareness\n\nhaving someone accompany the child or young person until they are used to the route\n\ntravelling with parents and carers, for children and young people who will not be able to travel on their own\n\nhow communication aids can help, if the child or young person uses them\n\nhow to safely ask for help when something goes wrong.\n\nLocal authorities should provide parents, carers and relevant professionals (such as teachers) with information to help them better support children and young people who are using public transport (for example, independent travel training, availability of concessionary fares).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on travel training\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: suitability and accessibility of environments.\n\nLoading. Please wait.\n\n# Employment\n\nEducation providers should ensure that independent careers information, advice and guidance is provided using the Gatsby benchmarks, to help disabled young people with severe complex needs think about their employment options. For more information on the Gatsby benchmarks, see the Department for Education's statutory guidance on careers guidance.\n\nLocal authorities and commissioners should ensure that supported internship programmes are available in their local area for young people, to help them develop job searching and employability skills, and to support them into employment.\n\nWhen commissioning employment support services for young people, local authorities should include a requirement in the service specification to provide a lead employment practitioner (for example, a job coach) for each young person who is going to undertake a supported internship. This practitioner should have expertise in helping young people with disabilities to find work, and the authority to coordinate work and direct the interagency team on issues related to employment.\n\nWhen commissioning employment support services for young people, local authorities should consider including a requirement in the service specification to provide a lead employment practitioner (for example, a job coach) for each young person who has employment as an outcome in their education, health and care (EHC) plan.\n\nEducation, health and social care practitioners should start discussing employment as a future option from the start of transition planning (by year\xa09, age\xa013 or 14, but ideally earlier than this). Follow this up with more specific discussions, and direct the young person and their family and carers to relevant sources of information.\n\nEducation, health and social care practitioners should consider making a vocational profile with young people who are considering employment, to identify their skills and what they want to do in the future. Do this well in advance of the move into post‑16 education.\n\nEducation, health and social care practitioners should work together when planning employment support and consider that young people may need to be involved in:\n\ntravel training, to help them prepare for a work commute\n\ndeveloping communication passports or communication plans to support them at work\n\nidentifying any environmental adaptations or equipment that they will need for work\n\nplanning their personal care needs at work\n\nplanning support if they are anxious about starting work\n\ntraining for employers, to help them communicate with and support the young person with their work.\n\nSupported internship providers should help disabled young people to find work by:\n\ncreating links with local employers, so they can identify job opportunities, address employer misconceptions about disabled young people, and explain what on-the-job support the interagency team can provide\n\ncontacting relevant support groups.\n\nFollowing a supported internship, and before ceasing the EHC plan, the current provider should work with the prospective employer to plan next steps for the young person after the internship ends:\n\nagree what changes will happen, and when\n\nagree who the young person can go to for help\n\nlook for ways the young person can use their experience from the internship in their job.\n\nLocal authorities should include information about support workers and job coaches in their special educational needs and disability (SEND) Local Offer, so that young people, their families and prospective employers know what help and resources are available. Funding for support workers and job coaches is available through the Department for Work and Pensions' Access to Work scheme.\n\nEncourage employers to train and appoint workplace buddies (who are not their line manager) for disabled young people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on employment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: preparation for employment.\n\nLoading. Please wait.", 'Recommendations on service organisation, integration and commissioning': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThese recommendations cover service organisation, including working culture, training, integrated working and commissioning. There are also recommendations in this guideline on:\n\ngeneral support for all disabled children and young people with severe complex needs\n\nspecialist support, covering palliative care, communication aids, environmental adaptations and accessibility, travel training, and employment.\n\nThe government's special educational needs and disability (SEND) code of practice is the primary guidance for processes around SEND.\n\nThis NICE guideline makes recommendations on how existing legislation and statutory guidance should be put into practice. When there is evidence that existing legislation and statutory guidance is not being implemented, the guideline recommendations reiterate this and provide further guidance to help with implementation.\n\n# All education, health and social care practitioners\n\n## Working culture\n\nEducation, health and social care practitioners should collaborate to develop a positive working culture and:\n\ntake time to develop positive relationships with each other\n\ntreat everyone involved in the care of the disabled child or young person with severe complex needs as equals\n\nencourage open discussion\n\nbe sensitive and constructive when challenging someone else's professional opinion.\n\n## Organising handovers\n\nIf the key practitioners involved need to change, organise a handover to avoid disruptions in care. Tell the child or young person and their family about the change and update any new practitioners on the child or young person's history.\n\n## Learning about other practitioners and services\n\nEducation, health and social care practitioners should learn about the responsibilities of other people and services involved in supporting the child or young person. They should use this knowledge to provide more wide-ranging and coordinated support and information (outside their own specialty) to the child or young person and their family and carers, and to reduce the number of different people the family have to contact.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on all education, health and social care practitioners\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n# Education, health and social care services\n\nThese recommendations also apply to local authorities when they provide services.\n\n## Working culture\n\nEducation, health and social care services and managers should ensure that practitioners have dedicated time for team and relationship building.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on working culture\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n## Key working support\n\nThese recommendations should be read alongside paragraph 2.21 of the special educational needs and disability (SEND) code of practice.\n\nThe level of key working support for disabled children and young people with severe complex needs should:\n\nbe flexible\n\nbe tailored to individual needs\n\ntake account of their family circumstances.\n\nSenior managers in education, health and social care services should work together to ensure that:\n\neach disabled child and young person with severe complex needs has a practitioner providing them with key working support\n\nthese practitioners have the training, time and resources needed to provide this support, taking into account their other commitments.\n\nManagers should ensure that interagency team members understand what key working support involves.\n\nThe practitioner who is assigned to provide key working support should:\n\nbecome part of the interagency team\n\nbe someone the child or young person is comfortable with\n\nget to know the child or young person well and understand their needs\n\nbe identified based on the child or young person's individual needs and preferences (for example, if they mainly have healthcare needs then a healthcare practitioner would be best).\n\nProvide children and young people and their families with contact details for the practitioner providing them with key working support.\n\nInteragency teams should work with managers to assign a practitioner to provide key working support for each child and young person.\n\nPractitioners providing key working support should:\n\ncoordinate meetings, timings and records between the different services involved, and with the child or young person and their family and carers (this should not be left to parents or carers to arrange themselves)\n\nkeep other practitioners updated with changes in the child or young person's care (for example, by sharing hospital letters with their school)\n\nhelp the child or young person and their family and carers to navigate services\n\nbe available for discussions between reviews and meetings if the child or young person has questions or needs more support.\n\nIf the practitioner who provides key working support needs to change, managers should:\n\nwork with the interagency team to assign a new practitioner (chosen based on the child or young person's needs and preferences, and not just because they do the same job as the old practitioner)\n\norganise a handover\n\nensure the new practitioner is updated on the child or young person's history, preferences, goals and ambitions\n\nensure the handover is supported to ensure continuity of care\n\nensure that everyone involved is told about the change (the child or young person, their family and carers, and all relevant education, health and social care practitioners).\n\nPractitioners who provide key working support should support families when they move area (in particular, to help families who move area regularly), by:\n\nidentifying practitioners in their new area to share relevant information with, to ensure continuity of care and support\n\ngiving a copy of this information to the child or young person and their family and carers\n\ntelling practitioners in their old area that the family are moving\n\ntelling practitioners who are responsible for providing environmental equipment that the family are moving.\n\nManagers should have a contingency plan for how to maintain consistency if the practitioner providing key working support leaves.\n\nEducation, health and social care services should have governance and information sharing arrangements in place to ensure that practitioners providing key working support can work effectively with all the different organisations involved.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on key working support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers\n\nevidence review N: commissioning, practice and service delivery models.\n\nLoading. Please wait.\n\n## Making processes easier to understand\n\nEducation, health and social care services should consider looking for ways to make what they do and how they work together more transparent to children and young people.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on making processes easier to understand\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n## Training for practitioners\n\nEducation, health and social care services should consider training practitioners to understand the roles of other people and services involved in the care of children and young people.\n\nEducation, health and social care services should work with local authorities to provide training for education practitioners on how to include and support disabled children and young people with severe complex needs in mainstream education.\n\nEducation, health and social care services should provide training for practitioners to help them recognise:\n\nsocial, emotional and mental health needs\n\ninternalising symptoms (such as anxiety and depression).\n\nEducation, health and social care services should work together to develop joint training for all practitioners on:\n\nworking with disabled children and young people with severe complex needs\n\ntaking their views into account, and supporting them to achieve their life goals\n\nhow to adapt communication for children and young people who communicate differently\n\nuse of communication aids.\n\nEducation, health and social care services should consider running training workshops for practitioners from all 3\xa0sectors, covering needs that are present in all settings (for example, safe eating and drinking, personal care and language development).\n\nEducation, health and social care services should provide practitioners with opportunities to observe practitioners from different sectors working with the child or young person.\n\nEducation, health and social care services should work with each other to agree consistent messages and ensure that their staff understand:\n\nhow their contributions affect education, health and care (EHC) needs assessments\n\nhow the contributions of individual staff fit together to show what support the child or young person needs\n\nhow their contributions will affect the EHC plan outcomes that will be agreed for the child or young person.\n\nWhen developing awareness training programmes, involve children and young people and parents and carers in:\n\ndeciding what to cover in the training\n\ndeciding how to structure and evaluate it\n\ndelivering the training (if appropriate).\n\nEducation, health and social care services should consider providing short-term observational placements for practitioners from other sectors (as part of induction and then annually). Design these placements to help practitioners learn about children and young people's needs in different contexts, and to understand how other services work to meet those needs.\n\nServices that provide short-term observational placements should ensure that interagency teams have a process for providing these placements.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on training for practitioners\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: supporting families and carers\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review L: enabling professionals to meet the needs of children and young people\n\nevidence review M: views and experiences of service providers.\n\nLoading. Please wait.\n\n## Delegated clinical tasks\n\nWhen training support workers to undertake delegated clinical tasks, registered healthcare professionals should follow guidance on training and competency from the Care Quality Commission, the General Medical Council, the Nursing and Midwifery Council, the Health and Care Professions Council, and the professional organisations that align to these. In particular, registered healthcare professionals should:\n\nonly train support workers to carry out delegated clinical tasks if these workers are employed and insured for these tasks, and accountable for their professional conduct\n\nafter delivering training, actively assess the competency of support workers to carry out delegated clinical tasks at the required standard\n\nensure that ongoing clinical supervision arrangements are in place for support workers.\n\nFor support workers who have been delegated clinical tasks by healthcare practitioners, health and social care employers should follow guidance on training and competency from the Care Quality Commission, the General Medical Council, the Nursing and Midwifery Council, the Health and Care Professions Council, and the professional organisations that align to these. In particular, health and social care employers should:\n\nensure support workers are competent to carry out these tasks\n\nensure the type of delegated work they are expected to carry out is specified in their job descriptions\n\nput indemnity insurance in place for delegated clinical tasks\n\nensure that training providers or other suitable organisations will provide ongoing supervision of support workers when a clinical competency must be assured to be at a required standard\n\nagree a joint incident investigation policy with relevant education, health and social care partner organisations (using the framework set out in the NHS Quality Board Position Statement on Quality in Integrated Care Systems), covering:\n\n\n\nreporting of incidents\n\nwho will lead investigations\n\nwhen a collaborative investigation is needed.\n\n\n\nFor parents and family members who have been delegated clinical tasks, healthcare practitioners should follow guidance from the Care Quality Commission, the General Medical Council, the Nursing and Midwifery Council, the Health and Care Professions Council and the professional organisations that align to these. In particular, practitioners should:\n\ntrain parents and family members to undertake delegated clinical tasks and use any equipment needed to undertake these tasks\n\nafter training, actively assess the competence of parents and family members to carry out delegated clinical tasks at the required standard\n\nprovide parents and family members with ongoing clinical support from an agreed named contact\n\nset up a process for parents and family members to report problems or to request further training.\n\n## Feedback\n\nEducation, health and social care services should periodically jointly request feedback from children and young people and their families and carers on how well they have worked together with the other services involved in their care and support.\n\nServices should periodically jointly request feedback from children and young people and their families and carers on how well they worked together with them.\n\nServices should have processes in place for addressing the feedback of young people and their families and carers, if they are not satisfied with the support they have received.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on delegated clinical tasks and feedback\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n# Interagency teams\n\n## Organising interagency teams\n\nEducation, health and social care services should:\n\norganise all the practitioners working with the child or young person into an interagency team\n\nensure that interagency teams include practitioners with the skills and experience to address all of the child or young person's needs (from birth to 25\xa0years).\n\nEducation, health and social care services should develop procedures for resolving disagreements that arise within interagency teams.\n\n## Meeting needs in all settings\n\nInteragency teams should ensure that the child or young person's needs are met in all settings (for example, if they communicate differently, make sure they have support at home and in school).\n\n## Sharing knowledge within the team\n\nInteragency team members should share their experiences of supporting the disabled child or young person within the team, so they can learn from each other and gain a broader understanding of the needs of the child or young person.\n\nIn interagency team meetings, members should share specialist knowledge and sources of support with practitioners outside of their speciality. This could include:\n\nchanges in clinical practice, legislation or statutory guidance\n\nparticular caring techniques\n\nprofessional networks\n\nother organisations that can provide support (such as patient organisations).\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on interagency teams\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review G: promoting and maintaining inclusion, independence and wellbeing\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review L: enabling professionals to meet the needs of children and young people.\n\nLoading. Please wait.\n\n# Local authorities and health commissioners\n\nWhen commissioning education, health and social care services for disabled children and young people with severe complex needs:\n\nfocus on early intervention and multi-agency involvement to identify, assess and address needs\n\nonly make long-distance placements if options to provide care and support close to home and within their community are not suitable for their needs and outcomes\n\nspecify outcomes in contracts, and avoid contracts that only describe what services should be provided\n\nthink about how each service will fit in and work with other services, and how commissioning changes in one service may affect other services and the ability to provide integrated education, health and social care support.\n\nLocal authorities and health commissioners should plan how funding and services will be organised across education, health and social care for young people once they turn\xa018 or transition to adult services, to ensure continuity of support to meet their needs and outcomes.\n\nDo not restrict access to services based solely on:\n\nwhat support people have previously received\n\nwhether or not they have a particular diagnosis, or no diagnosis at all (unless there is a medical reason for these restrictions).\n\nDo not deprioritise children and young people who are having an education, health and care (EHC) needs assessment solely to meet organisational targets, or because statutory deadlines have been missed.\n\n## Making referral and joint working easier\n\nCommissioners, local authorities and service providers should make referral and joint working easier by:\n\nestablishing clear processes and criteria for referring children and young people, both within services and between different services\n\nmaking information about these processes easily available, so practitioners know how and when to make a referral.\n\n## Involving children, young people, parents and carers in planning services\n\nWhen commissioning education, health and social care services, commissioners should:\n\ncheck with disabled children and young people with severe complex needs and their parents and carers, to ensure services meet the needs of the local population\n\ninvolve disabled children and young people and their parents and carers in planning services\n\nwork with children, young people and their parents and carers to ensure their participation is effective and their role in planning is clear\n\nfocus on outcomes and personalised services.\n\nInvolve disabled children and young people in the review of existing services, by asking for their feedback on how services are working.\n\nCommission services based on the needs of children and young people, rather than expecting them to just use the services that already exist.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on local authorities and health commissioners\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review C: combined approaches to identifying, assessing and monitoring health, social care and education needs\n\nevidence review K: barriers and facilitators of joined-up care\n\nevidence review M: views and experiences of service providers\n\nevidence review N: commissioning, practice and service delivery models.\n\nLoading. Please wait.\n\n## Coordinating EHC plan process changes with local services\n\nLocal authorities should consider notifying services and commissioners before making changes to their processes for producing EHC plans (for example, changes in the plan format or the information they require from practitioners).\n\nLocal authorities should consider involving services and commissioners with these changes, if they can do this without delaying support or assessments for children and young people.\n\n## Training\n\nLocal authorities should provide training on EHC plans and related processes for education, health and social care practitioners, covering:\n\nan explanation of the EHC needs assessment process and how an EHC plan is developed\n\nguidance on filling in templates and contributing advice and information to support an EHC plan.\n\nLocal authorities should provide training on how to write EHC plans for practitioners in their special educational needs and disability (SEND) team.\n\n## Short breaks\n\nLocal authorities must provide a range of short breaks for disabled children and young people with severe complex needs, in line with the Breaks for Carers of Disabled Children Regulations 2011.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on coordinating EHC plan process changes with local services, training and short breaks\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: supporting families and carers\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n## What to include in the SEND Local Offer\n\nLocal authorities should include the following in their SEND Local Offer:\n\na comprehensive explanation of their EHC needs assessment process, which:\n\n\n\nincludes any eligibility criteria\n\nmakes it clear that EHC needs assessments should be requested based on a child or young person's needs, and not on other factors (such as potential availability of funding)\n\n\n\ndetails of what services are available, and the roles of the different services and practitioners\n\na list of support groups for disabled children and young people who use assistive technologies\n\ndetails of the leisure activities (including social activities) and related support available to disabled children and young people\n\ndetails of the employment support they offer disabled young people.\n\nTell all children, young people and their families that they can give feedback on the SEND Local Offer, in line with the Children and Families Act 2014 and the SEND Regulations 2014.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on what to include in the SEND Local Offer\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: views and experiences of service users\n\nevidence review F: supporting participation in education and social activities\n\nevidence review H: preparation for employment\n\nevidence review I: suitability and accessibility of environments\n\nevidence review K: barriers and facilitators of joined-up care.\n\nLoading. Please wait.\n\n# Improving how local authorities, commissioners and services work together\n\nIntegrated care systems and local authorities should develop a joint commissioning framework to use when commissioning services across education, health and social care.\n\nCommissioners should specify in their contract requirements that education, health and social care services should work together in an integrated way to support disabled children and young people with severe complex needs.\n\nSenior managers in education, health and social care services should have formal processes in place to support interagency team working (see the recommendations on decision making and information sharing and privacy).\n\nEducation, health and social care providers should make arrangements or agreements setting out how they will work together in an integrated way to support disabled children and young people with severe complex needs.\n\nHealthcare professionals should check that children and young people with severe complex needs and a learning disability or autism are included on a locally maintained dynamic support register.\n\nHealth commissioners should ensure that education and social care services:\n\nknow about the dynamic support register\n\nare consulted regularly to ensure the register is maintained effectively.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on improving how local authorities, commissioners and services work together\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review G: promoting and maintaining inclusion, independence and wellbeing\n\nevidence review N: commissioning, practice and service delivery models.\n\nLoading. Please wait.", 'Terms used in this guideline': "This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n# Augmentative and alternative communication (AAC) services\n\nServices that help people with significant communication impairment. For more information, including eligibility criteria, see the NHS England service specification for specialised AAC services.\n\n# Awareness training programmes\n\nAny training programme that is:\n\nfor parents and carers or\n\nfor practitioners, but is focused on helping them work more effectively with the child, young person and their family or carers.\n\n# Communication aid\n\nAnything that helps a person communicate more effectively. Communication aids include paper-based systems (for example, letter or word boards), signing, and computer equipment.\n\n# Disabled children and young people with severe complex needs\n\nDisabled children and young people from birth to 25 years who:\n\nneed coordinated education, health and social care support because of their severe and complex needs and\n\nare eligible for an education, health and care plan, in line with the Children and Families Act 2014.\n\nSome recommendations in this guideline may be difficult or impossible to implement for babies or very young children. However, it is also difficult to give useful age cut-offs for particular recommendations. Children develop at different rates, and their development rate will be affected by their specific disabilities and health conditions. Any age cut-offs risk mistakenly excluding and disadvantaging some children. If a particular recommendation is not appropriate for a baby or young child, it is still important to involve them as far as possible in discussions and decisions about their care and support. For more information, see:\n\nrecommendation 1.1.47\n\nNICE's guideline on babies, children and young people's experience of healthcare.\n\n# End of life care\n\nIn this guideline, end of life care includes the care and support given in the final days, weeks and months of life, and the planning and preparation for this.\n\n# Environmental adaptations\n\nBuilding adaptations designed to make homes, schools and other buildings (such as short break settings) accessible to disabled children and young people. Adaptations include minor changes (such as fitting grab handles or levelling door thresholds) and major changes (such as specially adapted bathrooms or fitting ceiling track hoists).\n\n# Environmental control services\n\nServices that help people with complex physical disabilities use electronic devices (for example, the TV), if they cannot use the standard controls. For more information, see the NHS England service specification for environmental control services.\n\n# Interagency team\n\nThe existing team of key education, health and social care practitioners who are working together with the family to support the child or young person.\n\n# Local authorities\n\nThis includes individual and combined local authorities.\n\n# Named worker\n\nThis refers to the named worker as defined in the NICE guideline on transition from children's to adults' services.\n\n# Palliative care\n\nAn approach to care covering physical, emotional, social and spiritual support. Palliative care focuses on improving the quality of life for the child or young person and supporting their family members or carers, and includes managing distressing symptoms, providing respite care, and support with death and bereavement.\n\n# Parallel planning\n\nPlanning for end of life care while taking account of the often unpredictable course of life‑limiting conditions. It involves making multiple plans for care, and using the one that best fits the child or young person's circumstances at the time.\n\n# Parents and carers\n\nThis includes anyone with parental responsibility for disabled children and young people with severe complex needs, including corporate parents.\n\n# Special educational needs and disability (SEND) Local Offer\n\nThis explains what support services are available in the local area for children and young people with special educational needs or disabilities, and their families. Every local authority is responsible for writing a SEND Local Offer and making it publicly available.\n\n# Special educational need\n\nThese are defined in the SEND code of practice: 'A pupil has SEN [special educational needs] where their learning difficulty or disability calls for special educational provision, namely provision different from or additional to that normally available to pupils of the same age'.\n\n# Supported internships\n\nA study programme designed for young people who are aged\xa016 to 24 and who have an education, health and care plan. It provides them with the extra support they need to find employment. The internship includes support from a job coach.\n\nSupported internships are primarily based with an employer, and are normally designed to lead to a job when they finish. Because of this, a supported internship is usually the final year of education for a young person.\n\nFor more information, see the guidance on supported internships from the Department for Education.\n\n# Support workers (section 1.13 on employment)\n\nSee the Department for Work and Pensions' Access to Work Scheme.\n\n# Support workers (section 1.15 on education, health and social care services)\n\nAnyone other than a family member who has been delegated clinical tasks (including teachers, teaching assistants and other staff in education or care settings).", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Assistive technology\n\nHow effective is assistive technology in enabling disabled children and young people with severe complex needs to express their views to education, health, and social care services?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on communication aids\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: promoting and maintaining inclusion, independence and wellbeing.\n\nLoading. Please wait.\n\n## Environmental adaptations\n\nWhat are the most effective environmental adaptations to ensure the suitability and accessibility of the settings where disabled children and young people with severe complex needs receive education, health and social care support?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on environmental accessibility\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: suitability and accessibility of environments.\n\nLoading. Please wait.\n\n## Dedicated key workers\n\nWhat is the effectiveness of dedicated key workers for delivering joined-up services to meet the education, health and social care needs of disabled children and young people with severe complex needs?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on key working support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: commissioning, practice and service delivery models.\n\nLoading. Please wait.\n\n## Care close to home\n\nWhat are the most effective commissioning, practice and service delivery models to deliver joined-up services to meet the education, health and social care needs of disabled children and young people with severe complex needs while enabling them to stay close to home?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on local authorities and health commissioners\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: commissioning, practice and service delivery models.\n\nLoading. Please wait.\n\n## Short break services\n\nWhat components of short break services are most effective for disabled children and young people with severe complex needs and their families and carers?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on coordinating education, health and care (EHC) plan process changes with local services, training and short breaks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: supporting families and carers.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Telehealth and virtual platforms\n\nWhat is the effectiveness of telehealth and virtual platforms for communicating with disabled children and young people with severe complex needs and providing education, health and social care interventions?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on principles for working with children, young people and their families\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: involving children and young people.\n\nLoading. Please wait.\n\n## Joint commissioning arrangements\n\nWhat are the most effective joint commissioning arrangements for disabled children and young people with severe complex needs?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on local authorities and health commissioners\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: commissioning, practice and service delivery models.\n\nLoading. Please wait.", 'Rationale and impact for recommendations on supporting all disabled children and young people with severe complex needs': 'These sections briefly explain why the committee made the recommendations and how they might affect practice and services.\n\n# Principles for working with children, young people and their families\n\nRecommendations 1.1.1 to 1.1.12\n\n## Why the committee made the recommendations\n\nThere was moderate-quality qualitative evidence that:\n\nservice providers do not always use a person-centred approach, and do not adequately capture the child or young person\'s perspective\n\nthe potential of children and young people may be underestimated, while good education, health and care (EHC) plans should recognise their aspirations and think about long-term options.\n\nThe committee\'s understanding of the special educational needs and disability (SEND) code of practice is that it highlights the importance of supporting children and young people to achieve their ambitions. Based on the committee\'s experience, cultural backgrounds and preferences can impact on the views, life goals and ambitions of individuals, and so this should be taken into consideration to provide truly person-centred care.\n\nThere was moderate- and high-quality evidence that parents and carers felt positive when given the chance to provide their views, and that they felt negative when their views were ignored.\n\nIn the committee\'s experience, children and young people with the most complex needs may not be able to actively participate in planning or decision making. In this situation, taking into account the views of the people who know the child or young person best will help to ensure that the child or young person\'s perspective is fully represented.\n\nSupport needs are individual to each child or young person, and not everyone with the same diagnosis will need the same support. In the committee\'s experience, this is sometimes overlooked, and they made a recommendation to remind practitioners of this point.\n\nThe Children and Families Act 2014 requires arrangements to be made to provide the information and support that is necessary to enable children, young people and parents to participate in decisions. There was moderate-quality qualitative evidence that disabled children and young people and their families and carers value a person-centred approach. Despite this, in the committee\'s experience, children and young people are often not invited to participate in meetings where decisions are made about their support and are not actively included if they do attend. In the committee\'s experience not all children and young people want to, or are able to, attend meetings. However, it is still important to get their input in other ways to facilitate their participation in decisions.\n\nKeeping a record of how children and young people participate, and their contributions, can help to keep practitioners accountable.\n\nThe qualitative evidence highlighted multiple benefits from involving children and young people in their care and support:\n\nthere was low-quality evidence that this made them feel more positive\n\nthere was moderate-quality evidence that it made them show more confidence\n\nthere was moderate-quality evidence that their involvement gives practitioners a more accurate understanding of their needs, goals and ambitions.\n\nIn the committee\'s experience, it is important to find out which family members need to be involved (for example, in situations of family breakdown). They made a recommendation to cover this, so that practitioners do not make assumptions about family roles and structure.\n\nThere was moderate-quality qualitative evidence that drawing on the experience and expertise of families and carers would improve knowledge of the child or young person\'s needs. This is important, because there was also qualitative evidence of negative consequences when the child or young person\'s needs are not well understood.\n\nModerate-quality qualitative evidence showed that it is important to focus on the views of the children or young person, because these can differ from the views of their parents. This can be difficult to do. In the committee\'s experience, disabled children and young people with severe complex needs may need specialist support to participate, and their parents and carers need encouragement and support to help their child express their views.\n\nIn the committee\'s experience, and in light of the moderate-quality qualitative evidence previously discussed, it is important to regularly ask children and young people and their families and carers if they are satisfied with how they have been involved in decisions about their support, so that involvement is beneficial and not just tokenistic. And when children and young people are not satisfied with their involvement, it is equally important to find ways to address their concerns. The committee were not able to specify a time frame for doing this because it would depend on the services and support being received.\n\nThere was moderate-quality qualitative evidence that children and young people wanted practitioners to use the same approaches that their families and carers had been using to care for them at home. The committee agreed that this consistency was important if the approaches used have been beneficial. They also agreed that it was important to avoid practices that had been used in the past by families and found not to work well.\n\nThere was no evidence on the effectiveness of telehealth or virtual platforms for supporting disabled children and young people with severe complex needs. Therefore, the committee made a recommendation for research in this area.\n\n## How the recommendations might affect practice\n\nPractitioners will need more time, for example for discussions with children and young people and their families and carers to get their views. However, if practitioners spend more time getting these views, families are likely to have fewer queries, complaints and problems, resulting in time savings later on.\n\nReturn to recommendations\n\n# Communication formats and providing information\n\nRecommendations 1.1.13 to 1.1.27\n\n## Why the committee made the recommendations\n\nThere was low-quality qualitative evidence that children and young people and their families and carers appreciated when practitioners adapted their communication styles to suit the topic of conversation, and moderate-quality qualitative evidence that non-judgemental and non-directive communication was valued. Based on their experience, the committee agreed that practitioners do not always deal with sensitive conversations effectively and that it was important to prompt practitioners to be empathetic and supportive. This style of communication will help to address the family\'s feelings and help them to process the information they receive.\n\nLow-quality qualitative evidence also showed that a flexible approach to communication was important, taking into account the child or young person\'s age, developmental level and communication skills. Although this evidence was low quality, the committee were confident that having a flexible approach was necessary to enable children and young people to express their views. Local authorities also have a duty under the Children and Families Act 2014 to have regard to the views of disabled children and young people and those with special educational needs.\n\nIn the committee\'s experience, finding the child or young person\'s preferred communication formats is particularly important, because this group is more likely to communicate differently and to use communication aids.\n\nSome children and young people have a communication passport. In the committee\'s experience, practitioners can use this to learn about a child or young person\'s communication preferences without having to ask the family to repeat information they have already provided.\n\nThere was moderate-quality qualitative evidence that language barriers made it difficult for parents to find out about available services, and that more support was needed to help them understand and access support that was available. In the committee\'s experience parents and carers may also have disabilities or other problems that make it more difficult for them to communicate with practitioners and understand information.\n\nThere was qualitative evidence on communication formats and providing information:\n\nthere was low-quality evidence that children and young people and their families and carers needed more information and advice\n\nthere was moderate-quality evidence that the advice they received was limited\n\nthere was high-quality evidence that the advice they received was often based on outdated information.\n\nThe committee agreed that it is important to provide enough up-to-date information, support and advice to allow people to make more informed decisions. Based on the qualitative evidence and their experience, they highlighted areas where children and young people and their families and carers commonly wanted more information.\n\nThe recommendation on directing children and young people and their families and carers to sources of support and advice is based on:\n\nthe Children and Families Act 2014, which requires local authorities to make arrangements for providing advice and information about matters relating to special educational needs and disability available to children and young people with special educational needs or disabilities and their parents.\n\nthe SEND code of practice, which mentions SEND Information, Advice and Support services as an option for providing this information\n\nThe SEND Regulations 2014, which specify what information must be included in the SEND Local Offer, and include information about forums for parents and carers and support groups\n\nmoderate-quality qualitative evidence that children and young people benefited from speaking to peers who had experience with the education, health and care system.\n\nIn the committee\'s experience, practitioners providing information on peer support groups would have a professional duty of care to make sure that any sources of support they provide are quality-assured.\n\nModerate-quality qualitative evidence indicated that children and young people did not receive the level of support or involvement that they had expected from services. The committee agreed that practitioners needed to find out what expectations people had, in order to provide the support they wanted (if possible) and help them to understand what services can do. When it is not possible to meet people\'s expectations, it is also important to explain the reasons for this and explore alternatives.\n\n## How the recommendations might affect practice\n\nPractitioners might need more time to communicate with children and young people (depending on their preferred communication format) and their families and carers, and to find out about their expectations. This could mean that some more time is required for preparation, and consultation times are longer, which could create a resource impact for services. However, if practitioners spend more time helping children and young people to communicate and understand what services can do, they are likely to have fewer queries, complaints and problems, resulting in time savings later on from practitioners not having to address these. Training may be needed if the preferred communication method requires specialist knowledge.\n\nServices across education, health and social care will have to establish processes to share information and to allow more coordinated and joined-up working. Interagency training may also be needed, to ensure that practitioners understand relevant policies and processes and the role of other practitioners and services.\n\nReturn to recommendations\n\n# Preparing for and running meetings with children and young people\n\nRecommendations 1.1.28 to 1.1.43\n\n## Why the committee made the recommendations\n\nModerate-quality qualitative evidence indicated that parents and carers had differing views about involving children and young people in decisions about their care. Some parents and carers felt that participation was inappropriate for their child because of their age, or the nature of their special educational need or disability. Other parents and carers thought it was important to fully involve their child. The Children and Families Act 2014 requires local authorities to provide the information and support necessary to enable children, young people and parents to participate in decisions. As some of these decisions would take place during practitioner-led review meetings, the committee felt strongly that children and young people should be present at these meetings. However, given the concerns of parents and carers and the qualitative evidence that meetings can be intimidating for children and young people, they agreed it would be better to ask them how they would like to be involved.\n\nLow-quality qualitative evidence showed that children and young people are better able to communicate their views if they are given help to understand their options and prepare for meetings. In the committee\'s experience, if parents and carers discuss meetings with their child in advance, they can prepare in a more relaxed home environment. This also allows parents and carers to better understand their child\'s views in advance of the meeting.\n\nThese recommendations align with the sections of the Children and Families Act 2014 that cover providing the information and support necessary to enable children, young people and parents to participate in decisions. In addition, the committee\'s understanding of the SEND code of practice is that it recommends including time to prepare for discussions and meetings.\n\nThe committee also recommended helping parents and carers to complete documents before meetings because in their experience this can be difficult and confusing, and meetings may be dominated by completing paperwork if this has not been done in advance.\n\nIn the committee\'s experience the physical accessibility and cost of attending meetings can cause problems for children and young people and their parents and carers, so practitioners need to check this in advance.\n\nIn the committee\'s experience, children or young people are more likely to be motivated to participate in meetings if the issues being discussed are ones that are important to them. Therefore, it is important to get this information ahead of meetings. It is also crucially important that children and young people are able to meaningfully participate in decisions about their care and support, and this is one way to achieve this.\n\nQualitative evidence showed that children and young people had various levels of ability that affected their level of involvement and understanding. The committee agreed it was important to establish the age, communication ability and circumstances of the child or young person in advance of meetings, to ensure that they can meaningfully participate.\n\nThere was moderate-quality qualitative evidence that:\n\nchildren and young people want practitioners to make more effort to respect their privacy\n\nchildren and young people may be able to better communicate their views in smaller meetings or one-on-one\n\nattending meetings can be intimidating for children and young people.\n\nBased on this evidence, and their own experience, the committee highlighted ways that the structure and content of meetings could be improved (for example, having meetings in a place where the child or young person feels comfortable). The committee were confident that these recommendations would enable children and young people to participate more effectively in meetings and understand what is happening – both of which are key to their involvement in making informed decisions.\n\nIn response to moderate-quality qualitative evidence that practitioners do not always take a person-centred approach to meetings, the committee recommended considering the use of person-centred planning tools. In their experience, these tools help ensure that planning is based on information from the child or young person about their needs, wishes and what is important to them. This stops practitioners from making generic assumptions and taking prejudiced attitudes towards the child or young person as a result of their condition. These tools also focus on developing a plan to deliver the outcomes desired by the child or young person. Using a person-centred approach is specified in the SEND code of practice as a way to ensure that children, young people and parents are involved in all aspects of planning and decision making in the EHC needs assessment and planning process.\n\nIn the committee\'s experience, disabled children and young people with severe complex needs may need more time to process information and communicate their views. They may also give very brief answers to questions, and may need encouragement and additional time to expand on these. To ensure that they can meaningfully participate in meetings, the committee believed that children and young people needed adequate time to express their views and take in information, and practitioners needed to check that they have understood the information they are given.\n\nChildren and young people also need to be supported to communicate using their preferred method. Identifying their preferred communication method is particularly important, because this group is more likely to communicate differently and to use communication aids. In the committee\'s experience, children, young people and their families and carers benefit if meetings are recorded, because this gives them more time to process information.\n\nThere was moderate-quality qualitative evidence highlighting the importance of respecting children and young people\'s rights to privacy, and that attending meetings with large numbers of professionals can be intimidating. Therefore, the committee made recommendations to reflect this.\n\nThere was moderate-quality qualitative evidence that agreeing actions in front of other practitioners and parents improved accountability and made it more likely that practitioners would follow through on agreed actions.\n\nThe committee\'s understanding of the Children and Families Act 2014 is that it requires education and training provision to be integrated with health and social care provision. However, moderate-quality qualitative evidence showed that practitioners are often not collaborating effectively and either do not attend interagency meetings or do not prepare for meetings in advance. In the committee\'s experience, it is crucial that practitioners who know the child or young person and are involved in their support make all reasonable efforts to attend meetings. These practitioners need to come from all services involved, in order for the support provided to be fully integrated. However, the committee acknowledged that this may not always be possible. They used their experience to highlight:\n\nfactors to consider when deciding whether to go ahead with a meeting if a relevant practitioner cannot attend\n\nways to reduce the impact if the meeting does go ahead without a relevant practitioner.\n\nThe committee believe that siblings and friends have a different perspective to the practitioners caring for a disabled child or young person with severe complex needs. This different perspective can improve the practitioners\' understanding of the child or young person, and can demonstrate strengths and interests that the practitioners have not observed. This enables a broader view of what the child or young person is capable of, so practitioners can make better judgements about their future abilities and adjust outcomes accordingly. Based on this, the committee agreed that children and young people should have the opportunity to invite siblings or friends to share their views.\n\n## How the recommendations might affect practice\n\nPractitioners might need more time to plan how to involve children and young people in discussions and meetings. Meetings may also need to be longer, with more breaks, potentially taking more time. However, this should result in children and young people being able to more effectively participate and engage in discussions and decisions about their care and support, saving time later on by leaving fewer problems to deal with. Engagement with care will positively impact their care and outcomes and will outweigh any additional costs. In addition, if care is not person-centred, children and young people may end up with support that does not meet their needs. This may cost services much more further down the line.\n\nHolding review meetings outside of a school day might result in health and social care practitioners working alternative hours, and schools will need to negotiate patterns of annual directed time flexibly, including allowing teachers to use their planning, preparation and assessment time if meetings have to be held outside of the school day.\n\nServices that want to record meetings may have to buy equipment to do this. However, the recommendations allow them to use written records instead if needed.\n\nReturn to recommendations\n\n# Using a consistent approach\n\nRecommendation 1.1.44\n\n## Why the committee made the recommendation\n\nThere was moderate-quality qualitative evidence that using a consistent approach when interacting with children and young people was beneficial, in terms of making services more predictable across education, health and social care. This aligned with the experience of the committee that interacting in a consistent way helps children and young people know what to expect and feel safer and more confident in their interactions with services, so they made a recommendation in support of this.\n\n## How the recommendation might affect practice\n\nServices across education, health and social care services will have to share knowledge about the child or young person\'s preferences, such as method of communication, the way they like to be addressed, how they express agreement or disagreement, and positive behaviour support, so that all practitioners can use this information consistently.\n\nReturn to recommendation\n\n# Decision making\n\nRecommendations 1.1.45 to 1.1.50\n\n## Why the committee made the recommendations\n\nThere was moderate-quality qualitative evidence that parents did not always feel comfortable making decisions about their child\'s care, because they sometimes lacked the knowledge and expertise to do so. The committee believe it is very important for children and young people and their parents and carers to be involved in decision making as much as they are able to, so they made a recommendation in support of this. This recommendation also aligns with the Children and Families Act 2014.\n\nIn some situations, children will be unable to respond with intentional communication. The committee wanted to ensure that practitioners still tried to identify their preferences in these situations, to ensure their care and support is appropriate and to meet the requirement in the Children and Families Act 2014 to have regard to the views of disabled children and young people and those with special educational needs.\n\nThe SEND code of practice states that the views of parents must not be used as a proxy for the views of the young person. However, the committee agreed that this is not consistently done in practice. In particular, members of the committee who had been through this process themselves as young people explained that they were sometimes ignored, with practitioners assuming they did not understand and primarily addressing their parents.\n\nThe SEND code of practice briefly covers what to do when there are disagreements between parents and their children. There is also other relevant legislation and guidance on consent (such as the Mental Capacity Act and guidance from professional governance organisations). However, the committee are aware that practitioners need more guidance, as issues around decision making are complicated and practitioners are not always well informed in this area. The committee made recommendations to help practitioners when disagreements between parents and children or young people cannot be resolved, or when there are capacity issues.\n\n## How the recommendations might affect practice\n\nThe guidance in this area will make practice more consistent. Practitioners might need more time to communicate with children and young people, provide them with information, and help them formulate their views. Additional time may also be needed for getting the views of parents and carers, resolving disagreements and reaching shared decisions. However, if practitioners spend more time helping children and young people to communicate, they are likely to be more engaged with the process and have fewer queries, complaints and problems, resulting in time savings later on.\n\nReturn to recommendations\n\n# Information sharing and privacy\n\nRecommendations 1.1.51 to 1.1.57\n\n## Why the committee made the recommendations\n\nThere was moderate- and high-quality qualitative evidence that:\n\nservices do not always share information with each other, and when they do share it is not always done well because they do not understand what other services need to know\n\nchildren and young people and their families and carers have to repeat the same information to different services, and find this exhausting and difficult (particularly when repeating sensitive or distressing information)\n\nit is important to respect children and young people\'s right to privacy and right to be involved in decisions\n\nnot all services could access online electronic patient records, and that practitioners believed that being able to access these records would improve joint working, information sharing, and identification of severe complex needs in disabled children and young people.\n\nThe committee agreed that information sharing does not always happen effectively and that concerns about confidentiality, privacy, consent and security can have an impact. They therefore made recommendations to promote effective information sharing and address the concerns highlighted by the evidence.\n\nThe committee noted that while individual services have electronic patient record systems, there is no interagency record system across education, health and social care. This kind of system could be very useful, but it would be very expensive to develop and there would be data protection issues to consider. Therefore, the committee agreed that they could not make a recommendation in support of a shared electronic patient record system. Instead, they recommended that services work actively to ensure that other services can access relevant information when needed.\n\nOne specific area of information sharing highlighted by moderate-quality qualitative evidence was the development and sharing of behaviour management plans. The committee did not make a recommendation specifically on behaviour management plans, because not all disabled children and young people with severe complex needs will need a behaviour management plan. However, they agreed that when any specialised care plans have been made, these should be shared with the child or young person and their parents and carers, and all practitioners working with them. This will improve practitioner knowledge and understanding of the child or young person\'s needs.\n\n## How the recommendations might affect practice\n\nPractitioners might need a little more time to find out about the information sharing preferences of children and young people and their families. Services across education, health and social care may need to establish processes to share those preferences more effectively, if they have not already done so. Effective information sharing will ensure that children and young people and their families and carers do not have to repeat the same information to multiple practitioners, which can be distressing. Ineffective information sharing may lead to children and young people being provided with support that does not meet their needs and result in low satisfaction and complaints. This may cost services much more further down the line.\n\nReturn to recommendations\n\n# Identifying needs and involving other services\n\nRecommendations 1.2.1 to 1.2.8\n\n## Why the committee made the recommendations\n\nThere were only a few small studies in this area. Most of these studies focused on children and young people with autism, were very low quality, and reported on waiting times only. The committee did not feel the evidence could be generalised to the much wider population covered by the guideline and subsequently made recommendations based on their knowledge and experience.\n\nIn the committee\'s experience, emotional and mental health needs can go unrecognised and undiagnosed, because they are often obscured by the other needs of disabled children and young people with severe complex needs.\n\nIn the committee\'s experience severe complex needs and disabilities are normally first identified by health services. If the child is under compulsory school age, section 23 of the Children and Families Act 2014 requires health services to:\n\ntell their parents\n\ngive the parents the chance to discuss their opinion\n\ntell the parents about any voluntary organisations that can provide advice or assistance\n\ntell the appropriate local authority about the child.\n\nThis requirement only applies to children under compulsory school age, but the committee agreed to cover all children and young people in the recommendation because this process is helpful whatever age special educational needs are identified.\n\nIn line with their understanding of the SEND code of practice and the requirements of the Children and Families Act 2014, the committee also recommended directing families to SEND Information, Advice and Support services and the SEND Local Offer for their area. In the committee\'s experience this is not always done, and can result in parents independently sourcing inaccurate information. To ensure that children and young people receive the support they need, the committee agreed on the importance of linking health services up with education and social care services as soon as possible. They highlighted that appropriate consent to share data is needed for this.\n\nSometimes severe complex needs and disabilities are first identified by education services. In line with the recommendations for health services, the committee made recommendations for education services on involving health and social care services and starting discussions with children and young people and their families and carers. They also recommended informing parents and carers about support organisations in the SEND Local Offer, and directing them to SEND Information, Advice and Support services, in line with their understanding of the SEND code of practice and Children and Families Act 2014.\n\nBased on their experience, the committee made a recommendation on referrals for social care assessment for family support. The reasons for these referrals are often unclear, particularly around the emerging needs, and this can delay social care involvement and provision of support for the child or young person. The committee felt strongly that such preventable delays need to be avoided and were confident that including the reasons for the referral (including the emerging needs) would resolve this. They also agreed it was important to include any barriers to engaging with healthcare services in the referral to social care service, because in their experience families on low income may not be able to afford to travel to attend all health appointments, or be able to afford the equipment needed to attend appointments remotely. Including such barriers in the referral should result in potential solutions to this issue being explored.\n\nLow-quality qualitative evidence showed that families can be reluctant to engage with social care services because of fear and perceived stigma. The committee agreed that families can be confused by the difference between child protection social services and family support services, and made a recommendation to address this.\n\nIn the committee\'s experience, disabled children and young people are at increased risk of vulnerability, abuse and neglect. However, it is often incorrectly assumed that if the child or young person has a social worker from a disabled children\'s team, then this individual will pick up any safeguarding issues and there is less of a need to report concerns. The committee were confident that making a recommendation on the action needed if a safeguarding concern is identified would correct this misunderstanding.\n\n## How the recommendations might affect practice\n\nProfessionals might need more time to assess the needs a child or young person may have, and to share these with other services. They might also need more time to explain the education, health and care needs assessment process to children and young people and their families and carers. However, if practitioners spend more time on this, there will likely be fewer queries, complaints and problems, resulting in time savings later on.\n\nIf practitioners spend more time thinking about what support children and young people need from other services, services may start communicating with each other sooner and there may be fewer delays in making referrals. Practitioners may also make a small number of extra referrals to other services, because they have better knowledge of other agencies that can support the child or young person and their family and carers.\n\nReturn to recommendations\n\n# Requesting a needs assessment\n\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations\n\nThere was low-quality qualitative evidence that families and carers often felt that children and young people had to reach a crisis point before an EHC plan was considered necessary. The committee were confident that encouraging services to explain the process to families when special educational needs are first suspected should help to prevent children and young people reaching a crisis point. While the SEND code of practice already contains this information, the committee agreed that it would be more accessible if individual practitioners could provide it.\n\nThere was low-quality qualitative evidence that some practitioners felt like they were pressured to not apply for EHC plans because of a lack of funding, even though this would be a breach of the legislation. In the committee\'s experience this risk should be reduced if local authorities explain that an EHC needs assessment should be requested based on a child or young person\'s needs.\n\nThere was low- and moderate-quality qualitative evidence that access to services sometimes depends on the child or young person receiving a particular diagnosis. This excludes some disabled children and young people from support, because they can have severe complex needs but not have a specific, diagnosable health problem. While the committee\'s understanding of the SEND code of practice is that it allows local authorities to develop criteria to help decide if an EHC needs assessment is needed, they must be prepared to depart from these criteria if there is a compelling reason to do so. The SEND code of practice also specifies that \'…local authorities must not apply a "blanket" policy to particular groups of children or certain types of need…\'.\n\nThere was moderate-quality qualitative evidence that parents felt a need to constantly fight for the support their children needed, as support was not always provided if they did not arrange and manage things themselves. The committee agreed that families should not be responsible for managing processes (in particular, they should not have to manage the EHC needs assessment and EHC plan process themselves), and that practitioners should support families with this.\n\n## How the recommendations might affect practice\n\nPractitioners may need more time to explain the EHC needs assessment process and support families through this. However, if practitioners spend more time on this, families will likely have fewer queries, complaints and problems, resulting in time savings later on. It should also help prevent children and young people from getting to a crisis point, which is detrimental to their quality of life and costly to address.\n\nMore disabled children and young people with severe complex needs may be able to access services earlier if they are not excluded for not having a specific diagnosis. Similarly, if parents and carers have a better understanding of the EHC needs assessment process, they may be more likely to request an assessment and more children and young people may be accessing services.\n\nReturn to recommendations\n\n# Supporting children, young people and their families during a needs assessment\n\nRecommendations 1.3.5 to 1.3.11\n\n## Why the committee made the recommendations\n\nThere was moderate-quality qualitative evidence that children and young people and their families and carers did not understand the EHC needs assessment process. They also experienced a lack of transparency around how decisions about EHC needs assessment were made, the timings of reviews, and the processes for appeals and complaints. Explaining the process to people helps them to participate and reduces uncertainty. The 20‑week period specified in the recommendation for the EHC plan process is taken from the SEND Regulations 2014.\n\nIn the committee\'s experience, many EHC plans are not produced within the statutory timeframe and children, young people and their parents and carers have to seek updates and information about progress. The committee made a recommendation to address this issue.\n\nThere was moderate- and high-quality qualitative evidence that:\n\nchildren and young people and their families and carers do not receive the level of support or input that they had expected from services\n\nthey feel frustrated because it is not clear how resources are allocated\n\nchildren and young people, families and carers, and service providers felt that the level of support provided did not always reflect the needs of the child or young person, and that more assertive people were more likely to get the support they wanted.\n\nBased on this evidence, the committee made recommendations to ensure that children and young people and their families and carers are better informed about what services are available while they are waiting for a needs assessment. The committee also noted, based on their experience, that children and young people and their families and carers are not always asked for their views as part of the EHC needs assessment. This is required by the Children and Families Act 2014 and the SEND Regulations 2014, so the committee made recommendations to support this.\n\nThere was moderate-quality qualitative evidence that children and young people, their families and carers, and service providers all felt there was a lack of urgency about providing support until the child or young person reached a crisis point. Similarly, all these groups also felt that the crisis point could be avoided if support was provided earlier. This evidence aligned with the committee\'s experience, and they believed a lack of resources, issues with prioritisation, use of threshold criteria for accessing support, and statutory obligations all affected the situation. In response to this, the committee made a recommendation for services to work together before an EHC plan is issued to provide interim support and a simpler transition from interim support to the EHC plan, to keep people from reaching a crisis point. The EHC needs assessment process can take several weeks to complete. In addition, some services (such as schools) will conduct their own additional assessments, and there was high-quality qualitative evidence that this causes delays to the implementation of EHC plans. The committee agreed that support from education, health and social care was still needed during this process. These recommendations are in line with the committee\'s understanding of the SEND code of practice, which states \'where particular services are assessed as being needed…, their provision should be delivered in line with the relevant statutory guidance and should not be delayed until the EHC plan is complete\'.\n\n## How the recommendations might affect practice\n\nPractitioners may need more time to explain the EHC needs assessment process. However, if practitioners spend more time on this, families will likely have fewer queries, complaints and problems, resulting in time savings later on. It should also help prevent children and young people from getting to a crisis point, which is detrimental to their quality of life and costly to address.\n\nProfessionals may need slightly more time to explain what services are available and the criteria for accessing them. Services may need to work together to provide interagency training for education, health and social care practitioners on other services and their roles and responsibilities, to ensure practitioners can provide clear and relevant information. Providing this support to children and young people and their families is part of person-centred care. It may help children and young people in making decisions, and ensure that they get support that meets their needs. This prevents scarce resources from being wasted. It ultimately results in better choices, care and outcomes for disabled children and young people with severe complex needs.\n\nCommissioners will have to set up commissioning frameworks (or use existing frameworks), to reinforce a more coordinated approach to EHC needs assessments. This coordinated approach may mean holding more interagency team meetings and more effective communication between education, health and social care services. However, it will mean services and practitioners are able to work together more effectively to provide the support that is needed by children and young people.\n\nReturn to recommendations\n\n# Carrying out the needs assessment, timescales for the assessment, and when parents or carers decline an assessment\n\nRecommendations 1.3.12 to 1.3.15\n\n## Why the committee made the recommendations\n\nThe committee agreed it was important to make recommendations on the EHC needs assessment process, to make it more streamlined. In the committee\'s experience, children and young people need a more personalised plan that is specific to their age, level of understanding, communication needs, and circumstances. This was supported by moderate-quality qualitative evidence that the involvement and understanding of the child or young person was dependent on their level of ability.\n\nThere was moderate-quality qualitative evidence that some practitioners felt they did not have the chance to contribute relevant information they had about a child or young person to assessments led by other services. The committee considered it was very important that specialist knowledge about the needs of the child or young person from practitioners outside of the interagency team is included in the EHC needs assessment in order to fully assess a child or young person\'s needs.\n\nThere was low-quality qualitative evidence that early identification of needs and referral can be helpful in securing support for children and young people. To make sure that services are ready to provide support when it is needed, the committee felt strongly that practitioners and services need to make referrals as needs are identified, without waiting for the assessment process to finish. They were confident that doing this would help children and young people get the support they need sooner.\n\nThere was low-quality qualitative evidence that children and young people and their families and carers felt that the process of getting an EHC plan took too long, and needed a lot of effort on their part. Moderate-quality qualitative evidence showed service providers thought there was a lack of transparency about how decisions on EHC plans were made, timescales for review, and processes for appeals or complaints. The Children and Families Act 2014 and the SEND Regulations 2014 set out timescales for each stage of the process for EHC needs assessments and EHC plans, so the committee could not make different recommendations on this. However, they did highlight the time limits from the legislation, as the evidence and their own experience suggest that these time limits are not always adhered to.\n\nIn the committee\'s experience, there are circumstances when parents or carers decline assessments. This was reflected by moderate-quality qualitative evidence that parents and carers felt disillusioned with statutory provisions and thought there was little point in requesting help, so opted out of the process. The committee agreed that the reasons for declining assessments were varied, so this should be discussed with parents or carers to ensure that the best possible support can be provided for the child or young person. They also thought it was important to ensure parents and carers understood how to request an assessment in future (because their circumstances and views may change), and for professionals to consider whether declining an assessment may cause a safeguarding issue. The committee were confident that making this recommendation was necessary to ensure appropriate support could be given to parents and carers.\n\n## How the recommendations might affect practice\n\nServices will need to work in a more coordinated way, for example by ensuring a consistent approach when carrying out assessments, or by holding more meetings with each other. Commissioners across education, health and social care will have to set up or reinforce commissioning frameworks, to encourage a more coordinated approach to EHC needs assessments.\n\nMaking referrals as needs are identified (without waiting for the assessment process to finish) may result in earlier referrals and quicker turnover between services.\n\nThe recommendation on timescales for completing a needs assessment and producing an EHC plan helps spread awareness of existing statutory guidance and may reduce variation in practice.\n\nReturn to recommendations\n\n# Agreeing on outcomes for the EHC plan\n\nRecommendations 1.4.1 to 1.4.5\n\n## Why the committee made the recommendations\n\nThere was moderate-quality qualitative evidence that practitioners can have low expectations of disabled children and young people with severe complex needs and may underestimate their potential. This reflected the committee\'s experience that many children and young people have not had the chance to consider their aspirations for employment, independence, relationships and community involvement. This can lead to restricted goals and ambitions, and an EHC plan that does not reflect the genuine strengths, abilities and interests of the child or young person. The committee therefore highlighted ways to address this in the recommendations.\n\nThe committee\'s understanding of the SEND code of practice and legislation in the Children and Families Act 2014 is that parents and carers must be consulted throughout the EHC plan process. However, moderate-quality qualitative evidence suggested that sometimes this is limited and only done in a tokenistic way. Based on this, the committee emphasised the need to take the views of parents and carers into account throughout the process.\n\nThere was moderate-quality quantitative evidence that a lack of specific, measurable, attainable, relevant and timely (SMART) outcomes in EHC plans made it unclear what support will be needed, and who is responsible for providing it. The committee\'s understanding of the SEND code of practice was that it recommends that SMART outcomes should be used, but in the committees\' experience this is not always done. The committee recommended that practitioners consider using the outcome sandwich, because in their experience it is a helpful tool that can help practitioners to develop meaningful outcomes.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect effective practice, but are currently implemented to varying degrees by different services and will involve a change of practice for some providers. Longer consultations or additional follow-up may be needed to fully discuss the outcomes for EHC plans with children and young people and their parents and carers. Spending sufficient time deciding on outcomes for the EHC plan will help practitioners to provide person-centred care. It ensures children and young people are engaged with the process and that EHC plans align with their aspirations. If not done correctly, it can lead to restricted goals and ambitions, poor engagement, and ultimately lower quality of life and general wellbeing. A good process for developing outcomes will help children and young people with making decisions, ensures that they get support that meets their needs, and ensures that scarce resources are not wasted.\n\nReturn to recommendations\n\n# Providing information and advice for the EHC plan\n\nRecommendations 1.4.6 to 1.4.15\n\n## Why the committee made the recommendations\n\nCurrently, individual services contribute information and advice for EHC plans without knowing what the proposed outcomes are for the children and young people. This can lead to inconsistencies between the information and advice provided by different practitioners and services, and an EHC plan that is not practical to implement. These problems often lead to the statutory 20-week timeframe for producing an EHC plan being missed. Therefore, the committee felt strongly that recommendations were needed to address this issue. Based on their experience, the committee were confident that sharing the proposed outcomes with services would allow services to specify how they would help to achieve these outcomes when contributing advice and information. This would result in EHC plans that made sense and would support the agreed outcomes for each disabled child or young person with severe complex needs.\n\nAlthough recording the views of children and young people in EHC plans is mandatory, moderate-quality qualitative evidence indicated that this is not always done accurately or in enough detail. Practitioners often paraphrase the words of children and young people, and this can lead to inaccuracies.\n\nAdvice and information contributed by different services needs to be put in specific sections of the EHC plan when written by local authorities, so that commissioners can see which services need to be provided from which budget lines. In the committee\'s experience this is often done poorly, with a lack of distinction between what practical and therapeutic support is needed to educate or train the child or young person and what health and medical support they need to stay well. The committee were confident that including this information correctly in EHC plans would resolve these issues so that children and young people are provided with the support they need.\n\nModerate-quality qualitative evidence indicated that children and young people, their families and carers, and service providers thought that EHC plans were not clear on who is responsible for providing the support specified in the plan. Therefore, the committee recommended specifying the support needed to help children and young people achieve the outcomes in their EHC plans.\n\nModerate-quality qualitative evidence indicated that service providers lacked the expertise and knowledge needed to complete EHC plans. In addition, the committee\'s experience was that EHC plans are often based on old information and therefore do not fulfil their purpose. Preparing good-quality EHC plans is crucial to ensuring that disabled children and young people with severe complex needs get the support they need. To address this, the committee made recommendations for local authorities (who are ultimately responsible for the EHC plan process) and health commissioners, to ensure plans are brought up to the correct standard.\n\nModerate-quality qualitative evidence showed that children and young people\'s views are not always captured accurately, and that it is important to make sure views are not rewritten in a way that changes the meaning. Based on their experience, the committee recommended ways in which the child or young person\'s voice could be preserved when recording their views.\n\nModerate-quality qualitative evidence identified that it can be difficult for children and young people and their families and carers to understand the complicated terminology used in EHC plans. The evidence further highlighted that using accessible language would make it easier for children and young people to get involved, and improve accountability by ensuring everyone knows who is responsible for each part of the plan. The committee noted that certain sections of the plan would need to be written in technical language (for example information about health), but recommended that the outcomes and support provision sections should be written in clear language that can be understood by the child or young person and their families and carers. This aligns with the committee\'s understanding of the SEND code of practice, which states that \'EHC plans should be clear, concise, understandable and accessible to parents, children, young people, providers and practitioners\'.\n\nAs part of ensuring that children and young people understand and agree with the plan, the committee recommended that practitioners check it with them during the planning process. Moderate-quality qualitative evidence indicated that parents and carers felt more positive about the EHC process when their involvement was clearly valued and they had the chance to make amendments to the EHC plan. Parents and carers have valuable experience from caring for their child, including an understanding of their child\'s needs, so their contributions to the plan are useful. In addition, explaining how their concerns have been addressed in the plan is a simple way of showing how their involvement is valued.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect effective practice, and legislation and statutory guidance, but are currently implemented to varying degrees across education, health and social care. EHC plans are crucial, as they identify the educational, health and social care needs of disabled children and young people with severe complex needs and specify what support must be put in place to help achieve the desired outcomes.\n\nLocal authorities may need to change their practice to provide services with the proposed outcomes for children and young people. However, this would help services to provide more consistent information and advice, reduce the time needed to resolve inconsistencies, and lead to an EHC plan that is practical to implement. This will have a positive effect on the care and support received by children and young people and on their ability to achieve the desired outcomes. It should also make it easier to produce EHC plans within the statutory 20-week timeframe.\n\nSome providers may need to change their practice, and more staff time may be needed for follow-up and discussions of EHC plans with children and young people and their families and carers. Checking the draft plan with children, young people and their families will ensure that they understand the content of the plan and support that must be put in place to help them. This will help them to engage with the process and will make it more likely that the agreed care and support will be effective. All of this will positively impact their care and outcomes.\n\nReturn to recommendations\n\n# Reviewing progress and needs, and coordinating with EHC plan reviews\n\nRecommendations 1.4.16 to 1.4.20\n\n## Why the committee made the recommendations\n\nIn the committee\'s experience, the needs and circumstances of disabled children and young people with severe complex needs can change frequently. Therefore, the committee highlighted that professional reviews need to be regular. They could not specify exact timings as this would vary for different people. They also provided detail about when to conduct a professional assessment, to ensure that any change in needs is captured.\n\nThe local authority is responsible for making decisions about whether an EHC plan is still fit for purpose, whether any changes to the plan are needed, and whether to conduct a reassessment. To help local authorities with these decisions and ensure they have the latest information, the committee recommended that the results of any professional assessments conducted by individual services are shared with local authorities.\n\nThere was low-quality qualitative evidence that parents and carers spend a lot of time and effort contacting and coordinating between services, because services do not talk to each other. The committee looked at ways this could be addressed for the different reviews children and young people have. One possibility is the approach used for looked-after children and young people, who have coordinated EHC plan annual reviews and social care reviews with aligned review periods. The committee agreed that doing this for all children and young people would be helpful and make things simpler for families.\n\nLow-quality qualitative evidence indicated that children and young people and their families and carers were concerned that their support would be reduced if they acknowledged improvements or talked about the child or young person\'s strengths in the EHC plan. The committee agreed that this can be a problem in practice. They were confident that the level of support specified in the EHC plan should only be reduced if the child or young person no longer needs it, otherwise there was a risk that the improvements may not be maintained.\n\n## How the recommendations might affect practice\n\nThe recommendations on review and reassessment of EHC plans reinforce statutory requirements and current practice, so should represent no change in practice for services.\n\nThe recommendation to reduce the level of support only if the child or young person no longer needs it may mean a change in practice for some services. However, this will prevent avoidable crises that are caused by services reducing the level of support too early.\n\nReturn to recommendations\n\n# Funding\n\nRecommendations 1.4.21 and 1.4.22\n\n## Why the committee made the recommendations\n\nThere was moderate-quality qualitative evidence in this area, based on the views of practitioners. They reported a decrease in funding that has reduced availability of services and prevents them from providing person-centred, joined-up care. In response, the committee highlighted that under section 42 of the Children and Families Act 2014, local authorities and health commissioners have a duty to secure or arrange (respectively) the provision specified in EHC plans. They therefore recommended that sufficient funding should be provided to enable the support in EHC plans to be provided.\n\nThere was also moderate-quality qualitative evidence that practitioners\' requests for additional funding to support a child or young person can be refused without a reason being provided. This causes frustration, stops practitioners from providing clear information to children and young people and their families and carers, and can make it difficult to appeal the decision. Therefore, the committee recommended making the reasons for refusing additional resources clear to both practitioners and families.\n\n## How the recommendations might affect practice\n\nThe recommendations repeat legislation and statutory guidance, so there is no change in the resource impact on services. More funding may be needed in areas where local arrangements are not compliant with legislation and statutory guidance.\n\nPractitioners may need more time to explain why requests for additional resources have been refused, and to explain potential courses of action. It is difficult to say if this will have an impact on the appeals process. There may be more appeals because families understand the process better, or there may be fewer appeals because the reasons for not providing additional resources are clearer.\n\nReturn to recommendations\n\n# If children, young people and their families decline an EHC plan\n\nRecommendation 1.4.23\n\n## Why the committee made the recommendation\n\nIn the committee\'s experience, there are circumstances when parents or carers can decline an EHC plan. For example, if they are unhappy with the school named in the plan. The committee highlighted that in these circumstances, it is important to still engage with parents and carers, so that their children do not become lost to services and miss out on support.\n\n## How the recommendation might affect practice\n\nPractitioners may need more time for discussions with parents or carers who decline an EHC plan. However, this rarely happens, so the overall time impact will be small.\n\nReturn to recommendation\n\n# Personal budgets and direct payments\n\nRecommendations 1.5.1 to 1.5.5\n\n## Why the committee made the recommendations\n\nThere was moderate-quality qualitative evidence that:\n\npersonal budgets and direct payments can increase flexibility and give families greater choice about which services they use, but that they can also create additional responsibility for the family\n\nfamilies were unclear about whether they were entitled to a personal budget or direct payment, or how useful these were\n\nfamilies were unsure what they could use the funds for, whether personal budgets and direct payments improved their child\'s access to services, or whether either option would be applicable to their individual circumstances\n\nparents were not always sure if they were able or willing to take on the responsibility of a personal budget or direct payments, and they questioned whether they had sufficient knowledge to make care decisions\n\nparents were uncertain if choosing a personal budget or direct payments would affect how professionals were involved in their support.\n\nThe Special Educational Needs (Personal Budgets) Regulations 2014 requires local authorities to provide parents and young people with information on personal budgets, if the child or young person has an EHC plan or will be issued with one. Based on the evidence, the committee supplemented this statutory requirement with a recommendation on specific information that local authorities should provide on personal budgets and direct payments.\n\nIn the committee\'s experience, when services are commissioned through direct payments and families become the commissioners of care, there can be a loss of coordination between support purchased through direct payments and statutory support provided directly through health and social care providers. Given the emphasis in the legislation and the SEND code of practice on services working together, the committee used their experience to recommend that local authorities and health commissioners continue to ensure services coordinate even if they have been commissioned using direct payments.\n\nPersonal budgets are mandatory for people aged 18\xa0and over if they have a care and support plan, but they can choose whether or not to receive this budget as a direct payment. The committee agreed it was important to make people aware of this, as the difference between personal budgets and direct payments is not well understood.\n\nThere was moderate-quality qualitative evidence that families were concerned that personal budgets and direct payments would lead to uneven provision, shortages in provision and a reduction in services. Families did not want to be disadvantaged, and were concerned about having to prioritise within the constraints of a limited budget. They were also concerned that the budget may not be equivalent to the level of funding that is already available. In the committee\'s experience, direct payments are sometimes only large enough to cover the service itself but not any related costs. As a consequence, activities that the child or young person enjoyed previously may no longer be affordable, which could impact on their quality of life and ability to achieve the outcomes in their EHC plan. The committee were confident that if local authorities assessed the full cost of providing the services proposed in the needs assessment, this would help to address this problem.\n\n## How the recommendations might affect practice\n\nPractitioners may need more time to advise children and young people and their families about personal budgets (including personal health budgets) and direct payments. As a result of this advice, there may be a change in the uptake of personal budgets and direct payments.\n\nFor families receiving direct payments, health and education services are already required to assess the full cost of providing services proposed in the needs assessment. However, this may represent a change in practice for social care. Services may be encouraged to think differently about the approach to funding and provision, and consider including support costs (for example, transport costs or variable costs of accessing different provision) in direct payments.\n\nLocal authorities and health commissioners will need to apply the same frameworks and processes they use to ensure the quality of directly commissioned statutory support to the support commissioned by families through direct payments. This could include frameworks and processes on training and competency, information sharing, monitoring and review. Doing this will ensure that all services supporting children and young people will receive the information needed to provide effective advice and support.\n\nReturn to recommendations\n\n# Supporting parents and carers, and training\n\nRecommendations 1.6.1 to 1.6.12\n\n## Why the committee made the recommendations\n\nThere was evidence that parent training provided numerous benefits to parents and carers, improving their:\n\ncommunication\n\nability and confidence to meet the needs of their child\n\nrange of social contacts, providing them with social, emotional and practical support.\n\nHowever, the evidence varied between very low to high quality. Important differences were seen when the outcomes were measured on some scales, but not on others, indicating uncertainty in the results. Therefore, the committee interpreted the results with caution and used the evidence to recommend general elements of the interventions rather than recommending any specific intervention. They also supplemented the evidence with their own knowledge and experience.\n\nIn the committee\'s experience, families often report a desire to have been directed to services that can provide emotional and practical support to enable them to come to terms with their child\'s diagnosis.\n\nThere was very-low- to low-quality evidence that person-centred planning approaches were beneficial in helping to include parents and carers in care planning, so the committee recommended that these were considered. Moderate-quality qualitative evidence, supported by the committee\'s experience, showed that different families and carers want different levels of involvement in decision making. Some families want to be regularly involved in making decisions, whereas some prefer to be guided by professional advice. In addition, in the committee\'s experience, families change their minds about the level of involvement they want over time.\n\nModerate-quality qualitative evidence showed that parents felt that they coordinated most of the services for their child and were worried about what would happen if they could no longer do this. To ensure parents are prepared, the committee recommended that practitioners should consider providing information about available emotional and practical support options.\n\nThere was very-low- to high-quality evidence that training for parents and carers was beneficial, and low-quality qualitative evidence showed that families needed more support to provide care for a disabled child or young person with severe complex needs. Therefore, the committee recommended that services consider working together to co-produce training with parents and carers. The committee also identified areas that this training could cover, based on the evidence.\n\nIn the committee\'s experience, there is variation in the level of training that each family needs. Some families will want more in-depth training straight away, and others will not. The committee felt strongly that training needs to be appropriate to the needs of families, so that families are able to learn at the level that will be most beneficial to them. The committee felt equally strongly that practitioners who lead the training need to have skills that are appropriate for the content of the training, so that people are not going beyond their skillsets, because this could make the training ineffective. In addition, the committee agreed that people all learn differently, so using different teaching styles in training would be sensible.\n\nSome of the parent training interventions in the evidence were conducted in group format, and provided parents and carers with an opportunity to engage with each other and share experiences. The committee agreed that providing such opportunities would likely have a positive impact on parents and carers by helping them to learn from each other and develop support networks.\n\nThe committee have seen that not all families are ready to start training immediately (for example, if they have just received a diagnosis). Some families need more time, and the committee were confident that training would be more effective if families were able to start the training when they were ready.\n\nMore flexible options around training delivery (including session times, locations and formats) would make training sessions more accessible to parents and carers. Flexibility is particularly important for parents and carers of disabled children and young people, because their substantial caring responsibilities make it difficult to find time for the training.\n\n## How the recommendations might affect practice\n\nPractitioners may need more time to include and support parents and carers (for example, by directing them to sources of support and including them in care planning). However, all local areas should already have processes for doing this, so there should be no significant impact.\n\nParent and carer training is currently available and there are examples of good practice across the country. However, practice is variable, and the recommendations may result in additional costs for some services. For example, training content may need to be slightly modified, and group activities may need to be included to provide opportunities for parents and carers to discuss their experiences. Currently, services commission parent and carer training in isolation, or with only 2\xa0services working together. There might be costs associated with setting up the framework for a collaborative approach if services choose to do this, for example, more meetings and communication between services may be needed. However, collaborative working will make the training approach coordinated, cut out duplication of effort and result in efficiencies and cost savings to the organisations involved. It will also make practice more consistent. Most importantly, supporting parents and carers may avoid a breakdown in care, preventing crises and expensive care placements.\n\nReturn to recommendations\n\n# Social participation\n\nRecommendations 1.7.1 to 1.7.7\n\n## Why the committee made the recommendations\n\nIn the committee\'s experience, social inclusion is as important as care and education for improving the quality of life of disabled children and young people with severe complex needs, but this may be more difficult for children and young people who are not in education or work. So the committee made recommendations to raise awareness of this.\n\nThere was very-low-quality evidence from 1\xa0study that an adapted fitness programme increased positive social interactions for disabled children and young people with severe complex needs during group activities. The committee recommended considering adapted group activities (such as theatre) because some children and young people may prefer these to sports, and the committee agreed that children and young people are likely to have positive social interactions in other group activities as well. The committee agreed that the adaptations included in the fitness programme were an important part of the intervention and, therefore, recommended that providers adapt activities as needed.\n\nLocal authorities have a duty to provide short break services, but they will need to collaborate with voluntary and community organisations to provide a wide range of meaningful activities as part of these services. Moderate-quality qualitative evidence highlighted that short breaks provide benefits for children and young people, but also that services may only provide limited opportunities for activities, so the committee made a recommendation to address this. Local authorities will need to think about options for people living in rural areas, to prevent inequalities in access to these social activities.\n\nThe committee used their experience to make recommendations on ways services and practitioners could help children and young people to participate in social activities. This aligns with the committee\'s understanding of the SEND code of practice – that social inclusion should be included as a preparation for adulthood outcome in all EHC plans and reviews from year\xa09 onwards. The examples given are important areas of social participation that most people take for granted, but that disabled children and young people with severe complex needs may need assistance to get involved in.\n\nThere was some limited quantitative evidence that collaboration between health and education services can improve the ability of disabled children and young people with severe complex needs to communicate in classrooms. The main limitations with this evidence were that it was from only 1\xa0study, and there were issues with the study design. However, this evidence was consistent with high-quality qualitative evidence that education practitioners valued the opportunity to learn from health professionals. The committee were confident that this collaboration is important to ensure that:\n\nunaddressed health needs do not get in the way of social participation\n\nthe way that health needs are addressed is not itself a barrier to social participation (for example, healthcare appointments are not scheduled during activities that children and young people want to participate in).\n\nThe committee agreed that similar benefits could be seen in other settings if health and social care services collaborated.\n\n## How the recommendations might affect practice\n\nLocal authorities have a duty to provide short break services, and the recommended group activities would fall under this category of service. Because local authorities already have to fund these services, there should be no resource impact. However, the type of short break services provided may change. Short breaks are integral to any support package. They allow young people with disabilities and severe complex needs to meet friends, take part in activities, develop independence, and improve their quality of life.\n\nMore children and young people may be able to attend education settings or community activities. There may be a higher cost to services, but there will be improvements in the quality of life and wellbeing of disabled children and young people with severe complex needs.\n\nBecause there is already a legal duty to make reasonable adjustments, which would include the adaptations specified in the recommendation, there should be no change in practice or resource impact to making these adaptations.\n\nServices will need to set up or use existing frameworks for a collaborative approach for commissioning and providing activities that can help improve social participation.\n\nServices may need to hold more joint and coordinated meetings to allow them to work together more closely on supporting social participation.\n\nReturn to recommendations\n\n# Transition from children\'s to adults\' services\n\nRecommendations 1.8.1 to 1.8.14\n\n## Why the committee made the recommendations\n\nRegulations 20(6) and 21(6) in the SEND Regulations 2014 require local authorities to ensure that preparation for adulthood is covered in EHC plan reviews from year 9 onwards. However, moderate-quality qualitative evidence indicated that preparation and decision making for adulthood is insufficient and left too late. The committee made recommendations to emphasise these regulations.\n\nThere was low- and very-low-quality quantitative evidence that participation and inclusion were improved when a young adult team approach was used to help with transition from children\'s to adults\' services. There were important limitations to this evidence. In particular, the evidence came from only 1\xa0study, and there were issues with potential bias. However, this quantitative evidence was consistent with moderate-quality qualitative evidence that practitioners valued a child- or young-person-centred approach that encouraged a multidisciplinary team working around the child or young person to identify and meet their needs. The SEND code of practice states that high aspirations are crucial to the success of the child or young person and that discussions should focus on their strengths, capabilities and the outcomes they want to achieve. However, in the committee\'s experience, some practitioners are not following this approach and are instead focusing on short-term support that can more easily be achieved. So they agreed it was important to promote a focus on goals for adulthood and maximising independence.\n\nThe committee\'s understanding of the SEND code of practice is that local authorities should ensure there are pathways into employment, independent living and participation in society, and that they must work with children, young people and families to develop coordinated approaches to securing better outcomes for adult life. However, in the committee\'s experience, because most of the work on preparing for adulthood is done in educational settings, the focus is often on staying in education. In addition, there was qualitative evidence that young people need more support to understand their options and reach their full potential. The committee wanted to ensure that young people understood all their options and had time to prepare for them, so made recommendations to address this.\n\nIn the committee\'s experience, the transition from paediatrics to adult health services can cause problems, as not many adult services provide the same \'wrap round\' services as paediatrics. This can be a major source of concern for families, because paediatricians tend to coordinate care for the young person, and this coordination is then lost when the young person transfers to adult services. The committee agreed that for effective transition planning, healthcare professionals should find out what local services are available and involve them as needed to help with the transition.\n\nThe qualitative evidence highlighted various problems with preparations for adulthood:\n\nthere was low-quality evidence that education, health and social care services used different age thresholds for transition to adult services\n\nthere was low- to moderate-quality evidence that the process lacked coordination, and caused uncertainty and stress for young people\n\nthere was moderate-quality evidence that preparation is insufficient and left too late.\n\nIn the committee\'s experience, the variation between services in the ages used for non-statutory transitions creates gaps in the services that young people can access. This is significantly detrimental to the care and support young people receive and potentially exposes them to harm, so the committee were confident that a consistent approach was needed.\n\nThe committee felt strongly that services needed to work together to better coordinate transition, and needed to read the sections of the plan produced by other practitioners. If this was not done, they were confident that it would lead to a plan that is not practical to implement. They also recommended areas that young people and their families and carers should be given information about, so that they know what to expect and experience less uncertainty and stress.\n\nIn the committee\'s experience, practitioners do not always focus on long-term goals throughout the transition process. Planning and goals for adult life are only raised near the point of transition, which can make them seem overwhelming and unachievable for young people and their families. It is important to include short-term goals, to break down the long-term goals into manageable steps and help young people see how they can progress.\n\nNot all young people with severe complex needs will continue in education. The committee directed practitioners to relevant guidance to ensure that the needs of these people are still met.\n\nThere was moderate-quality qualitative evidence that having the same named worker throughout the process helped maintain consistency and a positive relationship between young people and services (named workers are recommended by the NICE guideline on transition from children\'s to adults\' services). It would not be possible to have the same named worker before and after transition, so the committee made a recommendation on handing over these responsibilities to maintain consistency and continuity of care.\n\nModerate-quality qualitative evidence showed that parents felt shut out once their child reached adulthood, so the committee recommended that parents and young people are given information to help them prepare for the change.\n\nThere was evidence relevant to other parts of the process:\n\nlimited, low-quality quantitative evidence that involving managers and parents in steering groups reduced levels of unmet needs and improved parents\' satisfaction\n\nlow- to high-quality qualitative evidence that young people and their parents and carers felt more positive when they were involved, and that the input of young people leads to a more accurate understanding of their needs\n\nlow- to moderate-quality quantitative evidence that parents were more satisfied with services when they had a transition worker.\n\nThese areas are covered in the NICE guideline on transition from children\'s to adults\' services. Because of this, the committee did not make new recommendations in these areas.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice and existing NICE guidance, and align with legislation and statutory guidance. However, more practitioner time might still be needed to meaningfully involve children and young people in transition planning. And education, health and social care practitioners might need to hold more joint and coordinated meetings, for example, to ensure that young people understood all their options, and to plan and set goals. Early planning will ensure that there is plenty of time to achieve the outcomes specified and that everything is not left to the final review, by which time it is too late to do any developmental work. Transition planning done in the right way will result in more efficient person-centred processes. It may potentially result in better long-term outcomes, with goals being achieved and overall savings to the services. It can also have important economic consequences, if young people are able to find employment or volunteer work.\n\nThere is variation in how far children and young people are involved in transition planning, and in the effectiveness of transition between children\'s and adults\' health services. The recommendations should make practice more consistent.\n\nThere may be a greater uptake of certain services, such as supported internships.\n\nReturn to recommendations', 'Rationale and impact for recommendations on specialist support for disabled children and young people with particular needs': "These sections briefly explain why the committee made the recommendations and how they might affect practice and services.\n\n# Palliative care and end of life care\n\nRecommendations 1.9.1 to 1.9.10\n\n## Why the committee made the recommendations\n\nIt was not possible to determine which aspects of practice and service delivery models improved outcomes, based on the limited, very-low-quality quantitative evidence available. So the committee made recommendations based on their knowledge and experience.\n\nHealth services will be the first to know when a child or young person needs a palliative or end of life care plan. It is important to find out if the child or young person has already documented their wishes (for example, in an advance care plan) before sharing information with other services.\n\nIn the committee's experience, other services are not always notified, and this can cause interruptions to the support provided to the child or young person. Health services should also consider providing training for other services, to help them understand how to best meet the changing needs of children and young people with palliative or end of life care plans.\n\nThe committee felt strongly that all services should continue to be involved. They were confident that doing this would improve planning, provide stable and consistent support, and give children and young people flexibility in which activities they want to continue. In their experience, there is a widespread belief that when children enter an end of life care process, they do not need much support beyond that offered by health services. This can lead to things that are important to the child or young person, such as community participation and maintaining social relationships, being overlooked.\n\nThere was moderate-quality qualitative evidence that education, health and care (EHC) plans are not always viewed as live documents that need reviewing and updating. However, the committee's understanding of the special educational needs and disability (SEND) code of practice is that EHC plans should be reviewed when there are significant changes in need, and the need for palliative or end of life care is a clear example of this. Changes in support need to be implemented as soon as possible because of the time pressures associated with end of life care. Similarly, regular reviews of the palliative or end of life care plans are needed, as the child or young person's needs can change frequently. The committee were not able to be more specific about the frequency of reviews because this would depend on individual circumstances.\n\nIt is important to consider the support needs of the child or young person's family, because these can be overlooked during palliative and end of life care, and families may not feel able to seek support in this situation if practitioners do not offer it.\n\n## How the recommendations might affect practice\n\nIt may be a change in practice for some services to continue social care and education support at the end of life. Services may need to work in a more coordinated way and be more explicit about the roles and responsibilities of different professionals.\n\nServices will have to consider how support might need to change for a child or young person who has an end of life care plan. As a result, they may request more reviews of EHC plans. Services will also need to consider how to provide interagency training, to ensure that practitioners can provide better palliative and end of life support to children and young people and their families and carers.\n\nReturn to recommendations\n\n# Communication aids\n\nRecommendations 1.10.1 to 1.10.6\n\n## Why the committee made the recommendations\n\nThere was very-low-quality evidence that assistive technology may increase interpersonal interactions, participation and inclusion. There were issues with the quality of the evidence (for example, there was only 1\xa0study and it was not conducted in the UK) and at follow\xa0up, not all of the participants had received the recommended assistive technology. This evidence was from a service that made recommendations on assistive technology but did not fund or provide this technology. Therefore, the committee agreed that a greater benefit may have been expected if the technology was provided.\n\nThere are existing augmentative and alternative communication services (local services, and NHS England specialised services) that provide support for people with communication needs. However, in the committee's experience, the specialised services are not well known and so are underused. This experience is consistent with moderate-quality qualitative evidence that practitioners and other staff lack the necessary skills and knowledge to work effectively to meet the needs of children and young people. It is important that staff know about the eligibility criteria for both local and specialised augmentative and alternative communication services, so that lack of knowledge is not a barrier to children and young people receiving support. The committee were aware that referrals are usually made by occupational therapists and speech and language therapists. However, the services accept referrals from other education, health and social care practitioners, so it is important that services do not cause delays by putting extra restrictions on who can make a referral.\n\nModerate-quality qualitative evidence highlighted that more training and multi-agency work is needed to communicate effectively with disabled children and young people. The committee also felt strongly that there needs to be agreement about who will maintain, service and insure communication aids, so that people know how to get support if equipment is damaged. In the committee's experience, these issues are often not resolved effectively, which means the equipment does not get used and children and young people's needs are not met. The committee were confident that making the responsibilities around these areas more explicit would resolve this issue.\n\nIn the committee's experience, it is also important to provide a paper-based backup for children and young people using powered communication aids, so that they can continue to communicate if the equipment breaks down.\n\nThere was moderate-quality qualitative evidence that using a consistent approach was beneficial for children and young people, as it is more predictable and helps them to generalise across different settings. As part of this, the committee encouraged services to think about how equipment can be used in multiple settings and across transitions, and how the child or young person and their families and carers can be involved in the assessment process. They also agreed that education, health and care services would need to coordinate with specialist services, to ensure that the child or young person can use their communication aid in all settings and get the most value out of their communication aid.\n\nThere was moderate-quality qualitative evidence that children and young people and their families and carers need more information and support to understand the services available to them, to help them make decisions and access services. To address this, the committee made a recommendation about providing information on support groups for children and young people who use assistive technologies. The SEND Regulations 2014 also specify that the SEND Local Offer must include information about available support groups.\n\nThere was a lack of evidence on whether assistive technology enabled disabled children and young people with severe complex needs to express their views. Because getting their views is central to the EHC needs assessment process and ensures that services and resources are allocated appropriately, the committee made a research recommendation on this.\n\n## How the recommendations might affect practice\n\nIn some areas, specialised augmentative and alternative communication services are underused. The recommendations may lead to an increase in referrals to these services. However, the specialised services are already funded by NHS England, so this will not lead to an increase in costs for local education, health and care services.\n\nThe availability of training on communication aids is variable, so providing training might represent a change in practice for some services. And practitioners may need to spend more time showing children and young people and their families and carers how to use communication aids. The amount of time required will vary depending on the complexity of the equipment and the number of people that need to be trained to use it. Training practitioners to use the equipment properly will ensure that the often costly equipment that has been assessed and prescribed will be used, and used correctly. It will improve outcomes, such as independence. It will also mitigate against the risk that only 1\xa0practitioner knows how to use the equipment, so if they stop working with the child or young person, the equipment stops being used, potentially resulting in a deterioration of the child or young person's health and wellbeing.\n\nThere are established frameworks in place for maintaining, servicing and insuring communication aids, for example those provided by NHS England specialised augmentative and alternative communication services. This particular recommendation is only highlighting that responsibilities around these areas should be stated more explicitly.\n\nReturn to recommendations\n\n# Environmental adaptations\n\nRecommendations 1.11.1 to 1.11.10\n\n## Why the committee made the recommendations\n\nIn the committee's experience, families often need support with the assessments needed to get environmental adaptations, and with the reassessments needed to ensure these adaptations are still appropriate when the child or young person's needs change.\n\nThere was very-low-quality evidence that assistive technology may increase interpersonal interactions, participation and inclusion. There were issues with the quality of the evidence (for example, there was only 1\xa0study and it was not conducted in the UK) and at follow\xa0up, not all of the participants had received the recommended assistive technology. This evidence was from a service that made recommendations on assistive technology but did not fund or provide this technology. Therefore, the committee agreed that a greater benefit may have been expected if the technology was provided.\n\nThe committee have seen that services do not always think about how environmental adaptation equipment will be used across multiple settings. Often, equipment is provided to a specific service rather than the child or young person, preventing them from using it in other places. The recommendation on this is supported by moderate-quality qualitative evidence, which showed that children and young people benefited from a consistent approach as it is more predictable and helps them to generalise across different settings.\n\nIn the committee's experience, training would also be useful for children and young people who are using environmental adaptations, as well as for their families. This is particularly important because there would be safety concerns if environmental adaptations are not used correctly, so the committee made recommendations on training staff and families in how to use environmental adaptations. The committee also felt strongly that there needs to be agreement about who will maintain, repair, service and insure the equipment, and that it is important that people know how to get support if it is damaged. In the committee's experience, these issues are often not resolved effectively, which means the equipment does not get used and children and young people's needs are not met. The committee were confident that making the responsibilities around these areas more explicit would resolve this issue.\n\nThere was moderate-quality qualitative evidence that children and young people and their families and carers need more information and support to understand the services available to them, to help them make decisions and access services. To address this, the committee made a recommendation about providing information on support groups for children and young people who use environmental adaptations. The SEND Regulations 2014 also specifies that the SEND Local Offer must include information about support groups.\n\nBased on the committee's experience, children and young people with environmental adaptation equipment can have difficulties when they move area, as it is not always possible to take equipment with them. This often has a negative impact on their quality of life, so the committee made recommendations to address this.\n\nThere are existing environmental control services that provide support for people with physical disabilities and multi-sensory impairments that restrict their ability to independently operate standard controls. However, in the committee's experience these specialist services are not well known and so are underused. This experience is consistent with moderate-quality qualitative evidence that practitioners and other staff lack the necessary skills and knowledge to work effectively to meet the needs of children and young people. It is important that staff are made aware of environmental control services, so that lack of knowledge is not a barrier to children and young people receiving support, and so that they refer children and young people if they meet the eligibility criteria. The committee were aware that referrals are usually made by occupational therapists. However, the services accept referrals from other education, health and social care practitioners, so it is important that services do not cause delays by putting extra restrictions on who can make a referral.\n\n## How the recommendations might affect practice\n\nIn some areas, specialised environmental control services are underused. The recommendations may lead to an increase in referrals to these services. However, the specialist services are already funded by NHS England, so this will not lead to an increase in costs for local education, health and care services.\n\nThe availability of training on environmental adaptations is variable, so providing training might represent a change in practice for some services. And practitioners will need to spend more time showing children and young people and their families and carers how to use these adaptations. The amount of time required will vary depending on the complexity of the equipment and the number of people that need to be trained to use it. Training practitioners to use the equipment properly will ensure that the often costly equipment that has been assessed and prescribed will be used, and used correctly. It will improve outcomes, such as independence. It will also mitigate against the risk that only 1\xa0practitioner knows how to use the equipment, so if they stop working with the child or young person, the equipment stops being used, potentially resulting in a deterioration of the child or young person's health and wellbeing. There may also be fewer injuries if children and young people know how to use the equipment correctly.\n\nThere are established frameworks in place for maintaining, servicing and insuring environmental equipment, for example frameworks provided by the environmental control services. This particular recommendation is only highlighting that responsibilities around these areas should be stated more explicitly.\n\nReturn to recommendations\n\n# Environmental accessibility\n\nRecommendations 1.11.11 to 1.11.15\n\n## Why the committee made the recommendations\n\nThere was no comparative evidence in this area. However, there is best practice and statutory guidance on environmental accessibility that the committee referred to. The Department for Education already requires regular assessment of the accessibility of education environments, but in the committee's experience this statute is not well known and is poorly understood. The committee agreed that health and social care services should also conduct annual assessments, to ensure that children and young people can access the full range of services they need and prevent barriers to access.\n\nIn the committee's experience, the results of accessibility assessments provide important information to help children and young people and their families and carers make decisions about which services to use. It is a statutory requirement for education providers to make their accessibility assessments publicly available, but the committee agreed that it could also be helpful for health and social care services to make this information publicly available because it would help families with decision making.\n\nStaff knowledge of disability and accessibility should also be assessed because, in order for environments to be fully accessible, staff need to be committed to this ideal and to making reasonable adjustments; physical adaptations alone are not enough.\n\nAccessibility assessments should be available for key public places that disabled children and young people need to access, to ensure they can access the provision specified in their EHC plans and to allow them to participate and feel included (for example, in after-school clubs that are not held at their school). Publicly funded organisations have a statutory duty to make reasonable adaptations to promote accessibility, but in the committee's experience some community organisations might not be aware of this duty or have sufficient knowledge about the required adaptations. Therefore, the committee agreed that interagency teams should ensure accessibility assessments are available.\n\nThere was no comparative evidence available on the effectiveness of adaptations to physical or sensory environments. Therefore, the committee recommended further research in this area.\n\n## How the recommendations might affect practice\n\nAnnual assessments of accessibility at a service level represent a change in practice for health and social care services. However, health and social care practitioners do already conduct accessibility assessments for individuals, to comply with legislation on access for disabled people. Overall this recommendation should not be a substantial change in practice. There may be some additional resources associated with setting accessibility assessments up and coordinating at a service level.\n\nAssessing staff knowledge of disability and accessibility as part of annual accessibility assessments should already be a part of any properly conducted assessment. However, this may represent a change in practice for underperforming services, which will have to improve their annual assessments.\n\nReturn to recommendations\n\n# Travel training\n\nRecommendations 1.12.1 to 1.12.4\n\n## Why the committee made the recommendations\n\nThere was some very-low-quality evidence that travel training increased independent public transport use by disabled children and young people with severe complex needs. The evidence was focused on travel to and from school, but the committee agreed it is important that training helps children and young people to go anywhere they need to, in order to increase independence and participation.\n\nThe recommendation is not limited to public transport, because in the committee's experience there will be some children and young people who cannot use public transport. For this group, being able to use other forms of transport (such as powered wheelchairs, taxis, or adapted cars that they can drive themselves) will significantly improve independence. The committee were confident that the same travel training process would apply, and there was no plausible reason the training would not work equally as well for these additional scenarios.\n\nBased on their experience, the committee agreed that local authorities should consider providing a training framework to support travel training for all disabled children and young people with severe complex needs. This was because local authorities sometimes commission third party organisations to provide the training. The committee agreed that an organisation needed to have overall responsibility for implementing travel training to ensure that it happens. They were confident that local authorities were the appropriate organisation to direct the recommendation to.\n\nThe topics that travel training could cover were based on topics covered in the study the committee reviewed, and on their knowledge and experience of some of the challenges and risks children and young people face when travelling independently.\n\nProviding information to parents, carers and relevant professionals was a key component of the travel training in the evidence, so the committee recommended that local authorities should do this.\n\nThe study on travel training also included providing disability awareness training for staff as part of the intervention. The committee agreed with this, as it would help disabled children and young people with severe complex needs to independently use public transport. However, as providers of public transport already have a statutory duty under the Equality Act 2010 to provide disability awareness training to their staff, the committee did not make recommendations on this.\n\n## How the recommendations might affect practice\n\nLocal authorities must make transport arrangements when needed to allow school-age children and young people to attend school. Travel training is one of the ways local authorities can do this for disabled children and young people with severe complex needs.\n\nHelp with travel to education and training for young people aged over\xa016 is covered by the Department for Education's statutory guidance on post-16 transport to education and training for local authorities. Local authorities are required to produce a transport policy statement, setting out any transport or other arrangements that they think are needed to allow young people to access education (this includes young people aged under 25 with EHC plans). Travel training is one of the arrangements that local authorities can use to help young people use public transport independently. Although there are other options, and there is no requirement for local authorities to provide travel training, in the committee's experience many of them do for this group.\n\nFor disabled young people with severe complex needs who are no longer in education, there is no requirement for local authorities to provide help with travel. In addition, the EHC plans for these children and young people will have ceased, removing a potential source of funding. However, the committee's view was that there is only a very small number of disabled young people who would actually use travel training when they are aged over 16 and not in education. So although there might be some additional costs to implement this recommendation, it would not have a significant resource impact.\n\nTravel training is not consistently available in all areas, so there will be a change in practice for local authorities that do not have a training framework. However, most EHC plans will already specify a need for travel training, either because independent travel is listed as an outcome in its own right or because it is a means to achieve another outcome (for example, employment). The recommendation is unlikely to have significant resource implications because the committee's understanding of the SEND code of practice is that local authorities should provide enough funding for all the provisions agreed in EHC plans.\n\nReturn to recommendations\n\n# Employment\n\nRecommendations 1.13.1 to 1.13.11\n\n## Why the committee made the recommendations\n\nThe evidence on joint-working practices to prepare disabled children and young people for employment ranged from very low to low quality. Concerns included a risk of bias, the small number of studies, and the fact that the studies were not conducted in the UK. Therefore, the committee supplemented the evidence with their own knowledge and experience.\n\nIn the committee's experience, there is variation in the assistance provided to guide children, young people and their families and carers through employment options in the SEND Local Offer and the information is not always easy to understand. To improve consistency, the committee recommended using the Gatsby benchmarks, which are also recommended in statutory guidance from the Department for Education.\n\nThere was no evidence on supported internships. However, there was evidence that follow-on support increased independence in disabled young people with severe complex needs. The components of follow-on support in this study and supported internships in the UK are similar, so the committee used this evidence to make recommendations on supported internships. In addition, the SEND code of practice focuses on preparing for adulthood outcomes (which includes employment) in EHC plans from year\xa09 onwards. However, young people with severe complex needs have a very low chance of progressing to employment without assistance. The committee were aware of evaluations of supported internship programmes that have been undertaken by the Department for Education and UK Government. These evaluations concluded that supported internships are effective at helping young people with severe complex needs into employment. Therefore, the committee were confident that supported internships should be made available.\n\nThere was very-low-quality evidence that a named responsible practitioner improved young people's ability and confidence in meeting workplace expectations. This supported the committee's experience. They were confident that an essential component of supported internships is a lead employment practitioner with expertise related to helping young people with disabilities to find work. This lead practitioner provides one-to-one support to the young person, to coach them on the workplace skills and processes they will need to understand. Without this support, the committee agreed that employment outcomes would be much less likely to be successful.\n\nThe committee also agreed that the same benefit was likely to be seen for young people with employment as an outcome in their EHC plan but who were not undertaking a supported internship. To support implementation of this, they recommended that providing a lead employment practitioner should be a requirement in service specifications for employment support services. In the committee's experience, the lead employment practitioner would usually be a job coach. However, as there are other practitioners that could carry out this role, the committee did not limit it in the recommendation.\n\nThere are existing professionals who are trained to perform the role of lead employment practitioner. However, many people who are not trained are still providing such employment support. It is essential to have someone trained in employment support because the severe complex needs of this group of young people mean that additional and bespoke support is needed to help them find work.\n\nThere was moderate-quality qualitative evidence that preparations for adulthood are insufficient, inconsistent and left too late. In the committee's experience, families and young people are left to research employment options at the point when the young person is looking for a job. Preparing for adulthood early on would lead to better outcomes, so the committee made recommendations to support this.\n\nThe committee agreed that vocational profiles can help young people to find the type of work they would be good at.\n\nIn the committee's experience, it is important for practitioners from all services to work together and consider what employment support the young person may need, to prevent barriers to young people effectively participating in employment support. The committee were confident that practitioners should do this so that the responsibility does not fall on the young person and their family or carers.\n\nBased on their experience, the committee recommended actions that supported internship providers can take to help young people move into paid employment or volunteer work when their supported internship ends. This is because this group will have additional hurdles to overcome compared with non-disabled people who are competing for the same jobs. Doing this will support employers to make reasonable adjustments around recruitment.\n\nThe committee agreed that young people and their families are not always aware of the support available from support workers and job coaches, and so recommended local authorities signpost to these services in the SEND Local Offer. It is a requirement of the SEND Regulations 2014 that the SEND Local Offer contains information about all services available in that local area.\n\nIn the committee's experience, mentors and workplace buddies are a useful source of support for young people, and make the start of their job go more smoothly for both the young person and the employer. It is important that workplace buddies are not the young person's line manager because the young person has to be able to share their anxieties with their buddy, so they can receive effective support before this results in a performance issue.\n\n## How the recommendations might affect practice\n\nCommissioners are already required to make suitable arrangements for disabled young people who are eligible to access supported internships, where these are provided as part of the post‑16 SEND Local Offer. The recommendations on this should make practice more consistent and effective, but may represent a change in practice for underperforming services or poorly served areas.\n\nMore practitioners will need to be trained to provide employment support for young people, so that every young person who is undertaking a supported internship can be provided with a lead employment practitioner. Further practitioners will need to be trained if local authorities also decide to provide a lead employment practitioner to those young people who have employment as an outcome in their EHC plan. However, because this is an outcome in the EHC plan, funding already exists to enable this training to happen. Therefore, there will not be a significant resource implication.\n\nReturn to recommendations", 'Rationale and impact for recommendations on working culture, training, service organisation, integration and commissioning': "These sections briefly explain why the committee made the recommendations and how they might affect practice and services.\n\n# All education, health and social care practitioners\n\nRecommendations 1.14.1 to 1.14.3\n\n## Why the committee made the recommendations\n\nThere was moderate-quality qualitative evidence on the experience of practitioners from different services working together:\n\nthere can be negative relationships between professionals, leading to disagreements\n\npractitioners agreed it was important to put aside their differences, to work together for the good of the child or young person\n\nmutual respect and viewing other practitioners as equal partners made it easier to voice opinions and challenge each other, which was seen to improve joint working\n\npractitioners valued each other's skills and knowledge, and wanted opportunities to learn from each other and build their expertise\n\nworking relationships improved when practitioners worked together frequently or for extended periods, and when they had the opportunity to meet face-to-face.\n\nTo address this evidence, the committee made a recommendation on collaborating to develop a positive working culture.\n\nModerate-quality qualitative evidence also showed that using a consistent approach when interacting with children and young people was beneficial. It made services more predictable for children and young people, and made things easier for them to understand when dealing with a new service. The recommendation on arranging handovers will help to improve consistency and reduce the need for children, young people and their families and carers to repeat information.\n\nThere was limited quantitative evidence that having a local assessment team reduced waiting times for assessment. However, there was only 1\xa0study in this area, focusing on children and young people with autism. It was very low quality, and reported on waiting times only. Because of these problems with the evidence, local assessment teams were not recommended.\n\nThe committee did agree that practitioners would be better able to coordinate with each other and provide information to children and young people if they understood the responsibilities of other practitioners and services involved in supporting the education, health and care needs of the child or young person. The need for more coordinated support was highlighted by moderate-quality qualitative evidence that service providers value the different skill sets and knowledge of others and opportunities to learn from each other and build expertise. In the committee's experience, service providers already gain an understanding of the responsibilities of other people and services in an ad\xa0hoc way; the recommendations would simply encourage a proactive approach.\n\n## How the recommendations might affect services\n\nThe recommendations reinforce principles of good practice and should not represent a change for most services. However, some underperforming services may have to implement more effective practices, for example around arranging handovers.\n\nServices will also have to develop interagency training for practitioners on other services and their roles and responsibilities. Extra practitioner time might be needed to provide more wide-ranging and coordinated support. However, if practitioners are better trained on the roles and responsibilities of other services, this may lead to more efficient and timely delivery of care, with less duplication.\n\nReturn to recommendations\n\n# Working culture\n\nRecommendation 1.15.1\n\n## Why the committee made the recommendation\n\nThere was moderate-quality qualitative evidence that joint working improved when practitioners had shared values and priorities. From their experience, the committee agreed there is difficulty in practitioners from different services building effective teams and relationships with each other without having dedicated time for this and support from managers.\n\n## How the recommendation might affect services\n\nServices will need to give practitioners dedicated time for team and relationship building.\n\nReturn to recommendation\n\n# Key working support\n\nRecommendations 1.15.2 to 1.15.12\n\n## Why the committee made the recommendations\n\nThere was no evidence comparing services that did and did not have key workers, so the committee made a research recommendation about the effectiveness of dedicated key workers. However, moderate-quality qualitative evidence showed that key workers are seen as important by families and practitioners, for being able to better understand the child or young person's needs, and for being able to coordinate services. Moderate-quality qualitative evidence also highlighted that having a single person for families to contact would simplify processes and be beneficial to joint working. The committee's understanding of the special educational needs and disability (SEND) code of practice is that it recommends that local authorities should adopt a key working approach, to provide a single point of regular and consistent contact, and help ensure holistic provision and coordination of services and support. However, in the committee's experience this is not happening consistently and there is variation in understanding of what key working may involve. The committee were confident that providing effective key working support to everyone who needs it requires flexibility in the support that is provided, tailoring of the support to individual needs and consideration of family circumstances.\n\nVery-low-quality qualitative evidence highlighted that families are less accepting of key workers who have not had much involvement with the family. To address this, the committee made a recommendation on how to choose a key worker who could actively engage and work well with the family.\n\nLow- and moderate-quality qualitative evidence also showed that:\n\nchildren, young people and their families spent a considerable amount of time chasing and coordinating services, conducting administrative work and arranging meetings\n\nmore information and support is needed to help children, young people and their families to understand and access services\n\nthere is a lack of communication between services.\n\nThe committee made a recommendation on the responsibilities of the practitioner providing key working support, to address the problems identified in the evidence. These responsibilities align with the committee's understanding of the key working functions set out in the SEND code of practice.\n\nBased on their experience, the committee were confident that key working support can only be effective if senior managers support practitioners, ensuring they have the training, time and resources needed and understand what key working support involves. Without involvement from senior managers, there is inconsistent provision. Some children and young people miss out on key working support, and others do not receive good-quality support.\n\nIn the committee's experience, information sharing and governance arrangements are needed to ensure that key working support functions can be delivered across different services.\n\nModerate-quality qualitative evidence showed that the continuity of key workers is important for consistency (particularly during transition to adult services), and that children and young people felt negatively when key worker support ended prematurely. Staff turnover is inevitable, so it is important that good handover and contingency plans are in place to maintain consistency and minimise the impact of changes on children and young people.\n\nIn the committee's experience, some families do not have a permanently fixed location and move frequently. This can cause difficulties with effective coordination of care and support and timely transfer of information. The committee made recommendations on the actions needed when families move to a new area, to prevent inequalities in access.\n\n## How the recommendations might affect services\n\nThe committee's understanding of the SEND code of practice is that it recommends a key working approach (paragraph 2.21). However, this has never been fully implemented, and practitioners providing key working support do not have enough allocated time to provide all these functions. Because the recommendations on key working support are in line with the committee's understanding of the SEND code of practice, there should not be a significant resource impact. However, practice is variable, and the implementation of these recommendations might require additional resources for services with suboptimal practices. Services will need to make changes to enable key working approaches. They will also need to ensure caseloads are manageable and practitioners have dedicated resources to deliver effective key working.\n\nA dedicated key worker role would be preferred, with a separate job description and role specification, rather than key working functions being allocated to members of the team on top of their existing roles. However, there was no evidence of effectiveness or cost effectiveness to justify a specific key worker post.\n\nUsing a key working approach will ensure a single point of regular and consistent contact to help ensure holistic provision and coordination of services and support. It will reduce the burden on families to coordinate care, meaning they no longer have to spend as much time away from their other commitments, including care for siblings and time off work, which should increase their ability to manage at home, avoiding the cost of expensive care placements. Because of the current lack of key working support, there are routine reports of communication and coordination failures (that is, different services not working well with each other), leading to inefficient processes, missed meetings and poor information provision. Using a key working approach will counteract this and ensure coordinated and seamless care, joined-up outcomes, and a reduction in complaints.\n\nThere is no bespoke training for practitioners who will be providing key working support. The essential skills needed involve project management, negotiation, and communication, and usually involve component-based training.\n\nReturn to recommendations\n\n# Making processes easier to understand\n\nRecommendation 1.15.13\n\n## Why the committee made the recommendation\n\nModerate-quality qualitative evidence highlighted that there is a lack of transparency about how decisions are made on education, health and care (EHC) plans, the timescales for reviews, and the processes for appeals or complaints. Although the evidence was only about the EHC plan process, the committee agreed, based on their experience, that having increased transparency about what services do and how they work together would improve the child or young person's understanding of how to navigate the system. It would also increase their confidence in the care and support they are receiving and empower them to be more assertive about their needs. So the committee agreed services should consider doing this.\n\n## How the recommendation might affect services\n\nMaking processes more consistent and transparent may mean more practitioner time is needed, to improve coordination and joined-up working, and for learning about the roles and responsibilities of other practitioners.\n\nReturn to recommendation\n\n# Training for practitioners\n\nRecommendations 1.15.14 to 1.15.23\n\n## Why the committee made the recommendations\n\nThe committee used themes from the qualitative evidence to make recommendations on training for education, health and social care services.\n\nModerate-quality evidence showed that joint working was negatively affected when practitioners did not understand the roles, responsibilities and expectations of other practitioners or services. Based on their experience, the committee agreed that training could help.\n\nModerate-quality evidence showed that education providers need support and training to help them integrate disabled children and young people with severe complex needs into mainstream education.\n\nHigh-quality evidence showed that practitioners do not always understand the social, emotional and mental health needs of disabled children and young people with severe complex needs. When these needs are not recognised and addressed, it can be more difficult for children and young people to get EHC plans. The committee agreed that training was needed to help practitioners recognise these needs.\n\nModerate-quality qualitative evidence showed that:\n\nservices often do not adequately capture the child or young person's perspective on what support they need\n\nthere is a lack of available training in how to adapt communication and make better use of communication aids for children and young people with communication difficulties; multi-agency work is needed to improve this.\n\nThe committee were confident that children, young people and parents and carers need to be involved in developing awareness training programmes that are for them or that help practitioners work more effectively with them, to ensure that training is targeted and relevant. This was supported by moderate-quality qualitative evidence that parents and carers felt positive when given the opportunity to provide their views, and praised practitioners who valued their expertise but maintained appropriate boundaries. In the committee's experience, the development of training programmes did not always involve children, young people or parents and carers.\n\nThere was very-low-quality quantitative evidence that practitioners were better able to meet the needs of disabled children and young people after gaining experience working in other settings. Although this experience was referred to as a secondment in the evidence, the committee agreed that the intervention more closely resembled short-term observational placements, and made recommendations in support of these. This was supported by moderate-quality qualitative evidence that service providers value the different skill sets and knowledge of practitioners from other sectors and opportunities to learn from each other and build expertise. Regular contact among professionals was valued as a way to improve relationships and effective team working. Low-quality evidence also suggested that sharing staff across multiple settings improved knowledge of the child or young person.\n\n## How the recommendations might affect services\n\nCurrently, while training is provided within each sector about support needs presenting across settings (for example, safe eating and drinking, and personal care), this training is not run jointly. Doing so would be a change in practice. Services will have to develop interagency training for practitioners, but this will reduce conflicting advice, encourage all 3\xa0sectors to work together more efficiently, cut out duplication, and potentially reduce training costs to individual services. Funds to provide the training already exist. Services will only need to reprioritise and reorganise their existing training budgets to deliver this. Joint training will enable practitioners to get insight into other professional perspectives, which should ultimately improve the support provided to disabled children and young people with severe complex needs.\n\nOther recommended training already exists (for example, training on the EHC needs assessment process, and recognising social, emotional and mental health needs). However, it is not available everywhere, and the recommendations may represent a change in practice for some services. This training could be provided in various low-cost ways, for example remotely, as pre-recorded sessions. The benefits of these training programmes could be substantial. For example, training to recognise social, emotional and mental health needs should result in those needs being identified sooner, so that earlier, less intensive interventions can be provided. It should also help prevent children and young people from reaching a crisis point that significantly affects their quality of life and is more costly to address.\n\nProviding short-term placements so practitioners can gain experience in a different sector is not widespread current practice. However, it is unlikely to have significant resource implications because employers already have funds set aside for training their workforce, and some of these funds could be used to fund the placements.\n\nChildren, young people and parents and carers are not always involved in the development of awareness training programmes, so this recommendation may represent a change in practice for some services. There may be some additional resources required, such as extra practitioner time, to help them get involved.\n\nReturn to recommendations\n\n# Delegated clinical tasks and feedback\n\nRecommendations 1.15.24 to 1.15.29\n\n## Why the committee made the recommendations\n\nThere was moderate-quality qualitative evidence from both families and service providers that professionals and staff lacked the necessary skills and knowledge to meet the needs of disabled children and young people with severe complex needs.\n\nIn moderate-quality qualitative evidence, families who were delivering interventions reported anxiety about not having enough time to discuss these interventions with professionals and staff and make sure they were doing them properly. The committee directed people to guidance from the relevant professional governance organisations because they provide advice on training and competency in delegated clinical tasks. Separate guidance was made for support workers and parents and family members, to reflect variances in the training, competency and support needs of these groups.\n\nThe committee were confident it was important that children, young people and their families and carers are asked for feedback because they may have different perspectives from practitioners and it is important to get this input to ensure they are getting effective care and support. Processes should be in place for addressing this feedback, so that improvements can be made.\n\n## How the recommendations might affect services\n\nThe recommendations in this area make other guidance more explicit. There are wide variations in practice across the country about how this guidance is understood and implemented, including some poor practice. The recommendations should make practice less variable. They may also prevent a breakdown in interagency working and prevent critical incidents that could have a detrimental effect on children and young people and substantial financial implications for services.\n\nReturn to recommendations\n\n# Interagency teams\n\nRecommendations 1.16.1 to 1.16.5\n\n## Why the committee made the recommendations\n\nThere was very-low-quality quantitative evidence that when practitioners work together as part of an interagency team, rather than working individually, children and young people benefit through increased participation, inclusion and educational achievement. Despite the low quality of the evidence, the committee were confident that working together in a coordinated way across education, health and social care services would improve care and support for children and young people. It is also important to ensure that interagency teams have the right practitioners, with the skills and experience to meet all of the child or young person's needs. Moderate-quality qualitative evidence reflected that a lack of skills, knowledge and training among practitioners was preventing them from working effectively to meet the needs of children and young people.\n\nIn the committee's experience, working relationships between practitioners improve when there is an opportunity to air and resolve disputes. The committee agreed that most services have existing procedures and policies to do this internally, but procedures for resolving interagency disagreements were needed to facilitate the joint integrated working emphasised by this guideline and the legislation.\n\nThere was evidence of an important benefit of a collaborative life skills programme involving an active partnership of parents, teachers and school clinicians in increasing the participation and inclusion, and educational achievement or attainment in disabled children and young people with severe complex needs. This evidence was very low quality so the committee did not recommend this specific intervention. However, they agreed on the importance of collaborative working across education, health and social care services to ensure that the child or young person's needs are accounted for in all settings.\n\nModerate- and high-quality qualitative evidence highlighted practitioners need more training to meet the needs of disabled children and young people with severe complex needs. However, there was limited evidence about what the content of this training should be. In the committee's experience, learning from other practitioners in the interagency team can be a useful way of finding out about the child or young person's needs and possible approaches for meeting those needs. This was consistent with low-quality qualitative evidence that sharing information increases understanding of the child or young person and their needs. There was also moderate-quality qualitative evidence that practitioners value the skills and knowledge of others, and want opportunities to learn from each other and build expertise.\n\nThere was limited evidence, based on the experiences of a traumatic brain injury consulting team, that workshops, inter-professional education and ongoing supervision improved the team's ability to meet the needs of children and young people. However, this approach was not recommended because the evidence was limited in terms of both quality and the population it covered, and it did not report how effective the consulting team were at supporting other practitioners.\n\nIn the committee's experience, individual members of the interagency team often have a wealth of specialist knowledge and information that can be used to improve the care and support provided to disabled children and young people with severe complex needs. The committee felt strongly that this knowledge and information should be shared between members of the interagency team and were confident that doing so would mean they can provide more comprehensive care and support and meet the child or young person's needs more effectively. Based on their experience, they suggested areas of specialist knowledge that could be shared.\n\nModerate-quality qualitative evidence showed that there can be negative relationships between professionals, leading to disagreements. In the committee's experience, interagency teams need the opportunity to air and resolve disputes to improve working relationships guided by policies and procedures that have been created for resolving interagency disagreements.\n\n## How the recommendations might affect services\n\nThere will already be a team of education, health and social care practitioners who are working together with the family to support the child or young person. The recommendation on interagency teams is about formally organising this, so it reinforces current practice. It may mean that interagency teams include a more comprehensive range of practitioners, with the skills and experience to address all the needs of the child or young person.\n\nThe recommendations imply greater sharing of knowledge within existing interagency team meetings. Teams that do not do this will have to set dedicated time at team meetings to discuss changes in practice, legislation or statutory guidance. Interagency teams already have ways of resolving disagreements between different practitioners. Some resources might be needed to agree and formalise these practices.\n\nReturn to recommendations\n\n# Local authorities and health commissioners\n\nRecommendations 1.17.1 to 1.17.8\n\n## Why the committee made the recommendations\n\nThe committee agreed that early intervention and multi-agency involvement will help to identify, assess and address the needs of disabled children and young people with severe complex needs and prevent them reaching crisis point. This was supported by moderate-quality qualitative evidence reporting that services can be slow to provide support until children and young people reach crisis points.\n\nSome disabled children and young people with severe complex needs are cared for in specialist residential placements that may be some distance from their home. The committee agreed that, for some children and young people, this may be the most effective option, because it is difficult to meet their support needs any other way. However, in the committee's experience, long-distance placements are also made for some children and young people because there are no local services available to provide the care they need, or because they do not meet the eligibility criteria for local services. The committee were confident that providing care within their community would be beneficial for children, young people and their families and carers, improving their quality of life and maintaining their family and social relationships. The committee therefore agreed, based on their experience, to recommend exploring all local options before using long-distance placements. They also made a research recommendation to establish the most effective commissioning, practice and service delivery models for enabling children and young people to stay close to home.\n\nIn the committee's experience, it is widespread practice for services to be commissioned and developed based on replicating existing services rather than based on services that meet the needs of the population. This approach does not necessarily consider what the outcomes of such services should be. Specifying outcomes in contracts would lead to services that are better equipped to meet the needs of disabled children and young people with severe complex needs.\n\nIn the committee's experience, services often work in isolation and do not consider the effect that changes in service structure or processes may have on other services involved in the care of disabled children and young people. This can cause delays and gaps in service provision.\n\nThere was moderate-quality qualitative evidence that the services provided often do not meet the needs of children and young people, because of a lack of funding and resources. This is a particular problem for young people over\xa016. There was also moderate-quality qualitative evidence that decisions on transition are left too late, further affecting young people. In the committee's experience, working together to plan how services will be funded and organised once young people turn\xa018 or transfer into adult services would ensure continuity of support and lead to more effective use of limited resources.\n\nThere may be health reasons to limit some specialised services based on diagnosis. However, in general the committee felt strongly that, in line with their understanding of the SEND code of practice, support should be provided based on needs rather than diagnosis. This was supported by moderate-quality qualitative evidence from both families and practitioners suggesting that this would minimise gaps in service provision.\n\nIn the committee's experience, services sometimes deprioritise children and young people on their waiting lists to meet organisational and statutory targets. If the statutory deadline for producing the EHC plan has been missed for a child, they may then be forced to wait even longer, as services prioritise meeting the deadline for other children or young people. Although this allows organisations to meet more statutory deadlines overall, in practice it penalises some children and young people for no practical reason and may exacerbate their needs. The committee were confident that a recommendation was needed to discourage this.\n\nThere was low-quality qualitative evidence of a lack of clear pathways for referral between services. This aligned with the experience of the committee, who felt strongly that the processes for referral needed to be more effective. They were confident that doing this will help practitioners provide effective and coordinated care and support to disabled children and young people with severe complex needs. They made recommendations on how to do this.\n\nThere was some evidence involving parents in steering committees and advisory groups could improve their quality of life. There was also moderate-quality qualitative evidence that using a more flexible approach would be beneficial. A flexible approach is when services work to meet the individual needs of the child or young person, rather than fitting the child or young person within existing rigid service models.\n\nModerate-quality qualitative evidence reported families feeling disillusioned with statutory provisions and seeing little point in requesting help, leading to occasions when they opted out of seeking support. The committee agreed that getting the views of service users on the effectiveness of services could potentially improve statutory provisions and subsequently reduce the disillusionment about current services. This is in line with the committee's understanding of the SEND code of practice, which specifies that children and young people with special educational needs and disabilities and their parents must be engaged in commissioning decisions, so that users' experiences, ambitions and expectations can shape decisions on the services provided. The committee's understanding of the SEND code of practice was also that children and young people with special educational needs and disabilities and their parents must be consulted when reviewing educational and training provision and social care provision.\n\nThe committee's understanding of the SEND code of practice is that services should be commissioned based on the needs of people in that area. However, in their experience the committee has seen the opposite happening, with people being expected to just use services that already exist. The committee made a recommendation to discourage this.\n\nThere was some evidence that dedicated funding for services, joint budgets and having a designated service manager improved parents' satisfaction and quality of life. However, this evidence was very limited and was specifically related to the provision of key workers. There was also insufficient information in the studies on the exact funding and commissioning arrangements. Therefore, the committee recommended further research into the most effective joint commissioning arrangements for disabled children and young people with severe complex needs.\n\n## How the recommendations might affect services\n\nThe recommendations reinforce existing legislation and statutory guidance and would only represent a change in practice for services that are not compliant with these.\n\nCoordinated and joint-working practices are not consistent. Commissioners will have to set up or use existing commissioning frameworks to reinforce joint working and to ensure that children, young people, parents and carers are involved in planning services. In practice, this will mean more practitioner time, more meetings and more communication between education, health and social care services.\n\nEducation, health, and social care services working together in an integrated way will deliver better, more joined-up, holistic services to children and young people with disabilities and severe complex needs to keep them supported within their families and local communities. This will lead to early identification of needs (before they reach a crisis), and reduce the need for expensive, often extended, hospital stays. This may also prevent expensive out-of-area placements. Ultimately, integrated ways of working achieve better outcomes for children and young people with severe complex needs, for example maintaining independence, improving health outcomes and quality of life, and general wellbeing. This would also improve educational outcomes by getting the right support for engaging in learning earlier.\n\nReturn to recommendations\n\n# Coordinating EHC plan process changes with local services, training and short breaks\n\nRecommendations 1.17.9 to 1.17.13\n\n## Why the committee made the recommendations\n\nThere was high-quality qualitative evidence that the paperwork and processes of EHC plans are revised without service providers being given any notice or consultation. The committee agreed that this is a source of inefficiency and frustration, and made recommendations to involve services and commissioners more closely in the process.\n\nThere was moderate-quality qualitative evidence that both service providers and families have trouble understanding the EHC plan process. Services are concerned about their lack of training and knowledge on how to support the development of EHC plans, which potentially leads to discrepancies and a lack of consistency. Local authorities are responsible for the EHC process, so the committee recommended that they provide training on this for practitioners. Producing good-quality EHC plans is crucial to ensuring that disabled children and young people with severe complex needs get the support that they need.\n\nIn the committee's experience, short breaks help parents and carers with the delivery of care by providing respite. This was supported by moderate-quality qualitative evidence. Although the Breaks for Carers of Disabled Children Regulations 2011 requires local authorities to provide short break services, in the committee's experience the range of options can be constrained by the resources currently available in their area. The committee were confident that the most successful and valuable short breaks are those provided in consultation with parents or carers, and tailored to their specific needs. Therefore, they highlighted the requirement in the regulations that a range of short breaks must be provided.\n\nThere is no evidence on the effectiveness of short breaks. So it is not clear which aspects of short breaks are most effective or why children and young people and their families and carers prefer some short breaks over others. The committee agreed that a research recommendation was needed to determine which components of short break services are most effective.\n\n## How the recommendations might affect services\n\nLocal authorities will have to spend more time explaining EHC plan process changes to education, health and social care services. If practitioners understand the process better, this will lead to production of better EHC plans, and ultimately more efficient delivery of services, increased transparency, and more timely care.\n\nTraining on the EHC needs assessment process already exists within most services. This training could be provided in various low-cost ways, for example remotely, as pre-recorded sessions. Such training will reduce conflicting advice and encourage all 3\xa0sectors to work together more efficiently, minimising duplication.\n\nRecommendations on short breaks reiterate the duty under the Breaks for Carers of Disabled Children Regulations 2011.\n\nReturn to recommendations\n\n# What to include in the SEND Local Offer\n\nRecommendations 1.17.14 and 1.17.15\n\n## Why the committee made the recommendations\n\nIn the committee's experience, not everyone knows that the SEND Local Offer provides information about the services and support that are available for disabled children and young people and their families. To prevent inequality in access, they made recommendations about what should be included in the SEND Local Offer.\n\nThe SEND Regulations 2014 specify what information must be included in the SEND Local Offer. A variety of themes from the qualitative evidence highlighted areas where information provision was poor or lacking. The committee used these themes to make recommendations highlighting what local authorities should include in their SEND Local Offer, that were consistent with the regulations and guidance in the SEND code of practice.\n\nThe committee mentioned eligibility criteria used in the EHC needs assessment process in response to low-quality qualitative evidence. This showed that families thought their child had to reach a crisis point before an EHC plan was considered necessary.\n\nIn response to low-quality qualitative evidence that practitioners felt pressure not to apply for an EHC plan because of funding issues, the committee recommended explaining the criteria for an EHC needs assessment.\n\nThere was qualitative evidence that children and young people and their families and carers need more information to understand and access available services. Assistive technology is highlighted because there were specific concerns in the qualitative evidence about the lack of training and knowledge of staff in this area.\n\nThe committee agreed, based on their experience, that details of social activities should be included. This is because social inclusion is as important as care and education for improving the quality of life of disabled children and young people.\n\nProviding details of support to assist with preparation for adulthood and independent living in the SEND Local Offer is a requirement of the SEND Regulations 2014. The SEND code of practice provides guidance on what information about employment should be provided. In the committee's experience, employment may be a daunting prospect for disabled children and young people, but this can be improved when local authorities make the available services clear.\n\nIn line with the Children and Families Act 2014 and SEND Regulations 2014, local authorities must involve children, young people and their parents in planning and reviewing the content of the SEND Local Offer, which gives families the opportunity to say what services they think are needed and raise issues if they are not happy with what is available.\n\n## How the recommendations might affect services\n\nThe information local authorities include in their SEND Local Offers varies, and the recommendations will help reduce this variation. Local authorities that do not currently provide this information may need to spend more time and resources collecting it and including it in the SEND Local Offer.\n\nReturn to recommendations\n\n# Improving how local authorities, commissioners and services work together\n\nRecommendations 1.18.1 to 1.18.6\n\n## Why the committee made the recommendations\n\nThere is a joint commissioning duty in the Children and Families Act 2014, between clinical commissioning groups and local authorities. However, this is only happening in parts of the system. There is no universally established framework at an organisational level to enable joint working across all 3\xa0sectors. Many of the recommendations in this guideline emphasise the need for joint working, but the ability of services to implement these would be limited without a framework being established at an organisational level. The committee noted that the commissioning duty of clinical commissioning groups is being absorbed by integrated care systems and therefore the same duty should apply to the relationship between integrated care systems and local authorities, so they recommended developing a joint commissioning framework.\n\nIn the committee's view, interagency team working will only be effective if there is a formal commitment, setting out how providers and services should work together in an integrated way. The committee were confident that effective interagency team working is of central importance to improving support for disabled children and young people with severe complex needs, and so made recommendations on how to achieve this. Based on their experience, they agreed that the mechanisms to achieve effective integrated working would be for commissioners to specify how services should work together in contract requirements; for senior managers in all services to have processes in place to support interagency team working; and for providers to have agreements setting out how they will work together.\n\nClinical commissioning groups are required to develop and maintain dynamic support registers. However, education and social care services are often not aware of these registers. Dynamic support registers are a useful source of information on children and young people who are likely to need additional support. In turn, this should make it easier to recognise early signs that might lead to a crisis, and enable extra support to prevent unnecessary hospitalisation.\n\n## How the recommendations might affect services\n\nIntegrated care systems are replacing clinical commissioning groups and may need to work collaboratively with local authorities where they are not already doing so, which potentially could have some resource implications. Joint commissioning of services is currently only being done for particular provisions, for example some patient advice and support services, some bespoke packages for post‑16s, and some short breaks. Developing a joint commissioning framework would be a change in practice. Given the integral part local authorities play in the identification, assessment and care pathways for children and young people with disabilities and severe complex needs, joint working (facilitated by a joint commissioning framework) is essential to bring meaningful improvements in the care of these children and young people.\n\nA joint commissioning framework across education, health and social care will enable collaborative working, coordination, consistency and efficiencies for all parties involved. It will enable holistic care and a less fragmented experience. It will also allow practitioners to deliver person-centred care that addresses their needs across the 3\xa0sectors, and ultimately, it will result in better care and support for the person. For example, better joined-up working will lead to early identification of needs (before they reach a crisis). This may prevent expensive out-of-area placements and prolonged hospital stays. It will improve health outcomes because the right care can be started early, avoiding the delays in care that exacerbate problems. This would also improve educational outcomes by getting the right support for engaging in learning earlier.\n\nEducation, health and social care services will have to make their processes more joined-up and coordinated. They may need more joint and collaborative meetings. Commissioners will need to establish frameworks for collaborative and cooperative working.\n\nDynamic support registers are an existing requirement, so there should not be a significant resource implication from this recommendation. There may need to be a change in practice in areas where these are not being used.\n\nReturn to recommendations", 'Context': "It is important that education, health and social care services work together to effectively meet the changing needs of disabled children and young people with severe complex needs. But there are a variety of challenges to doing so.\n\nThe lives of disabled children and young people with severe complex needs can be improved by education, health and social care services that:\n\nare joined-up\n\nare tailored to the needs of the individual child or young person\n\ninvolve children and young people in decisions about their education, health and social care\n\ninvolve families and carers in decisions about their child's education, health and social care\n\nincorporate support for families and carers.\n\nThis guideline focuses on delivering integrated education, health and social care services. It is designed to help local authorities, health commissioners, and education, health and social care providers and practitioners to implement the special educational needs and disability (SEND) code of practice in order to improve outcomes for this group of children and young people and their families and carers.\n\nThe guideline covers disabled children and young people with severe complex needs who:\n\nneed coordinated education, health and social care support because of their severe and complex needs and\n\nare eligible for an education, health and care plan, in line with the Children and Families Act 2014.\n\nThe guideline does not make recommendations specific to particular disabilities or health conditions.\n\nThe guideline includes recommendations on:\n\ninvolving children, young people and their families in their care\n\ncommunication and providing information\n\nplanning and running meetings with children and young people\n\nidentifying needs\n\neducation, health and care (EHC) needs assessment and EHC plans\n\nsupport and training for parents and carers\n\nsocial participation\n\ntransition\n\npalliative and end of life care\n\nenvironmental adaptations\n\nemployment\n\nworking culture\n\ntraining for practitioners\n\nservice organisation\n\njoint working and integrated support\n\njoint commissioning."}	https://www.nice.org.uk/guidance/ng213	This guideline covers support for disabled children and young people with severe complex needs, from birth to 25 years. It aims to encourage education, health and social care services to work together and provide more coordinated support to children and young people, and their families and carers.
229aa04d4b10a65f99f01f173f3eb05a21a7d254	nice	MRI-based technologies for assessing non-alcoholic fatty liver disease	MRI-based technologies for assessing non-alcoholic fatty liver disease Evidence-based recommendations on MRI-based technologies for assessing non-alcoholic fatty liver disease. # Recommendations There is not enough evidence to recommend LiverMultiScan or magnetic resonance elastography (MRE) to assess non-alcoholic fatty liver disease (NAFLD) in people: with indeterminate or discordant results from previous fibrosis testing when transient elastography or acoustic radiation force impulse (ARFI) elastography is unsuitable or has not worked. Further research is recommended (see the section on further research) on: how the test results affect care decisions the test accuracy or prognostic ability of LiverMultiScan the test accuracy or prognostic ability of MRE. Why the committee made these recommendations Assessing what stage NAFLD is at can help to make decisions about care. Sometimes a biopsy is needed, which is invasive and can cause severe complications like bleeding or death. LiverMultiScan and MRE are non-invasive MRI-based tests that aim to assess the stage of NAFLD to help make decisions about care, and reduce biopsy use. LiverMultiScan aims to identify a stage of NAFLD called non-alcoholic steatohepatitis (NASH). It is not clear how diagnosing NASH affects care decisions, partly because there are currently no medicines approved for treating NASH. This may change in the future, because there are medicines for NASH in clinical trials. Also, the clinical evidence on test accuracy and how well it can predict clinical outcomes (prognostic ability) is uncertain. There is only 1 low-quality study on whether using LiverMultiScan can reduce biopsy use. MRE aims to identify how much liver scarring (fibrosis) there is. The company provided thresholds for staging fibrosis. There is no evidence assessing MRE's accuracy using the company's thresholds for advanced fibrosis and cirrhosis. There is also no evidence on how MRE might affect care decisions for the people who would have it in the NHS. The cost effectiveness of the tests is likely to depend on how much they can reduce biopsy use. In the economic model, the tests were cost effective when assuming no biopsy was done after them. But, based on available evidence, clinical experts said they would be unlikely to use the tests without a confirmatory biopsy. When assuming confirmatory biopsy would be done after all positive MRI test results, the cost-effectiveness estimates for LiverMultiScan are higher than what NICE normally considers a cost-effective use of NHS resources. MRE may be cost effective but the estimates are uncertain, largely because the cost of using MRE in the NHS is uncertain. More evidence is needed, particularly on how LiverMultiScan or MRE test results would affect decisions about care. Also, more information is needed about whether MRI-based tests help people make lifestyle choices to help prevent or slow NAFLD progression. So, research is recommended.# The diagnostic tests # Clinical need and practice ## The condition Non-alcoholic fatty liver disease (NAFLD) is the term for a range of conditions caused by a build‑up of fat in the liver. NAFLD develops in 4 stages: simple fatty liver (steatosis): a largely harmless build‑up of fat in the liver cells non-alcoholic steatohepatitis (NASH): build‑up of fat leads to inflammation fibrosis: persistent inflammation causes scar tissue to develop in the liver and nearby blood vessels, but the liver still functions normally cirrhosis: severe scarring from chronic inflammation, causing permanent damage, which can lead to liver failure and liver cancer. ## Diagnosis NAFLD is usually diagnosed using ultrasound. There are several non-invasive tests available to assess the level of fibrosis in NAFLD, including blood-based tests and imaging, such as transient elastography or acoustic radiation force impulse (ARFI) elastography. Specific tests and pathways used vary across the country. NICE's guideline on NAFLD recommends considering using the enhanced liver fibrosis (ELF) test to look for advanced liver fibrosis in people with NAFLD. If the result of the ELF test is 10.51 or above, the NICE guideline for cirrhosis in over 16s recommends testing for cirrhosis using transient or ARFI elastography. Routine liver blood tests are not recommended to rule out NAFLD or test for advanced fibrosis. The British Society of Gastroenterology (BSG) guideline on NAFLD recommends testing for fibrosis in people with NAFLD using the NAFLD fibrosis score or FIB‑4. If these scores indicate an intermediate risk, then transient elastography or the ELF test can be used to further clarify the diagnosis. If the non-invasive tests are not able to exclude advanced fibrosis, BSG recommends that liver biopsy is considered to stage the level of inflammation and fibrosis, and to rule out other concomitant liver disease. Biopsy results are used to decide referral and treatment strategies for people with NAFLD. The NICE guideline for cirrhosis in over 16s recommends that liver biopsy is considered to diagnose cirrhosis when transient elastography is not suitable. NASH is diagnosed using biopsy. However, liver biopsy is an invasive procedure that is associated with well-recognised complications including bleeding and death. NICE's guideline on NAFLD includes a research recommendation to identify which non-invasive tests most accurately identify NASH in people with NAFLD. The British Society of Paediatric Gastroenterology Hepatology and Nutrition guideline on fatty liver recommends that, if available, non-invasive markers of fibrosis should be used to assess NAFLD in children. In certain situations, referral for review at a national paediatric liver unit may be appropriate. Liver biopsy may be done in these units to confirm histological diagnosis or assess for NASH, fibrosis or cirrhosis. ## Management Treatment for NAFLD with no or minimal fibrosis is education on risk factors for advanced fibrosis and advice on weight management. According to NICE's guideline on NAFLD, people with advanced fibrosis may be offered pioglitazone or vitamin E. There are currently no medicines available specifically for NAFLD or NASH, but people with NASH or advanced fibrosis may enter clinical trials for new therapies. The NICE guideline on cirrhosis in over 16s recommends that people with cirrhosis have monitoring for end-stage liver disease and liver cancer every 6 months, have testing for varices, are offered treatment for complications of cirrhosis (for example, variceal band ligation), and potentially are offered prophylactic treatment depending on comorbidities. # The interventions ## LiverMultiScan LiverMultiScan is a standalone software application produced by Perspectum that provides quantitative multiparametric analysis of non-contrast MRI. LiverMultiScan is intended to help clinicians diagnose and stage liver disease by non-invasively imaging the liver. LiverMultiScan uses iron-corrected T1 (cT1), proton density fat fraction (PDFF) and T2- MRI protocols for its analyses. cT1 outputs are measured in milliseconds (ms), and correlate with liver fibro-inflammation. MRI PDFF is an MRI estimate of fat content and is expressed as a percentage. T2- is a measure correlated with the iron content of the liver and is used to produce the cT1 scan. The diagnosis indicated by the cT1 output and the clinical recommendations proposed by the company are as follows: less than 800 ms: fatty liver no inflammation present reassess with MRI in 3 years ms to 875 ms: NASH recommend lifestyle modification manage type 2 diabetes and cardiovascular disease monitor disease status with MRI after 6 months more than 875 ms: high-risk NASH reassess with MRI every 6 months consider liver biopsy if cirrhosis is suspected cancer surveillance consider inclusion in NASH therapeutic trials. ## Magnetic resonance elastography Magnetic resonance elastography (MRE) combines MRI with low-frequency vibrations to create a 2D or 3D elastogram showing the stiffness of tissue. In addition to the usual MRI, an external mechanical driver passes vibrations through a flexible tube to a passive driver placed on a person's abdomen over the liver. The driver is manufactured by Resoundant. MRE is intended to generate acoustic vibrations in the body during an MRI exam to assess tissue elasticity for diagnostic purposes. MRE is used for detecting and evaluating different stages of fibrosis and is usually added to a conventional abdominal MRI protocol. MRE outputs are provided in kilopascals (kPa). The company stated that MRE liver stiffness outputs can be used to stage liver fibrosis as follows: more than 2.9 kPa: any fibrosis more than 3.3 kPa: significant fibrosis more than 3.9 kPa: advanced fibrosis more than 4.8 kPa: cirrhosis.Before the second committee meeting, the company stated that these thresholds were suggestions and that other thresholds could be used depending on intended use. # The comparator ## No further testing before a decision to do a biopsy or any other care decision After testing as described in sections 2.2 to 2.5, in the absence of MRI-based testing, no other tests would be done before a decision to do a biopsy or any other care decision.# Committee discussion The diagnostics advisory committee considered evidence on MRI-based technologies for assessing non-alcoholic fatty liver disease (NAFLD) from several sources, including a diagnostics assessment report and an overview of that report. Full details of all the evidence are in the project documents for this guidance on the NICE website. # Reducing liver biopsies would substantially benefit patients and carers A patient expert explained that liver biopsy has many drawbacks for people with liver disease and their carers. These include the risk of complications, needing to take time off work or education to attend the procedure and for recovery, and the time it takes for biopsy results to be determined and communicated to people and their primary care team. MRI is much less invasive and has fewer associated risks, although some people cannot tolerate MRI scans. MRI may also not be suitable for people with a very high body mass index (BMI) because of the size of the scanner bore. The committee considered evidence from a survey (McKay et al. 2021) that reported that some people found biopsy very uncomfortable and caused psychological stress, but most found MRI to be harmless and tolerable. A patient expert described the impact of having to watch their child have biopsies, and their preference for non-invasive tests. The committee noted that liver biopsy can also have issues such as sampling error (that is, a biopsy can only sample a small part of the liver, which may miss affected areas). Perspectum, the company that manufactures LiverMultiScan, highlighted literature that states that biopsies sample 1/50,000th of the liver. MRI-based testing can image the whole liver. Liver biopsy results also depend on the experience of the pathologist who reports the biopsy and show intra- and inter-operator variability. The committee also noted that the risk of complications from liver biopsy is higher for people with a very high BMI, who are at higher risk of having NAFLD. Clinical experts noted that biopsy use is generally decreasing, but it is still an important option in some situations. At consultation, stakeholders highlighted the increasing prevalence of NAFLD in children, and that any technologies that could improve the non-invasive diagnosis of liver conditions for children would be beneficial. They noted that the risk associated with liver biopsy is greater in children because they take place under general anaesthetic. The committee concluded that technologies that could reduce the need for liver biopsy would be likely to substantially benefit people and carers, in terms of health and impact on their lives. # The impact of a diagnosis of NASH on clinical management is very uncertain Perspectum stated that LiverMultiScan should be used to distinguish non-alcoholic steatohepatitis (NASH) from simple fatty liver (see section 2.9). The committee recognised that the risk of disease progression and adverse outcomes is increased with stage of NAFLD. Clinical experts highlighted that clinical management of NASH (if fibrosis is not detected) is generally the same as for simple fatty liver. They explained that there is currently no difference in the extent of lifestyle-based interventions offered based on stage of liver disease. They emphasised that the level of fibrosis or presence of cirrhosis are the main drivers of decisions about care. A clinical expert commented that if a specialist in secondary care identified a person with NASH but no fibrosis, they would discharge them back to primary care. The company stated that cT1 results are correlated with adverse outcomes in liver disease. It further commented that the potential benefits of NASH detection could be to inform biopsy use, monitoring frequency, treatment options for comorbidities, and the extent of lifestyle advice offered. The external assessment group (EAG) noted that its assessment had modelled the use of MRI to inform biopsy use. Clinical experts commented that the progression of NAFLD can be slow and the impact of more frequent monitoring on earlier detection of disease progression is uncertain. They also highlighted that quality standard recommendations on managing NAFLD from the British Association for the Study of the Liver and the British Society of Gastroenterology NAFLD Special Interest Group state that people with low risk of significant fibrosis should be reassessed in the community every 3 years. The NICE guideline on NAFLD does not include any recommendations for interventions for people with a diagnosis of NASH, although it does include a research recommendation for non-invasive tests for NASH (see section 2.4). The committee acknowledged that new medicines for NASH are currently being developed and used in clinical trials, but these are not routinely used in the NHS. Routine availability of these treatments would likely increase the clinical impact of a NASH diagnosis. The committee concluded that, based on current practice, the impact of a diagnosis of NASH on clinical management is very uncertain. # Introducing MRI for people with NAFLD could have a large impact on radiology capacity The current pathway for NAFLD does not include testing with MRI. The committee noted that introducing routine MRI testing into the care pathway for NAFLD would significantly increase demand on MRI services. Perspectum suggested that the number of people with NAFLD referred for MRI would be low compared with the overall demand for MRI. Radiologist experts highlighted that wait times for MRI scans in the NHS are already long, with services working at full capacity (see section 3.12). Introducing MRI for NAFLD would either increase waiting times for MRI (for all indications, including cancer detection) or need further MRI capacity to be added to the NHS, including more scanners and trained staff, at considerable cost. If recurring scans are needed for monitoring purposes, then this would further add to the impact on MRI services. The committee concluded that greater adoption of MRI testing for NAFLD would have a large impact on the NHS. It further concluded that the benefit of introducing MRI into the NAFLD pathway would have to be very clear to justify the impact on MRI services. # Clinical effectiveness ## No test accuracy evidence was found for MRI when transient or ARFI elastography is unsuitable or has not worked Ultrasound-based tests such as transient elastography and acoustic radiation force impulse (ARFI) elastography are typically done before liver biopsy is considered (see sections 2.2 to 2.5). However, these tests are not suitable for people with a high BMI because they have a high chance of not working, particularly with central obesity. Clinical experts considered that MRI-based tests could have particular benefit for the NHS when transient or ARFI elastography has not worked or is unsuitable. This population was identified as one of interest for this evaluation during scoping. Some studies identified included this population, but diagnostic accuracy data was not reported separately from the general study population. ## There is very little evidence on the impact of MRI-based tests on decisions about care Only 1 study was identified showing the impact of an MRI-based test (LiverMultiScan) on decisions about care, specifically the level of biopsy use (see section 3.6). There was no data on the impact of magnetic resonance elastography (MRE) on decisions about care. Clinical advice to NICE during scoping was that assessment of liver health by MRI-based technologies could help motivate people with NAFLD to engage with lifestyle changes. This could help slow or even reverse progression of liver disease. The committee acknowledged that McKay et al. (2021) provided evidence that LiverMultiScan improved some people's understanding of NAFLD. However, no data was available to determine whether LiverMultiScan or MRE affected people's adherence to lifestyle advice or interventions. Perspectum highlighted that there was evidence from other clinical areas, such as cardiology, that imaging can influence people's lifestyle choices. People with NAFLD are likely to have overweight or obesity and it was unclear to the committee the extent to which information provided by the tests would further incentivise lifestyle changes (for example, losing weight, which could have benefits beyond slowing NAFLD progression). Clinical experts highlighted that how test results affect behaviour is complex, and that they already use some quantitative data, such as weight and BMI, to incentivise lifestyle changes. The EAG highlighted the possibility that negative test results could disincentivise lifestyle changes. A further suggested benefit of MRI-based tests was on decisions about monitoring frequency. The committee recalled that the NAFLD progression can be slow. The impact of more frequent monitoring on earlier detection of disease progression is uncertain (see section 3.2). No data was identified on the impact of the tests on decisions about monitoring frequency or impact of test use on earlier detection of more advanced liver disease. Clinical experts also said that MRI could be used to help with targeting a subsequent biopsy, but no data was found on this use. People with a South Asian family background may have a more centralised distribution of body fat than the wider population, which may increase risk of NAFLD. People with a learning disability or people taking antipsychotics may be more likely to have metabolic disorders leading to NAFLD. The committee noted that the technologies may be particularly beneficial for these groups, but concluded that there was not enough data to support this. ## Direct evidence on the effect of LiverMultiScan on biopsy use is low quality Only RADIcAL1 (a phase 4 open-label randomised controlled trial comparing LiverMultiScan with local standard care in people with suspected NAFLD) gave direct evidence on the impact of MRI-based tests on decisions about care. This trial assessed the number of liver biopsies avoided by using LiverMultiScan. The study was not published, but data was available from a clinical study report provided by the company. The EAG highlighted that the population in RADIcAL1 was broader than the population for this assessment. The committee noted that a relatively small number of people had a liver biopsy (55 out of 802). It further noted that the authors of the study report commented that the low number of people having biopsies was likely because there are no current treatment options for NASH. Therefore, unless the clinician suspects advanced fibrosis, the clinical management will be the same for simple fatty liver or NASH. A lower proportion of people had 'unnecessary' biopsies (defined by the study authors as biopsy with a negative NASH result) in the LiverMultiScan trial arm (9 out of 22; 41%) compared with the standard care arm (16 out of 31; 52%), although this was not statistically significant (EAG calculated odds ratio 0.65, 95% confidence interval 0.22 to 1.96). The committee and EAG noted concerns with the quality of the study, including the low number of people who had biopsy, and the lack of information about previous testing or rationale for deciding to do a biopsy. The committee also noted that there was no information on the number of necessary biopsies that had been missed because of the result of LiverMultiScan (see section 3.10). ## No data for MRE was identified in the scope population, or at the company's specified cut-off values for advanced fibrosis or cirrhosis The EAG's diagnostic test accuracy review included data for people with NAFLD who had not had a diagnosis of advanced fibrosis or cirrhosis. No studies were identified that assessed test accuracy in the exact populations defined during scoping: people who have indeterminate or discordant results from fibrosis testing, or when transient or ARFI elastography has not worked or is unsuitable to assess fibrosis. Clinical experts reiterated that the MRE test was likely to be most useful in populations when non-invasive tests for fibrosis (such as transient elastography) could not be used, for example, because of high BMI. No diagnostic accuracy data for MRE was identified that used MRE to test for advanced fibrosis or cirrhosis using the thresholds defined by the company (3.9 kPa for advanced fibrosis, and 4.8 kPa for cirrhosis). Before the second committee meeting, the company stated that these thresholds were examples, and that other thresholds could be used depending on intended use. The committee concluded that more evidence was needed for MRE in the population of interest, at thresholds defined by the company for significant and advanced fibrosis and cirrhosis (see the section on further research). # Cost effectiveness ## The disutility from missed diagnosis of liver disease is highly uncertain In the EAG's model, liver disease that was missed by using MRI-based tests was assumed to be correctly identified 6 months later. The EAG used a value of 0.03 quality adjusted life years (QALYs) per year for the disutility associated with the liver disease that was initially missed by the tests. This disutility over the 6‑month time horizon of the model had a large effect on the incremental cost-effectiveness ratio (ICER). This was because the QALY losses from false-negative results from MRI testing were often larger than the QALY gains from avoiding liver biopsy. This meant the MRI tests caused a loss of QALYs. The source of the disutility value was taken from NICE's guideline on NAFLD, and was based on the difference in QALYs expected between treated and untreated NASH. The committee and Perspectum questioned the validity of this value. The EAG agreed and explained that it was unable to identify any alternative data to inform this parameter. Clinical experts highlighted that the progression of NAFLD can be slow and is often asymptomatic, and that the disutility accumulated over the short time horizon of the model is likely low. The EAG stated the disutility could be interpreted as a loss of QALYs from delayed diagnosis, which could happen some time after a diagnosis is made. Before the second committee meeting, Perspectum suggested that the QALY loss associated with false-negative results should be 0 because there was no strong evidence to determine the size of the disutility. The EAG stated if missing liver disease has no impact on health-related quality of life, then there would be no value to doing the test. However, it provided scenario analyses in which no disutility associated with missed liver disease was included in the base-case model, and cautioned that this should be considered exploratory analysis. It also highlighted that all ICERs exceeded £100,000 per QALY gained in this analysis. The committee concluded that the disutility associated with a missed diagnosis of liver disease is highly uncertain, but this should not be modelled as 0. ## The model potentially underestimates the costs and impact of more MRI use The EAG's model included costs of doing MRI, but not any costs for changes to NHS infrastructure that may be needed for more MRI use. The EAG commented that the implications for NHS service provision would be significant. This is because of increased staffing levels and changes in infrastructure needed to accommodate the high demand for MRI scans for people with NAFLD. The committee recalled its conclusion that more MRI testing in NAFLD would have a significant impact on demand for MRI. This could mean purchasing more MRI scanners or increased waiting times for MRI scans (see section 3.3). The committee concluded that the true cost of introducing MRI to the care pathway for NAFLD would likely be higher than estimated in the model. ## Based on current data, a biopsy is likely to be done after a positive MRI test result The EAG's base-case model assumed that all people with a positive result from MRI testing would then be referred for a confirmatory biopsy. In comments submitted on the diagnostics assessment report, the companies suggested that a positive test result was sufficient for a diagnosis for some people, and that a confirmatory biopsy was not always necessary. The EAG noted that there was no data to inform any assumption about the effect of a positive MRI test result on the clinical decision to do a biopsy. It explained that, based on clinical advice, it considered it appropriate to assume a confirmatory biopsy would be needed. However, before the second committee meeting, the EAG did a scenario analysis in which no confirmatory biopsy was done after a positive MRI result. In this analysis, LiverMultiScan and MRE dominated (were less expensive and more effective than) the biopsy-only strategy. The EAG cautioned that the costs and QALYs associated with false positives from MRI tests (which would be assumed to be detected if confirmatory biopsy was done) were unknown and not modelled. Also, this assumption did not take into account that biopsies may be done to obtain information other than staging NAFLD. Clinical experts highlighted that biopsy is important for differential diagnosis. For LiverMultiScan, a positive result was stated by the company to distinguish NASH from simple fatty liver (see section 3.2), and not to stage fibrosis. If a test for fibrosis was needed, a biopsy may still be done. There was also limited data on the impact of tests on biopsy use, and the only study identified (RADIcAL1, see section 3.6) found about a 30% decrease in biopsy use, rather than 100% as in the EAG's scenario. Perspectum stated that LiverMultiScan would not entirely replace biopsy but could help identify people who could benefit most from it. Clinical experts commented that current data on test performance was not sufficient to be confident in a diagnosis without a biopsy. The committee concluded that if further data provides reassurance on test performance, a follow‑up biopsy may not always be needed, but it is inappropriate to assume that the tests can replace biopsy entirely. ## How much the tests affect decisions about care for people who do not want a biopsy is unclear Perspectum stated that between 5% (South Warwickshire Foundation Trust) and 50% (feedback from clinicians to company) of people offered liver biopsy decline the procedure. It suggested that MRI could be an appropriate method of staging liver disease in these people. The EAG modelled a scenario in which no biopsy was done in either the intervention or comparator arms (to represent people who would not have a biopsy in current practice). It estimated the number of additional QALYs LiverMultiScan would need to generate to achieve an ICER of £30,000 per QALY gained. The committee noted that it was still unclear for this population what changes to care would be made based on the MRI test results and therefore how the additional QALYs could be generated. ## Time to test is not accounted for in the model Perspectum stated that people can wait up to 18 months for a liver biopsy. It questioned whether this was incorporated in the model, noting that reducing time to testing could be an uncaptured benefit for the MRI-based tests. The EAG confirmed that wait times had not been included in the model. Clinical and patient experts stated that their experience of wait times for liver biopsy were much lower than suggested by the company, between 2 days and 6 months. The committee considered data submitted by Perspectum before the second committee meeting on the average waiting time to a first outpatient appointment, and to treatment, in gastroenterology departments across 7 hospitals, representing the longest waits in the 7 main regions of England. These varied between 19 and 38 weeks. The committee noted that there are currently significant wait times for MRI, although this can vary across the country, and that introducing MRI to the NAFLD care pathway could further increase the wait (see section 3.3). Therefore, it was not appropriate to assume that an MRI test would be done as soon as needed, and any quicker time to test compared with biopsy was very uncertain. A patient expert commented that if confirmatory biopsy was needed after a positive MRI test result (see section 3.10), introducing MRI could also increase the time to diagnosis compared with a pathway in which liver biopsy is done without a preceding MRI test. The EAG commented that it had looked for data on the impact of the MRI tests on time to diagnosis but was unable to find any. The committee concluded that there was no evidence to demonstrate that adding MRI to the NAFLD pathway would reduce time to diagnosis, and while there was the potential for this to be a benefit of testing, the size of any benefit was highly uncertain. The extent of any benefit may depend on what actions could be taken based on MRI tests alone. The extent of impact on QALYs of a quicker diagnosis from testing is also uncertain (see section 3.8). ## The impact of complications from biopsy is uncertain Values used in the EAG's model for the costs and disutility associated with complications from liver biopsy were questioned by stakeholders. Perspectum stated that the cost used for biopsy complications (£8.54 per liver biopsy) was too low and was based on assumptions. It suggested that costs from a recent economic evaluation of LiverMultiScan for people with autoimmune hepatitis (Bajre et al. 2022) would be more appropriate (£168.67 per liver biopsy). The EAG did a threshold analysis that found that the cost of complications would have to increase by more than 10,000% for the ICERs from the base-case model to reach a threshold of £30,000 per QALY gained, if using LiverMultiScan to test for advanced NASH. Perspectum also queried the disutility values assigned to complications from liver biopsy, including those from death. It stated that the QALY loss from biopsy complications used in the model was based on a calculation error from a previous economic analysis (Stevenson et al. 2012), so was underestimated by a factor of 10. The EAG did a scenario analysis using the corrected disutility from biopsy complications, and found that the ICERs remained above £100,000 per QALY gained for all strategies. It also did a threshold analysis that found that the QALY decrement from complications in its base case would have to increase by almost 20,000% to get an ICER of £30,000 per QALY gained if using LiverMultiScan to test for advanced NASH. The committee agreed that the impact of complications from biopsy was uncertain. It concluded that the costs and QALYs would have to change by a large amount from the values used in the EAG's base case for the interventions to be cost effective. ## In the EAG's base case, LiverMultiScan is dominated or has much higher ICERs than are usually considered acceptable Perspectum stated that LiverMultiScan was intended to distinguish NASH from simple fatty liver. So, the committee focused its considerations for LiverMultiScan on the cost-effectiveness estimates provided by the EAG for NASH, advanced NASH, and high risk of progressive disease (defined as NASH or at least F2 fibrosis). In the base case, LiverMultiScan was dominated by the biopsy-only pathway. This was because of the QALY losses incurred by false-negative results, which the committee recalled were very uncertain (see section 3.8). This QALY loss was removed in a scenario analysis, which improved cost effectiveness (the test no longer reduced QALYs). However, the ICERs were above £118,000 per QALY gained. The EAG commented that this scenario is not plausible as it would imply there was no impact of a correct or incorrect diagnosis, and consequently no point to testing. The EAG commented that the cost effectiveness of LiverMultiScan would be above £30,000 per QALY gained even if the test was assumed to have 100% accuracy. Threshold analyses indicated that the population prevalence of the condition being tested for would have to be much lower than found in the study by Eddowes et al. (which was used in the EAG's base case) for LiverMultiScan to be cost effective. The committee noted that the extent of decrease in biopsy use caused by LiverMultiScan use estimated by the model (up to about 30% reduction) was similar to that seen in RADIcAL1. ## MRE could be cost effective, but this is highly dependent on the cost per test Resoundant, the company that manufactures the technology used in MRE, stated that no additional cost per scan would be necessary for MRE if the hardware was already available. The EAG used 2 cost per scan estimates for MRE. The first estimate assumed that MRE was already installed, so the cost of a scan was the only cost of doing an MRI (that is, no additional cost for using MRE). Based on accuracy estimates to detect significant fibrosis (at least F2), MRE dominated the biopsy-only pathway. The second estimate assumed that MRE would need to be installed and added an additional £59.50 per scan on top of the cost of doing an MRI. The EAG noted that this additional cost was uncertain, being based on several assumptions, many of which there was no evidence for. Using this cost, the ICER for detecting significant fibrosis was over £225,000 per QALY gained. Radiology experts in the committee stated that MRE is not widely available in the NHS, so the second cost-effectiveness estimate is more realistic. The EAG did not model MRE to detect advanced fibrosis (at least F3) or cirrhosis because no data was identified using the thresholds the company specified to NICE (see section 3.7). The committee also had concerns that using different costs based on whether or not a test is already available could result in inequality based on geographical location. The committee concluded that the cost of MRE was a significant factor in whether or not the test could be cost effective, and that the true cost was highly uncertain. Further clarification of the cost per person of MRE testing in the NHS would benefit future decision making. ## Test accuracy data for MRE is needed in the scope population The EAG provided cost-effectiveness estimates for MRE using data from Imajo et al. (2021). It highlighted that this population was broader than the scope population, and that a subgroup analysis based on the scope population was not possible. Clinical experts commented that MRE could have a role in the NHS if used when previous tests such as transient or ARFI elastography either could not be done, had not worked, or gave discordant results, in line with the scope population. The committee concluded that data on MRE performance is needed in populations that match the scope, from either subgroup analysis of existing studies, or further accuracy studies. ## Several assumptions in the model need further consideration once more data is available The EAG made several assumptions in its economic model, including that: after an initial negative result from an MRI test (less than 875 ms), a second MRI test would be done at 6 months the second MRI test at 6 months was 100% accurate (that is, no liver disease remains undetected after 6 months). Perspectum commented on the diagnostic assessment report that the pathway used in the model did not reflect its clinical advice for use of LiverMultiScan. It explained that, in line with its advice, people would only have a follow‑up LiverMultiScan if their cT1 score was between 800 ms and 875 ms. People with a score below 800 ms would be discharged to primary care and their condition monitored every 3 years as per local guidance (see section 2.9). The EAG modelled a scenario in which people with LiverMultiScan results less than 800 ms had no further testing. ICERs remained above £200,000 per QALY gained. The EAG also noted that extending the time before a follow‑up test would reduce the cost effectiveness of the MRI-based tests. This is because those with false-negative results from the first test would accrue disutility from undiagnosed liver disease over a longer period (see section 3.8). A stakeholder also questioned the assumption that the second test done at 6 months would be 100% accurate. The EAG acknowledged that this was a simplifying assumption that favoured the MRI-based tests. The committee recalled liver biopsies can have sampling errors (see section 3.1), but that accuracy estimates used in the model were from studies that used liver biopsy as a reference standard. This may be unfavourable towards the MRI tests. The committee concluded that several assumptions used in the model would need reconsidering when more clinical data is available. This would improve the reliability of the cost-effectiveness estimates. ## The EAG's model is suitable for decision making Stakeholders questioned values used in the economic model (see section 3.8, section 3.13 and section 3.17). The EAG acknowledged uncertainty in model inputs. It highlighted that it had done extensive analyses to investigate how much parameters would have to change by for its base-case ICER to become cost effective. Perspectum said that the EAG should have varied uncertain parameters together, rather than one at a time in threshold analyses. The company provided its preferred model parameters for biopsy complications, QALY loss associated with false-negative test results and biopsies. Perspectum ran analyses using these values and no cost for a second MRI scan using LiverMultiScan, based on the company proposing to pay for any follow‑up scans done after an initial negative result. Using Perspectum's preferred inputs, and assuming no cost for a follow‑up scan, LiverMultiScan had ICERs below £30,000 per QALY gained when testing for NASH or advanced NASH. The EAG noted that the cost of complications used came from a 2022 economic evaluation of LiverMultiScan for people with autoimmune hepatitis (see section 3.13), and that the discounted MRI cost did not factor in the general cost of an MRI in the NHS (£148.24 in the EAG's base case). The EAG's threshold analyses showed that the model parameters would have to change in its base case by what the EAG considered an unfeasibly large degree for LiverMultiScan to have an ICER under £30,000 per QALY gained. So, the EAG considered that the conclusions of its analyses were robust to uncertainty in these parameters. The committee agreed and concluded that although there was considerable uncertainty in the model's parameters, the EAG's model and accompanying analyses were suitable for decision making. It also recalled that several assumptions in the model were highly favourable to the MRI tests (see section 3.17). ## More data would help determine LiverMultiScan's accuracy There was limited data on test accuracy, with only 1 small study identified for LiverMultiScan that explicitly included the scope population (Eddowes et al. 2018). Perspectum stated that other relevant biopsy-paired evidence had been submitted and inappropriately excluded by the EAG. The EAG explained that evidence had been excluded because it reported populations that had been used in other studies (that were included in the EAG's report), or were not the focus of the assessment, or did not report validation against liver biopsy (see the diagnostic assessment report, addendum 2). The committee considered that the accuracy estimates used in the EAG's model from the Eddowes study were not particularly high (for example, for advanced NASH, 64% sensitivity and 62% specificity). Unpublished accuracy data from RADIcAL1 was provided by the company at consultation on draft guidance, which reported higher specificity (90%) for advanced NASH. However, this was from only 18 people. The committee considered that further data on test accuracy would be highly beneficial to help estimate true test accuracy. It noted that validation against biopsy may underestimate test performance because of issues with sampling bias (see section 3.1). There may also be issues with getting a biopsy result for a reference standard if this is not clinically indicated, or a person refuses biopsy. Clinical experts noted that LiverMultiScan outputs are correlated with fibro-inflammation (see section 2.9), and cannot provide information on hepatocyte ballooning, one of the histological components of NASH. The committee considered that studies showing how well LiverMultiScan results predicted later clinical events could be used as an alternative to assess test performance. Perspectum stated that such data is becoming available. One study was identified by the EAG for LiverMultiScan (Jayaswal et al. 2021). However, this study included multiple liver disease aetiologies (people with NAFLD, alcohol-related liver disease and viral hepatitis), and the study did not report results for NAFLD separately. The committee concluded that it would be beneficial to see further test accuracy data for LiverMultiScan compared with biopsy, or evidence for LiverMultiScan's prognostic ability for clinical outcomes. ## More data is needed to assess MRE performance at set thresholds No studies were identified using MRE in the scope population (see section 3.7), and no studies assessed MRE using the thresholds that the company stated for advanced fibrosis or cirrhosis. Before the second committee meeting, the company commented that it does not have stated manufacturer cut-offs. The committee concluded that more data on the test accuracy of MRE is needed using prespecified thresholds set by the company, done in a population not used to derive these thresholds (external validation). Data showing prognostic ability for clinical outcomes could be another measure of test performance. ## There is considerable uncertainty about how LiverMultiScan results would affect care in the NHS Clinical experts said it is not clear what care decisions LiverMultiScan results would affect, or how people may adhere to lifestyle advice or interventions based on results. The clinical impact of a NASH diagnosis is uncertain (see section 3.2), and there was little evidence for the effect of LiverMultiScan results on clinical management (see section 3.5). The only available direct evidence for the impact of LiverMultiScan outputs on the number of liver biopsies was of poor quality (see section 3.6). The committee recognised that future approvals of drug treatments for NASH may make the role of LiverMultiScan and NASH diagnosis clearer. Clinical experts also commented that it is unclear how LiverMultiScan can distinguish fibrosis from inflammation (see section 3.19). If this is not possible, a positive result could be because of either fibrosis or inflammation, and it was not clear how the technique could identify NASH alone. Further tests may be needed to make decisions about care. The committee concluded that there is considerable uncertainty about how LiverMultiScan results would affect care in the NHS and how people follow lifestyle advice, and that these are key elements of determining the cost effectiveness of the test. # Research considerations ## Research should represent how the tests would be used in practice and include people who could particularly benefit from testing The committee specified that further research should be in a population representative of how the tests would be used in practice, and should include people who could particularly benefit from testing. It mentioned that MRI-based testing may particularly benefit people with a high BMI for whom other liver tests such as transient elastography may not work as well (see section 3.1). People who would decline an offered biopsy were highlighted by a company as a group who could particularly benefit from access to more non-invasive test options (see section 3.11). Stakeholders noted that the risks of biopsy are higher for children (see section 3.1) and that more non-invasive test options could reduce risk.# Recommendations for further research Further research is recommended on: the impact of LiverMultiScan test results on decisions about care, such as the decision to do a liver biopsy, or on adherence to lifestyle interventions (see section 3.5) the test accuracy of LiverMultiScan compared with biopsy, or the prognostic ability of LiverMultiScan to predict clinical outcomes (see section 3.19). Further research is recommended on: the impact of magnetic resonance elastography (MRE) test results on decisions about care, such as the decision to do a liver biopsy, or on adherence to lifestyle interventions (see section 3.5) the test accuracy of MRE to assess the level of fibrosis or presence of cirrhosis compared with biopsy at thresholds specified by the company, or the prognostic ability of MRE to predict clinical outcomes (see section 3.20).	{'Recommendations': "There is not enough evidence to recommend LiverMultiScan or magnetic resonance elastography (MRE) to assess non-alcoholic fatty liver disease (NAFLD) in people:\n\nwith indeterminate or discordant results from previous fibrosis testing\n\nwhen transient elastography or acoustic radiation force impulse (ARFI) elastography is unsuitable or has not worked.\n\nFurther research is recommended (see the section on further research) on:\n\nhow the test results affect care decisions\n\nthe test accuracy or prognostic ability of LiverMultiScan\n\nthe test accuracy or prognostic ability of MRE.\n\nWhy the committee made these recommendations\n\nAssessing what stage NAFLD is at can help to make decisions about care. Sometimes a biopsy is needed, which is invasive and can cause severe complications like bleeding or death. LiverMultiScan and MRE are non-invasive MRI-based tests that aim to assess the stage of NAFLD to help make decisions about care, and reduce biopsy use.\n\nLiverMultiScan aims to identify a stage of NAFLD called non-alcoholic steatohepatitis (NASH). It is not clear how diagnosing NASH affects care decisions, partly because there are currently no medicines approved for treating NASH. This may change in the future, because there are medicines for NASH in clinical trials. Also, the clinical evidence on test accuracy and how well it can predict clinical outcomes (prognostic ability) is uncertain. There is only 1\xa0low-quality study on whether using LiverMultiScan can reduce biopsy use.\n\nMRE aims to identify how much liver scarring (fibrosis) there is. The company provided thresholds for staging fibrosis. There is no evidence assessing MRE's accuracy using the company's thresholds for advanced fibrosis and cirrhosis. There is also no evidence on how MRE might affect care decisions for the people who would have it in the NHS.\n\nThe cost effectiveness of the tests is likely to depend on how much they can reduce biopsy use. In the economic model, the tests were cost effective when assuming no biopsy was done after them. But, based on available evidence, clinical experts said they would be unlikely to use the tests without a confirmatory biopsy. When assuming confirmatory biopsy would be done after all positive MRI test results, the cost-effectiveness estimates for LiverMultiScan are higher than what NICE normally considers a cost-effective use of NHS resources. MRE may be cost effective but the estimates are uncertain, largely because the cost of using MRE in the NHS is uncertain.\n\nMore evidence is needed, particularly on how LiverMultiScan or MRE test results would affect decisions about care. Also, more information is needed about whether MRI-based tests help people make lifestyle choices to help prevent or slow NAFLD progression. So, research is recommended.", 'The diagnostic tests': "# Clinical need and practice\n\n## The condition\n\nNon-alcoholic fatty liver disease (NAFLD) is the term for a range of conditions caused by a build‑up of fat in the liver. NAFLD develops in 4\xa0stages:\n\nsimple fatty liver (steatosis): a largely harmless build‑up of fat in the liver cells\n\nnon-alcoholic steatohepatitis (NASH): build‑up of fat leads to inflammation\n\nfibrosis: persistent inflammation causes scar tissue to develop in the liver and nearby blood vessels, but the liver still functions normally\n\ncirrhosis: severe scarring from chronic inflammation, causing permanent damage, which can lead to liver failure and liver cancer.\n\n## Diagnosis\n\nNAFLD is usually diagnosed using ultrasound. There are several non-invasive tests available to assess the level of fibrosis in NAFLD, including blood-based tests and imaging, such as transient elastography or acoustic radiation force impulse (ARFI) elastography. Specific tests and pathways used vary across the country.\n\nNICE's guideline on NAFLD recommends considering using the enhanced liver fibrosis (ELF) test to look for advanced liver fibrosis in people with NAFLD. If the result of the ELF test is 10.51 or above, the NICE guideline for cirrhosis in over\xa016s recommends testing for cirrhosis using transient or ARFI elastography. Routine liver blood tests are not recommended to rule out NAFLD or test for advanced fibrosis.\n\nThe British Society of Gastroenterology (BSG) guideline on NAFLD recommends testing for fibrosis in people with NAFLD using the NAFLD fibrosis score or FIB‑4. If these scores indicate an intermediate risk, then transient elastography or the ELF test can be used to further clarify the diagnosis. If the non-invasive tests are not able to exclude advanced fibrosis, BSG recommends that liver biopsy is considered to stage the level of inflammation and fibrosis, and to rule out other concomitant liver disease. Biopsy results are used to decide referral and treatment strategies for people with NAFLD. The NICE guideline for cirrhosis in over\xa016s recommends that liver biopsy is considered to diagnose cirrhosis when transient elastography is not suitable. NASH is diagnosed using biopsy. However, liver biopsy is an invasive procedure that is associated with well-recognised complications including bleeding and death. NICE's guideline on NAFLD includes a research recommendation to identify which non-invasive tests most accurately identify NASH in people with NAFLD.\n\nThe British Society of Paediatric Gastroenterology Hepatology and Nutrition guideline on fatty liver recommends that, if available, non-invasive markers of fibrosis should be used to assess NAFLD in children. In certain situations, referral for review at a national paediatric liver unit may be appropriate. Liver biopsy may be done in these units to confirm histological diagnosis or assess for NASH, fibrosis or cirrhosis.\n\n## Management\n\nTreatment for NAFLD with no or minimal fibrosis is education on risk factors for advanced fibrosis and advice on weight management. According to NICE's guideline on NAFLD, people with advanced fibrosis may be offered pioglitazone or vitamin\xa0E. There are currently no medicines available specifically for NAFLD or NASH, but people with NASH or advanced fibrosis may enter clinical trials for new therapies.\n\nThe NICE guideline on cirrhosis in over\xa016s recommends that people with cirrhosis have monitoring for end-stage liver disease and liver cancer every 6\xa0months, have testing for varices, are offered treatment for complications of cirrhosis (for example, variceal band ligation), and potentially are offered prophylactic treatment depending on comorbidities.\n\n# The interventions\n\n## LiverMultiScan\n\nLiverMultiScan is a standalone software application produced by Perspectum that provides quantitative multiparametric analysis of non-contrast MRI. LiverMultiScan is intended to help clinicians diagnose and stage liver disease by non-invasively imaging the liver.\n\nLiverMultiScan uses iron-corrected T1 (cT1), proton density fat fraction (PDFF) and T2* MRI protocols for its analyses. cT1 outputs are measured in milliseconds (ms), and correlate with liver fibro-inflammation. MRI\xa0PDFF is an MRI estimate of fat content and is expressed as a percentage. T2* is a measure correlated with the iron content of the liver and is used to produce the cT1 scan. The diagnosis indicated by the cT1 output and the clinical recommendations proposed by the company are as follows:\n\nless than 800\xa0ms: fatty liver\n\n\n\nno inflammation present\n\nreassess with MRI in 3\xa0years\n\n\n\nms to 875\xa0ms: NASH\n\n\n\nrecommend lifestyle modification\n\nmanage type\xa02 diabetes and cardiovascular disease\n\nmonitor disease status with MRI after 6\xa0months\n\n\n\nmore than 875\xa0ms: high-risk NASH\n\n\n\nreassess with MRI every 6\xa0months\n\nconsider liver biopsy if cirrhosis is suspected\n\ncancer surveillance\n\nconsider inclusion in NASH therapeutic trials.\n\n\n\n## Magnetic resonance elastography\n\nMagnetic resonance elastography (MRE) combines MRI with low-frequency vibrations to create a 2D or 3D elastogram showing the stiffness of tissue. In addition to the usual MRI, an external mechanical driver passes vibrations through a flexible tube to a passive driver placed on a person's abdomen over the liver. The driver is manufactured by Resoundant. MRE is intended to generate acoustic vibrations in the body during an MRI exam to assess tissue elasticity for diagnostic purposes.\n\nMRE is used for detecting and evaluating different stages of fibrosis and is usually added to a conventional abdominal MRI protocol. MRE outputs are provided in kilopascals (kPa). The company stated that MRE liver stiffness outputs can be used to stage liver fibrosis as follows:\n\nmore than 2.9\xa0kPa: any fibrosis\n\nmore than 3.3\xa0kPa: significant fibrosis\n\nmore than 3.9\xa0kPa: advanced fibrosis\n\nmore than 4.8\xa0kPa: cirrhosis.Before the second committee meeting, the company stated that these thresholds were suggestions and that other thresholds could be used depending on intended use.\n\n# The comparator\n\n## No further testing before a decision to do a biopsy or any other care decision\n\nAfter testing as described in sections\xa02.2 to\xa02.5, in the absence of MRI-based testing, no other tests would be done before a decision to do a biopsy or any other care decision.", 'Committee discussion': "The diagnostics advisory committee considered evidence on MRI-based technologies for assessing non-alcoholic fatty liver disease (NAFLD) from several sources, including a diagnostics assessment report and an overview of that report. Full details of all the evidence are in the project documents for this guidance on the NICE website.\n\n# Reducing liver biopsies would substantially benefit patients and carers\n\nA patient expert explained that liver biopsy has many drawbacks for people with liver disease and their carers. These include the risk of complications, needing to take time off work or education to attend the procedure and for recovery, and the time it takes for biopsy results to be determined and communicated to people and their primary care team. MRI is much less invasive and has fewer associated risks, although some people cannot tolerate MRI scans. MRI may also not be suitable for people with a very high body mass index (BMI) because of the size of the scanner bore. The committee considered evidence from a survey (McKay et al. 2021) that reported that some people found biopsy very uncomfortable and caused psychological stress, but most found MRI to be harmless and tolerable. A patient expert described the impact of having to watch their child have biopsies, and their preference for non-invasive tests. The committee noted that liver biopsy can also have issues such as sampling error (that is, a biopsy can only sample a small part of the liver, which may miss affected areas). Perspectum, the company that manufactures LiverMultiScan, highlighted literature that states that biopsies sample 1/50,000th of the liver. MRI-based testing can image the whole liver. Liver biopsy results also depend on the experience of the pathologist who reports the biopsy and show intra- and inter-operator variability. The committee also noted that the risk of complications from liver biopsy is higher for people with a very high BMI, who are at higher risk of having NAFLD. Clinical experts noted that biopsy use is generally decreasing, but it is still an important option in some situations. At consultation, stakeholders highlighted the increasing prevalence of NAFLD in children, and that any technologies that could improve the non-invasive diagnosis of liver conditions for children would be beneficial. They noted that the risk associated with liver biopsy is greater in children because they take place under general anaesthetic. The committee concluded that technologies that could reduce the need for liver biopsy would be likely to substantially benefit people and carers, in terms of health and impact on their lives.\n\n# The impact of a diagnosis of NASH on clinical management is very uncertain\n\nPerspectum stated that LiverMultiScan should be used to distinguish non-alcoholic steatohepatitis (NASH) from simple fatty liver (see section\xa02.9). The committee recognised that the risk of disease progression and adverse outcomes is increased with stage of NAFLD. Clinical experts highlighted that clinical management of NASH (if fibrosis is not detected) is generally the same as for simple fatty liver. They explained that there is currently no difference in the extent of lifestyle-based interventions offered based on stage of liver disease. They emphasised that the level of fibrosis or presence of cirrhosis are the main drivers of decisions about care. A clinical expert commented that if a specialist in secondary care identified a person with NASH but no fibrosis, they would discharge them back to primary care. The company stated that cT1 results are correlated with adverse outcomes in liver disease. It further commented that the potential benefits of NASH detection could be to inform biopsy use, monitoring frequency, treatment options for comorbidities, and the extent of lifestyle advice offered. The external assessment group (EAG) noted that its assessment had modelled the use of MRI to inform biopsy use. Clinical experts commented that the progression of NAFLD can be slow and the impact of more frequent monitoring on earlier detection of disease progression is uncertain. They also highlighted that quality standard recommendations on managing NAFLD from the British Association for the Study of the Liver and the British Society of Gastroenterology NAFLD Special Interest Group state that people with low risk of significant fibrosis should be reassessed in the community every 3\xa0years. The NICE guideline on NAFLD does not include any recommendations for interventions for people with a diagnosis of NASH, although it does include a research recommendation for non-invasive tests for NASH (see section\xa02.4). The committee acknowledged that new medicines for NASH are currently being developed and used in clinical trials, but these are not routinely used in the NHS. Routine availability of these treatments would likely increase the clinical impact of a NASH diagnosis. The committee concluded that, based on current practice, the impact of a diagnosis of NASH on clinical management is very uncertain.\n\n# Introducing MRI for people with NAFLD could have a large impact on radiology capacity\n\nThe current pathway for NAFLD does not include testing with MRI. The committee noted that introducing routine MRI testing into the care pathway for NAFLD would significantly increase demand on MRI services. Perspectum suggested that the number of people with NAFLD referred for MRI would be low compared with the overall demand for MRI. Radiologist experts highlighted that wait times for MRI scans in the NHS are already long, with services working at full capacity (see section\xa03.12). Introducing MRI for NAFLD would either increase waiting times for MRI (for all indications, including cancer detection) or need further MRI capacity to be added to the NHS, including more scanners and trained staff, at considerable cost. If recurring scans are needed for monitoring purposes, then this would further add to the impact on MRI services. The committee concluded that greater adoption of MRI testing for NAFLD would have a large impact on the NHS. It further concluded that the benefit of introducing MRI into the NAFLD pathway would have to be very clear to justify the impact on MRI services.\n\n# Clinical effectiveness\n\n## No test accuracy evidence was found for MRI when transient or ARFI elastography is unsuitable or has not worked\n\nUltrasound-based tests such as transient elastography and acoustic radiation force impulse (ARFI) elastography are typically done before liver biopsy is considered (see sections\xa02.2 to\xa02.5). However, these tests are not suitable for people with a high BMI because they have a high chance of not working, particularly with central obesity. Clinical experts considered that MRI-based tests could have particular benefit for the NHS when transient or ARFI elastography has not worked or is unsuitable. This population was identified as one of interest for this evaluation during scoping. Some studies identified included this population, but diagnostic accuracy data was not reported separately from the general study population.\n\n## There is very little evidence on the impact of MRI-based tests on decisions about care\n\nOnly 1\xa0study was identified showing the impact of an MRI-based test (LiverMultiScan) on decisions about care, specifically the level of biopsy use (see section\xa03.6). There was no data on the impact of magnetic resonance elastography (MRE) on decisions about care. Clinical advice to NICE during scoping was that assessment of liver health by MRI-based technologies could help motivate people with NAFLD to engage with lifestyle changes. This could help slow or even reverse progression of liver disease. The committee acknowledged that McKay et al. (2021) provided evidence that LiverMultiScan improved some people's understanding of NAFLD. However, no data was available to determine whether LiverMultiScan or MRE affected people's adherence to lifestyle advice or interventions. Perspectum highlighted that there was evidence from other clinical areas, such as cardiology, that imaging can influence people's lifestyle choices. People with NAFLD are likely to have overweight or obesity and it was unclear to the committee the extent to which information provided by the tests would further incentivise lifestyle changes (for example, losing weight, which could have benefits beyond slowing NAFLD progression). Clinical experts highlighted that how test results affect behaviour is complex, and that they already use some quantitative data, such as weight and BMI, to incentivise lifestyle changes. The EAG highlighted the possibility that negative test results could disincentivise lifestyle changes. A further suggested benefit of MRI-based tests was on decisions about monitoring frequency. The committee recalled that the NAFLD progression can be slow. The impact of more frequent monitoring on earlier detection of disease progression is uncertain (see section\xa03.2). No data was identified on the impact of the tests on decisions about monitoring frequency or impact of test use on earlier detection of more advanced liver disease. Clinical experts also said that MRI could be used to help with targeting a subsequent biopsy, but no data was found on this use. People with a South Asian family background may have a more centralised distribution of body fat than the wider population, which may increase risk of NAFLD. People with a learning disability or people taking antipsychotics may be more likely to have metabolic disorders leading to NAFLD. The committee noted that the technologies may be particularly beneficial for these groups, but concluded that there was not enough data to support this.\n\n## Direct evidence on the effect of LiverMultiScan on biopsy use is low quality\n\nOnly RADIcAL1 (a phase\xa04 open-label randomised controlled trial comparing LiverMultiScan [n=403] with local standard care [n=399] in people with suspected NAFLD) gave direct evidence on the impact of MRI-based tests on decisions about care. This trial assessed the number of liver biopsies avoided by using LiverMultiScan. The study was not published, but data was available from a clinical study report provided by the company. The EAG highlighted that the population in RADIcAL1 was broader than the population for this assessment. The committee noted that a relatively small number of people had a liver biopsy (55 out of 802). It further noted that the authors of the study report commented that the low number of people having biopsies was likely because there are no current treatment options for NASH. Therefore, unless the clinician suspects advanced fibrosis, the clinical management will be the same for simple fatty liver or NASH. A lower proportion of people had 'unnecessary' biopsies (defined by the study authors as biopsy with a negative NASH result) in the LiverMultiScan trial arm (9 out of 22; 41%) compared with the standard care arm (16 out of 31; 52%), although this was not statistically significant (EAG calculated odds ratio 0.65, 95% confidence interval 0.22 to 1.96). The committee and EAG noted concerns with the quality of the study, including the low number of people who had biopsy, and the lack of information about previous testing or rationale for deciding to do a biopsy. The committee also noted that there was no information on the number of necessary biopsies that had been missed because of the result of LiverMultiScan (see section\xa03.10).\n\n## No data for MRE was identified in the scope population, or at the company's specified cut-off values for advanced fibrosis or cirrhosis\n\nThe EAG's diagnostic test accuracy review included data for people with NAFLD who had not had a diagnosis of advanced fibrosis or cirrhosis. No studies were identified that assessed test accuracy in the exact populations defined during scoping: people who have indeterminate or discordant results from fibrosis testing, or when transient or ARFI elastography has not worked or is unsuitable to assess fibrosis. Clinical experts reiterated that the MRE test was likely to be most useful in populations when non-invasive tests for fibrosis (such as transient elastography) could not be used, for example, because of high BMI. No diagnostic accuracy data for MRE was identified that used MRE to test for advanced fibrosis or cirrhosis using the thresholds defined by the company (3.9\xa0kPa for advanced fibrosis, and 4.8\xa0kPa for cirrhosis). Before the second committee meeting, the company stated that these thresholds were examples, and that other thresholds could be used depending on intended use. The committee concluded that more evidence was needed for MRE in the population of interest, at thresholds defined by the company for significant and advanced fibrosis and cirrhosis (see the section on further research).\n\n# Cost effectiveness\n\n## The disutility from missed diagnosis of liver disease is highly uncertain\n\nIn the EAG's model, liver disease that was missed by using MRI-based tests was assumed to be correctly identified 6\xa0months later. The EAG used a value of 0.03 quality adjusted life years (QALYs) per year for the disutility associated with the liver disease that was initially missed by the tests. This disutility over the 6‑month time horizon of the model had a large effect on the incremental cost-effectiveness ratio (ICER). This was because the QALY losses from false-negative results from MRI testing were often larger than the QALY gains from avoiding liver biopsy. This meant the MRI tests caused a loss of QALYs. The source of the disutility value was taken from NICE's guideline on NAFLD, and was based on the difference in QALYs expected between treated and untreated NASH. The committee and Perspectum questioned the validity of this value. The EAG agreed and explained that it was unable to identify any alternative data to inform this parameter. Clinical experts highlighted that the progression of NAFLD can be slow and is often asymptomatic, and that the disutility accumulated over the short time horizon of the model is likely low. The EAG stated the disutility could be interpreted as a loss of QALYs from delayed diagnosis, which could happen some time after a diagnosis is made. Before the second committee meeting, Perspectum suggested that the QALY loss associated with false-negative results should be\xa00 because there was no strong evidence to determine the size of the disutility. The EAG stated if missing liver disease has no impact on health-related quality of life, then there would be no value to doing the test. However, it provided scenario analyses in which no disutility associated with missed liver disease was included in the base-case model, and cautioned that this should be considered exploratory analysis. It also highlighted that all ICERs exceeded £100,000 per QALY gained in this analysis. The committee concluded that the disutility associated with a missed diagnosis of liver disease is highly uncertain, but this should not be modelled as\xa00.\n\n## The model potentially underestimates the costs and impact of more MRI use\n\nThe EAG's model included costs of doing MRI, but not any costs for changes to NHS infrastructure that may be needed for more MRI use. The EAG commented that the implications for NHS service provision would be significant. This is because of increased staffing levels and changes in infrastructure needed to accommodate the high demand for MRI scans for people with NAFLD. The committee recalled its conclusion that more MRI testing in NAFLD would have a significant impact on demand for MRI. This could mean purchasing more MRI scanners or increased waiting times for MRI scans (see section\xa03.3). The committee concluded that the true cost of introducing MRI to the care pathway for NAFLD would likely be higher than estimated in the model.\n\n## Based on current data, a biopsy is likely to be done after a positive MRI test result\n\nThe EAG's base-case model assumed that all people with a positive result from MRI testing would then be referred for a confirmatory biopsy. In comments submitted on the diagnostics assessment report, the companies suggested that a positive test result was sufficient for a diagnosis for some people, and that a confirmatory biopsy was not always necessary. The EAG noted that there was no data to inform any assumption about the effect of a positive MRI test result on the clinical decision to do a biopsy. It explained that, based on clinical advice, it considered it appropriate to assume a confirmatory biopsy would be needed. However, before the second committee meeting, the EAG did a scenario analysis in which no confirmatory biopsy was done after a positive MRI result. In this analysis, LiverMultiScan and MRE dominated (were less expensive and more effective than) the biopsy-only strategy. The EAG cautioned that the costs and QALYs associated with false positives from MRI tests (which would be assumed to be detected if confirmatory biopsy was done) were unknown and not modelled. Also, this assumption did not take into account that biopsies may be done to obtain information other than staging NAFLD. Clinical experts highlighted that biopsy is important for differential diagnosis. For LiverMultiScan, a positive result was stated by the company to distinguish NASH from simple fatty liver (see section\xa03.2), and not to stage fibrosis. If a test for fibrosis was needed, a biopsy may still be done. There was also limited data on the impact of tests on biopsy use, and the only study identified (RADIcAL1, see section\xa03.6) found about a 30% decrease in biopsy use, rather than 100% as in the EAG's scenario. Perspectum stated that LiverMultiScan would not entirely replace biopsy but could help identify people who could benefit most from it. Clinical experts commented that current data on test performance was not sufficient to be confident in a diagnosis without a biopsy. The committee concluded that if further data provides reassurance on test performance, a follow‑up biopsy may not always be needed, but it is inappropriate to assume that the tests can replace biopsy entirely.\n\n## How much the tests affect decisions about care for people who do not want a biopsy is unclear\n\nPerspectum stated that between 5% (South Warwickshire Foundation Trust) and 50% (feedback from clinicians to company) of people offered liver biopsy decline the procedure. It suggested that MRI could be an appropriate method of staging liver disease in these people. The EAG modelled a scenario in which no biopsy was done in either the intervention or comparator arms (to represent people who would not have a biopsy in current practice). It estimated the number of additional QALYs LiverMultiScan would need to generate to achieve an ICER of £30,000 per QALY gained. The committee noted that it was still unclear for this population what changes to care would be made based on the MRI test results and therefore how the additional QALYs could be generated.\n\n## Time to test is not accounted for in the model\n\nPerspectum stated that people can wait up to 18\xa0months for a liver biopsy. It questioned whether this was incorporated in the model, noting that reducing time to testing could be an uncaptured benefit for the MRI-based tests. The EAG confirmed that wait times had not been included in the model. Clinical and patient experts stated that their experience of wait times for liver biopsy were much lower than suggested by the company, between 2\xa0days and 6\xa0months. The committee considered data submitted by Perspectum before the second committee meeting on the average waiting time to a first outpatient appointment, and to treatment, in gastroenterology departments across 7\xa0hospitals, representing the longest waits in the 7\xa0main regions of England. These varied between 19\xa0and 38\xa0weeks. The committee noted that there are currently significant wait times for MRI, although this can vary across the country, and that introducing MRI to the NAFLD care pathway could further increase the wait (see section\xa03.3). Therefore, it was not appropriate to assume that an MRI test would be done as soon as needed, and any quicker time to test compared with biopsy was very uncertain. A patient expert commented that if confirmatory biopsy was needed after a positive MRI test result (see section\xa03.10), introducing MRI could also increase the time to diagnosis compared with a pathway in which liver biopsy is done without a preceding MRI test. The EAG commented that it had looked for data on the impact of the MRI tests on time to diagnosis but was unable to find any. The committee concluded that there was no evidence to demonstrate that adding MRI to the NAFLD pathway would reduce time to diagnosis, and while there was the potential for this to be a benefit of testing, the size of any benefit was highly uncertain. The extent of any benefit may depend on what actions could be taken based on MRI tests alone. The extent of impact on QALYs of a quicker diagnosis from testing is also uncertain (see section\xa03.8).\n\n## The impact of complications from biopsy is uncertain\n\nValues used in the EAG's model for the costs and disutility associated with complications from liver biopsy were questioned by stakeholders. Perspectum stated that the cost used for biopsy complications (£8.54 per liver biopsy) was too low and was based on assumptions. It suggested that costs from a recent economic evaluation of LiverMultiScan for people with autoimmune hepatitis (Bajre et al. 2022) would be more appropriate (£168.67 per liver biopsy). The EAG did a threshold analysis that found that the cost of complications would have to increase by more than 10,000% for the ICERs from the base-case model to reach a threshold of £30,000 per QALY gained, if using LiverMultiScan to test for advanced NASH. Perspectum also queried the disutility values assigned to complications from liver biopsy, including those from death. It stated that the QALY loss from biopsy complications used in the model was based on a calculation error from a previous economic analysis (Stevenson et al. 2012), so was underestimated by a factor of 10. The EAG did a scenario analysis using the corrected disutility from biopsy complications, and found that the ICERs remained above £100,000 per QALY gained for all strategies. It also did a threshold analysis that found that the QALY decrement from complications in its base case would have to increase by almost 20,000% to get an ICER of £30,000 per QALY gained if using LiverMultiScan to test for advanced NASH. The committee agreed that the impact of complications from biopsy was uncertain. It concluded that the costs and QALYs would have to change by a large amount from the values used in the EAG's base case for the interventions to be cost effective.\n\n## In the EAG's base case, LiverMultiScan is dominated or has much higher ICERs than are usually considered acceptable\n\nPerspectum stated that LiverMultiScan was intended to distinguish NASH from simple fatty liver. So, the committee focused its considerations for LiverMultiScan on the cost-effectiveness estimates provided by the EAG for NASH, advanced NASH, and high risk of progressive disease (defined as NASH or at least F2 fibrosis). In the base case, LiverMultiScan was dominated by the biopsy-only pathway. This was because of the QALY losses incurred by false-negative results, which the committee recalled were very uncertain (see section\xa03.8). This QALY loss was removed in a scenario analysis, which improved cost effectiveness (the test no longer reduced QALYs). However, the ICERs were above £118,000 per QALY gained. The EAG commented that this scenario is not plausible as it would imply there was no impact of a correct or incorrect diagnosis, and consequently no point to testing. The EAG commented that the cost effectiveness of LiverMultiScan would be above £30,000 per QALY gained even if the test was assumed to have 100% accuracy. Threshold analyses indicated that the population prevalence of the condition being tested for would have to be much lower than found in the study by Eddowes et al. (which was used in the EAG's base case) for LiverMultiScan to be cost effective. The committee noted that the extent of decrease in biopsy use caused by LiverMultiScan use estimated by the model (up to about 30% reduction) was similar to that seen in RADIcAL1.\n\n## MRE could be cost effective, but this is highly dependent on the cost per test\n\nResoundant, the company that manufactures the technology used in MRE, stated that no additional cost per scan would be necessary for MRE if the hardware was already available. The EAG used 2\xa0cost per scan estimates for MRE. The first estimate assumed that MRE was already installed, so the cost of a scan was the only cost of doing an MRI (that is, no additional cost for using MRE). Based on accuracy estimates to detect significant fibrosis (at least F2), MRE dominated the biopsy-only pathway. The second estimate assumed that MRE would need to be installed and added an additional £59.50 per scan on top of the cost of doing an MRI. The EAG noted that this additional cost was uncertain, being based on several assumptions, many of which there was no evidence for. Using this cost, the ICER for detecting significant fibrosis was over £225,000 per QALY gained. Radiology experts in the committee stated that MRE is not widely available in the NHS, so the second cost-effectiveness estimate is more realistic. The EAG did not model MRE to detect advanced fibrosis (at least F3) or cirrhosis because no data was identified using the thresholds the company specified to NICE (see section\xa03.7). The committee also had concerns that using different costs based on whether or not a test is already available could result in inequality based on geographical location. The committee concluded that the cost of MRE was a significant factor in whether or not the test could be cost effective, and that the true cost was highly uncertain. Further clarification of the cost per person of MRE testing in the NHS would benefit future decision making.\n\n## Test accuracy data for MRE is needed in the scope population\n\nThe EAG provided cost-effectiveness estimates for MRE using data from Imajo et al. (2021). It highlighted that this population was broader than the scope population, and that a subgroup analysis based on the scope population was not possible. Clinical experts commented that MRE could have a role in the NHS if used when previous tests such as transient or ARFI elastography either could not be done, had not worked, or gave discordant results, in line with the scope population. The committee concluded that data on MRE performance is needed in populations that match the scope, from either subgroup analysis of existing studies, or further accuracy studies.\n\n## Several assumptions in the model need further consideration once more data is available\n\nThe EAG made several assumptions in its economic model, including that:\n\nafter an initial negative result from an MRI test (less than 875\xa0ms), a second MRI test would be done at 6\xa0months\n\nthe second MRI test at 6\xa0months was 100% accurate (that is, no liver disease remains undetected after 6\xa0months). Perspectum commented on the diagnostic assessment report that the pathway used in the model did not reflect its clinical advice for use of LiverMultiScan. It explained that, in line with its advice, people would only have a follow‑up LiverMultiScan if their cT1 score was between 800\xa0ms and 875\xa0ms. People with a score below 800\xa0ms would be discharged to primary care and their condition monitored every 3\xa0years as per local guidance (see section\xa02.9). The EAG modelled a scenario in which people with LiverMultiScan results less than 800\xa0ms had no further testing. ICERs remained above £200,000 per QALY gained. The EAG also noted that extending the time before a follow‑up test would reduce the cost effectiveness of the MRI-based tests. This is because those with false-negative results from the first test would accrue disutility from undiagnosed liver disease over a longer period (see section\xa03.8). A stakeholder also questioned the assumption that the second test done at 6\xa0months would be 100% accurate. The EAG acknowledged that this was a simplifying assumption that favoured the MRI-based tests. The committee recalled liver biopsies can have sampling errors (see section\xa03.1), but that accuracy estimates used in the model were from studies that used liver biopsy as a reference standard. This may be unfavourable towards the MRI tests. The committee concluded that several assumptions used in the model would need reconsidering when more clinical data is available. This would improve the reliability of the cost-effectiveness estimates.\n\n## The EAG's model is suitable for decision making\n\nStakeholders questioned values used in the economic model (see section\xa03.8, section\xa03.13 and section\xa03.17). The EAG acknowledged uncertainty in model inputs. It highlighted that it had done extensive analyses to investigate how much parameters would have to change by for its base-case ICER to become cost effective. Perspectum said that the EAG should have varied uncertain parameters together, rather than one at a time in threshold analyses. The company provided its preferred model parameters for biopsy complications, QALY loss associated with false-negative test results and biopsies. Perspectum ran analyses using these values and no cost for a second MRI scan using LiverMultiScan, based on the company proposing to pay for any follow‑up scans done after an initial negative result. Using Perspectum's preferred inputs, and assuming no cost for a follow‑up scan, LiverMultiScan had ICERs below £30,000 per QALY gained when testing for NASH or advanced NASH. The EAG noted that the cost of complications used came from a 2022 economic evaluation of LiverMultiScan for people with autoimmune hepatitis (see section\xa03.13), and that the discounted MRI cost did not factor in the general cost of an MRI in the NHS (£148.24 in the EAG's base case). The EAG's threshold analyses showed that the model parameters would have to change in its base case by what the EAG considered an unfeasibly large degree for LiverMultiScan to have an ICER under £30,000 per QALY gained. So, the EAG considered that the conclusions of its analyses were robust to uncertainty in these parameters. The committee agreed and concluded that although there was considerable uncertainty in the model's parameters, the EAG's model and accompanying analyses were suitable for decision making. It also recalled that several assumptions in the model were highly favourable to the MRI tests (see section\xa03.17).\n\n## More data would help determine LiverMultiScan's accuracy\n\nThere was limited data on test accuracy, with only 1\xa0small study identified for LiverMultiScan that explicitly included the scope population (Eddowes et al. 2018). Perspectum stated that other relevant biopsy-paired evidence had been submitted and inappropriately excluded by the EAG. The EAG explained that evidence had been excluded because it reported populations that had been used in other studies (that were included in the EAG's report), or were not the focus of the assessment, or did not report validation against liver biopsy (see the diagnostic assessment report, addendum\xa02). The committee considered that the accuracy estimates used in the EAG's model from the Eddowes study were not particularly high (for example, for advanced NASH, 64% sensitivity and 62% specificity). Unpublished accuracy data from RADIcAL1 was provided by the company at consultation on draft guidance, which reported higher specificity (90%) for advanced NASH. However, this was from only 18\xa0people. The committee considered that further data on test accuracy would be highly beneficial to help estimate true test accuracy. It noted that validation against biopsy may underestimate test performance because of issues with sampling bias (see section\xa03.1). There may also be issues with getting a biopsy result for a reference standard if this is not clinically indicated, or a person refuses biopsy. Clinical experts noted that LiverMultiScan outputs are correlated with fibro-inflammation (see section\xa02.9), and cannot provide information on hepatocyte ballooning, one of the histological components of NASH. The committee considered that studies showing how well LiverMultiScan results predicted later clinical events could be used as an alternative to assess test performance. Perspectum stated that such data is becoming available. One study was identified by the EAG for LiverMultiScan (Jayaswal et al. 2021). However, this study included multiple liver disease aetiologies (people with NAFLD, alcohol-related liver disease and viral hepatitis), and the study did not report results for NAFLD separately. The committee concluded that it would be beneficial to see further test accuracy data for LiverMultiScan compared with biopsy, or evidence for LiverMultiScan's prognostic ability for clinical outcomes.\n\n## More data is needed to assess MRE performance at set thresholds\n\nNo studies were identified using MRE in the scope population (see section\xa03.7), and no studies assessed MRE using the thresholds that the company stated for advanced fibrosis or cirrhosis. Before the second committee meeting, the company commented that it does not have stated manufacturer cut-offs. The committee concluded that more data on the test accuracy of MRE is needed using prespecified thresholds set by the company, done in a population not used to derive these thresholds (external validation). Data showing prognostic ability for clinical outcomes could be another measure of test performance.\n\n## There is considerable uncertainty about how LiverMultiScan results would affect care in the NHS\n\nClinical experts said it is not clear what care decisions LiverMultiScan results would affect, or how people may adhere to lifestyle advice or interventions based on results. The clinical impact of a NASH diagnosis is uncertain (see section\xa03.2), and there was little evidence for the effect of LiverMultiScan results on clinical management (see section\xa03.5). The only available direct evidence for the impact of LiverMultiScan outputs on the number of liver biopsies was of poor quality (see section\xa03.6). The committee recognised that future approvals of drug treatments for NASH may make the role of LiverMultiScan and NASH diagnosis clearer. Clinical experts also commented that it is unclear how LiverMultiScan can distinguish fibrosis from inflammation (see section\xa03.19). If this is not possible, a positive result could be because of either fibrosis or inflammation, and it was not clear how the technique could identify NASH alone. Further tests may be needed to make decisions about care. The committee concluded that there is considerable uncertainty about how LiverMultiScan results would affect care in the NHS and how people follow lifestyle advice, and that these are key elements of determining the cost effectiveness of the test.\n\n# Research considerations\n\n## Research should represent how the tests would be used in practice and include people who could particularly benefit from testing\n\nThe committee specified that further research should be in a population representative of how the tests would be used in practice, and should include people who could particularly benefit from testing. It mentioned that MRI-based testing may particularly benefit people with a high BMI for whom other liver tests such as transient elastography may not work as well (see section\xa03.1). People who would decline an offered biopsy were highlighted by a company as a group who could particularly benefit from access to more non-invasive test options (see section\xa03.11). Stakeholders noted that the risks of biopsy are higher for children (see section\xa03.1) and that more non-invasive test options could reduce risk.", 'Recommendations for further research': 'Further research is recommended on:\n\nthe impact of LiverMultiScan test results on decisions about care, such as the decision to do a liver biopsy, or on adherence to lifestyle interventions (see section\xa03.5)\n\nthe test accuracy of LiverMultiScan compared with biopsy, or the prognostic ability of LiverMultiScan to predict clinical outcomes (see section\xa03.19).\n\nFurther research is recommended on:\n\nthe impact of magnetic resonance elastography (MRE) test results on decisions about care, such as the decision to do a liver biopsy, or on adherence to lifestyle interventions (see section\xa03.5)\n\nthe test accuracy of MRE to assess the level of fibrosis or presence of cirrhosis compared with biopsy at thresholds specified by the company, or the prognostic ability of MRE to predict clinical outcomes (see section\xa03.20).'}	https://www.nice.org.uk/guidance/dg50	Evidence-based recommendations on MRI-based technologies for assessing non-alcoholic fatty liver disease.
1c0940d34e3428c25cf0c87d23bec69ff1a15559	nice	Nivolumab with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma	Nivolumab with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma Evidence-based recommendations on nivolumab (Opdivo) with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in adults. # Recommendations Nivolumab with platinum- and fluoropyrimidine-based chemotherapy is recommended, within its marketing authorisation, as an option for untreated HER2‑negative, advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 5 or more. Nivolumab is only recommended if the company provides it according to the commercial arrangement. Why the committee made these recommendations There are no curative treatment options for HER2‑negative, advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma that expresses PD‑L1 with a CPS of 5 or more. The usual treatment is palliative chemotherapy. Most people have platinum- and fluoropyrimidine-based chemotherapy with capecitabine plus oxaliplatin (XELOX) or fluorouracil plus oxaliplatin with folinic acid (FOLFOX). Clinical trial evidence shows that nivolumab plus XELOX or FOLFOX increases the length of time before gastric, gastro-oesophageal junction or oesophageal adenocarcinoma gets worse compared with XELOX or FOLFOX alone. Evidence also shows that people live longer if they have nivolumab plus XELOX or FOLFOX compared with XELOX or FOLFOX alone. But, it is uncertain how long people lived beyond the trial period and for how long nivolumab's benefit lasted. People with these conditions on average have a short life expectancy, so nivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates for nivolumab are within what NICE considers an acceptable use of NHS resources. So, nivolumab with platinum- and fluoropyrimidine-based chemotherapy is recommended.# Information about nivolumab # Marketing authorisation indication Nivolumab (Opdivo, Bristol Myers Squibb) is indicated for use 'in combination with fluoropyrimidine- and platinum-based combination chemotherapy for the first-line treatment of adult patients with HER2‑negative advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours express PD‑L1 with a combined positive score (CPS) ≥ 5'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for nivolumab. # Price The list price of nivolumab is £439 per 40 mg/4 ml concentrate for solution for infusion vial; £1,097 per 100 mg/10 ml concentrate for solution for infusion vial; and £2,633 per 240 mg/24 ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed July 2022). The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence. # The condition ## Gastric, gastro-oesophageal junction and oesophageal adenocarcinoma have a poor prognosis and a large impact on quality of life The patient experts explained that gastric, gastro-oesophageal junction and oesophageal adenocarcinoma significantly impact quality of life. They explained that major symptoms include difficulty swallowing and malnutrition, which can lead to severe fatigue, weight loss and the need to use a feeding tube. These symptoms can be painful and distressing, limiting people's ability to live normally and participate in social events. Diagnosis is often at an advanced stage, and around 40% of all new cases are diagnosed in people aged 75 and over. Gastric, gastro-oesophageal junction and oesophageal adenocarcinoma are more common in men than women, although the patient experts report that increasing numbers of younger people and women are being diagnosed. The committee concluded that advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma have a poor prognosis and a large impact on quality of life. ## People would welcome a new treatment option The patient and clinical experts explained that there are no curative treatment options for untreated HER2‑negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma. Standard first-line treatment for people with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and no significant comorbidities is palliative chemotherapy. NICE's guideline on oesophago-gastric cancer: assessment and management in adults recommends dual therapy with fluorouracil or capecitabine plus cisplatin or oxaliplatin, or triple therapy with epirubicin. The clinical experts explained that dual therapy regimens are preferred and that most people would have capecitabine and oxaliplatin (XELOX). This is because oxaliplatin is better tolerated than cisplatin and has a shorter infusion time. Some people may be offered fluorouracil with oxaliplatin and folinic acid (FOLFOX). People having FOLFOX treatment need more hospital visits (every 2 weeks) than people having XELOX (every 3 weeks). The patient and clinical experts agreed that there is unmet clinical need in this population. Nivolumab is an immunotherapy and has a different mechanism of action to chemotherapy. NICE's technology appraisal guidance recommends pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced oesophageal and gastro-oesophageal junction cancer in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more. The committee noted that some people would be eligible for nivolumab plus chemotherapy but not pembrolizumab plus chemotherapy. As a result, there remains an unmet need in people with gastric cancer and a CPS of between 5 and 10 who cannot have pembrolizumab. The committee concluded that patients and clinicians would welcome a new treatment for untreated HER2‑negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma. ## XELOX is the key comparator for this appraisal The company suggested that XELOX and FOLFOX were the relevant comparators for this appraisal. The evidence review group (ERG) agreed with this approach and noted that most people would have XELOX because it is more convenient and cheaper than FOLFOX. Clinical experts also confirmed the company's approach and noted that dual chemotherapy regimens have similar efficacy. The committee concluded that XELOX was the key comparator for this appraisal. # Clinical evidence ## Nivolumab plus chemotherapy improves progression-free survival and overall survival compared with chemotherapy alone CheckMate 649 (n=1,581) was an open-label randomised multicentre trial (including 38 patients from 5 UK centres) that compared nivolumab plus XELOX or FOLFOX with XELOX or FOLFOX alone. It included people with untreated and unresectable, advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma who had an ECOG performance status of 0 to 1. People with known HER2‑positive status and untreated central nervous system metastases were excluded from the study. The average age in the trial was 60.1 years. The primary outcomes were progression-free survival and overall survival in people whose tumours express PD‑L1 with a CPS of 5 or more (n=955). Results from the latest data cut were based on a minimum follow-up of 24 months and showed that: nivolumab plus chemotherapy improved progression‑free survival compared with chemotherapy alone (hazard ratio 0.70, 95% confidence interval 0.60 to 0.81) nivolumab plus chemotherapy improved overall survival compared with chemotherapy alone (HR 0.70, 95% CI 0.61 to 0.81).The committee noted that this data was mature (meaning that more than half the trial population had disease progression or died during the follow-up period). The committee concluded that adding nivolumab to platinum- and fluoropyrimidine-based combination chemotherapy improved progression-free survival and overall survival compared with chemotherapy alone. ## CheckMate 649 data is generalisable to NHS clinical practice In the first committee meeting, the ERG heard clinical advice suggesting that the trial population, with a mean age of 60.1 years and ECOG performance status of 0 to 1 (see section 3.4), was younger and fitter than the population seen in NHS clinical practice. The ERG thought the best available estimates were that people seen in the NHS with advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma had an average age between 64 and 66 (Cancer Research UK and Royal Marsden Hospital Trust data). The clinical experts explained that the average age of the trial population is expected to be younger than that of people seen in the NHS with these conditions. They agreed there is no evidence that treatment would be less effective in older people and stated that treatment should be based on patient fitness and comorbidities, regardless of age and performance status. The company noted that the trial age is aligned with UK data sources and that there is limited evidence to suggest outcomes differ between ECOG performance status scores. The committee concluded that CheckMate 649 data is generalisable to NHS clinical practice. # Long-term remission and cure ## Some people may have long-term remission, but their life expectancy may be shorter than the general population The company considered that evidence from CheckMate 649 suggested that the hazard of progression or death in people whose disease had not yet progressed decreases over time and plateaus at 30 months. The company proposed that people who had no disease progression 30 months or more after starting treatment were in 'long-term remission'. The company's estimates of the risk of dying in people with long-term remission were the same as the general population. The ERG noted that this meant the company assumed that people whose cancer had not progressed by 30 months after starting treatment were cured and had the same lifespan as the general population. The company considered that other evidence showing long-term survival in some people supports this assumption, for example, COUGAR‑02, ATTRACTION‑2, Chau 2009 and Royal Marsden Hospital Trust data. The ERG considered that none of the long-term evidence supported the cure assumption. The number of people in CheckMate 649 at 30 months was too low for conclusions about cure to be made. The clinical experts agreed that long-term data supporting a cure assumption does not exist. However, the clinical and patient experts explained that long-term survival is likely for some people because this has been seen with other immunotherapy treatments. The clinical expert said that about 4% of people could be expected to achieve long-term remission with chemotherapy and that they expect nivolumab could double the number to 8%. The NHS clinical lead noted that disease in long-term remission can relapse, but this is uncommon. The clinical experts said that people in long-term remission have a low burden of disease and their quality of life is good. However, their fitness is unlikely to return to pre-treatment levels because of long-term toxicities with chemotherapy, such as irreversible neuropathy. They expected the mortality rate in people with long-term remission to be higher than that of the general population because they previously had advanced cancer and cytotoxic chemotherapy. The committee concluded that some people are likely to have long-term remission, but it was unclear if they were cured. The committee further concluded that people in whom disease did not recur would still be expected to have a shorter life expectancy than people who have not had this type of advanced cancer and chemotherapy. # The company's economic model ## The company's updated model is suitable for decision making In the first committee meeting, the company used a cohort-based semi-Markov model with 4 states: pre-progression, progressed disease, long-term remission, and death. All people in the pre-progression state at 30 months entered the long-term remission state and were assumed to have the same risk of dying as the general population and were assumed to be effectively cured (see section 3.6). The ERG explained that the company's model was unnecessarily complicated and differed from the 3‑state partitioned survival models often used in NICE appraisals of cancer treatments. The model did not use overall survival data directly, even though this was as mature as the progression-free survival data used to derive overall survival estimates. The company modelled overall survival indirectly by using blinded independent central review progression-free survival data from CheckMate 649. The ERG explained that the company's model survival estimates were higher than the overall survival seen in the trial. Because the company's model did not correspond with the CheckMate 649 data, the ERG stated that the model long-term survival estimates and cost-effectiveness results lack reliability. It suggested that a 3-state partitioned survival model could use the survival data from CheckMate 649 directly. The committee agreed with the ERG that 3‑state partitioned survival models are suitable and noted that the inclusion of the long-term remission state in the company's original model made the model unsuitable for decision making. After consultation, the company presented a new partitioned survival model, which the committee concluded was appropriate for decision making. # Survival modelling ## Progression-free survival is modelled appropriately In the updated company base case, long-term survival with nivolumab was estimated using a semi-parametric approach. Kaplan–Meier estimates were directly used from CheckMate 649 for the first 6.44 months. This cut-off was chosen to reflect the fact that high-frequency assessments, which could influence the timing of progression-free survival measurements, had ended. After this point, each treatment arm was extrapolated using a log-normal distribution. The ERG agreed with the modelling approach and distribution choice, noting that there was no clinical evidence other than CheckMate 649 to choose between alternative parametric distributions. The committee concluded the method and distribution chosen for the projection of progression-free survival beyond the trial data was appropriate. ## There are differences in the company's and ERG's approaches to modelling overall survival, but both are appropriate The company and ERG suggested different approaches to extrapolate overall survival. In terms of similarities, both used a semi-parametric method which used CheckMate 649 Kaplan–Meier data for the first 6.44 months and then extrapolated the data using a parametric distribution. The company's base case used the Gompertz distribution whereas the ERG presented results using the Gompertz and generalised gamma distributions. In terms of differences, each used different approaches to ensure that mortality hazards were never lower than those of the general population (see section 3.6). The company's approach added the excess mortality of the condition to the general population mortality. However, the ERG adjusted the extrapolation so that the mortality hazards were never below those of the general population. In a previous committee meeting, the ERG did not have enough information to assess the company's modelling approach and thought that the approach presented may have been implemented incorrectly. The ERG thought that the company may have double-counted deaths in its approach. Once the company fully explained how it had implemented its modelled overall survival, the ERG was satisfied and found it reasonable. The committee concluded that although the company and the ERG had different ways to model overall survival, both were reasonable. ## After stopping treatment, nivolumab's treatment effect may not last for a person's lifetime People in CheckMate 649 could continue to have nivolumab for a maximum of 24 months, even if their cancer had not progressed at this time. The marketing authorisation for nivolumab has this 24‑month stopping rule. The model had an assumption that people would continue to experience treatment effect benefit after stopping treatment. The clinical experts and company suggested some persistence of benefit is plausible after stopping nivolumab because nivolumab enhances the immune system to mediate an anti-tumour response against cancer cells, resulting in tumour destruction. The company stated that the trial had a 49.5‑month follow up. During this time, there was no evidence of a treatment waning effect; that is a reduction in the treatment effect for nivolumab plus XELOX compared with XELOX alone after 24 months. The company also suggested that trials of nivolumab for treating melanoma or non-small-cell lung cancer suggested a long-term benefit of nivolumab in those cancers. The committee noted that it did not have enough comparator data from these trials to confirm no treatment waning. This is because the trials may have had different rules on stopping nivolumab to CheckMate 649 and it was unclear whether any persistence of effect after stopping nivolumab would be consistent across different tumour types. The committee agreed that it was unproven that the benefit of a 24‑month course of nivolumab would last indefinitely after it was stopped. It agreed it was more likely that the effect would wear off at some stage. The committee noted that both the company and ERG had provided treatment waning scenarios. In these scenarios the risk of death in the nivolumab plus XELOX arm became the same as the XELOX arm at 6.5 years in the company's scenario and 5 years in the ERG's model. The committee commented that this suggested that the treatment benefit of nivolumab ceased abruptly at these times. It commented that this contrasted with ways of modelling treatment waning seen in some other appraisals. That is, in which the treatment benefit is modelled to start decreasing at the point people stop treatment and gradually decreases over a period of time until there is no treatment benefit over the comparator. The committee noted that: The company's 6.5‑year cut-off was based on the longest available follow-up data from CheckMate 067. This trial compared nivolumab plus ipilimumab or nivolumab alone with ipilimumab in people with advanced melanoma. The company thought the ERG's cut-off was too pessimistic given that the company's observed trial data at 4 years did not show a sustained increase in the risk of dying as shown in the ERG's scenario. The ERG considered its own 5‑year cut-off to be arbitrary and non-evidence-based, but reflective of assumptions in previous appraisals which assumed a 3‑year persistence of benefit after stopping nivolumab. NICE's technology appraisal guidance on pembrolizumab with chemotherapy for oesophageal and gastro-oesophageal cancer had applied a treatment waning effect between 5 and 7 years. However, this did not imply that the company's choice of 6.5 years was valid for this appraisal, which included a population with predominantly gastric cancer, and a different treatment. The committee recognised that there was no evidence underpinning either the 5‑ or 6.5‑year treatment waning assumption or a lifetime treatment effect. The committee concluded that nivolumab's treatment effect may not last for a person's lifetime after treatment is stopped. Although treatment waning is uncertain, it would take both the company's and ERG's scenarios on treatment waning into account in its decision making. ## The company's and ERG's approaches give plausible results at 20 years, but these are uncertain The committee recalled that the company's preferred parametric distribution for extrapolating overall survival was the Gompertz distribution, and the ERG considered both generalised gamma and Gompertz distributions (see section 3.9). The committee noted that the choice of parametric distribution and the treatment waning assumption had a particularly large effect on the modelled long-term overall survival after 5 years in the nivolumab plus XELOX arm. This also had a large effect on the cost‑effectiveness estimates for nivolumab plus XELOX compared with XELOX alone. The committee noted: The ERG's approach using Gompertz distribution predicted that after 20 years, 5.9% of people who had nivolumab plus XELOX would be alive, compared with 0.5% predicted by the ERG's preferred generalised gamma distribution. In the XELOX-only arm, the ERG's approach using Gompertz distribution predicted that 0.9% of people would be alive after 20 years, compared with 0.2% predicted by the ERG's preferred generalised gamma distribution. Applying the ERG's 5‑year treatment waning scenario to the ERG approach using the Gompertz distribution predicted that 3.1% of people in the nivolumab plus XELOX arm would be alive at 20 years. The company's approach using a Gompertz distribution predicted that slightly fewer people would be alive at 20 years than predicted using the ERG's approach with a Gompertz distribution. Applying the 5‑year cut-off and 6.5‑year cut-off for treatment waning resulted in just under 3% and just over 3% of people predicted to be alive at 20 years, respectively (the precise estimates are academic in confidence and cannot be presented here). Of the 20‑year survival estimates for nivolumab plus XELOX (5.9% Gompertz, 3.1% Gompertz with treatment waning, and 0.5% generalised gamma), the clinical experts considered those using the Gompertz distribution and including waning were plausible. The committee noted consultation comments on the second appraisal consultation document that stated that, for most people with this type of cancer, life expectancy is short and the focus should not be on a small proportion of people alive at 20 years. The committee agreed that long-term projections affecting only a few people were highly uncertain. However, differences in the cost-effectiveness estimates were driven by the effect of different modelling assumptions on these long-term predictions and it needed to reach a decision on what was plausible. The committee concluded that both the company's and ERG's approaches using a Gompertz distribution and assuming treatment waning gave potentially plausible results at 20 years, but these were uncertain. # Other assumptions and inputs in the economic model ## Utility values, model baseline age and adjustments for missed doses are appropriate for decision making After technical engagement both the company and ERG made several changes to the model and agreed on the following assumptions and inputs: applying the company's new adjustment of costs for chemotherapy and nivolumab for missed doses setting the model's mean baseline age to 64.15 years based on Cancer Research UK data, instead of CheckMate 649 data using the company's utility values based on CheckMate 649 data.The CheckMate 649 data that was used to inform utility values cannot be reported here because it is academic in confidence. The clinical experts agreed with the company's and ERG's approach. The committee concluded that the utility values, model baseline age and adjustments for missed doses used in the model were appropriate for decision making. # Cost-effectiveness estimates ## The company's base-case ICERS using the 5- and 6.5-year treatment waning assumptions are potentially plausible, but are still uncertain The cost-effectiveness results include nivolumab's confidential discount (see section 2.4). At the third meeting: the company's base case (using a Gompertz distribution to model overall survival) without treatment waning provided a probabilistic incremental cost-effectiveness ratio (ICER) of £46,221 per quality-adjusted life year (QALY) gained for nivolumab plus XELOX compared with XELOX alone the company's base case using a 6.5‑year treatment waning assumption provided a probabilistic ICER of £49,365 per QALY gained the company's scenario using a 5‑year treatment waning assumption provided a probabilistic ICER of £51,331 per QALY gained the ERG's approach to modelling overall survival using a Gompertz distribution without treatment waning provided a probabilistic ICER of £41,527 per QALY gained the ERG's approach using a Gompertz distribution with 5‑year treatment waning applied provided a probabilistic ICER of £49,869 per QALY gained. The committee considered the ICERs resulting from scenarios using a Gompertz distribution with the 5- or 6.5‑year treatment waning assumptions were potentially plausible but were still uncertain. After the third committee meeting the company updated its commercial arrangement and submitted updated results for the company and ERG scenarios which included an assumption of treatment waning at both 5-years and 6.5 years. The change to the commercial arrangement resulted in ICERs that were well below £50,000 per QALY gained. # End of life ## End of life criteria are met The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered whether nivolumab with platinum- and fluoropyrimidine-based combination chemotherapy meets the end of life criteria for people with untreated HER2‑negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma that expresses PD‑L1 with a CPS of 5 or more. The company and ERG both agreed, based on their analyses, that average life expectancy in this population is less than 24 months. The observed median overall survival benefit with nivolumab plus XELOX or FOLFOX in CheckMate 649 was larger than the additional 3‑month extension to life needed by the criteria (the data cannot be reported here because it is academic in confidence). The committee concluded that nivolumab met the end of life criteria. ## Because of the uncertainty, an ICER well below £50,000 per QALY gained is needed for this technology to be considered cost effective NICE's guide to the methods of technology appraisal notes that the appraisal committee does not use a precise maximum acceptable ICER above which a technology would automatically be defined as not cost effective, or below which it would. Also, consideration of the cost effectiveness of a technology is necessary, but is not the sole basis for decision making. Therefore, NICE considers that the influence of other factors upon the decision to recommend a technology is greater when the ICER is closer to the top of the acceptable range. Judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee had concluded that end of life criteria applied (see section 3.14). At the second committee meeting the committee stated that the ICER should sit comfortably below £50,000 for nivolumab plus XELOX to be considered a cost-effective use of NHS resources. This was because of high levels of uncertainty around long-term survival and treatment effect waning. The committee was aware that there is an unmet need (see section 3.2) and that the company had provided an updated patient access scheme for the third committee meeting. It had not been presented with any evidence to reduce the uncertainty about long-term survival and treatment effect waning, so its conclusions on an acceptable ICER remained the same. Following the third meeting the company's updated commercial arrangement reduced the ICERs from the company and ERG approaches (see section 3.13) to comfortably below £50,000 per QALY gained. # Equalities ## There are no equality issues relevant to the recommendations No equality or social value judgement issues were identified. # Conclusion ## Nivolumab is recommended for use in the NHS Extrapolation of CheckMate 649 overall survival data using a semi-parametric approach with a Gompertz distribution and accounting for treatment waning produced plausible 20‑year survival outcomes. However, the most appropriate method to model overall survival remains unclear and the long-term survival estimates are highly uncertain. End of life criteria applied. The committee concluded that nivolumab is a cost-effective use of NHS resources because the most plausible scenarios resulted in ICERs comfortably below £50,000 per QALY gained (see section 3.15). The committee concluded that nivolumab with platinum- and fluoropyrimidine-based chemotherapy is recommended for treating HER2‑negative, advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma that expresses PD‑L1 with a CPS of 5 or more.	{'Recommendations': "Nivolumab with platinum- and fluoropyrimidine-based chemotherapy is recommended, within its marketing authorisation, as an option for untreated HER2‑negative, advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 5 or more. Nivolumab is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThere are no curative treatment options for HER2‑negative, advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma that expresses PD‑L1 with a CPS of 5 or more. The usual treatment is palliative chemotherapy. Most people have platinum- and fluoropyrimidine-based chemotherapy with capecitabine plus oxaliplatin (XELOX) or fluorouracil plus oxaliplatin with folinic acid (FOLFOX).\n\nClinical trial evidence shows that nivolumab plus XELOX or FOLFOX increases the length of time before gastric, gastro-oesophageal junction or oesophageal adenocarcinoma gets worse compared with XELOX or FOLFOX alone. Evidence also shows that people live longer if they have nivolumab plus XELOX or FOLFOX compared with XELOX or FOLFOX alone. But, it is uncertain how long people lived beyond the trial period and for how long nivolumab's benefit lasted.\n\nPeople with these conditions on average have a short life expectancy, so nivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates for nivolumab are within what NICE considers an acceptable use of NHS resources. So, nivolumab with platinum- and fluoropyrimidine-based chemotherapy is recommended.", 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol Myers Squibb) is indicated for use 'in combination with fluoropyrimidine- and platinum-based combination chemotherapy for the first-line treatment of adult patients with HER2‑negative advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours express PD‑L1 with a combined positive score (CPS) ≥ 5'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for nivolumab.\n\n# Price\n\nThe list price of nivolumab is £439 per 40\xa0mg/4\xa0ml concentrate for solution for infusion vial; £1,097 per 100\xa0mg/10\xa0ml concentrate for solution for infusion vial; and £2,633 per 240\xa0mg/24\xa0ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed July 2022).\n\nThe company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Gastric, gastro-oesophageal junction and oesophageal adenocarcinoma have a poor prognosis and a large impact on quality of life\n\nThe patient experts explained that gastric, gastro-oesophageal junction and oesophageal adenocarcinoma significantly impact quality of life. They explained that major symptoms include difficulty swallowing and malnutrition, which can lead to severe fatigue, weight loss and the need to use a feeding tube. These symptoms can be painful and distressing, limiting people's ability to live normally and participate in social events. Diagnosis is often at an advanced stage, and around 40% of all new cases are diagnosed in people aged 75 and over. Gastric, gastro-oesophageal junction and oesophageal adenocarcinoma are more common in men than women, although the patient experts report that increasing numbers of younger people and women are being diagnosed. The committee concluded that advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma have a poor prognosis and a large impact on quality of life.\n\n## People would welcome a new treatment option\n\nThe patient and clinical experts explained that there are no curative treatment options for untreated HER2‑negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma. Standard first-line treatment for people with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and no significant comorbidities is palliative chemotherapy. NICE's guideline on oesophago-gastric cancer: assessment and management in adults recommends dual therapy with fluorouracil or capecitabine plus cisplatin or oxaliplatin, or triple therapy with epirubicin. The clinical experts explained that dual therapy regimens are preferred and that most people would have capecitabine and oxaliplatin (XELOX). This is because oxaliplatin is better tolerated than cisplatin and has a shorter infusion time. Some people may be offered fluorouracil with oxaliplatin and folinic acid (FOLFOX). People having FOLFOX treatment need more hospital visits (every 2\xa0weeks) than people having XELOX (every 3\xa0weeks). The patient and clinical experts agreed that there is unmet clinical need in this population. Nivolumab is an immunotherapy and has a different mechanism of action to chemotherapy. NICE's technology appraisal guidance recommends pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced oesophageal and gastro-oesophageal junction cancer in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more. The committee noted that some people would be eligible for nivolumab plus chemotherapy but not pembrolizumab plus chemotherapy. As a result, there remains an unmet need in people with gastric cancer and a CPS of between 5 and 10 who cannot have pembrolizumab. The committee concluded that patients and clinicians would welcome a new treatment for untreated HER2‑negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma.\n\n## XELOX is the key comparator for this appraisal\n\nThe company suggested that XELOX and FOLFOX were the relevant comparators for this appraisal. The evidence review group (ERG) agreed with this approach and noted that most people would have XELOX because it is more convenient and cheaper than FOLFOX. Clinical experts also confirmed the company's approach and noted that dual chemotherapy regimens have similar efficacy. The committee concluded that XELOX was the key comparator for this appraisal.\n\n# Clinical evidence\n\n## Nivolumab plus chemotherapy improves progression-free survival and overall survival compared with chemotherapy alone\n\nCheckMate\xa0649 (n=1,581) was an open-label randomised multicentre trial (including 38\xa0patients from 5\xa0UK centres) that compared nivolumab plus XELOX or FOLFOX with XELOX or FOLFOX alone. It included people with untreated and unresectable, advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma who had an ECOG performance status of 0\xa0to\xa01. People with known HER2‑positive status and untreated central nervous system metastases were excluded from the study. The average age in the trial was 60.1 years. The primary outcomes were progression-free survival and overall survival in people whose tumours express PD‑L1 with a CPS of 5 or more (n=955). Results from the latest data cut were based on a minimum follow-up of 24\xa0months and showed that:\n\nnivolumab plus chemotherapy improved progression‑free survival compared with chemotherapy alone (hazard ratio [HR] 0.70, 95%\xa0confidence interval [CI] 0.60 to 0.81)\n\nnivolumab plus chemotherapy improved overall survival compared with chemotherapy alone (HR 0.70, 95% CI 0.61 to 0.81).The committee noted that this data was mature (meaning that more than half the trial population had disease progression or died during the follow-up period). The committee concluded that adding nivolumab to platinum- and fluoropyrimidine-based combination chemotherapy improved progression-free survival and overall survival compared with chemotherapy alone.\n\n## CheckMate\xa0649 data is generalisable to NHS clinical practice\n\nIn the first committee meeting, the ERG heard clinical advice suggesting that the trial population, with a mean age of 60.1\xa0years and ECOG performance status of 0 to 1 (see section\xa03.4), was younger and fitter than the population seen in NHS clinical practice. The ERG thought the best available estimates were that people seen in the NHS with advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma had an average age between 64 and 66 (Cancer Research UK and Royal Marsden Hospital Trust data). The clinical experts explained that the average age of the trial population is expected to be younger than that of people seen in the NHS with these conditions. They agreed there is no evidence that treatment would be less effective in older people and stated that treatment should be based on patient fitness and comorbidities, regardless of age and performance status. The company noted that the trial age is aligned with UK data sources and that there is limited evidence to suggest outcomes differ between ECOG performance status scores. The committee concluded that CheckMate\xa0649 data is generalisable to NHS clinical practice.\n\n# Long-term remission and cure\n\n## Some people may have long-term remission, but their life expectancy may be shorter than the general population\n\nThe company considered that evidence from CheckMate\xa0649 suggested that the hazard of progression or death in people whose disease had not yet progressed decreases over time and plateaus at 30\xa0months. The company proposed that people who had no disease progression 30\xa0months or more after starting treatment were in 'long-term remission'. The company's estimates of the risk of dying in people with long-term remission were the same as the general population. The ERG noted that this meant the company assumed that people whose cancer had not progressed by 30\xa0months after starting treatment were cured and had the same lifespan as the general population. The company considered that other evidence showing long-term survival in some people supports this assumption, for example, COUGAR‑02, ATTRACTION‑2, Chau 2009 and Royal Marsden Hospital Trust data. The ERG considered that none of the long-term evidence supported the cure assumption. The number of people in CheckMate\xa0649 at 30\xa0months was too low for conclusions about cure to be made. The clinical experts agreed that long-term data supporting a cure assumption does not exist. However, the clinical and patient experts explained that long-term survival is likely for some people because this has been seen with other immunotherapy treatments. The clinical expert said that about 4% of people could be expected to achieve long-term remission with chemotherapy and that they expect nivolumab could double the number to 8%. The NHS clinical lead noted that disease in long-term remission can relapse, but this is uncommon. The clinical experts said that people in long-term remission have a low burden of disease and their quality of life is good. However, their fitness is unlikely to return to pre-treatment levels because of long-term toxicities with chemotherapy, such as irreversible neuropathy. They expected the mortality rate in people with long-term remission to be higher than that of the general population because they previously had advanced cancer and cytotoxic chemotherapy. The committee concluded that some people are likely to have long-term remission, but it was unclear if they were cured. The committee further concluded that people in whom disease did not recur would still be expected to have a shorter life expectancy than people who have not had this type of advanced cancer and chemotherapy.\n\n# The company's economic model\n\n## The company's updated model is suitable for decision making\n\nIn the first committee meeting, the company used a cohort-based semi-Markov model with 4\xa0states: pre-progression, progressed disease, long-term remission, and death. All people in the pre-progression state at 30\xa0months entered the long-term remission state and were assumed to have the same risk of dying as the general population and were assumed to be effectively cured (see section\xa03.6). The ERG explained that the company's model was unnecessarily complicated and differed from the 3‑state partitioned survival models often used in NICE appraisals of cancer treatments. The model did not use overall survival data directly, even though this was as mature as the progression-free survival data used to derive overall survival estimates. The company modelled overall survival indirectly by using blinded independent central review progression-free survival data from CheckMate\xa0649. The ERG explained that the company's model survival estimates were higher than the overall survival seen in the trial. Because the company's model did not correspond with the CheckMate\xa0649 data, the ERG stated that the model long-term survival estimates and cost-effectiveness results lack reliability. It suggested that a 3-state partitioned survival model could use the survival data from CheckMate\xa0649 directly. The committee agreed with the ERG that 3‑state partitioned survival models are suitable and noted that the inclusion of the long-term remission state in the company's original model made the model unsuitable for decision making. After consultation, the company presented a new partitioned survival model, which the committee concluded was appropriate for decision making.\n\n# Survival modelling\n\n## Progression-free survival is modelled appropriately\n\nIn the updated company base case, long-term survival with nivolumab was estimated using a semi-parametric approach. Kaplan–Meier estimates were directly used from CheckMate\xa0649 for the first 6.44\xa0months. This cut-off was chosen to reflect the fact that high-frequency assessments, which could influence the timing of progression-free survival measurements, had ended. After this point, each treatment arm was extrapolated using a log-normal distribution. The ERG agreed with the modelling approach and distribution choice, noting that there was no clinical evidence other than CheckMate\xa0649 to choose between alternative parametric distributions. The committee concluded the method and distribution chosen for the projection of progression-free survival beyond the trial data was appropriate.\n\n## There are differences in the company's and ERG's approaches to modelling overall survival, but both are appropriate\n\nThe company and ERG suggested different approaches to extrapolate overall survival. In terms of similarities, both used a semi-parametric method which used CheckMate\xa0649 Kaplan–Meier data for the first 6.44\xa0months and then extrapolated the data using a parametric distribution. The company's base case used the Gompertz distribution whereas the ERG presented results using the Gompertz and generalised gamma distributions. In terms of differences, each used different approaches to ensure that mortality hazards were never lower than those of the general population (see section\xa03.6). The company's approach added the excess mortality of the condition to the general population mortality. However, the ERG adjusted the extrapolation so that the mortality hazards were never below those of the general population. In a previous committee meeting, the ERG did not have enough information to assess the company's modelling approach and thought that the approach presented may have been implemented incorrectly. The ERG thought that the company may have double-counted deaths in its approach. Once the company fully explained how it had implemented its modelled overall survival, the ERG was satisfied and found it reasonable. The committee concluded that although the company and the ERG had different ways to model overall survival, both were reasonable.\n\n## After stopping treatment, nivolumab's treatment effect may not last for a person's lifetime\n\nPeople in CheckMate\xa0649 could continue to have nivolumab for a maximum of 24\xa0months, even if their cancer had not progressed at this time. The marketing authorisation for nivolumab has this 24‑month stopping rule. The model had an assumption that people would continue to experience treatment effect benefit after stopping treatment. The clinical experts and company suggested some persistence of benefit is plausible after stopping nivolumab because nivolumab enhances the immune system to mediate an anti-tumour response against cancer cells, resulting in tumour destruction. The company stated that the trial had a 49.5‑month follow up. During this time, there was no evidence of a treatment waning effect; that is a reduction in the treatment effect for nivolumab plus XELOX compared with XELOX alone after 24\xa0months. The company also suggested that trials of nivolumab for treating melanoma or non-small-cell lung cancer suggested a long-term benefit of nivolumab in those cancers. The committee noted that it did not have enough comparator data from these trials to confirm no treatment waning. This is because the trials may have had different rules on stopping nivolumab to CheckMate\xa0649 and it was unclear whether any persistence of effect after stopping nivolumab would be consistent across different tumour types. The committee agreed that it was unproven that the benefit of a 24‑month course of nivolumab would last indefinitely after it was stopped. It agreed it was more likely that the effect would wear off at some stage. The committee noted that both the company and ERG had provided treatment waning scenarios. In these scenarios the risk of death in the nivolumab plus XELOX arm became the same as the XELOX arm at 6.5\xa0years in the company's scenario and 5\xa0years in the ERG's model. The committee commented that this suggested that the treatment benefit of nivolumab ceased abruptly at these times. It commented that this contrasted with ways of modelling treatment waning seen in some other appraisals. That is, in which the treatment benefit is modelled to start decreasing at the point people stop treatment and gradually decreases over a period of time until there is no treatment benefit over the comparator. The committee noted that:\n\nThe company's 6.5‑year cut-off was based on the longest available follow-up data from CheckMate\xa0067. This trial compared nivolumab plus ipilimumab or nivolumab alone with ipilimumab in people with advanced melanoma.\n\nThe company thought the ERG's cut-off was too pessimistic given that the company's observed trial data at 4\xa0years did not show a sustained increase in the risk of dying as shown in the ERG's scenario.\n\nThe ERG considered its own 5‑year cut-off to be arbitrary and non-evidence-based, but reflective of assumptions in previous appraisals which assumed a 3‑year persistence of benefit after stopping nivolumab.\n\nNICE's technology appraisal guidance on pembrolizumab with chemotherapy for oesophageal and gastro-oesophageal cancer had applied a treatment waning effect between 5 and 7\xa0years. However, this did not imply that the company's choice of 6.5\xa0years was valid for this appraisal, which included a population with predominantly gastric cancer, and a different treatment. The committee recognised that there was no evidence underpinning either the 5‑ or 6.5‑year treatment waning assumption or a lifetime treatment effect. The committee concluded that nivolumab's treatment effect may not last for a person's lifetime after treatment is stopped. Although treatment waning is uncertain, it would take both the company's and ERG's scenarios on treatment waning into account in its decision making.\n\n## The company's and ERG's approaches give plausible results at 20\xa0years, but these are uncertain\n\nThe committee recalled that the company's preferred parametric distribution for extrapolating overall survival was the Gompertz distribution, and the ERG considered both generalised gamma and Gompertz distributions (see section\xa03.9). The committee noted that the choice of parametric distribution and the treatment waning assumption had a particularly large effect on the modelled long-term overall survival after 5\xa0years in the nivolumab plus XELOX arm. This also had a large effect on the cost‑effectiveness estimates for nivolumab plus XELOX compared with XELOX alone. The committee noted:\n\nThe ERG's approach using Gompertz distribution predicted that after 20\xa0years, 5.9% of people who had nivolumab plus XELOX would be alive, compared with 0.5% predicted by the ERG's preferred generalised gamma distribution. In the XELOX-only arm, the ERG's approach using Gompertz distribution predicted that 0.9% of people would be alive after 20\xa0years, compared with 0.2% predicted by the ERG's preferred generalised gamma distribution.\n\nApplying the ERG's 5‑year treatment waning scenario to the ERG approach using the Gompertz distribution predicted that 3.1% of people in the nivolumab plus XELOX arm would be alive at 20\xa0years.\n\nThe company's approach using a Gompertz distribution predicted that slightly fewer people would be alive at 20\xa0years than predicted using the ERG's approach with a Gompertz distribution. Applying the 5‑year cut-off and 6.5‑year cut-off for treatment waning resulted in just under 3% and just over 3% of people predicted to be alive at 20\xa0years, respectively (the precise estimates are academic in confidence and cannot be presented here). Of the 20‑year survival estimates for nivolumab plus XELOX (5.9% Gompertz, 3.1% Gompertz with treatment waning, and 0.5% generalised gamma), the clinical experts considered those using the Gompertz distribution and including waning were plausible. The committee noted consultation comments on the second appraisal consultation document that stated that, for most people with this type of cancer, life expectancy is short and the focus should not be on a small proportion of people alive at 20\xa0years. The committee agreed that long-term projections affecting only a few people were highly uncertain. However, differences in the cost-effectiveness estimates were driven by the effect of different modelling assumptions on these long-term predictions and it needed to reach a decision on what was plausible. The committee concluded that both the company's and ERG's approaches using a Gompertz distribution and assuming treatment waning gave potentially plausible results at 20\xa0years, but these were uncertain.\n\n# Other assumptions and inputs in the economic model\n\n## Utility values, model baseline age and adjustments for missed doses are appropriate for decision making\n\nAfter technical engagement both the company and ERG made several changes to the model and agreed on the following assumptions and inputs:\n\napplying the company's new adjustment of costs for chemotherapy and nivolumab for missed doses\n\nsetting the model's mean baseline age to 64.15\xa0years based on Cancer Research UK data, instead of CheckMate\xa0649 data\n\nusing the company's utility values based on CheckMate\xa0649 data.The CheckMate\xa0649 data that was used to inform utility values cannot be reported here because it is academic in confidence. The clinical experts agreed with the company's and ERG's approach. The committee concluded that the utility values, model baseline age and adjustments for missed doses used in the model were appropriate for decision making.\n\n# Cost-effectiveness estimates\n\n## The company's base-case ICERS using the 5- and 6.5-year treatment waning assumptions are potentially plausible, but are still uncertain\n\nThe cost-effectiveness results include nivolumab's confidential discount (see section\xa02.4). At the third meeting:\n\nthe company's base case (using a Gompertz distribution to model overall survival) without treatment waning provided a probabilistic incremental cost-effectiveness ratio (ICER) of £46,221 per quality-adjusted life year (QALY) gained for nivolumab plus XELOX compared with XELOX alone\n\nthe company's base case using a 6.5‑year treatment waning assumption provided a probabilistic ICER of £49,365 per QALY gained\n\nthe company's scenario using a 5‑year treatment waning assumption provided a probabilistic ICER of £51,331 per QALY gained\n\nthe ERG's approach to modelling overall survival using a Gompertz distribution without treatment waning provided a probabilistic ICER of £41,527 per QALY gained\n\nthe ERG's approach using a Gompertz distribution with 5‑year treatment waning applied provided a probabilistic ICER of £49,869 per QALY gained. The committee considered the ICERs resulting from scenarios using a Gompertz distribution with the 5- or 6.5‑year treatment waning assumptions were potentially plausible but were still uncertain. After the third committee meeting the company updated its commercial arrangement and submitted updated results for the company and ERG scenarios which included an assumption of treatment waning at both 5-years and 6.5 years. The change to the commercial arrangement resulted in ICERs that were well below £50,000 per QALY gained.\n\n# End of life\n\n## End of life criteria are met\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It considered whether nivolumab with platinum- and fluoropyrimidine-based combination chemotherapy meets the end of life criteria for people with untreated HER2‑negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma that expresses PD‑L1 with a CPS of 5 or more. The company and ERG both agreed, based on their analyses, that average life expectancy in this population is less than 24\xa0months. The observed median overall survival benefit with nivolumab plus XELOX or FOLFOX in CheckMate\xa0649 was larger than the additional 3‑month extension to life needed by the criteria (the data cannot be reported here because it is academic in confidence). The committee concluded that nivolumab met the end of life criteria.\n\n## Because of the uncertainty, an ICER well below £50,000 per QALY gained is needed for this technology to be considered cost effective\n\nNICE's guide to the methods of technology appraisal notes that the appraisal committee does not use a precise maximum acceptable ICER above which a technology would automatically be defined as not cost effective, or below which it would. Also, consideration of the cost effectiveness of a technology is necessary, but is not the sole basis for decision making. Therefore, NICE considers that the influence of other factors upon the decision to recommend a technology is greater when the ICER is closer to the top of the acceptable range. Judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee had concluded that end of life criteria applied (see section\xa03.14). At the second committee meeting the committee stated that the ICER should sit comfortably below £50,000 for nivolumab plus XELOX to be considered a cost-effective use of NHS resources. This was because of high levels of uncertainty around long-term survival and treatment effect waning. The committee was aware that there is an unmet need (see section\xa03.2) and that the company had provided an updated patient access scheme for the third committee meeting. It had not been presented with any evidence to reduce the uncertainty about long-term survival and treatment effect waning, so its conclusions on an acceptable ICER remained the same. Following the third meeting the company's updated commercial arrangement reduced the ICERs from the company and ERG approaches (see section\xa03.13) to comfortably below £50,000 per QALY gained.\n\n# Equalities\n\n## There are no equality issues relevant to the recommendations\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Nivolumab is recommended for use in the NHS\n\nExtrapolation of CheckMate\xa0649 overall survival data using a semi-parametric approach with a Gompertz distribution and accounting for treatment waning produced plausible 20‑year survival outcomes. However, the most appropriate method to model overall survival remains unclear and the long-term survival estimates are highly uncertain. End of life criteria applied. The committee concluded that nivolumab is a cost-effective use of NHS resources because the most plausible scenarios resulted in ICERs comfortably below £50,000 per QALY gained (see section\xa03.15). The committee concluded that nivolumab with platinum- and fluoropyrimidine-based chemotherapy is recommended for treating HER2‑negative, advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma that expresses PD‑L1 with a CPS of 5 or more."}	https://www.nice.org.uk/guidance/ta857	Evidence-based recommendations on nivolumab (Opdivo) with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in adults.
6e5b50ce238598efa4aa452f28584efdaf820065	nice	Lenvatinib with pembrolizumab for untreated advanced renal cell carcinoma	Lenvatinib with pembrolizumab for untreated advanced renal cell carcinoma Evidence-based recommendations on lenvatinib (Kisplyx) with pembrolizumab (Keytruda) for untreated advanced renal cell carcinoma in adults. # Recommendations Lenvatinib with pembrolizumab is recommended as an option for untreated advanced renal cell carcinoma in adults, only if: their disease is intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria and nivolumab with ipilimumab would otherwise be offered and the companies provide lenvatinib and pembrolizumab according to the commercial arrangements. This recommendation is not intended to affect treatment with lenvatinib with pembrolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Current treatment for untreated advanced renal cell carcinoma includes pazopanib, tivozanib or sunitinib. Cabozantinib, and nivolumab plus ipilimumab, are also recommended for intermediate- or poor-risk cancer as defined by the International Metastatic Renal Cell Carcinoma Database Consortium. Clinical trial evidence suggests that people having lenvatinib plus pembrolizumab have longer before their disease gets worse than people having sunitinib. Pazopanib and tivozanib are thought to have similar clinical effectiveness to sunitinib, so lenvatinib plus pembrolizumab is also likely to be more effective than them. Results of indirect comparisons are uncertain, but suggest that lenvatinib plus pembrolizumab may increase the time people have before their disease gets worse compared with cabozantinib, and compared with nivolumab plus ipilimumab. In favourable-risk cancer, all the cost-effectiveness estimates are above the range that NICE considers an acceptable use of NHS resources, so lenvatinib plus pembrolizumab is not recommended for this group. In intermediate- and poor-risk cancer, the cost-effectiveness estimates are only within the range that NICE considers an acceptable use of NHS resources when nivolumab plus ipilimumab would otherwise be offered. So, lenvatinib plus pembrolizumab is recommended for this group.# Information about lenvatinib with pembrolizumab # Marketing authorisation indication Pembrolizumab (Keytruda, MSD), in combination with lenvatinib (Kisplyx, Eisai), is indicated for 'the first-line treatment of advanced renal cell carcinoma in adults'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for pembrolizumab. # Price The price of lenvatinib is £1,437 per 30 4‑mg or 10‑mg capsules (excluding VAT; BNF online accessed July 2022). The price of pembrolizumab is £2,630 per 100 mg per 4‑ml vial (excluding VAT; BNF online accessed July 2022).The companies have commercial arrangements. These make lenvatinib and pembrolizumab available to the NHS with discounts. The sizes of the discounts are commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of the discounts.# Committee discussion The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence. # New targeted treatment ## People with untreated renal cell carcinoma would welcome a new treatment option Advanced renal cell carcinoma has a devastating impact on people's life expectancy and quality of life. Symptoms can vary widely, and depend on the location of metastases, but can include blood in urine, persistent pain in the lower back or side, extreme tiredness, loss of appetite, persistent hypertension and night sweats. Advanced or metastatic renal cell carcinoma has a poor prognosis, with 5‑year survival rates of approximately 12%. Patient experts described how the disease can have a devastating impact on a person's quality of life, and that it is not just limited to physical health, but also has a substantial impact on mental health and wellbeing. This is in part because of a lack of available treatment options, leading to people experiencing a lack of hope for the future. The clinical experts highlighted that an effective combined programmed death 1 (PD‑1) inhibitor and anti-vascular endothelial growth factor (anti‑VEGF) treatment would be welcomed by clinicians and patients to improve outcomes for people with untreated disease. The committee concluded that people with untreated renal cell carcinoma would welcome a new treatment option. # Comparators ## Relevant comparators for advanced renal cell carcinoma depend on IMDC risk score The companies explained that clinicians assess advanced renal cell carcinoma on presentation using the International Metastatic Renal Cell Carcinoma (IMDC) risk score. This measure uses a range of criteria to determine whether a person has favourable, intermediate or poor risk of survival. Risk level is determined using 6 risk factors including Karnofsky performance status score, time from original diagnosis, and levels of haemoglobin, serum calcium, neutrophils and platelets. The likelihood of survival is considered intermediate ('intermediate risk') when there are 1 or 2 risk factors, and poor ('poor risk') when there are 3 or more risk factors. People without any risk factors are considered to have 'favourable risk'. This baseline score is used to determine treatment options. The clinical experts explained that people with poor risk scores are more likely to have more aggressive disease, which is more responsive to immunotherapy, and those with favourable risk scores are more likely to have less aggressive disease that is more sensitive to anti-VEGF tyrosine kinase inhibitors (TKIs). The clinical experts explained that the anti‑VEGF TKI treatments sunitinib, pazopanib and tivozanib are options for treating advanced renal cell carcinoma irrespective of risk. But for people with intermediate- and poor-risk disease, cabozantinib, and nivolumab plus ipilimumab are treatment options, with nivolumab plus ipilimumab usually preferred for people who are medically fit enough to have it. For people who are not medically fit enough, cabozantinib is more likely to be offered. Nivolumab plus ipilimumab was available through the Cancer Drugs Fund for several years, and was recommended for routine commissioning in February 2022. The Cancer Drugs Fund clinical lead explained that the high number of people currently receiving nivolumab plus ipilimumab in the NHS suggests that it has become an established treatment option. The committee agreed that people will have different treatments according to their IMDC risk scores, and concluded that the most appropriate comparators for lenvatinib plus pembrolizumab differ according to the IMDC risk subgroups. It further concluded that nivolumab plus ipilimumab is a relevant comparator for people with an intermediate or poor IMDC risk score. # Clinical evidence ## Key evidence for lenvatinib plus pembrolizumab comes from the CLEAR trial, which is generalisable to NHS clinical practice The companies presented evidence from the CLEAR trial, a phase 3 randomised controlled trial of lenvatinib plus pembrolizumab (n=355) compared with sunitinib (n=357) in advanced renal cell carcinoma. The primary endpoint of the trial was progression-free survival, with overall survival, overall response rate, adverse events and health-related quality of life as secondary endpoints. Most of the participants in both groups had previously had a nephrectomy. The trial stratified people by risk score, with approximately two thirds in the intermediate- and poor-risk subgroup, and one third in the favourable-risk subgroup. The clinical experts explained that this represented the split seen in clinical practice, and was also typical of other clinical trials in advanced renal cell carcinoma. They further explained that the baseline characteristics were generally well balanced across the 2 treatment arms and were comparable to those of other clinical trials in the same indication. The committee concluded that the trial was generalisable to NHS clinical practice. ## Lenvatinib plus pembrolizumab provides a survival benefit compared with sunitinib The companies presented evidence from 2 data cuts: a final progression-free survival data cut from August 2020, and an updated overall survival data cut from March 2021 which had a median overall survival follow up of 33 months. The trial results demonstrated a progression-free survival benefit with lenvatinib plus pembrolizumab over sunitinib in the whole population and across all risk groups. It further demonstrated an overall survival gain for lenvatinib plus pembrolizumab in the all-risk population and in the intermediate- and poor-risk subgroup, but results in the favourable-risk subgroup were less certain. The companies explained that the CLEAR trial was not powered to provide robust analysis for the different risk subgroups, and that the results for the favourable-risk subgroup in particular could not be considered robust. But the committee recalled that different treatments are available for the different risk groups. The committee concluded that lenvatinib plus pembrolizumab seemed to provide a survival benefit compared with sunitinib. ## Subsequent therapy use is generalisable to treatment in the NHS More people in the sunitinib arm of the CLEAR trial had subsequent treatment than those in the lenvatinib plus pembrolizumab arm. There were also differences in the types of treatments received between arms; specifically, people in the sunitinib arm were more likely to have a PD‑1 inhibitor. The clinical experts commented that this was in line with expected use, because people who do not have a PD‑1 inhibitor at first line and are medically fit enough are likely to have one in a later line of therapy. The committee concluded that subsequent therapy use was generalisable to treatment in the NHS. # Indirect treatment comparison ## The EAG prefers a proportional hazards network meta-analysis despite uncertainty about whether the proportional hazards assumption holds The CLEAR trial provided direct evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib. The committee recalled that previous NICE technology appraisals (tivozanib for treating advanced renal cell carcinoma, cabozantinib for untreated advanced renal cell carcinoma, nivolumab with ipilimumab for untreated advanced renal cell carcinoma and avelumab with axitinib for untreated advanced renal cell carcinoma) had concluded that sunitinib and pazopanib are likely of equivalent clinical effectiveness, and that tivozanib may have a similar effect to sunitinib or pazopanib. The committee agreed with these conclusions. It recalled that for people with intermediate- or poor-risk disease, cabozantinib, and nivolumab plus ipilimumab, are the relevant treatment options. For these comparisons, network meta-analyses (NMAs) were needed. Both companies provided NMAs for the trial outcomes, and the external assessment group (EAG) provided its own NMAs. For time-to-event outcomes presented as hazard ratios (progression-free survival and overall survival), the EAG assessed the validity of the within-trial progression-free survival and overall survival proportional hazards assumptions, for the intermediate- and poor-risk subgroup and the favourable-risk subgroup, and the all-risk population. It concluded that the proportional hazards assumption was violated for progression-free survival in the intermediate- and poor-risk subgroup. The committee recalled that when the proportional hazards assumption holds, the hazard ratio represents an average of the relative treatment effect during the trial follow-up period, and is proportional over time. When the proportional hazards assumption is violated, the hazard ratio is not applicable to all time points across the trial follow-up periods. This means that estimated hazard ratios may not produce accurate projections of relative survival across treatment arms beyond the observed trial follow-up period. In such cases, alternative flexible modelling approaches that relax the proportional hazards assumption, such as fractional polynomial NMAs, may be used. But the EAG cautioned that the results from these approaches can also be highly uncertain and difficult to interpret. On balance, the EAG preferred a proportional hazards NMA approach for the indirect treatment comparisons. ## The companies provided results from fractional polynomial NMAs, but these are highly uncertain The 2 companies submitted alternative approaches to the NMAs, including fractional polynomial NMAs, to estimate time-varying hazard ratios in which relative treatment effect changed over time. The companies considered that the proportional hazards assumption was violated for progression-free survival and overall survival in at least 1 of the trials. Their view was that the results from the fractional polynomial NMAs gave more plausible results than the proportional hazards approach preferred by the EAG (see section 3.6). The EAG cautioned that the estimates from these flexible modelling techniques can be unintuitive and difficult to interpret. For example, flexible models that appear similar according to model fit statistics for the observed period may generate very different long-term survival estimates. Because of these limitations, the EAG explained that it does not consider the results of the fractional polynomial NMAs to be appropriate for clinical decision making. Although the results of proportional hazards NMAs when the proportional hazards assumption is violated are also uncertain, the EAG suggested that they are less uncertain than the results from more flexible models such as fractional polynomial NMAs. The committee considered the relative merits of each approach. It concluded that the proportional hazards assumption had not been shown to be violated and the fractional polynomial NMAs were highly uncertain. ## Both approaches are associated with uncertainty, but the results of the EAG's proportional hazards NMAs could be used for decision making The EAG's proportional hazards NMA approach demonstrated that there was a numerical advantage in terms of overall survival for lenvatinib plus pembrolizumab compared with cabozantinib and compared with nivolumab plus ipilimumab in the intermediate- and poor-risk subgroup. But neither of these numerical advantages was statistically significant. MSD noted that the EAG had applied a constant hazard ratio for the comparison of lenvatinib plus pembrolizumab against cabozantinib, and suggested that applying time-varying hazards was more appropriate. The committee agreed with the EAG that the proportional hazards assumption was violated for progression-free survival in the intermediate- and poor-risk subgroup, and that the results should be interpreted cautiously. It further noted the need for caution in interpreting the results of the treatment comparison in the favourable-risk subgroup and the all-risk population. The committee concluded that although the proportional hazards and more flexible fractional polynomial approaches to the NMAs were both associated with uncertainty, the EAG's approach was less uncertain and was appropriate for decision making. It noted that both approaches to the indirect treatment comparisons contained significant uncertainty that would need to be considered in its decision making. The committee further concluded that, without additional evidence, the proportional hazards approach preferred by the EAG could be used for decision making but the uncertainty would be taken into consideration. # Economic model ## The model structure is suitable for decision making The companies both used a partitioned-survival economic model that included 3 health states: pre-progression, post-progression and death. The EAG adapted MSD's model for its analysis, using different assumptions and parameter choices, because it included results for the favourable-risk subgroup. The committee concluded that the model structure was generally appropriate and consistent with models used in other appraisals for advanced renal cell carcinoma. ## The EAG's extrapolation of progression-free survival is plausible but uncertain To extrapolate progression-free survival in the model, the companies took broadly similar approaches by fitting a series of distributions to the data from the CLEAR trial. They assessed statistical fit using the Akaike information criterion (AIC) and Bayesian information criterion (BIC), with the distribution producing the lowest AIC and BIC taken as being the best-fitting distribution. For the intermediate- and poor-risk subgroup, both companies selected the exponential distribution for lenvatinib plus pembrolizumab, as this had the best statistical fit with both the AIC and BIC and also had a good visual fit to the tail of the Kaplan–Meier curve. The EAG agreed with this selection. For cabozantinib, Eisai and the EAG used the hazard ratio from their respective NMAs applied to the extrapolation for lenvatinib plus pembrolizumab. MSD considered that the hazard ratio from the EAG's analysis was implausible because it overestimated median progression-free survival for cabozantinib when compared with median progression-free survival from the CABOSUN trial (which compared cabozantinib against sunitinib in people with advanced renal cell carcinoma and intermediate- or poor-risk disease). MSD believed that the hazard ratio from its fractional polynomial NMA was a more clinically plausible estimate, being slightly closer to the median progression-free survival for cabozantinib from CABOSUN. The EAG disagreed with the rationale of MSD's criticism, because it is not methodologically appropriate to make a naive treatment comparison across different clinical trials. The EAG repeated its view that the uncertainty in extrapolating survival using fractional polynomial NMAs is greater than the uncertainty associated with using a proportional hazards approach that assumes a constant hazard ratio, even if the proportional hazards assumption may be violated. For the comparison of lenvatinib plus pembrolizumab against nivolumab plus ipilimumab, the EAG used the hazard ratio from its NMA. For the favourable-risk subgroup, the companies and the EAG selected survival curves using the same methodological approach, and agreed on the appropriateness of the selections. The committee noted MSD's view that the fractional polynomial NMA time-varying hazard ratio should be preferred over the EAG's fixed effects proportional hazards NMA. It concluded that the EAG's extrapolations for progression-free survival were clinically plausible, but that there was some uncertainty because of the limitations of the NMAs. ## The EAG's extrapolation of overall survival in the intermediate- and poor-risk subgroup is suitable for decision making For overall survival, the companies and EAG used the same approach for curve selection as described for progression-free survival (see section 3.10). For the intermediate- and poor-risk subgroup, the companies selected independent exponential distributions for lenvatinib plus pembrolizumab and sunitinib despite it not being the best fitting according to AIC statistics. They did this because these were the most conservative overall survival extrapolations, which also aligned better with long-term survival predictions from clinical experts. Other distributions in which the curves did not cross were the Weibull, log-normal, and log-logistic. The companies explained that the log-normal and log-logistic distributions produced overly optimistic extrapolations for the intermediate- and poor-risk subgroup, and so were discounted. The EAG was satisfied that the companies' approach was methodologically appropriate, but felt that the exponential distribution was not a good visual fit to the observed data from CLEAR. When the EAG examined the CLEAR trial's overall survival Kaplan–Meier data, it observed that the lenvatinib plus pembrolizumab overall survival hazard was constant beyond 50 weeks. So, it considered that the companies' choice of an exponential distribution was appropriate, but that Kaplan–Meier data should be used up to the point that censoring and small numbers of events made the data too uncertain (120 weeks). The EAG then appended the exponential distribution (based on the hazard between 50 and 150 weeks) to the CLEAR trial overall survival Kaplan–Meier data from 120 weeks onwards. The companies felt that this approach was not methodologically robust, particularly because the cut-off point was not well justified or clinically validated, and so seemed arbitrary. They felt the extrapolation should use all the available data to be clinically plausible, not just extrapolating from the tail end of the data, which is the most uncertain data from which to extrapolate. For the extrapolation of overall survival for cabozantinib, the companies expressed the same criticism of the EAG approach as they had for progression-free survival (see section 3.10). Specifically, they said that the EAG's NMA overestimated overall survival for cabozantinib when contrasted with the median overall survival seen in the CABOSUN trial, and that the estimate from MSD's fractional polynomial NMA gave a more plausible result that should be considered for decision making. The committee noted again the EAG's view that the rationale of this critique was not methodologically robust. The committee concluded that the EAG's NMAs for overall survival in the intermediate- and poor-risk subgroup were appropriate for decision making. ## The EAG's extrapolation of overall survival is not clinically plausible in the favourable-risk subgroup For the favourable-risk subgroup, there was considerable uncertainty around the validity of the CLEAR trial overall survival estimates because of the low number of events experienced by these people. The companies explained their view, informed by clinical expert opinion, that long-term overall survival for lenvatinib plus pembrolizumab would not be expected to fall below that of sunitinib. So, they considered that any model in which this occurred during extrapolation was clinically implausible. MSD had selected the exponential distribution for extrapolating overall survival for lenvatinib plus pembrolizumab, based on clinical expert opinion. The EAG explained that the exponential distribution had the lowest AIC score, was a poor fit to the CLEAR trial overall survival Kaplan–Meier data, and was likely overoptimistic. The EAG considered that survival in the favourable-risk subgroup should be no worse than survival in the intermediate- and poor-risk subgroup. Of the 7 distributions considered by MSD, 4 produced 10‑year survival estimates that were above the EAG 10‑year survival estimates for the intermediate- and poor-risk subgroup. Of these, the EAG selected the log-logistic distribution because it had the highest AIC and BIC scores. For estimating overall survival for sunitinib, the EAG explained that the 2 distributions (gamma and Weibull) selected by MSD were equally plausible; the EAG preferred the gamma distribution. The committee noted MSD's view that this distribution was optimistic for sunitinib relative to historical benchmarks, but that any other distribution would only increase this survival prediction even further. MSD agreed with the EAG that survival projections for the favourable-risk population should be higher than for the intermediate- and poor-risk subgroup, to preserve clinical plausibility. The committee noted that the Kaplan–Meier plots for the observed overall survival data for lenvatinib plus pembrolizumab in the favourable-risk subgroup were very close to that for sunitinib, with the curves almost overlaid. So, the overall survival extrapolation for sunitinib was not clinically plausible because the gamma distribution likely overestimated survival for sunitinib compared with lenvatinib plus pembrolizumab. The committee agreed that this discrepancy might be because of low patient numbers and the low number of events experienced by people in the favourable-risk subgroup, and concluded that the overall survival extrapolations in the favourable-risk subgroup were not clinically plausible. # Utility values in the economic model ## A time-to-death approach for modelling health-related quality of life is appropriate for decision making Both companies used EQ‑5D‑3L data from the CLEAR trial to estimate utility values. Eisai used the health state utility value approach, with treatment-specific utilities in the progression-free health state. MSD used a time-to-death approach in its base case, and explored the impact of using the health state utility approach in a scenario analysis. The EAG preferred the MSD time-to-death approach and incorporated it in its base case. It considered it to best reflect the health-related quality of life of long-term survivors, in the context of limited EQ‑5D‑3L data to inform post-progression utility values. The committee noted that CLEAR had a lot of long-term survivors who had moved on from first-line treatment and were still doing well on a subsequent treatment. This was particularly true of the sunitinib arm, in which people would be offered an immunotherapy at second line, compared with people in the lenvatinib plus pembrolizumab arm who would not have another immunotherapy. In this context, a health state utility value approach may be biased because of the different treatments. The committee noted that MSD's and the EAG's scenario analyses showed that the choice of utility approach did not substantially affect the cost-effectiveness estimates. It concluded that because of the wide heterogeneity in people whose disease progressed in the CLEAR trial, particularly in relation to subsequent treatments, the time-to-death approach was acceptable for decision making. ## Subsequent treatment costs after cabozantinib are likely to be underestimated in the model After treatment with cabozantinib in the intermediate- and poor-risk subgroup, people are usually offered either nivolumab monotherapy or other standard oral second-line options. Clinical advice to the EAG was that 60% of patients treated with cabozantinib would have nivolumab and 40% of patients would have a TKI. MSD's clinical advisers considered that 80% would have nivolumab. The clinical experts stated that in the NHS, it may be that even more than 80% would be offered nivolumab. This is because immunotherapy treatments offer people the greatest chance of disease control when used as early as possible, and so only people who are unable to tolerate nivolumab would be offered an anti-VEGF TKI. The committee concluded that the treatment costs for the cabozantinib arm in the model are likely to be underestimated. ## A 2-year stopping rule is in line with the evidence and appropriate for pembrolizumab The economic model used Kaplan–Meier data from the CLEAR trial to determine when people stopped treatment with pembrolizumab. The trial protocol stated that a 24‑month treatment duration with pembrolizumab (no more than 35 3‑weekly treatment cycles) should be used. People would sometimes miss a treatment cycle, for example because of feeling too fatigued, and this led to some people remaining on treatment beyond the 2‑year time point. The committee noted that this assumption depended on what happens in clinical practice, and whether a 35‑cycle or 2‑year cut off is used. The Cancer Drugs Fund clinical lead explained that the NHS can implement the committee's preference as expressed in the economic model. The clinical experts agreed and suggested that 35 cycles is likely easier to monitor from a clinical perspective and allows a full course of treatment to be provided if a treatment cycle is missed, but that 2 years is the more commonly used cut-off point. The committee concluded that, in line with the trial evidence, it is appropriate for the economic model to limit the use of pembrolizumab to 2 years. ## The waning of any treatment effect is uncertain The committee was aware that the EAG base case did not include waning of treatment effect for pembrolizumab. The EAG had concluded that pembrolizumab treatment is limited to 2 years but lenvatinib treatment can continue after this time point. The EAG acknowledged that although there is uncertainty in the long-term treatment effect of pembrolizumab, it is not possible to plausibly separate out any potential waning of treatment effect. Comments received during draft guidance consultation noted potential inconsistencies with previous appraisals. The EAG noted a similar challenge with the long-term effect of nivolumab with ipilimumab, in which ipilimumab is restricted to 4 cycles of treatment but nivolumab treatment can continue. The EAG provided a number of scenarios around the assumption for treatment discontinuation and long-term benefits. The committee concluded that a treatment waning effect is plausible but uncertain. # Cost-effectiveness estimates ## Because of the uncertainty, an acceptable ICER is around £20,000 per QALY gained NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the high levels of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be around £20,000 per QALY gained. ## Lenvatinib plus pembrolizumab is only cost effective when compared with nivolumab plus ipilimumab The committee considered the cost-effectiveness results for the all-risk population, the intermediate- and poor-risk subgroup, and the favourable-risk subgroup. Because of the included confidential patient access schemes, the ICERs cannot be reported here. In the all-risk population and the favourable-risk subgroup, the cost-effectiveness estimates were above the range that NICE considers an acceptable use of NHS resources when lenvatinib plus pembrolizumab was compared with all relevant comparators. In the intermediate- and poor-risk subgroup, the cost-effectiveness estimates were above the range that NICE considers an acceptable use of NHS resources when lenvatinib plus pembrolizumab was compared with cabozantinib, but were within the range when it was compared with nivolumab plus ipilimumab. After consultation, the company that produces nivolumab and ipilimumab (BMS) provided additional analysis of 60‑month follow-up data from the CheckMate 214 trial that compared nivolumab plus ipilimumab with sunitinib. The EAG incorporated this additional progression-free survival, overall survival and time-to-treatment-discontinuation data into its NMAs. The committee noted that this did not affect the cost-effectiveness results. # Equality ## There are no equality issues No equality issues were identified during the appraisal. # Conclusion ## Lenvatinib plus pembrolizumab is recommended in intermediate- or poor-risk disease when nivolumab plus ipilimumab would otherwise be offered The committee concluded that lenvatinib plus pembrolizumab was likely more effective than the treatments currently offered in the NHS for renal cell carcinoma, but that the most plausible cost-effectiveness estimates were above what NICE considers an acceptable use of NHS resources for most comparators. The exception was people with intermediate- or poor-risk disease who would otherwise be offered nivolumab plus ipilimumab. The committee recalled that further treatment options would be appreciated, and recalled earlier statements from the clinical experts that people with poor risk scores are more likely to have more aggressive disease, which is more responsive to immunotherapy. It further recalled that for people with intermediate- and poor-risk disease, treatment options are cabozantinib, and nivolumab plus ipilimumab, with nivolumab plus ipilimumab usually preferred for people who are medically fit enough to have it. So, lenvatinib plus pembrolizumab is recommended in intermediate- or poor-risk disease when nivolumab plus ipilimumab would otherwise be offered.	{'Recommendations': 'Lenvatinib with pembrolizumab is recommended as an option for untreated advanced renal cell carcinoma in adults, only if:\n\ntheir disease is intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria and\n\nnivolumab with ipilimumab would otherwise be offered and\n\nthe companies provide lenvatinib and pembrolizumab according to the commercial arrangements.\n\nThis recommendation is not intended to affect treatment with lenvatinib with pembrolizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for untreated advanced renal cell carcinoma includes pazopanib, tivozanib or sunitinib. Cabozantinib, and nivolumab plus ipilimumab, are also recommended for intermediate- or poor-risk cancer as defined by the International Metastatic Renal Cell Carcinoma Database Consortium.\n\nClinical trial evidence suggests that people having lenvatinib plus pembrolizumab have longer before their disease gets worse than people having sunitinib. Pazopanib and tivozanib are thought to have similar clinical effectiveness to sunitinib, so lenvatinib plus pembrolizumab is also likely to be more effective than them. Results of indirect comparisons are uncertain, but suggest that lenvatinib plus pembrolizumab may increase the time people have before their disease gets worse compared with cabozantinib, and compared with nivolumab plus ipilimumab.\n\nIn favourable-risk cancer, all the cost-effectiveness estimates are above the range that NICE considers an acceptable use of NHS resources, so lenvatinib plus pembrolizumab is not recommended for this group. In intermediate- and poor-risk cancer, the cost-effectiveness estimates are only within the range that NICE considers an acceptable use of NHS resources when nivolumab plus ipilimumab would otherwise be offered. So, lenvatinib plus pembrolizumab is recommended for this group.', 'Information about lenvatinib with pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, MSD), in combination with lenvatinib (Kisplyx, Eisai), is indicated for 'the first-line treatment of advanced renal cell carcinoma in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nThe price of lenvatinib is £1,437 per 30 4‑mg or 10‑mg capsules (excluding VAT; BNF online accessed July\xa02022). The price of pembrolizumab is £2,630 per 100\xa0mg per 4‑ml vial (excluding VAT; BNF online accessed July\xa02022).The companies have commercial arrangements. These make lenvatinib and pembrolizumab available to the NHS with discounts. The sizes of the discounts are commercial in confidence. It is the companies' responsibility to let relevant NHS organisations know details of the discounts.", 'Committee discussion': "The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# New targeted treatment\n\n## People with untreated renal cell carcinoma would welcome a new treatment option\n\nAdvanced renal cell carcinoma has a devastating impact on people's life expectancy and quality of life. Symptoms can vary widely, and depend on the location of metastases, but can include blood in urine, persistent pain in the lower back or side, extreme tiredness, loss of appetite, persistent hypertension and night sweats. Advanced or metastatic renal cell carcinoma has a poor prognosis, with 5‑year survival rates of approximately 12%. Patient experts described how the disease can have a devastating impact on a person's quality of life, and that it is not just limited to physical health, but also has a substantial impact on mental health and wellbeing. This is in part because of a lack of available treatment options, leading to people experiencing a lack of hope for the future. The clinical experts highlighted that an effective combined programmed death 1 (PD‑1) inhibitor and anti-vascular endothelial growth factor (anti‑VEGF) treatment would be welcomed by clinicians and patients to improve outcomes for people with untreated disease. The committee concluded that people with untreated renal cell carcinoma would welcome a new treatment option.\n\n# Comparators\n\n## Relevant comparators for advanced renal cell carcinoma depend on IMDC risk score\n\nThe companies explained that clinicians assess advanced renal cell carcinoma on presentation using the International Metastatic Renal Cell Carcinoma (IMDC) risk score. This measure uses a range of criteria to determine whether a person has favourable, intermediate or poor risk of survival. Risk level is determined using 6 risk factors including Karnofsky performance status score, time from original diagnosis, and levels of haemoglobin, serum calcium, neutrophils and platelets. The likelihood of survival is considered intermediate ('intermediate risk') when there are 1\xa0or 2 risk factors, and poor ('poor risk') when there are 3 or more risk factors. People without any risk factors are considered to have 'favourable risk'. This baseline score is used to determine treatment options. The clinical experts explained that people with poor risk scores are more likely to have more aggressive disease, which is more responsive to immunotherapy, and those with favourable risk scores are more likely to have less aggressive disease that is more sensitive to anti-VEGF tyrosine kinase inhibitors (TKIs). The clinical experts explained that the anti‑VEGF TKI treatments sunitinib, pazopanib and tivozanib are options for treating advanced renal cell carcinoma irrespective of risk. But for people with intermediate- and poor-risk disease, cabozantinib, and nivolumab plus ipilimumab are treatment options, with nivolumab plus ipilimumab usually preferred for people who are medically fit enough to have it. For people who are not medically fit enough, cabozantinib is more likely to be offered. Nivolumab plus ipilimumab was available through the Cancer Drugs Fund for several years, and was recommended for routine commissioning in February\xa02022. The Cancer Drugs Fund clinical lead explained that the high number of people currently receiving nivolumab plus ipilimumab in the NHS suggests that it has become an established treatment option. The committee agreed that people will have different treatments according to their IMDC risk scores, and concluded that the most appropriate comparators for lenvatinib plus pembrolizumab differ according to the IMDC risk subgroups. It further concluded that nivolumab plus ipilimumab is a relevant comparator for people with an intermediate or poor IMDC risk score.\n\n# Clinical evidence\n\n## Key evidence for lenvatinib plus pembrolizumab comes from the CLEAR trial, which is generalisable to NHS clinical practice\n\nThe companies presented evidence from the CLEAR trial, a phase\xa03 randomised controlled trial of lenvatinib plus pembrolizumab (n=355) compared with sunitinib (n=357) in advanced renal cell carcinoma. The primary endpoint of the trial was progression-free survival, with overall survival, overall response rate, adverse events and health-related quality of life as secondary endpoints. Most of the participants in both groups had previously had a nephrectomy. The trial stratified people by risk score, with approximately two thirds in the intermediate- and poor-risk subgroup, and one third in the favourable-risk subgroup. The clinical experts explained that this represented the split seen in clinical practice, and was also typical of other clinical trials in advanced renal cell carcinoma. They further explained that the baseline characteristics were generally well balanced across the 2 treatment arms and were comparable to those of other clinical trials in the same indication. The committee concluded that the trial was generalisable to NHS clinical practice.\n\n## Lenvatinib plus pembrolizumab provides a survival benefit compared with sunitinib\n\nThe companies presented evidence from 2 data cuts: a final progression-free survival data cut from August\xa02020, and an updated overall survival data cut from March\xa02021 which had a median overall survival follow up of 33\xa0months. The trial results demonstrated a progression-free survival benefit with lenvatinib plus pembrolizumab over sunitinib in the whole population and across all risk groups. It further demonstrated an overall survival gain for lenvatinib plus pembrolizumab in the all-risk population and in the intermediate- and poor-risk subgroup, but results in the favourable-risk subgroup were less certain. The companies explained that the CLEAR trial was not powered to provide robust analysis for the different risk subgroups, and that the results for the favourable-risk subgroup in particular could not be considered robust. But the committee recalled that different treatments are available for the different risk groups. The committee concluded that lenvatinib plus pembrolizumab seemed to provide a survival benefit compared with sunitinib.\n\n## Subsequent therapy use is generalisable to treatment in the NHS\n\nMore people in the sunitinib arm of the CLEAR trial had subsequent treatment than those in the lenvatinib plus pembrolizumab arm. There were also differences in the types of treatments received between arms; specifically, people in the sunitinib arm were more likely to have a PD‑1 inhibitor. The clinical experts commented that this was in line with expected use, because people who do not have a PD‑1 inhibitor at first line and are medically fit enough are likely to have one in a later line of therapy. The committee concluded that subsequent therapy use was generalisable to treatment in the NHS.\n\n# Indirect treatment comparison\n\n## The EAG prefers a proportional hazards network meta-analysis despite uncertainty about whether the proportional hazards assumption holds\n\nThe CLEAR trial provided direct evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib. The committee recalled that previous NICE technology appraisals (tivozanib for treating advanced renal cell carcinoma, cabozantinib for untreated advanced renal cell carcinoma, nivolumab with ipilimumab for untreated advanced renal cell carcinoma and avelumab with axitinib for untreated advanced renal cell carcinoma) had concluded that sunitinib and pazopanib are likely of equivalent clinical effectiveness, and that tivozanib may have a similar effect to sunitinib or pazopanib. The committee agreed with these conclusions. It recalled that for people with intermediate- or poor-risk disease, cabozantinib, and nivolumab plus ipilimumab, are the relevant treatment options. For these comparisons, network meta-analyses (NMAs) were needed. Both companies provided NMAs for the trial outcomes, and the external assessment group (EAG) provided its own NMAs. For time-to-event outcomes presented as hazard ratios (progression-free survival and overall survival), the EAG assessed the validity of the within-trial progression-free survival and overall survival proportional hazards assumptions, for the intermediate- and poor-risk subgroup and the favourable-risk subgroup, and the all-risk population. It concluded that the proportional hazards assumption was violated for progression-free survival in the intermediate- and poor-risk subgroup. The committee recalled that when the proportional hazards assumption holds, the hazard ratio represents an average of the relative treatment effect during the trial follow-up period, and is proportional over time. When the proportional hazards assumption is violated, the hazard ratio is not applicable to all time points across the trial follow-up periods. This means that estimated hazard ratios may not produce accurate projections of relative survival across treatment arms beyond the observed trial follow-up period. In such cases, alternative flexible modelling approaches that relax the proportional hazards assumption, such as fractional polynomial NMAs, may be used. But the EAG cautioned that the results from these approaches can also be highly uncertain and difficult to interpret. On balance, the EAG preferred a proportional hazards NMA approach for the indirect treatment comparisons.\n\n## The companies provided results from fractional polynomial NMAs, but these are highly uncertain\n\nThe 2 companies submitted alternative approaches to the NMAs, including fractional polynomial NMAs, to estimate time-varying hazard ratios in which relative treatment effect changed over time. The companies considered that the proportional hazards assumption was violated for progression-free survival and overall survival in at least 1 of the trials. Their view was that the results from the fractional polynomial NMAs gave more plausible results than the proportional hazards approach preferred by the EAG (see section\xa03.6). The EAG cautioned that the estimates from these flexible modelling techniques can be unintuitive and difficult to interpret. For example, flexible models that appear similar according to model fit statistics for the observed period may generate very different long-term survival estimates. Because of these limitations, the EAG explained that it does not consider the results of the fractional polynomial NMAs to be appropriate for clinical decision making. Although the results of proportional hazards NMAs when the proportional hazards assumption is violated are also uncertain, the EAG suggested that they are less uncertain than the results from more flexible models such as fractional polynomial NMAs. The committee considered the relative merits of each approach. It concluded that the proportional hazards assumption had not been shown to be violated and the fractional polynomial NMAs were highly uncertain.\n\n## Both approaches are associated with uncertainty, but the results of the EAG's proportional hazards NMAs could be used for decision making\n\nThe EAG's proportional hazards NMA approach demonstrated that there was a numerical advantage in terms of overall survival for lenvatinib plus pembrolizumab compared with cabozantinib and compared with nivolumab plus ipilimumab in the intermediate- and poor-risk subgroup. But neither of these numerical advantages was statistically significant. MSD noted that the EAG had applied a constant hazard ratio for the comparison of lenvatinib plus pembrolizumab against cabozantinib, and suggested that applying time-varying hazards was more appropriate. The committee agreed with the EAG that the proportional hazards assumption was violated for progression-free survival in the intermediate- and poor-risk subgroup, and that the results should be interpreted cautiously. It further noted the need for caution in interpreting the results of the treatment comparison in the favourable-risk subgroup and the all-risk population. The committee concluded that although the proportional hazards and more flexible fractional polynomial approaches to the NMAs were both associated with uncertainty, the EAG's approach was less uncertain and was appropriate for decision making. It noted that both approaches to the indirect treatment comparisons contained significant uncertainty that would need to be considered in its decision making. The committee further concluded that, without additional evidence, the proportional hazards approach preferred by the EAG could be used for decision making but the uncertainty would be taken into consideration.\n\n# Economic model\n\n## The model structure is suitable for decision making\n\nThe companies both used a partitioned-survival economic model that included 3 health states: pre-progression, post-progression and death. The EAG adapted MSD's model for its analysis, using different assumptions and parameter choices, because it included results for the favourable-risk subgroup. The committee concluded that the model structure was generally appropriate and consistent with models used in other appraisals for advanced renal cell carcinoma.\n\n## The EAG's extrapolation of progression-free survival is plausible but uncertain\n\nTo extrapolate progression-free survival in the model, the companies took broadly similar approaches by fitting a series of distributions to the data from the CLEAR trial. They assessed statistical fit using the Akaike information criterion (AIC) and Bayesian information criterion (BIC), with the distribution producing the lowest AIC and BIC taken as being the best-fitting distribution. For the intermediate- and poor-risk subgroup, both companies selected the exponential distribution for lenvatinib plus pembrolizumab, as this had the best statistical fit with both the AIC and BIC and also had a good visual fit to the tail of the Kaplan–Meier curve. The EAG agreed with this selection. For cabozantinib, Eisai and the EAG used the hazard ratio from their respective NMAs applied to the extrapolation for lenvatinib plus pembrolizumab. MSD considered that the hazard ratio from the EAG's analysis was implausible because it overestimated median progression-free survival for cabozantinib when compared with median progression-free survival from the CABOSUN trial (which compared cabozantinib against sunitinib in people with advanced renal cell carcinoma and intermediate- or poor-risk disease). MSD believed that the hazard ratio from its fractional polynomial NMA was a more clinically plausible estimate, being slightly closer to the median progression-free survival for cabozantinib from CABOSUN. The EAG disagreed with the rationale of MSD's criticism, because it is not methodologically appropriate to make a naive treatment comparison across different clinical trials. The EAG repeated its view that the uncertainty in extrapolating survival using fractional polynomial NMAs is greater than the uncertainty associated with using a proportional hazards approach that assumes a constant hazard ratio, even if the proportional hazards assumption may be violated. For the comparison of lenvatinib plus pembrolizumab against nivolumab plus ipilimumab, the EAG used the hazard ratio from its NMA. For the favourable-risk subgroup, the companies and the EAG selected survival curves using the same methodological approach, and agreed on the appropriateness of the selections. The committee noted MSD's view that the fractional polynomial NMA time-varying hazard ratio should be preferred over the EAG's fixed effects proportional hazards NMA. It concluded that the EAG's extrapolations for progression-free survival were clinically plausible, but that there was some uncertainty because of the limitations of the NMAs.\n\n## The EAG's extrapolation of overall survival in the intermediate- and poor-risk subgroup is suitable for decision making\n\nFor overall survival, the companies and EAG used the same approach for curve selection as described for progression-free survival (see section\xa03.10). For the intermediate- and poor-risk subgroup, the companies selected independent exponential distributions for lenvatinib plus pembrolizumab and sunitinib despite it not being the best fitting according to AIC statistics. They did this because these were the most conservative overall survival extrapolations, which also aligned better with long-term survival predictions from clinical experts. Other distributions in which the curves did not cross were the Weibull, log-normal, and log-logistic. The companies explained that the log-normal and log-logistic distributions produced overly optimistic extrapolations for the intermediate- and poor-risk subgroup, and so were discounted. The EAG was satisfied that the companies' approach was methodologically appropriate, but felt that the exponential distribution was not a good visual fit to the observed data from CLEAR. When the EAG examined the CLEAR trial's overall survival Kaplan–Meier data, it observed that the lenvatinib plus pembrolizumab overall survival hazard was constant beyond 50\xa0weeks. So, it considered that the companies' choice of an exponential distribution was appropriate, but that Kaplan–Meier data should be used up to the point that censoring and small numbers of events made the data too uncertain (120\xa0weeks). The EAG then appended the exponential distribution (based on the hazard between 50\xa0and 150\xa0weeks) to the CLEAR trial overall survival Kaplan–Meier data from 120\xa0weeks onwards. The companies felt that this approach was not methodologically robust, particularly because the cut-off point was not well justified or clinically validated, and so seemed arbitrary. They felt the extrapolation should use all the available data to be clinically plausible, not just extrapolating from the tail end of the data, which is the most uncertain data from which to extrapolate. For the extrapolation of overall survival for cabozantinib, the companies expressed the same criticism of the EAG approach as they had for progression-free survival (see section\xa03.10). Specifically, they said that the EAG's NMA overestimated overall survival for cabozantinib when contrasted with the median overall survival seen in the CABOSUN trial, and that the estimate from MSD's fractional polynomial NMA gave a more plausible result that should be considered for decision making. The committee noted again the EAG's view that the rationale of this critique was not methodologically robust. The committee concluded that the EAG's NMAs for overall survival in the intermediate- and poor-risk subgroup were appropriate for decision making.\n\n## The EAG's extrapolation of overall survival is not clinically plausible in the favourable-risk subgroup\n\nFor the favourable-risk subgroup, there was considerable uncertainty around the validity of the CLEAR trial overall survival estimates because of the low number of events experienced by these people. The companies explained their view, informed by clinical expert opinion, that long-term overall survival for lenvatinib plus pembrolizumab would not be expected to fall below that of sunitinib. So, they considered that any model in which this occurred during extrapolation was clinically implausible. MSD had selected the exponential distribution for extrapolating overall survival for lenvatinib plus pembrolizumab, based on clinical expert opinion. The EAG explained that the exponential distribution had the lowest AIC score, was a poor fit to the CLEAR trial overall survival Kaplan–Meier data, and was likely overoptimistic. The EAG considered that survival in the favourable-risk subgroup should be no worse than survival in the intermediate- and poor-risk subgroup. Of the 7 distributions considered by MSD, 4 produced 10‑year survival estimates that were above the EAG 10‑year survival estimates for the intermediate- and poor-risk subgroup. Of these, the EAG selected the log-logistic distribution because it had the highest AIC and BIC scores. For estimating overall survival for sunitinib, the EAG explained that the 2 distributions (gamma and Weibull) selected by MSD were equally plausible; the EAG preferred the gamma distribution. The committee noted MSD's view that this distribution was optimistic for sunitinib relative to historical benchmarks, but that any other distribution would only increase this survival prediction even further. MSD agreed with the EAG that survival projections for the favourable-risk population should be higher than for the intermediate- and poor-risk subgroup, to preserve clinical plausibility. The committee noted that the Kaplan–Meier plots for the observed overall survival data for lenvatinib plus pembrolizumab in the favourable-risk subgroup were very close to that for sunitinib, with the curves almost overlaid. So, the overall survival extrapolation for sunitinib was not clinically plausible because the gamma distribution likely overestimated survival for sunitinib compared with lenvatinib plus pembrolizumab. The committee agreed that this discrepancy might be because of low patient numbers and the low number of events experienced by people in the favourable-risk subgroup, and concluded that the overall survival extrapolations in the favourable-risk subgroup were not clinically plausible.\n\n# Utility values in the economic model\n\n## A time-to-death approach for modelling health-related quality of life is appropriate for decision making\n\nBoth companies used EQ‑5D‑3L data from the CLEAR trial to estimate utility values. Eisai used the health state utility value approach, with treatment-specific utilities in the progression-free health state. MSD used a time-to-death approach in its base case, and explored the impact of using the health state utility approach in a scenario analysis. The EAG preferred the MSD time-to-death approach and incorporated it in its base case. It considered it to best reflect the health-related quality of life of long-term survivors, in the context of limited EQ‑5D‑3L data to inform post-progression utility values. The committee noted that CLEAR had a lot of long-term survivors who had moved on from first-line treatment and were still doing well on a subsequent treatment. This was particularly true of the sunitinib arm, in which people would be offered an immunotherapy at second line, compared with people in the lenvatinib plus pembrolizumab arm who would not have another immunotherapy. In this context, a health state utility value approach may be biased because of the different treatments. The committee noted that MSD's and the EAG's scenario analyses showed that the choice of utility approach did not substantially affect the cost-effectiveness estimates. It concluded that because of the wide heterogeneity in people whose disease progressed in the CLEAR trial, particularly in relation to subsequent treatments, the time-to-death approach was acceptable for decision making.\n\n## Subsequent treatment costs after cabozantinib are likely to be underestimated in the model\n\nAfter treatment with cabozantinib in the intermediate- and poor-risk subgroup, people are usually offered either nivolumab monotherapy or other standard oral second-line options. Clinical advice to the EAG was that 60% of patients treated with cabozantinib would have nivolumab and 40% of patients would have a TKI. MSD's clinical advisers considered that 80% would have nivolumab. The clinical experts stated that in the NHS, it may be that even more than 80% would be offered nivolumab. This is because immunotherapy treatments offer people the greatest chance of disease control when used as early as possible, and so only people who are unable to tolerate nivolumab would be offered an anti-VEGF TKI. The committee concluded that the treatment costs for the cabozantinib arm in the model are likely to be underestimated.\n\n## A 2-year stopping rule is in line with the evidence and appropriate for pembrolizumab\n\nThe economic model used Kaplan–Meier data from the CLEAR trial to determine when people stopped treatment with pembrolizumab. The trial protocol stated that a 24‑month treatment duration with pembrolizumab (no more than 35 3‑weekly treatment cycles) should be used. People would sometimes miss a treatment cycle, for example because of feeling too fatigued, and this led to some people remaining on treatment beyond the 2‑year time point. The committee noted that this assumption depended on what happens in clinical practice, and whether a 35‑cycle or 2‑year cut off is used. The Cancer Drugs Fund clinical lead explained that the NHS can implement the committee's preference as expressed in the economic model. The clinical experts agreed and suggested that 35\xa0cycles is likely easier to monitor from a clinical perspective and allows a full course of treatment to be provided if a treatment cycle is missed, but that 2\xa0years is the more commonly used cut-off point. The committee concluded that, in line with the trial evidence, it is appropriate for the economic model to limit the use of pembrolizumab to 2\xa0years.\n\n## The waning of any treatment effect is uncertain\n\nThe committee was aware that the EAG base case did not include waning of treatment effect for pembrolizumab. The EAG had concluded that pembrolizumab treatment is limited to 2\xa0years but lenvatinib treatment can continue after this time point. The EAG acknowledged that although there is uncertainty in the long-term treatment effect of pembrolizumab, it is not possible to plausibly separate out any potential waning of treatment effect. Comments received during draft guidance consultation noted potential inconsistencies with previous appraisals. The EAG noted a similar challenge with the long-term effect of nivolumab with ipilimumab, in which ipilimumab is restricted to 4\xa0cycles of treatment but nivolumab treatment can continue. The EAG provided a number of scenarios around the assumption for treatment discontinuation and long-term benefits. The committee concluded that a treatment waning effect is plausible but uncertain.\n\n# Cost-effectiveness estimates\n\n## Because of the uncertainty, an acceptable ICER is around £20,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the high levels of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be around £20,000 per QALY gained.\n\n## Lenvatinib plus pembrolizumab is only cost effective when compared with nivolumab plus ipilimumab\n\nThe committee considered the cost-effectiveness results for the all-risk population, the intermediate- and poor-risk subgroup, and the favourable-risk subgroup. Because of the included confidential patient access schemes, the ICERs cannot be reported here. In the all-risk population and the favourable-risk subgroup, the cost-effectiveness estimates were above the range that NICE considers an acceptable use of NHS resources when lenvatinib plus pembrolizumab was compared with all relevant comparators. In the intermediate- and poor-risk subgroup, the cost-effectiveness estimates were above the range that NICE considers an acceptable use of NHS resources when lenvatinib plus pembrolizumab was compared with cabozantinib, but were within the range when it was compared with nivolumab plus ipilimumab. After consultation, the company that produces nivolumab and ipilimumab (BMS) provided additional analysis of 60‑month follow-up data from the CheckMate\xa0214 trial that compared nivolumab plus ipilimumab with sunitinib. The EAG incorporated this additional progression-free survival, overall survival and time-to-treatment-discontinuation data into its NMAs. The committee noted that this did not affect the cost-effectiveness results.\n\n# Equality\n\n## There are no equality issues\n\nNo equality issues were identified during the appraisal.\n\n# Conclusion\n\n## Lenvatinib plus pembrolizumab is recommended in intermediate- or poor-risk disease when nivolumab plus ipilimumab would otherwise be offered\n\nThe committee concluded that lenvatinib plus pembrolizumab was likely more effective than the treatments currently offered in the NHS for renal cell carcinoma, but that the most plausible cost-effectiveness estimates were above what NICE considers an acceptable use of NHS resources for most comparators. The exception was people with intermediate- or poor-risk disease who would otherwise be offered nivolumab plus ipilimumab. The committee recalled that further treatment options would be appreciated, and recalled earlier statements from the clinical experts that people with poor risk scores are more likely to have more aggressive disease, which is more responsive to immunotherapy. It further recalled that for people with intermediate- and poor-risk disease, treatment options are cabozantinib, and nivolumab plus ipilimumab, with nivolumab plus ipilimumab usually preferred for people who are medically fit enough to have it. So, lenvatinib plus pembrolizumab is recommended in intermediate- or poor-risk disease when nivolumab plus ipilimumab would otherwise be offered."}	https://www.nice.org.uk/guidance/ta858	Evidence-based recommendations on lenvatinib (Kisplyx) with pembrolizumab (Keytruda) for untreated advanced renal cell carcinoma in adults.
3d3e0ba3b2fd2201b647df3302f6b5b7a43a9c5e	nice	Transcutaneous electrical stimulation of the trigeminal nerve for ADHD	Transcutaneous electrical stimulation of the trigeminal nerve for ADHD Evidence-based recommendations on transcutaneous electrical stimulation of the trigeminal nerve for ADHD. This involves a single-use electrode patch stuck to the forehead, which sends small electrical pulses through the skin during sleep. # Recommendations Evidence on the safety and efficacy of transcutaneous electrical stimulation of the trigeminal nerve for attention deficit hyperactivity disorder (ADHD) is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. Further research could be in the form of multicentre, sham‑controlled (or other suitable comparator) trials and should include details of patient selection, treatment protocols, adherence and long-term outcomes.# The condition, current treatments and procedure # The condition Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder characterised by the core symptoms of hyperactivity, impulsivity and inattention, which are judged excessive for the person's age or level of overall development. Symptoms are usually evident in childhood and may persist into adulthood. # Current treatments Treatment for ADHD may be non-pharmacological, pharmacological or a combination of both. Non-pharmacological treatment includes cognitive behavioural therapy and parent‑training programmes (for parents of children and young people with ADHD). Pharmacological treatment includes central nervous system stimulants such as methylphenidate and amphetamines, and non-stimulants such as atomoxetine. # The procedure In this procedure, an external trigeminal nerve stimulation device is worn on the clothes and attached by wires to a single-use adhesive patch which is worn overnight. The patch contains 2 electrodes placed over the left and right V1 branches of the trigeminal nerve on the forehead. The stimulator bilaterally stimulates the trigeminal nerve for approximately 8 hours. For children, parents or carers attach the device. In a typical treatment course, stimulation is given nightly for approximately 4 weeks. Treatment duration may vary; a clinical response may take longer, and continued therapy may be needed. The mechanism of action is not completely understood. The trigeminal nerve connects to regions of the brain that may be associated with selective maintenance of attention and arousal, and it is thought that its stimulation improves the symptoms of ADHD.	{'Recommendations': 'Evidence on the safety and efficacy of transcutaneous electrical stimulation of the trigeminal nerve for attention deficit hyperactivity disorder (ADHD) is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research could be in the form of multicentre, sham‑controlled (or other suitable comparator) trials and should include details of patient selection, treatment protocols, adherence and long-term outcomes.', 'The condition, current treatments and procedure': "# The condition\n\nAttention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder characterised by the core symptoms of hyperactivity, impulsivity and inattention, which are judged excessive for the person's age or level of overall development. Symptoms are usually evident in childhood and may persist into adulthood.\n\n# Current treatments\n\nTreatment for ADHD may be non-pharmacological, pharmacological or a combination of both. Non-pharmacological treatment includes cognitive behavioural therapy and parent‑training programmes (for parents of children and young people with ADHD). Pharmacological treatment includes central nervous system stimulants such as methylphenidate and amphetamines, and non-stimulants such as atomoxetine.\n\n# The procedure\n\nIn this procedure, an external trigeminal nerve stimulation device is worn on the clothes and attached by wires to a single-use adhesive patch which is worn overnight. The patch contains 2\xa0electrodes placed over the left and right V1 branches of the trigeminal nerve on the forehead. The stimulator bilaterally stimulates the trigeminal nerve for approximately 8\xa0hours. For children, parents or carers attach the device. In a typical treatment course, stimulation is given nightly for approximately 4\xa0weeks. Treatment duration may vary; a clinical response may take longer, and continued therapy may be needed.\n\nThe mechanism of action is not completely understood. The trigeminal nerve connects to regions of the brain that may be associated with selective maintenance of attention and arousal, and it is thought that its stimulation improves the symptoms of ADHD."}	https://www.nice.org.uk/guidance/ipg748	Evidence-based recommendations on transcutaneous electrical stimulation of the trigeminal nerve for ADHD. This involves a single-use electrode patch stuck to the forehead, which sends small electrical pulses through the skin during sleep.
481d76140691b3adb30d49867a54cf958f244a66	nice	Laparoscopic insertion of a magnetic ring for gastro-oesophageal reflux disease	Laparoscopic insertion of a magnetic ring for gastro-oesophageal reflux disease Evidence-based recommendations on laparoscopic insertion of a magnetic ring for gastro-oesophageal reflux disease. This involves placing a ring of beads outside of the food pipe, just above the stomach. Magnets inside the beads hold them together to keep the food pipe closed but are weak enough to move apart to allow food or liquid to be swallowed. The aim is to prevent acid reflux. # Recommendations Evidence on the safety and efficacy of laparoscopic insertion of a magnetic ring for gastro-oesophageal reflux disease (GORD) is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page. Patient selection, and the procedure, should be done by clinicians who have specific training in the procedure, and experience in upper gastrointestinal laparoscopic surgery and managing GORD.# The condition, current treatments and procedure # The condition Gastro-oesophageal reflux disease (GORD) is a common condition in which acid from the stomach flows back up into the oesophagus. It is usually caused by the sphincter at the lower end of the oesophagus becoming weakened. Symptoms of GORD can be directly related to reflux episodes (such as heartburn, regurgitation, chest pain and nausea) or be caused by complications of the disease (such as dysphagia and respiratory difficulties). Repeated episodes of GORD can damage the lining of the oesophagus and lead to oesophageal ulceration, oesophageal stricture and Barrett's oesophagus. # Current treatments NICE's guideline on GORD and dyspepsia in adults: investigation and management describes managing GORD in adults. The standard treatments for symptomatic GORD are lifestyle modification and drug therapy. People may be offered anti-reflux surgery (usually laparoscopic fundoplication) if their symptoms do not improve, or if they develop complications despite medication or they have an intolerance to medication. Endoscopic interventions (such as endoscopic radiofrequency ablation at the gastro‑oesophageal junction) and electrical stimulation of the lower oesophageal sphincter can also be used. # The procedure The aim of laparoscopic insertion of a magnetic ring for GORD is to relieve reflux-related symptoms (such as heartburn or regurgitation) without impeding the ability to swallow, belch or vomit. The procedure is done under general anaesthesia. Using a laparoscopic approach, a specially designed sizing tool is placed around the distal oesophagus to assess the size of implant needed. The sizing tool is then removed, and the implant is placed at the gastro-oesophageal junction, with the posterior vagus nerve trunk located outside the magnetic ring. The ends of the implant are secured together to hold it in place. Intraoperative endoscopy may be used to help identify the anatomic gastro-oesophageal junction and to assess device position. The implant consists of a ring of interlinked beads, each with a weak magnetic force that holds the beads together and reduces reflux. When the person swallows, the magnetic force is overcome, allowing the ring to open. After swallowing, magnetic attraction brings the beads together and the distal oesophagus is again closed.	{'Recommendations': 'Evidence on the safety and efficacy of laparoscopic insertion of a magnetic ring for gastro-oesophageal reflux disease (GORD) is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection, and the procedure, should be done by clinicians who have specific training in the procedure, and experience in upper gastrointestinal laparoscopic surgery and managing GORD.', 'The condition, current treatments and procedure': "# The condition\n\nGastro-oesophageal reflux disease (GORD) is a common condition in which acid from the stomach flows back up into the oesophagus. It is usually caused by the sphincter at the lower end of the oesophagus becoming weakened. Symptoms of GORD can be directly related to reflux episodes (such as heartburn, regurgitation, chest pain and nausea) or be caused by complications of the disease (such as dysphagia and respiratory difficulties). Repeated episodes of GORD can damage the lining of the oesophagus and lead to oesophageal ulceration, oesophageal stricture and Barrett's oesophagus.\n\n# Current treatments\n\nNICE's guideline on GORD and dyspepsia in adults: investigation and management describes managing GORD in adults. The standard treatments for symptomatic GORD are lifestyle modification and drug therapy. People may be offered anti-reflux surgery (usually laparoscopic fundoplication) if their symptoms do not improve, or if they develop complications despite medication or they have an intolerance to medication. Endoscopic interventions (such as endoscopic radiofrequency ablation at the gastro‑oesophageal junction) and electrical stimulation of the lower oesophageal sphincter can also be used.\n\n# The procedure\n\nThe aim of laparoscopic insertion of a magnetic ring for GORD is to relieve reflux-related symptoms (such as heartburn or regurgitation) without impeding the ability to swallow, belch or vomit.\n\nThe procedure is done under general anaesthesia. Using a laparoscopic approach, a specially designed sizing tool is placed around the distal oesophagus to assess the size of implant needed. The sizing tool is then removed, and the implant is placed at the gastro-oesophageal junction, with the posterior vagus nerve trunk located outside the magnetic ring. The ends of the implant are secured together to hold it in place. Intraoperative endoscopy may be used to help identify the anatomic gastro-oesophageal junction and to assess device position.\n\nThe implant consists of a ring of interlinked beads, each with a weak magnetic force that holds the beads together and reduces reflux. When the person swallows, the magnetic force is overcome, allowing the ring to open. After swallowing, magnetic attraction brings the beads together and the distal oesophagus is again closed."}	https://www.nice.org.uk/guidance/ipg749	Evidence-based recommendations on laparoscopic insertion of a magnetic ring for gastro-oesophageal reflux disease. This involves placing a ring of beads outside of the food pipe, just above the stomach. Magnets inside the beads hold them together to keep the food pipe closed but are weak enough to move apart to allow food or liquid to be swallowed. The aim is to prevent acid reflux.
afcb5be8c76aad12d9b64c55a4ace0e4374b90da	nice	Hip fracture: management	Hip fracture: management This guideline covers managing hip fracture in adults. It aims to improve care from the time people aged 18 and over are admitted to hospital through to when they return to the community. Recommendations emphasise the importance of early surgery and coordinating care through a multidisciplinary Hip Fracture Programme to help people recover faster and regain their mobility. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Some aspects of hip fracture management are already covered by NICE guidance and are therefore outside the scope of this guideline. To ensure comprehensive management and continuity, the following NICE guidance should be referred to when developing a complete programme of care for each patient: NICE technology appraisal guidance on preventing osteoporotic fragility fractures in postmenopausal women (alendronate, denosumab, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide). NICE guidelines on falls in older people, pressure ulcers, nutrition support for adults, dementia, surgical site infections, venous thromboembolism in over 16s, delirium and osteoporosis: assessing the risk of fragility fracture. # Imaging options in occult hip fracture Offer MRI if hip fracture is suspected despite negative X‑rays of the hip of an adequate standard. If MRI is not available within 24 hours or is contraindicated, consider CT. # Timing of surgery Perform surgery on the day of, or the day after, admission. Identify and treat correctable comorbidities immediately so that surgery is not delayed by: anaemia anticoagulation volume depletion electrolyte imbalance uncontrolled diabetes uncontrolled heart failure correctable cardiac arrhythmia or ischaemia acute chest infection exacerbation of chronic chest conditions. # Analgesia Assess the person's pain: immediately upon presentation at hospital and within 30 minutes of administering initial analgesia and hourly until settled on the ward and regularly as part of routine nursing observations throughout admission. Offer immediate analgesia to people presenting at hospital with suspected hip fracture, including people with cognitive impairment. Ensure analgesia is sufficient to allow movements necessary for investigations (as indicated by the ability to tolerate passive external rotation of the leg), and for nursing care and rehabilitation. Offer paracetamol every 6 hours preoperatively unless contraindicated. Offer additional opioids if paracetamol alone does not provide sufficient preoperative pain relief. Consider adding nerve blocks if paracetamol and opioids do not provide sufficient preoperative pain relief, or to limit opioid dosage. Nerve blocks should be administered by trained personnel. Do not use nerve blocks as a substitute for early surgery. Offer paracetamol every 6 hours postoperatively unless contraindicated. Offer additional opioids if paracetamol alone does not provide sufficient postoperative pain relief. Non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended. # Anaesthesia Offer people a choice of spinal or general anaesthesia after discussing the risks and benefits. Consider intraoperative nerve blocks for all people undergoing surgery. # Planning the theatre team Schedule hip fracture surgery on a planned trauma list. Consultants or senior staff should supervise trainee and junior members of the anaesthesia, surgical and theatre teams when they carry out hip fracture procedures. # Surgical procedures Operate on people with the aim to allow them to fully weight bear (without restriction) in the immediate postoperative period. Offer replacement arthroplasty (total hip replacement or hemiarthroplasty) to people with a displaced intracapsular hip fracture. Consider total hip replacement rather than hemiarthroplasty for people with a displaced intracapsular hip fracture who: were able to walk independently out of doors with no more than the use of a stick and do not have a condition or comorbidity that makes the procedure unsuitable for them and are expected to be able to carry out activities of daily living independently beyond 2 years. For a short explanation of why the committee made the 2023 recommendation and how it might affect practice, see the rationale and impact section on total hip replacement versus hemiarthroplasty . Full details of the evidence and the committee's discussion are in evidence review B: total hip replacement versus hemiarthroplasty. Loading. Please wait. Use cemented implants in people undergoing surgery with arthroplasty. The Association of Anaesthetists of Great Britain and Ireland, British Orthopaedic Association and British Geriatric Society have produced a safety guideline on reducing the risk from cemented hemiarthroplasty for hip fracture. The guideline is not NICE accredited. Hospitals should aim to use a single type of cemented femoral component for hemiarthroplasties as standard treatment for displaced intracapsular hip fracture management. If equivalent cemented femoral component designs are available, organisations should take into account overall costs, including training needs, and how familiar the team is with the component. Record long-term data on hemiarthroplasties, including patient-reported outcomes and adverse events, for submission to a national registry. For a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on femoral component design used for hemiarthroplasties . Full details of the evidence and the committee's discussion are in evidence review A: femoral component design used for hemiarthroplasties. Loading. Please wait. Consider an anterolateral approach in favour of a posterior approach when inserting a hemiarthroplasty. Use extramedullary implants such as a sliding hip screw in preference to an intramedullary nail in people with trochanteric fractures above and including the lesser trochanter (except reverse oblique). Use an intramedullary nail to treat people with a subtrochanteric fracture. # Mobilisation strategies Offer people a physiotherapy assessment and, unless medically or surgically contraindicated, mobilisation on the day after surgery. Offer people mobilisation at least once a day and ensure regular physiotherapy review. # Multidisciplinary management From admission, offer people a formal, acute, orthogeriatric or orthopaedic ward-based Hip Fracture Programme that includes all of the following: -rthogeriatric assessment rapid optimisation of fitness for surgery early identification of individual goals for multidisciplinary rehabilitation to recover mobility and independence, and to facilitate return to pre‑fracture residence and long-term wellbeing continued, coordinated, orthogeriatric and multidisciplinary review liaison or integration with related services, particularly mental health, falls prevention, bone health, primary care and social services clinical and service governance responsibility for all stages of the pathway of care and rehabilitation, including those delivered in the community. If a hip fracture complicates or precipitates a terminal illness, the multidisciplinary team should still consider the role of surgery as part of a palliative care approach that: minimises pain and other symptoms and establishes the person's own priorities for rehabilitation and considers the person's wishes about their end-of-life care. Healthcare professionals should deliver care that minimises the person's risk of delirium and maximises their independence, by: actively looking for cognitive impairment when people first present with hip fracture reassessing people to identify delirium that may arise during their admission -ffering individualised care in line with NICE's guideline on delirium. Consider early supported discharge as part of the Hip Fracture Programme, provided the Hip Fracture Programme multidisciplinary team remains involved, and the person: is medically stable and has the mental ability to participate in continued rehabilitation and is able to transfer and mobilise short distances and has not yet achieved their full rehabilitation potential, as discussed with the person, carer and family. Only consider intermediate care (continued rehabilitation in a community hospital or residential care unit) if all of the following criteria are met: intermediate care is included in the Hip Fracture Programme and the Hip Fracture Programme team retains the clinical lead, including patient selection, agreement of length of stay and ongoing objectives for intermediate care and the Hip Fracture Programme team retains the managerial lead, ensuring that intermediate care is not resourced as a substitute for an effective acute hospital programme. People admitted from care or nursing homes should not be excluded from rehabilitation programmes in the community or hospital, or as part of an early supported discharge programme. # Patient and carer information Offer patients (or, as appropriate, their carer and/or family) verbal and printed information about treatment and care including: diagnosis choice of anaesthesia choice of analgesia and other medications surgical procedures possible complications postoperative care rehabilitation programme long-term outcomes healthcare professionals involved. # Recommendations for research The 2011, 2017 and 2023 guideline committees have made the following recommendations for research. The 2011 committee's full set of recommendations for research are detailed in the full guideline. As part of the 2017 update, the standing committee removed the recommendation for research on displaced intracapsular hip fractures and made an additional recommendation for research on undisplaced intracapsular hip fractures. Full details are available in section 3.5 of the full guideline addendum. # Imaging options in occult hip fracture In people with a continuing suspicion of a hip fracture but whose radiographs are normal, what is the clinical and cost effectiveness of CT compared with MRI, in confirming or excluding the fracture? ## Why this is important The Guideline Development Group's consensus decision to recommend CT over a radionuclide bone scan as an alternative to MRI to detect occult hip fractures reflects current NHS practice but assumes that advances in technology have made the reliability of CT comparable with that of MRI. If modern CT can be shown to have similar reliability and accuracy to MRI, then this has considerable implications because of its widespread availability out of hours and lower cost. It is therefore a high priority to confirm or refute this assumption by direct randomised comparison. The study design would need to retain MRI as the 'gold standard' for cases of uncertainty and to standardise the criteria, expertise and procedures for radiological assessment. Numbers required would depend on the degree of sensitivity and specificity (the key outcome criteria) set as target requirement for comparability, but need not necessarily be very large. # Anaesthesia What is the clinical and cost effectiveness of regional versus general anaesthesia on postoperative morbidity in people with hip fracture? ## Why this is important No recent randomised controlled trials were identified that fully address this question. The evidence is old and does not reflect current practice. In addition, in most of the studies the patients are sedated before regional anaesthesia is administered, and this is not taken into account when analysing the results. The study design for the proposed research would be best addressed by a randomised controlled trial. This would ideally be a multicentre trial including 3,000 participants in each arm. This is achievable given that there are about 70,000 to 75,000 hip fractures a year in the UK. The study should have 3 arms that look at spinal anaesthesia versus spinal anaesthesia plus sedation versus general anaesthesia; this would separate those with regional anaesthesia from those with regional anaesthesia plus sedation. The study would also need to control for surgery, especially type of fracture, prosthesis and grade of surgeon. A qualitative research component would also be helpful to study patient preference for type of anaesthesia. # Undisplaced intracapsular hip fractures For people with undisplaced (or non-displaced) intracapsular hip fracture, what features should be used to characterise the injury and what are the optimal clinical and cost-effective management strategies? ## Why this is important Between 5% and 15% of people with an intracapsular hip fracture will have an undisplaced fracture. There is variation in the UK in how undisplaced intracapsular hip fractures are recognised, resulting in some people not being offered the most appropriate treatment. Research is needed to help healthcare professionals understand the clinical characteristics of people who have undisplaced hip fracture (on anterior-posterior and lateral X‑rays) and how this relates to the effectiveness of different treatment strategies. The committee also noted a paucity of evidence for 2 of the interventions (total hip replacement and hemiarthroplasty) that could potentially be useful for people with undisplaced intracapsular hip fracture. A randomised controlled trial comparing these interventions would be beneficial. # Intensive rehabilitation therapies after hip fracture What is the clinical and cost effectiveness of additional intensive physiotherapy and/or occupational therapy (for example, progressive resistance training) after hip fracture? ## Why this is important The rapid restoration of physical and self-care functions is critical to recovery from hip fracture, particularly where the goal is to return the person to preoperative levels of function and residence. Approaches that are worthy of future development and investigation include progressive resistance training, progressive balance and gait training, supported treadmill gait re‑training, dual task training and activities of daily living training. The optimal time point at which these interventions should be started requires clarification. The ideal study design is a randomised controlled trial. Initial studies may have to focus on proof of concept and be mindful of costs. A phase 3 randomised controlled trial is required to determine clinical effectiveness and cost effectiveness. The ideal sample size will be around 400 to 500 patients, and the primary outcome should be physical function and health-related quality of life. Outcomes should also include falls. A formal sample size calculation will need to be undertaken. Outcomes should be followed over a minimum of 1 year, and compare if possible, either the recovery curve for restoration of function or time to attainment of functional goals. # Early supported discharge in care home patients What is the clinical and cost effectiveness of early supported discharge on mortality, quality of life and functional status in people with hip fracture who are admitted from a care home? ## Why this is important Residents of care and nursing homes account for about 30% of all people with hip fracture admitted to hospital. Two-thirds of these come from care homes and the remainder from nursing homes. These people are frailer, more functionally dependent and have a higher prevalence of cognitive impairment than people admitted from their own homes. One-third of those admitted from a care home are discharged to a nursing home and one-fifth are readmitted to hospital within 3 months. There are no clinical trials to define the optimal rehabilitation pathway following hip fracture for these people and therefore represent a discrete cohort where the existing meta-analyses do not apply. As a consequence, many people are denied structured rehabilitation and are discharged back to their care home or nursing home with very little or no rehabilitation input. Given the patient frailty and comorbidities, rehabilitation may have no effect on clinical outcomes for this group. However, the fact that they already live in a home where they are supported by trained care staff clearly provides an opportunity for a systematic approach to rehabilitation. Early multidisciplinary rehabilitation based in care homes or nursing homes would take advantage of the day-to-day care arrangements already in place and provide additional NHS support to deliver naturalistic rehabilitation, where problems are tackled in the person's residential setting. Early supported multidisciplinary rehabilitation could reduce hospital stay, improve early return to function, and affect both readmission rates and the level of NHS‑funded nursing care required. The research would follow a 2‑stage design: (1) an initial feasibility study to refine the selection criteria and process for reliable identification and characterisation of those considered most likely to benefit, together with the intervention package and measures for collaboration between the Hip Fracture Programme team, care-home staff and other community-based professionals and (2) a cluster randomised controlled comparison (for example, with 2 or more intervention units and matched control units) set against agreed outcome criteria. The latter should include those specified above, together with measures of the impact on care-home staff activity and cost, as well as qualitative data from patients on relevant quality-of-life variables. # Long-term effectiveness of total hip replacement What is the long-term clinical and cost effectiveness for adults (including different subgroups) undergoing total hip replacement compared with hemiarthroplasty for displaced intracapsular hip fracture? For a short explanation of why the committee made this recommendation for research, see the rationale section on total hip replacement versus hemiarthroplasty . Full details of the evidence and the committee's discussion are in evidence review B: total hip replacement versus hemiarthroplasty. Loading. Please wait. # Femoral component design In adults undergoing hemiarthroplasty for displaced intracapsular hip fracture (including in different subgroups), which femoral component design has the best long-term outcomes? For a short explanation of why the committee made this recommendation for research, see the rationale section on femoral component design used for hemiarthroplasties . Full details of the evidence and the committee's discussion are in evidence review A: femoral component design used for hemiarthroplasties. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Total hip replacement versus hemiarthroplasty Recommendation 1.6.3 ## Why the committee made the recommendation The committee discussed the clinical evidence on total hip arthroplasty versus hemiarthroplasty. They agreed that although some studies showed greater benefits for total hip arthroplasty, this was not clinically or statistically significant for most outcomes. However, a combination of the clinical evidence and the health economic model developed as part of the guideline indicated that total hip arthroplasty may have some benefits and be more cost effective than hemiarthroplasty beyond 2 years. The committee noted that although recommendation 1.6.2 states that clinicians should offer arthroplasty (either total hip arthroplasty or hemiarthroplasty) to people with a displaced intracapsular hip fracture, hemiarthroplasty tends to be used more often than total hip arthroplasty. The evidence was not strong enough for them to recommend total hip arthroplasty for everyone with a displaced intracapsular fracture. Based on their clinical knowledge and experience, the committee discussed how the long-term outcomes considered in the health economic model were important but may not be relevant to some people. For example, older people may not live long enough to experience the long-term benefits of total hip arthroplasty, and people who are not very mobile may be less concerned about the potential consequences of having a hemiarthroplasty, such as wear on the acetabulum. The committee agreed that hemiarthroplasty was a less complicated procedure than total hip arthroplasty and could result in lower dislocation rates and less blood loss. The health economic evidence on the long-term cost effectiveness and potential clinical benefits of total hip arthroplasty led the committee to recommend that clinicians should consider the procedure for those who are most likely to benefit from it beyond 2 years. The list of criteria in the recommendation represents the past (a person's level of independence before the fracture), present (how they currently present in hospital and if they are fit for the procedure on that day) and future (how much they are likely to benefit beyond 2 years). Including this list gives clinicians more discretion over who to offer total hip arthroplasty to and prevents the procedure being offered to some people who may get the same, or more, benefit from hemiarthroplasty. The committee discussed how some people with significant cognitive impairments may be at increased risk of dislocations and could be less likely to benefit from total hip arthroplasty. However, they agreed that the evidence for this was too limited to make a specific recommendation for this population. The risk of dislocation can also vary depending on the severity and type of cognitive impairment, or how much support the person has. They agreed that cognitive impairment is one of many important comorbidities that should be considered when making treatment decisions. It is more important for clinicians to think about comorbidities in the context of functionality rather than whether or not a person has them. The committee also agreed that decisions about whether someone is likely to benefit most from total hip arthroplasty or hemiarthroplasty would normally be made as part of a multidisciplinary team. The committee discussed the potential long-term benefit of total hip arthroplasty in specific groups of people, in particular younger age groups with fewer or less severe comorbidities. As the evidence did not provide much long-term data, and results were not reported for different age categories, it was agreed that further research should be carried out to inform future recommendations. A recommendation for research on long-term effectiveness of total hip replacement was therefore included to highlight the importance of comparing the effectiveness of total hip arthroplasty with hemiarthroplasty in the long term and determining the effect of each type of arthroplasty on different population subgroups. ## How the recommendation might affect practice The recommendation allows clinicians to use their discretion in deciding who is offered total hip arthroplasty. It should prevent people with mild forms of cognitive impairment being excluded from total hip arthroplasty unnecessarily. As more data becomes available on the long-term benefits of total hip arthroplasty in specific subgroups, there may be an increase in the number of people who are considered for total hip arthroplasty. Return to recommendation # Femoral component design used for hemiarthroplasties Recommendations 1.6.5 to 1.6.7 ## Why the committee made the recommendations The committee discussed the evidence on people who had been given Thompson, Exeter/Unitrax or Exeter Trauma Stem (ETS) components and agreed that health‑related quality of life, mobility, mortality, unplanned return to theatre and adverse-event outcomes were similar across all groups. The committee noted that although there were no cost-effectiveness studies, there was a large amount of variability in femoral component costs across the country for a given type of femoral component and between different types of femoral component. The Thompson component was cheaper than the ETS or Exeter/Unitrax component, but the committee were aware of future regulatory changes requiring data about implants, meaning that some older designs are unlikely to be used in the future. Without further evidence on other cemented components currently in use, they were unable to recommend one femoral component over another. To choose the most cost-effective option, the committee agreed it was important for hospitals to consider not only the cost of the component itself, but also the cost of training needs when switching to a new component, alongside any future costs relating to adverse outcomes. There may also be other considerations, in addition to costs. For example, some hospitals may choose to use a femoral component that is suitable for both hemiarthroplasty and total hip arthroplasty to allow consistency and greater efficiency in practice. The committee thought it was important from a training and development perspective that medical teams become familiar with implanting 1 single type of component as standard. They agreed that more research was needed on the effectiveness of different components. The committee agreed that although the observational evidence was for femoral components not used in the UK, it did emphasise the importance of registry data in exploring longer-term adverse outcomes such as periprosthetic fracture in trauma patients who had undergone hemiarthroplasty. Recording data on hemiarthroplasties for submission to a national registry, such as the National Joint Registry, will help to provide real-world data on the long-term effectiveness and safety of different femoral components in trauma patients. The committee commented that the 2011 recommendation to use a proven femoral component design (based on Orthopaedic Device Evaluation Panel ratings) came from evidence of people having elective surgery. They queried whether femoral component designs for elective patients who have arthritis were appropriate for trauma patients, given that arthritis often puts people at greater risk of fractures. Therefore, the committee drafted a recommendation for research on femoral component design that would allow data for this fragility fracture population to be captured. Registry data could also be used to evaluate long-term effectiveness in specific subpopulations such as people from different ethnic backgrounds and other groups for which there is currently no evidence. ## How the recommendations might affect practice By recommending 1 femoral component as standard for hemiarthroplasties, surgical teams will become familiar operating with this prosthesis and need less training in different components. Hospitals or trusts will also choose a component that provides the best value for money, but within the context of training requirements, team familiarity and overall costs. The National Joint Registry already collects data on total hip arthroplasties. Collecting data on hemiarthroplasties in this, or a similar database, may require some extra administrative work. But the real-world data will be valuable in helping future decision makers choose the most clinically and cost-effective femoral component. Having further research on the effectiveness of different femoral components in people from different population groups will also help inform decisions and address health inequalities in this area. Return to recommendations# Context Hip fracture refers to a fracture occurring in the area between the edge of the femoral head and 5 cm below the lesser trochanter (see figure 1 in the full guideline). These fractures are generally divided into 2 main groups. Those above the insertion of the capsule of the hip joint are termed intracapsular, subcapital or femoral neck fractures. Those below the insertion are extracapsular. The extracapsular group is split further into trochanteric (inter- or pertrochanteric and reverse oblique) and subtrochanteric. Hip fracture is a major public health issue due to an ever-increasing ageing population. About 65,000 hip fractures occur each year and the annual cost (not including the considerable cost of social care) for all UK hip fracture cases is about £1 billion. About 10% of people with a hip fracture die within 1 month and about one‑third within 12 months. Most of the deaths are due to associated conditions and not to the fracture itself, reflecting the high prevalence of comorbidity. Because the occurrence of fall and fracture often signals underlying ill health, a comprehensive multidisciplinary approach is required from presentation to subsequent follow‑up, including the transition from hospital to community. This guideline covers the management of hip fracture from admission to secondary care through to final return to the community and discharge from specific follow‑up. It assumes that anyone clinically suspected of having a hip fracture will normally be referred for immediate hospital assessment. It excludes (other than by cross‑reference) aspects covered by parallel NICE guidance, most notably primary and secondary prevention of fragility fractures, but recognises the importance of effective linkage to these closely related elements of comprehensive care. Although hip fracture is predominantly a phenomenon of later life (the National Hip Fracture Database reports the average age of a person with hip fracture as 84 years for men and 83 for women), it may occur at any age in people with osteoporosis or osteopenia, and this guidance is applicable to adults across the age spectrum. Management of hip fracture has improved through the research and reporting of key skills, especially by collaborative teams specialising in the care of older people (using the general designation 'orthogeriatrics'). These skills are applicable in hip fracture irrespective of age, and the guidance includes recommendations that cover the needs of younger people by drawing on such skills in an organised manner. Although not a structured service delivery evaluation, the Guideline Development Group was required to extend its remit to cover essential implications for service organisation within the NHS where these are fundamental to hip fracture management, and this has been done. The NICE surveillance review identified new studies that were consistent with the current recommendations. However, because of a low level of compliance (around 30% nationally) with the recommendation to offer total hip replacement to people with displaced intracapsular hip fractures, we have updated this part of the guideline. The 2017 update also covers interventions for undisplaced intracapsular hip fractures, which were not covered in the original guideline. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nSome aspects of hip fracture management are already covered by NICE guidance and are therefore outside the scope of this guideline. To ensure comprehensive management and continuity, the following NICE guidance should be referred to when developing a complete programme of care for each patient:\n\nNICE technology appraisal guidance on preventing osteoporotic fragility fractures in postmenopausal women (alendronate, denosumab, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide).\n\nNICE guidelines on falls in older people, pressure ulcers, nutrition support for adults, dementia, surgical site infections, venous thromboembolism in over\xa016s, delirium and osteoporosis: assessing the risk of fragility fracture.\n\n# Imaging options in occult hip fracture\n\nOffer MRI if hip fracture is suspected despite negative X‑rays of the hip of an adequate standard. If MRI is not available within 24\xa0hours or is contraindicated, consider CT. [2011, amended 2014]\n\n# Timing of surgery\n\nPerform surgery on the day of, or the day after, admission. \n\nIdentify and treat correctable comorbidities immediately so that surgery is not delayed by:\n\nanaemia\n\nanticoagulation\n\nvolume depletion\n\nelectrolyte imbalance\n\nuncontrolled diabetes\n\nuncontrolled heart failure\n\ncorrectable cardiac arrhythmia or ischaemia\n\nacute chest infection\n\nexacerbation of chronic chest conditions. \n\n# Analgesia\n\nAssess the person's pain:\n\nimmediately upon presentation at hospital and\n\nwithin 30\xa0minutes of administering initial analgesia and\n\nhourly until settled on the ward and\n\nregularly as part of routine nursing observations throughout admission. \n\nOffer immediate analgesia to people presenting at hospital with suspected hip fracture, including people with cognitive impairment. \n\nEnsure analgesia is sufficient to allow movements necessary for investigations (as indicated by the ability to tolerate passive external rotation of the leg), and for nursing care and rehabilitation. \n\nOffer paracetamol every 6\xa0hours preoperatively unless contraindicated. \n\nOffer additional opioids if paracetamol alone does not provide sufficient preoperative pain relief. \n\nConsider adding nerve blocks if paracetamol and opioids do not provide sufficient preoperative pain relief, or to limit opioid dosage. Nerve blocks should be administered by trained personnel. Do not use nerve blocks as a substitute for early surgery. \n\nOffer paracetamol every 6\xa0hours postoperatively unless contraindicated. \n\nOffer additional opioids if paracetamol alone does not provide sufficient postoperative pain relief. \n\nNon-steroidal anti-inflammatory drugs (NSAIDs) are not recommended. \n\n# Anaesthesia\n\nOffer people a choice of spinal or general anaesthesia after discussing the risks and benefits. \n\nConsider intraoperative nerve blocks for all people undergoing surgery. \n\n# Planning the theatre team\n\nSchedule hip fracture surgery on a planned trauma list. \n\nConsultants or senior staff should supervise trainee and junior members of the anaesthesia, surgical and theatre teams when they carry out hip fracture procedures. \n\n# Surgical procedures\n\nOperate on people with the aim to allow them to fully weight bear (without restriction) in the immediate postoperative period. \n\nOffer replacement arthroplasty (total hip replacement or hemiarthroplasty) to people with a displaced intracapsular hip fracture. \n\nConsider total hip replacement rather than hemiarthroplasty for people with a displaced intracapsular hip fracture who:\n\nwere able to walk independently out of doors with no more than the use of a stick and\n\ndo not have a condition or comorbidity that makes the procedure unsuitable for them and\n\nare expected to be able to carry out activities of daily living independently beyond 2\xa0years. \n\nFor a short explanation of why the committee made the 2023 recommendation and how it might affect practice, see the rationale and impact section on total hip replacement versus hemiarthroplasty\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: total hip replacement versus hemiarthroplasty.\n\nLoading. Please wait.\n\nUse cemented implants in people undergoing surgery with arthroplasty. The Association of Anaesthetists of Great Britain and Ireland, British Orthopaedic Association and British Geriatric Society have produced a safety guideline on reducing the risk from cemented hemiarthroplasty for hip fracture. The guideline is not NICE accredited.\n\nHospitals should aim to use a single type of cemented femoral component for hemiarthroplasties as standard treatment for displaced intracapsular hip fracture management. \n\nIf equivalent cemented femoral component designs are available, organisations should take into account overall costs, including training needs, and how familiar the team is with the component. \n\nRecord long-term data on hemiarthroplasties, including patient-reported outcomes and adverse events, for submission to a national registry. \n\nFor a short explanation of why the committee made the 2023 recommendations and how they might affect practice, see the rationale and impact section on femoral component design used for hemiarthroplasties\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: femoral component design used for hemiarthroplasties.\n\nLoading. Please wait.\n\nConsider an anterolateral approach in favour of a posterior approach when inserting a hemiarthroplasty. \n\nUse extramedullary implants such as a sliding hip screw in preference to an intramedullary nail in people with trochanteric fractures above and including the lesser trochanter (except reverse oblique). [2011, amended 2023]\n\nUse an intramedullary nail to treat people with a subtrochanteric fracture. \n\n# Mobilisation strategies\n\nOffer people a physiotherapy assessment and, unless medically or surgically contraindicated, mobilisation on the day after surgery. \n\nOffer people mobilisation at least once a day and ensure regular physiotherapy review. \n\n# Multidisciplinary management\n\nFrom admission, offer people a formal, acute, orthogeriatric or orthopaedic ward-based Hip Fracture Programme that includes all of the following:\n\northogeriatric assessment\n\nrapid optimisation of fitness for surgery\n\nearly identification of individual goals for multidisciplinary rehabilitation to recover mobility and independence, and to facilitate return to pre‑fracture residence and long-term wellbeing\n\ncontinued, coordinated, orthogeriatric and multidisciplinary review\n\nliaison or integration with related services, particularly mental health, falls prevention, bone health, primary care and social services\n\nclinical and service governance responsibility for all stages of the pathway of care and rehabilitation, including those delivered in the community. \n\nIf a hip fracture complicates or precipitates a terminal illness, the multidisciplinary team should still consider the role of surgery as part of a palliative care approach that:\n\nminimises pain and other symptoms and\n\nestablishes the person's own priorities for rehabilitation and\n\nconsiders the person's wishes about their end-of-life care. \n\nHealthcare professionals should deliver care that minimises the person's risk of delirium and maximises their independence, by:\n\nactively looking for cognitive impairment when people first present with hip fracture\n\nreassessing people to identify delirium that may arise during their admission\n\noffering individualised care in line with NICE's guideline on delirium. \n\nConsider early supported discharge as part of the Hip Fracture Programme, provided the Hip Fracture Programme multidisciplinary team remains involved, and the person:\n\nis medically stable and\n\nhas the mental ability to participate in continued rehabilitation and\n\nis able to transfer and mobilise short distances and\n\nhas not yet achieved their full rehabilitation potential, as discussed with the person, carer and family. \n\nOnly consider intermediate care (continued rehabilitation in a community hospital or residential care unit) if all of the following criteria are met:\n\nintermediate care is included in the Hip Fracture Programme and\n\nthe Hip Fracture Programme team retains the clinical lead, including patient selection, agreement of length of stay and ongoing objectives for intermediate care and\n\nthe Hip Fracture Programme team retains the managerial lead, ensuring that intermediate care is not resourced as a substitute for an effective acute hospital programme. \n\nPeople admitted from care or nursing homes should not be excluded from rehabilitation programmes in the community or hospital, or as part of an early supported discharge programme. \n\n# Patient and carer information\n\nOffer patients (or, as appropriate, their carer and/or family) verbal and printed information about treatment and care including:\n\ndiagnosis\n\nchoice of anaesthesia\n\nchoice of analgesia and other medications\n\nsurgical procedures\n\npossible complications\n\npostoperative care\n\nrehabilitation programme\n\nlong-term outcomes\n\nhealthcare professionals involved. ", 'Recommendations for research': "The 2011, 2017 and 2023 guideline committees have made the following recommendations for research.\n\nThe 2011 committee's full set of recommendations for research are detailed in the full guideline.\n\nAs part of the 2017 update, the standing committee removed the recommendation for research on displaced intracapsular hip fractures and made an additional recommendation for research on undisplaced intracapsular hip fractures. Full details are available in section 3.5 of the full guideline addendum.\n\n# Imaging options in occult hip fracture\n\nIn people with a continuing suspicion of a hip fracture but whose radiographs are normal, what is the clinical and cost effectiveness of CT compared with MRI, in confirming or excluding the fracture?\n\n## Why this is important\n\nThe Guideline Development Group's consensus decision to recommend CT over a radionuclide bone scan as an alternative to MRI to detect occult hip fractures reflects current NHS practice but assumes that advances in technology have made the reliability of CT comparable with that of MRI. If modern CT can be shown to have similar reliability and accuracy to MRI, then this has considerable implications because of its widespread availability out of hours and lower cost. It is therefore a high priority to confirm or refute this assumption by direct randomised comparison. The study design would need to retain MRI as the 'gold standard' for cases of uncertainty and to standardise the criteria, expertise and procedures for radiological assessment. Numbers required would depend on the degree of sensitivity and specificity (the key outcome criteria) set as target requirement for comparability, but need not necessarily be very large. \n\n# Anaesthesia\n\nWhat is the clinical and cost effectiveness of regional versus general anaesthesia on postoperative morbidity in people with hip fracture?\n\n## Why this is important\n\nNo recent randomised controlled trials were identified that fully address this question. The evidence is old and does not reflect current practice. In addition, in most of the studies the patients are sedated before regional anaesthesia is administered, and this is not taken into account when analysing the results. The study design for the proposed research would be best addressed by a randomised controlled trial. This would ideally be a multicentre trial including 3,000\xa0participants in each arm. This is achievable given that there are about 70,000\xa0to 75,000\xa0hip fractures a year in the UK. The study should have 3\xa0arms that look at spinal anaesthesia versus spinal anaesthesia plus sedation versus general anaesthesia; this would separate those with regional anaesthesia from those with regional anaesthesia plus sedation. The study would also need to control for surgery, especially type of fracture, prosthesis and grade of surgeon.\n\nA qualitative research component would also be helpful to study patient preference for type of anaesthesia. \n\n# Undisplaced intracapsular hip fractures\n\nFor people with undisplaced (or non-displaced) intracapsular hip fracture, what features should be used to characterise the injury and what are the optimal clinical and cost-effective management strategies?\n\n## Why this is important\n\nBetween 5% and 15% of people with an intracapsular hip fracture will have an undisplaced fracture. There is variation in the UK in how undisplaced intracapsular hip fractures are recognised, resulting in some people not being offered the most appropriate treatment. Research is needed to help healthcare professionals understand the clinical characteristics of people who have undisplaced hip fracture (on anterior-posterior and lateral X‑rays) and how this relates to the effectiveness of different treatment strategies.\n\nThe committee also noted a paucity of evidence for 2\xa0of the interventions (total hip replacement and hemiarthroplasty) that could potentially be useful for people with undisplaced intracapsular hip fracture. A randomised controlled trial comparing these interventions would be beneficial. \n\n# Intensive rehabilitation therapies after hip fracture\n\nWhat is the clinical and cost effectiveness of additional intensive physiotherapy and/or occupational therapy (for example, progressive resistance training) after hip fracture?\n\n## Why this is important\n\nThe rapid restoration of physical and self-care functions is critical to recovery from hip fracture, particularly where the goal is to return the person to preoperative levels of function and residence. Approaches that are worthy of future development and investigation include progressive resistance training, progressive balance and gait training, supported treadmill gait re‑training, dual task training and activities of daily living training. The optimal time point at which these interventions should be started requires clarification.\n\nThe ideal study design is a randomised controlled trial. Initial studies may have to focus on proof of concept and be mindful of costs. A phase\xa03 randomised controlled trial is required to determine clinical effectiveness and cost effectiveness. The ideal sample size will be around 400\xa0to 500\xa0patients, and the primary outcome should be physical function and health-related quality of life. Outcomes should also include falls. A formal sample size calculation will need to be undertaken. Outcomes should be followed over a minimum of 1\xa0year, and compare if possible, either the recovery curve for restoration of function or time to attainment of functional goals. \n\n# Early supported discharge in care home patients\n\nWhat is the clinical and cost effectiveness of early supported discharge on mortality, quality of life and functional status in people with hip fracture who are admitted from a care home?\n\n## Why this is important\n\nResidents of care and nursing homes account for about 30% of all people with hip fracture admitted to hospital. Two-thirds of these come from care homes and the remainder from nursing homes. These people are frailer, more functionally dependent and have a higher prevalence of cognitive impairment than people admitted from their own homes. One-third of those admitted from a care home are discharged to a nursing home and one-fifth are readmitted to hospital within 3\xa0months. There are no clinical trials to define the optimal rehabilitation pathway following hip fracture for these people and therefore represent a discrete cohort where the existing meta-analyses do not apply. As a consequence, many people are denied structured rehabilitation and are discharged back to their care home or nursing home with very little or no rehabilitation input.\n\nGiven the patient frailty and comorbidities, rehabilitation may have no effect on clinical outcomes for this group. However, the fact that they already live in a home where they are supported by trained care staff clearly provides an opportunity for a systematic approach to rehabilitation. Early multidisciplinary rehabilitation based in care homes or nursing homes would take advantage of the day-to-day care arrangements already in place and provide additional NHS support to deliver naturalistic rehabilitation, where problems are tackled in the person's residential setting.\n\nEarly supported multidisciplinary rehabilitation could reduce hospital stay, improve early return to function, and affect both readmission rates and the level of NHS‑funded nursing care required.\n\nThe research would follow a 2‑stage design: (1) an initial feasibility study to refine the selection criteria and process for reliable identification and characterisation of those considered most likely to benefit, together with the intervention package and measures for collaboration between the Hip Fracture Programme team, care-home staff and other community-based professionals and (2) a cluster randomised controlled comparison (for example, with 2\xa0or more intervention units and matched control units) set against agreed outcome criteria. The latter should include those specified above, together with measures of the impact on care-home staff activity and cost, as well as qualitative data from patients on relevant quality-of-life variables. \n\n# Long-term effectiveness of total hip replacement\n\nWhat is the long-term clinical and cost effectiveness for adults (including different subgroups) undergoing total hip replacement compared with hemiarthroplasty for displaced intracapsular hip fracture? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on total hip replacement versus hemiarthroplasty\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: total hip replacement versus hemiarthroplasty.\n\nLoading. Please wait.\n\n# Femoral component design\n\nIn adults undergoing hemiarthroplasty for displaced intracapsular hip fracture (including in different subgroups), which femoral component design has the best long-term outcomes? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on femoral component design used for hemiarthroplasties\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: femoral component design used for hemiarthroplasties.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Total hip replacement versus hemiarthroplasty\n\nRecommendation 1.6.3\n\n## Why the committee made the recommendation\n\nThe committee discussed the clinical evidence on total hip arthroplasty versus hemiarthroplasty. They agreed that although some studies showed greater benefits for total hip arthroplasty, this was not clinically or statistically significant for most outcomes. However, a combination of the clinical evidence and the health economic model developed as part of the guideline indicated that total hip arthroplasty may have some benefits and be more cost effective than hemiarthroplasty beyond 2\xa0years. The committee noted that although recommendation 1.6.2 states that clinicians should offer arthroplasty (either total hip arthroplasty or hemiarthroplasty) to people with a displaced intracapsular hip fracture, hemiarthroplasty tends to be used more often than total hip arthroplasty. The evidence was not strong enough for them to recommend total hip arthroplasty for everyone with a displaced intracapsular fracture.\n\nBased on their clinical knowledge and experience, the committee discussed how the long-term outcomes considered in the health economic model were important but may not be relevant to some people. For example, older people may not live long enough to experience the long-term benefits of total hip arthroplasty, and people who are not very mobile may be less concerned about the potential consequences of having a hemiarthroplasty, such as wear on the acetabulum. The committee agreed that hemiarthroplasty was a less complicated procedure than total hip arthroplasty and could result in lower dislocation rates and less blood loss.\n\nThe health economic evidence on the long-term cost effectiveness and potential clinical benefits of total hip arthroplasty led the committee to recommend that clinicians should consider the procedure for those who are most likely to benefit from it beyond 2\xa0years. The list of criteria in the recommendation represents the past (a person's level of independence before the fracture), present (how they currently present in hospital and if they are fit for the procedure on that day) and future (how much they are likely to benefit beyond 2\xa0years). Including this list gives clinicians more discretion over who to offer total hip arthroplasty to and prevents the procedure being offered to some people who may get the same, or more, benefit from hemiarthroplasty.\n\nThe committee discussed how some people with significant cognitive impairments may be at increased risk of dislocations and could be less likely to benefit from total hip arthroplasty. However, they agreed that the evidence for this was too limited to make a specific recommendation for this population. The risk of dislocation can also vary depending on the severity and type of cognitive impairment, or how much support the person has. They agreed that cognitive impairment is one of many important comorbidities that should be considered when making treatment decisions. It is more important for clinicians to think about comorbidities in the context of functionality rather than whether or not a person has them. The committee also agreed that decisions about whether someone is likely to benefit most from total hip arthroplasty or hemiarthroplasty would normally be made as part of a multidisciplinary team.\n\nThe committee discussed the potential long-term benefit of total hip arthroplasty in specific groups of people, in particular younger age groups with fewer or less severe comorbidities. As the evidence did not provide much long-term data, and results were not reported for different age categories, it was agreed that further research should be carried out to inform future recommendations. A recommendation for research on long-term effectiveness of total hip replacement was therefore included to highlight the importance of comparing the effectiveness of total hip arthroplasty with hemiarthroplasty in the long term and determining the effect of each type of arthroplasty on different population subgroups.\n\n## How the recommendation might affect practice\n\nThe recommendation allows clinicians to use their discretion in deciding who is offered total hip arthroplasty. It should prevent people with mild forms of cognitive impairment being excluded from total hip arthroplasty unnecessarily. As more data becomes available on the long-term benefits of total hip arthroplasty in specific subgroups, there may be an increase in the number of people who are considered for total hip arthroplasty.\n\nReturn to recommendation\n\n# Femoral component design used for hemiarthroplasties\n\nRecommendations 1.6.5 to 1.6.7\n\n## Why the committee made the recommendations\n\nThe committee discussed the evidence on people who had been given Thompson, Exeter/Unitrax or Exeter Trauma Stem (ETS) components and agreed that health‑related quality of life, mobility, mortality, unplanned return to theatre and adverse-event outcomes were similar across all groups. The committee noted that although there were no cost-effectiveness studies, there was a large amount of variability in femoral component costs across the country for a given type of femoral component and between different types of femoral component.\n\nThe Thompson component was cheaper than the ETS or Exeter/Unitrax component, but the committee were aware of future regulatory changes requiring data about implants, meaning that some older designs are unlikely to be used in the future. Without further evidence on other cemented components currently in use, they were unable to recommend one femoral component over another.\n\nTo choose the most cost-effective option, the committee agreed it was important for hospitals to consider not only the cost of the component itself, but also the cost of training needs when switching to a new component, alongside any future costs relating to adverse outcomes. There may also be other considerations, in addition to costs. For example, some hospitals may choose to use a femoral component that is suitable for both hemiarthroplasty and total hip arthroplasty to allow consistency and greater efficiency in practice. The committee thought it was important from a training and development perspective that medical teams become familiar with implanting 1\xa0single type of component as standard. They agreed that more research was needed on the effectiveness of different components.\n\nThe committee agreed that although the observational evidence was for femoral components not used in the UK, it did emphasise the importance of registry data in exploring longer-term adverse outcomes such as periprosthetic fracture in trauma patients who had undergone hemiarthroplasty. Recording data on hemiarthroplasties for submission to a national registry, such as the National Joint Registry, will help to provide real-world data on the long-term effectiveness and safety of different femoral components in trauma patients.\n\nThe committee commented that the 2011 recommendation to use a proven femoral component design (based on Orthopaedic Device Evaluation Panel ratings) came from evidence of people having elective surgery. They queried whether femoral component designs for elective patients who have arthritis were appropriate for trauma patients, given that arthritis often puts people at greater risk of fractures. Therefore, the committee drafted a recommendation for research on femoral component design that would allow data for this fragility fracture population to be captured. Registry data could also be used to evaluate long-term effectiveness in specific subpopulations such as people from different ethnic backgrounds and other groups for which there is currently no evidence.\n\n## How the recommendations might affect practice\n\nBy recommending 1\xa0femoral component as standard for hemiarthroplasties, surgical teams will become familiar operating with this prosthesis and need less training in different components. Hospitals or trusts will also choose a component that provides the best value for money, but within the context of training requirements, team familiarity and overall costs.\n\nThe National Joint Registry already collects data on total hip arthroplasties. Collecting data on hemiarthroplasties in this, or a similar database, may require some extra administrative work. But the real-world data will be valuable in helping future decision makers choose the most clinically and cost-effective femoral component. Having further research on the effectiveness of different femoral components in people from different population groups will also help inform decisions and address health inequalities in this area.\n\nReturn to recommendations", 'Context': "Hip fracture refers to a fracture occurring in the area between the edge of the femoral head and 5\xa0cm below the lesser trochanter (see figure\xa01 in the full guideline). These fractures are generally divided into 2\xa0main groups. Those above the insertion of the capsule of the hip joint are termed intracapsular, subcapital or femoral neck fractures. Those below the insertion are extracapsular. The extracapsular group is split further into trochanteric (inter- or pertrochanteric and reverse oblique) and subtrochanteric.\n\nHip fracture is a major public health issue due to an ever-increasing ageing population. About 65,000\xa0hip fractures occur each year and the annual cost (not including the considerable cost of social care) for all UK hip fracture cases is about £1\xa0billion. About 10% of people with a hip fracture die within 1\xa0month and about one‑third within 12\xa0months. Most of the deaths are due to associated conditions and not to the fracture itself, reflecting the high prevalence of comorbidity. Because the occurrence of fall and fracture often signals underlying ill health, a comprehensive multidisciplinary approach is required from presentation to subsequent follow‑up, including the transition from hospital to community.\n\nThis guideline covers the management of hip fracture from admission to secondary care through to final return to the community and discharge from specific follow‑up. It assumes that anyone clinically suspected of having a hip fracture will normally be referred for immediate hospital assessment. It excludes (other than by cross‑reference) aspects covered by parallel NICE guidance, most notably primary and secondary prevention of fragility fractures, but recognises the importance of effective linkage to these closely related elements of comprehensive care. Although hip fracture is predominantly a phenomenon of later life (the National Hip Fracture Database reports the average age of a person with hip fracture as 84\xa0years for men and 83\xa0for women), it may occur at any age in people with osteoporosis or osteopenia, and this guidance is applicable to adults across the age spectrum. Management of hip fracture has improved through the research and reporting of key skills, especially by collaborative teams specialising in the care of older people (using the general designation 'orthogeriatrics'). These skills are applicable in hip fracture irrespective of age, and the guidance includes recommendations that cover the needs of younger people by drawing on such skills in an organised manner.\n\nAlthough not a structured service delivery evaluation, the Guideline Development Group was required to extend its remit to cover essential implications for service organisation within the NHS where these are fundamental to hip fracture management, and this has been done.\n\nThe NICE surveillance review identified new studies that were consistent with the current recommendations. However, because of a low level of compliance (around 30% nationally) with the recommendation to offer total hip replacement to people with displaced intracapsular hip fractures, we have updated this part of the guideline. The 2017 update also covers interventions for undisplaced intracapsular hip fractures, which were not covered in the original guideline.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients."}	https://www.nice.org.uk/guidance/cg124	This guideline covers managing hip fracture in adults. It aims to improve care from the time people aged 18 and over are admitted to hospital through to when they return to the community. Recommendations emphasise the importance of early surgery and coordinating care through a multidisciplinary Hip Fracture Programme to help people recover faster and regain their mobility.
4ec50ade613506ecbd508b80c68ed6996380b580	nice	Mobocertinib for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy	Mobocertinib for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy Evidence-based recommendations on mobocertinib (EXKIVITY) for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy in adults. # Recommendations Mobocertinib is recommended, within its marketing authorisation, as an option for treating locally advanced or metastatic non-small-cell lung cancer (NSCLC) after platinum-based chemotherapy in adults whose tumours have epidermal growth factor receptor (EGFR) exon 20 insertion mutations. It is recommended only if the company provides it according to the commercial arrangement. Why the committee made these recommendations Current treatment for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations after platinum-based chemotherapy can include platinum-based chemotherapy again, immunotherapies, and docetaxel with or without nintedanib. Indirect comparisons using real-world evidence on immunotherapies and docetaxel with or without nintedanib, suggest that mobocertinib increases how long people live, and how long they have before their cancer gets worse. But this is uncertain because there is no direct comparison, and because of the way the real-world evidence was chosen and presented. So, the cost-effectiveness estimates are also uncertain. Mobocertinib meets NICE's criteria to be considered a life-extending treatment at the end of life. Despite the uncertainty in the cost-effectiveness estimates, they are within what NICE considers an acceptable use of NHS resources for end of life treatments. So, mobocertinib is recommended.# Information about mobocertinib # Marketing authorisation indication Mobocertinib (EXKIVITY, Takeda) 'as monotherapy is indicated for the treatment of adult patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received prior platinum-based chemotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for mobocertinib. # Price The list price for mobocertinib is £7,751 per pack of 112 capsules, each containing 40 mg of the active ingredient (excluding VAT; BNF online, accessed October 2022). The company has a commercial arrangement. This makes mobocertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical management ## People with EGFR exon 20 insertion mutation-positive advanced NSCLC will welcome a new treatment option that is targeted and well tolerated The clinical experts explained that epidermal growth factor receptor (EGFR) exon 20 insertion mutations are rare, and only seen in a few people with non-small-cell lung cancer (NSCLC). Compared with other EGFR mutations, they are more common in women, people from an East Asian family background and people who do not smoke. Exon 20 insertion mutations are also associated with poorer outcomes than other EGFR mutations. The patient experts explained that, in people with exon 20 insertion mutation-positive NSCLC, the condition has a significant effect on their quality of life, and that of their families and carers. The patient experts highlighted the need for targeted treatments that have a lower toxicity and better survival outcomes than current treatments. The clinical experts explained that there is no standard treatment for exon 20 insertion mutation-positive NSCLC (see section 3.2), and no treatment options that specifically target the mutations. The committee concluded that there is an unmet need for more effective treatment options that specifically target the exon 20 insertion mutations. # Comparators ## EGFR tyrosine kinase inhibitors are not appropriate comparators The clinical experts explained that there is no standard treatment pathway for people with exon 20 insertion mutation-positive NSCLC. Treatment choice depends on stage of disease, PD‑L1 status, and patient and clinician preference. Treatment options can include docetaxel with or without nintedanib, immunotherapy (such as atezolizumab, nivolumab or pembrolizumab) or best supportive care. Because there is no established standard treatment pathway, the company included a blended comparator arm in its submission. In its base case, the comparators were atezolizumab, and docetaxel with or without nintedanib. The clinical experts explained that EGFR tyrosine kinase inhibitors (TKIs) have limited efficacy when there are exon 20 insertion mutations. Because of this, they are rarely used in this population and are unlikely to represent standard care in the NHS. The NHS England Cancer Drugs Fund clinical lead (from here, the Cancer Drugs Fund lead) stated that EGFR TKI use is not considered routine practice in the NHS. The committee concluded that EGFR TKIs were not an appropriate comparator. ## Using a blended comparator arm increases uncertainty The company's approach compared mobocertinib with the average clinical effectiveness across all treatments in a blended comparator arm. The company explained that there was no robust way to define standard care (see section 3.2), making it unfeasible to identify a single treatment that would be displaced by mobocertinib. So, the most relevant comparator can only be accurately reflected by a blended comparator group, meaning that a full incremental analysis is not possible. The efficacy data for the blended comparator arm came from real-world evidence from 93 people across multiple treatment arms. The treatments included chemotherapy (with or without monoclonal antibodies), immunotherapy with chemotherapy, immunotherapy and EGFR TKIs. The company explained that their choice of blended comparators reflected the treatments used in 2 real-world evidence sources: US cohort data from the Flatiron study retrospective cohort data from the German Chart Review.The committee noted that EGFR TKIs have limited efficacy in people with exon 20 insertion mutations (see section 3.2). The ERG explained that including an ineffective treatment option (that is, EGFR TKIs) in the blended comparator may have led to overestimating the comparative effectiveness of mobocertinib. Also, the company included costs for a different blend of treatments (see section 3.13). In its response to the consultation, the company did scenario analyses that excluded EGFR TKIs from the real-world data for the blended comparator arm. This reduced the incremental cost-effectiveness ratio (ICER). The company did not exclude EGFR TKIs from the real-world data in its base-case analysis. This was because it reduced the sample size of the population and because the clinical experts stated that the outcomes of the real-world evidence reflected the outcomes in UK clinical practice. The ERG noted that the results of the scenarios excluding people having EGFR TKIs from the real-world data were counterintuitive. It said that it would expect excluding EGFR TKIs to result in a decrease in incremental quality-adjusted life years (QALYs), given the change in hazard ratios presented in the company's submission. The ERG was unable to verify and reproduce these analyses because of the lack of detail and justification provided. But it suspected that the method of modelling survival may have been flawed. It stated that its preference would have been to exclude people having EGFR TKIs from the real-world data in its base-case analysis. But this was not done because of the counterintuitive results provided by the company. The committee concluded that the effect of excluding EGFR TKIs from the real-world data for the blended comparator arm was uncertain. It also concluded that uncertainty remained about mobocertinib's relative effectiveness compared with current treatments. # Clinical evidence ## Mobocertinib is clinically effective, but the size of this benefit compared with current treatments is difficult to establish The main evidence for mobocertinib came from the platinum pretreated cohort (n=114) in Study AP32788‑15‑101. This was a single-arm, open-label, multicentre, phase 1 and 2 trial. Results from November 2021 showed a median investigator-assessed progression-free survival of 7.33 months (95% confidence interval 5.55 to 8.84) and a median overall survival of 20.17 months (95% CI 14.88 to 25.26). The clinical experts considered these results to be clinically meaningful. Overall, the committee concluded that Study AP32788‑15‑101 showed clinically meaningful results for mobocertinib. But it thought that the lack of direct comparative evidence meant the size of benefit compared with current treatments was difficult to establish. ## The approach used to identify real-world evidence for the blended comparator arm may not be robust and is associated with uncertainty There was no comparator in Study AP32788‑15‑101 (see section 3.4). Also, no relevant trials were identified in the company's literature review of clinical trials and real-world studies comparing mobocertinib with the relevant comparators in people with EGFR exon 20 insertion mutations. So, the company did an adjusted indirect treatment comparison comparing mobocertinib with a blended comparator (see section 3.3) using real-world evidence. Because exon 20 insertion mutations affect the outcomes of people with NSCLC, the real-world evidence included was limited to people with NSCLC with these mutations. This evidence came from Flatiron and the German Chart Review (see section 3.3). The ERG highlighted that the clinical evidence may not have been generalisable because neither Study AP32788‑15‑101 nor the real-world evidence sources were from the UK. The company stated that, based on feedback from UK oncologists and health economists, it thought the evidence from the real-world evidence sources was generalisable to the UK. The ERG noted that the company did not provide a full, justified rationale for its choice of real-world evidence sources. Also, it was concerned that the literature had not been reviewed systematically. So, the company may have missed relevant sources. The committee noted that there may be additional relevant real-world evidence sources that were not identified by the company. To address this concern, the company provided a comparison of the baseline characteristics, index treatments and clinical efficacy outcomes between the pooled real-world evidence sources used in the blended comparator arm and Minchom et al. (2021). This study was used for NICE's technology appraisal guidance in development for amivantamab for treating EGFR exon 20 insertion mutation-positive advanced NSCLC after platinum-based chemotherapy. The company noted that, despite differences in baseline characteristics and index treatments between the sources of real-world evidence, there were no meaningful differences in outcomes. The committee noted that the company had chosen to only include the initial line of therapy after platinum-based chemotherapy in the Flatiron database. But, in Minchom et al., all lines of therapy after platinum-based chemotherapy were included. The company stated that this was to avoid double-counting and that their clinical experts had said the effect of previous lines of therapy was uncertain. Survival in people who went on to have subsequent lines of therapy may have been shorter because their condition was more advanced. But, also, their survival may have been longer because only the fittest individuals would go on to have subsequent treatments. The committee noted that it was surprised by the similarity in outcomes, given this difference in baseline characteristics. Also, the ERG noted that the company did not state how it identified Flatiron and the German chart review, or why they were chosen rather than other sources of real-world evidence. It emphasised that a systematic approach is the preferred way to identify real-world evidence. It explained that a direct comparison with Minchom et al. was not appropriate because this study was not identified systematically. The committee was concerned that the company had not provided enough information on how the sources were chosen from the pool of all potential data sources. It concluded that the approach to identifying real-world evidence to use in the blended comparator arm may not have been robust and was associated with uncertainty. ## The way the company has used real-world evidence is associated with some areas of uncertainty and may bias the results The committee noted that, in general, there are several key differences between real-world evidence and clinical trials. Specific to this appraisal, efficacy and safety endpoints were followed up regularly in Study AP32788‑15‑101, but there were no scheduled visits in routine care in the real-world evidence. Also, treatment monitoring and follow up on treatment adherence may have differed between Study AP32788‑15‑101 and routine care. This would have affected the efficacy and safety results. Progressed disease is less accurately captured in retrospective studies such as Flatiron and the German Chart Review than in prospective studies such as Study AP32788‑15‑101, in which people generally have closer monitoring. The company also highlighted that the definition of the index-line of treatment differed between the German Chart Review and Flatiron. In the German Chart Review, baseline characteristics were collected at diagnosis or study entry and not at the start of each treatment line. So, the data from routine care may have been subject to bias. After the first committee meeting, the company provided more information about differences in baseline data collection and index-line treatment definition between Study AP32788‑15‑101 and the real-world evidence sources. It noted that the small differences between timepoints for collection of baseline data and definition of index treatment were expected to have a minimal effect on comparability between the sources. The committee acknowledged the known limitations with real-world evidence. But it considered that it can be valuable for resolving gaps in knowledge when best-practice methods are applied, such as those described in the NICE real-world evidence framework. It also acknowledged the rarity of exon 20 insertion mutation-positive NSCLC and the lack of direct comparative efficacy data. This meant that the real-world evidence may have been the best available source of evidence for the comparator arm. At the first committee meeting, the committee was concerned that the company had not provided enough information on data provenance, accuracy and suitability, and had not explored the effect of missing data. To address these concerns, the company provided additional information on the real-world evidence sources used in the model. It provided completed DataSAT and RECORD‑PE real-world evidence checklists for both real-world evidence sources. It also did several scenario analyses: exploring the effect of excluding EGFR TKIs from the real-world data (see section 3.3) using the sources of real-world evidence separately (rather than pooled).The company emphasised the strengths of the real-world evidence, including that it was mature, and that the baseline characteristics and efficacy outcomes between the 2 studies, and cost-effectiveness results when using each study separately, were similar. The committee acknowledged the additional information provided by the company. Overall, the committee concluded that some areas of uncertainty remained and some of this uncertainty was currently unresolvable. It noted that the level of uncertainty could have been reduced if the company had shown that a systematic approach had been taken to selecting real-world evidence sources. The committee concluded that it would take this uncertainty into account in its decision making. # Indirect treatment comparison ## The company's indirect comparison is acceptable for decision making, but using this is associated with uncertainty To account for differences in populations between Study AP32788‑15‑101 and the real-world evidence sources, the company adjusted for key prognostic variables and baseline characteristics. These were identified before the analysis by a targeted review and an oncologist survey. These results were further validated by clinical experts. Five common prognostic factors were identified. The data was adjusted using an inverse probability of treatment weighting method. Because of missing data from Flatiron, only brain metastases, age and time since advanced diagnosis were included in the base-case adjustments. Eastern Cooperative Oncology Group (ECOG) performance status and number of lines of previous treatment were excluded. At the first committee meeting, the ERG suggested using the multiple imputation method to adjust for ECOG performance status. In response, the company provided scenario analyses: imputing missing data as ECOG performance status 0 imputing missing data as ECOG performance status 1 using a complete case approach that excluded all people with missing data.These scenarios had a small effect on the ICER. The company stated that all people included in the real-world evidence sources had previously had platinum-based chemotherapy, followed by immunotherapy, chemotherapy or EGFR TKIs. This meant that they were likely to have an ECOG performance status of 0 or 1, rather than of 2 or higher (which indicates a poorer level of functioning). The Cancer Drugs Fund lead explained that, in England, most treatments for lung cancer are only commissioned for people with an ECOG performance status of 0 or 1. But the committee noted that the Flatiron database is in the US. So, it was uncertain whether people with an ECOG performance status of 2 or higher would be included in the relevant population in this database. The committee was also concerned that the company had been unable to adjust for number of previous lines of therapy between Study AP32788‑15‑101 and the real-world evidence sources. This was because the company had chosen to only include the initial line of therapy had after platinum-based chemotherapy in the Flatiron database (see section 3.5). The committee noted that about 60% of people included in Study AP32788‑15‑101 had had 2 or more previous lines of treatment. So, it was concerned that lines of previous treatment had not been included as a prognostic factor in the indirect treatment comparison. It concluded that this increased uncertainty in the results. Also, at the first committee meeting, the ERG was concerned that the method of inclusion of prognostic factors was poorly justified, and that all possible confounding variables should have been included. In response, the company provided scenario analyses in which smoking status and gender were included in the inverse probability of treatment weighting. This reduced the ICER. The ERG noted that this suggested that the company's base-case approach of including prognostic factors in the indirect comparison was likely conservative. But the ERG noted that the company did not assess other factors that could have been included, such as race and type of previous therapy. The committee considered that the indirect treatment comparison was associated with uncertainty. It concluded that this was because of the risk of confounding noted by the ERG, and the potential evidence selection issues associated with the blended comparator data (see section 3.5 and section 3.6). ## Results from the indirect treatment comparison show statistically significant improvements with mobocertinib, but are uncertain The indirect comparison showed statistically significant improvements in overall survival and progression-free survival with mobocertinib compared with the blended comparator arm. This was evidenced by the pooled real-world evidence analysis from the November 2021 data cut (overall survival hazard ratio 0.56, 95% CI 0.39 to 0.81; progression-free survival hazard ratio 0.54, 95% CI 0.36 to 0.82). The ERG explained that the results of the analyses were associated with uncertainties. These included that they were limited by the number of covariates included for adjustment and that there were issues with the company's approach to comparing clinical trial and real-world data (see section 3.7). Overall, the committee concluded that the indirect treatment comparison showed a statistically significant improvement with mobocertinib compared with standard care, but that the exact level of improvement was uncertain. # Utility values in the economic model ## There is uncertainty surrounding the most appropriate utility values to use in the economic model The company mapped EQ‑5D‑5L data from Study AP32788‑15‑101 to EQ‑5D‑3L. The mapped EQ‑5D‑3L utility scores were analysed using a type of regression model. This model included baseline utility, progression status and ongoing treatment emergent adverse event (TEAE) status of grade 3 or more. In the base case, the company used health-state specific utilities without TEAEs, which were included separately. The ERG noted that the company's approach to selecting utility values was reasonable. But the ERG also noted that the utility values for progression-free and progressed disease were higher than what was used in past appraisals in NSCLC (that is, NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy and on nintedanib for previously treated locally advanced, metastatic or locally recurrent NSCLC). The exact utility values are considered confidential by the company and cannot be reported here. The company noted that using EQ‑5D data from a relevant clinical trial is in line with NICE's reference case. It also noted that its clinical experts had stated that utility values from non-mutationally driven NSCLC are not comparable with the population relevant for this appraisal. The committee noted that the utility values for both the progression-free survival and progressed-disease states were high compared with those for the general population and those used in past appraisals. It also noted that the difference between the utility values in the progression-free survival and progressed-disease states was smaller than has been seen in past appraisals. It noted that utility values in Study AP32788‑15‑101 were collected up until 30 days after the end of treatment. It also noted that compliance dropped from greater than 95% at all points during the trial period to 62% at the end of treatment visit and to 52% 30 days after last dose visit. So, the utility data collected in the trial only captured a short amount of time in the progressed-disease health state. The committee also considered that mobocertinib is an oral treatment and can be taken at home, which may present additional quality-of-life benefits compared with intravenous therapies (such as nivolumab). It concluded that there was uncertainty surrounding the most appropriate utility values to use in the economic model. It also concluded that the true utility values could fall somewhere between the utility values collected from Study AP32788‑15‑101 and the values from NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy. # Assumptions in the economic model ## The company's model structure is suitable for decision making The company used a partitioned survival model with 3 mutually exclusive health states: progression-free survival, progressed disease and death. This approach allowed the company to use outcome data from the adjusted treatment comparison. It also enabled the clinical benefits of mobocertinib to be captured by reflecting the increased proportion of people expected to be alive or progression free over time. The committee agreed that the model structure was suitable for decision making. ## The ERG's choice of survival curves are more plausible than the company's The company fitted parametric models to the Kaplan–Meier curves for weighted overall survival, progression-free survival and time to treatment discontinuation (TTD) for the mobocertinib and blended comparator treatment arms. Across all outcomes, hazards were assumed to be proportional between treatment arms, and joint models were fitted with treatment as a covariate. In its original submission, the company fitted a joint generalised gamma distribution for overall survival and a joint exponential distribution for both progression-free survival and TTD. At the first committee meeting, the ERG disagreed with the company's choice of progression-free survival and TTD models. This was because the observed progression-free survival and TTD hazard functions (rate at which events occurred) were not constant over time. This contradicted the underlying properties of an exponential distribution, making the distribution unsuitable. The ERG also highlighted that the exponential distribution had the worst statistical fits compared with other distributions. It preferred the generalised gamma distribution for progression-free survival and the Gompertz distribution for TTD. In response to consultation, the company used a generalised gamma distribution for overall survival, progression-free survival and TTD. It explained that it preferred using the generalised gamma distribution for TTD in its base case because it aligned with the distribution used to model progression-free survival. The company noted that: Using a Gompertz distribution for TTD led to a mismatch between the TTD and progression-free survival curves, in which the cancer continued to progress without treatment stopping, which lacked face validity. There was little difference between statistical fit for the Gompertz and generalised gamma distributions. The generalised gamma better aligned with clinical expert feedback suggesting no one would be having treatment by year 5.The company presented a scenario analysis using the Gompertz distribution for TTD, which increased the ICER. The ERG considered that the company did not provide enough new compelling justification on why the mismatch between TTD and progression-free survival distributions was a problem in this case. The committee retained its preference for the Gompertz distribution for TTD. It agreed that the ERG's choice of survival curves was more plausible than the company's choice of survival curves. ## It is appropriate to exclude treatment effect waning from the modelling The company's base case assumed that mobocertinib's treatment effect continued throughout the time horizon. The company explained that the survival data for mobocertinib was mature. Also, mobocertinib is usually given until progression and no stopping rules apply. The company assumed that any treatment effect waning would have been captured in the trial follow-up period. The ERG agreed with the company's approach. The committee noted that treatment effect waning has typically been applied in previous appraisals for immunotherapies when stopping rules have been applied. It also noted the limited impact of the treatment effect waning scenario done by the ERG. Based on this, the committee concluded that it was appropriate to exclude treatment effect waning from the modelling. ## The mismatch of efficacy, cost and disutility increases uncertainty, but the company's approach to costs is conservative The company included costs and disutility of adverse events for docetaxel with or without nintedanib, and atezolizumab in the blended comparator arm. Efficacy outcomes were included from other treatments, for example, EGFR TKIs. But EGFR TKIs were not considered to be appropriate comparators (see section 3.2), so the company excluded their costs and disutilities. The company also highlighted that atezolizumab's list price is the cheapest, and that it is the most frequently used immunotherapy. So, the exclusion of pembrolizumab and nivolumab was a conservative assumption. The ERG highlighted that only 8 out of 93 people in the pooled real-world evidence had had 1 of the 3 treatments in the blended comparator arm. This resulted in a mismatch between the treatments used in the real-world evidence that informed efficacy and the treatments that informed the cost and adverse events disutility in the model. The committee saw scenarios including the costs of EGFR TKIs and immunotherapies. It agreed that the company had taken a conservative approach by excluding the costs of EGFR TKIs and immunotherapy treatments. As previously noted by the committee (see section 3.2), including EGFR TKIs in the efficacy outcomes could have underestimated the comparator efficacy. The committee concluded that the mismatch of efficacy, and cost and disutility of adverse events data increased the uncertainty in the cost-effectiveness results. But it acknowledged that the company's approach to costs was conservative. # Costs in the economic model ## Exon 20 insertion mutation testing costs should be included in the economic model In line with section 5.9.1 of NICE's guide to the methods of technology appraisal, the NICE scope for mobocertinib states that the 'costs associated with diagnostic testing for EGFR in people with NSCLC who would not otherwise have been tested' should be modelled. The company did not include exon 20 insertion mutation testing in the economic modelling for mobocertinib. It explained that these costs were expected to be included in routine NHS testing. The Cancer Drugs Fund lead explained that the gold standard for detecting exon 20 insertion mutations is next generation sequencing. But the availability of this varies across the NHS. Many treatment centres use polymerase chain reaction (PCR) instead, which is expected to identify about 50% of people with exon 20 insertion mutation-positive NSCLC. Because of this, using mobocertinib (or other exon 20 insertion mutation targeted treatments) in the NHS would mean switching from current local PCR testing to next generation sequencing at Genomic Laboratory Hubs. This could result in a 50% increase in detecting people with exon 20 insertion mutation-positive NSCLC. But the Cancer Drugs Fund lead suggested that this increase may only be 33% because there is already some next generation sequencing testing being done. They explained that it would be appropriate to add a testing cost of £550 per person with exon 20 insertion mutation-positive NSCLC. This cost would account for a 2% incidence of exon 20 insertion mutations, and the standard cost of adding a mutation test onto a next generation sequencing panel of £34. The company presented scenario analyses including the cost of genomic testing in the mobocertinib arm only and in both treatment arms in the model. The ERG stated that if exon 20 insertion mutation testing is not embedded in NHS practice for people with NSCLC, then additional diagnostic testing would be applicable with the introduction of mobocertinib. The committee concluded that exon 20 insertion costs should be included in the mobocertinib arm of the economic model. # End of life ## Mobocertinib meets the criteria to be considered a life-extending treatment at the end of life The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that mobocertinib met the criteria for being a life-extending treatment for people with short life expectancy (normally less than 24 months). Both the company's base case and the model using the committee's preferred assumptions predicted a mean and median overall survival with current standard care of substantially less than 24 months. The mean overall survival for the blended comparator arm was 16.2 months from the company's base-case model. Having considered the survival data from the real-world evidence, the committee concluded that mobocertinib met the end of life criterion for short life expectancy. The company's and ERG's modelling suggested that mobocertinib was associated with a gain in overall survival of substantially more than 3 months. The company's base-case model showed a mean overall survival of 27.1 months for mobocertinib, an increase of 10.8 months. The committee noted the uncertainty in the real-world evidence and model estimates previously discussed (see section 3.8). It concluded that, despite the uncertainty in the size of the survival gain, mobocertinib met both of NICE's criteria to be considered a life-extending treatment at the end of life. # Cost-effectiveness results ## Because of the uncertainty, the maximum acceptable ICER would be below £50,000 per QALY gained NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. It recalled its conclusion from the first meeting that an acceptable ICER would be around £20,000 per QALY gained. But the committee also agreed that the end of life criteria applied to mobocertinib. When the end of life weighting was applied, the committee said that the maximum acceptable ICER would be substantially less than £50,000 per QALY gained. The committee acknowledged that, since the first committee meeting, the company had attempted to reduce the uncertainty around the use and selection of real-world evidence. But it noted the high level of outstanding uncertainty in the company's model, specifically: the lack of direct comparative evidence the lack of fully incremental analysis because of using a blended comparator the effect of evidence selection issues because of the lack of a systematic approach to identifying real-world evidence sources the potential for residual confounding in the indirect treatment comparison.The committee also took into account the lack of targeted treatment options available for this specific mutation, the emotional burden on people with EGFR exon 20 insertion mutation-positive NSCLC and their caregivers. It also heard that people with lung cancer may experience stigma, which could delay them seeking treatment. It noted the rarity of EGFR exon 20 insertion mutation-positive NSCLC and the difficulties this can create in generating evidence. The fact that mobocertinib met the end of life criteria in this indication was also considered. Taking these factors into account and the uncertainty that remained, the committee concluded that an acceptable ICER would need to be below the maximum acceptable ICER for end of life treatments (£50,000 per QALY gained) to be considered a cost-effective use of NHS resources. ## The cost-effectiveness estimates are uncertain but are likely within what NICE considers to be an acceptable use of NHS resources The company's updated base-case ICER for mobocertinib compared with the blended comparator arm was markedly below £50,000 per QALY gained. This was when confidential commercial arrangements for mobocertinib and all the comparators were included, so the exact ICERs cannot be reported here. The company's base case included the following assumptions, which were preferred by the committee: excluding the costs of EGFR TKIs from the blended comparator arm (see section 3.13) a joint generalised gamma model for overall survival and progression-free survival (see section 3.11) using the individual patient weighting method for the indirect treatment comparison (see section 3.7) excluding treatment waning (see section 3.12).The company's updated base case used a joint generalised gamma distribution for TTD. This differed from the committee's preferred approach, which was to use a joint Gompertz distribution for TTD (see section 3.11). The committee considered the scenario including its preferred assumptions using a joint Gompertz model for TTD and the additional testing costs for EGFR exon 20 insertion mutation testing. It noted that the ICER for this scenario was also below £50,000 per QALY gained. The exact ICERs are commercial in confidence and cannot be reported here. But the committee noted that there was uncertainty about the most appropriate utility values to use in the economic model and that the utility values from the company's trial lacked face validity (see section 3.9). It also noted that a scenario analysis using utility values from NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy produced an ICER slightly above £50,000 per QALY gained. But the committee also noted that some of the assumptions included in the company's base-case analysis were conservative, for example, excluding the costs of pembrolizumab and nivolumab in the blended comparator arm. The committee considered the uncertainty and the range in the cost-effectiveness estimates. But it agreed that the most plausible ICER was sufficiently below £50,000 per QALY gained to be considered an acceptable use of NHS resources. # Other factors ## Mobocertinib is innovative but all benefits are captured in the analysis The committee considered mobocertinib to be innovative because it represents a step-change in the treatment of exon 20 insertion mutation-positive NSCLC. The company did not present any evidence to suggest that there were additional benefits that were not captured in the QALY calculations. The committee considered the unmet need and the burden of stigma in its deliberations, and recognised that mobocertinib provides important benefits for people with exon 20 insertion mutation-positive NSCLC. But it did not consider that there were any additional benefits that had not been captured in the QALY calculations. ## There are no equality issues relevant to the recommendations The company explained that exon 20 insertion mutation-positive NSCLC is associated with a higher prevalence in people from an East Asian family background. Differences in prevalence cannot usually be resolved in a technology appraisal, although the committee can consider whether a specific equality issue has a significant impact on access to treatment. Also, the recommendation for mobocertinib is for the full population in the marketing authorisation. So, the committee agreed that its recommendations would not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no equality issues relevant to the recommendations. # Conclusion ## Mobocertinib is recommended for routine use The committee concluded that there was substantial uncertainty in the cost-effectiveness estimates. But it agreed that the most likely estimates are within what NICE considers a cost-effective use of NHS resources when the end of life modifier is applied. So, mobocertinib is recommended as an option for treating EGFR exon 20 insertion mutation-positive advanced NSCLC after platinum-based chemotherapy.	{'Recommendations': "Mobocertinib is recommended, within its marketing authorisation, as an option for treating locally advanced or metastatic non-small-cell lung cancer (NSCLC) after platinum-based chemotherapy in adults whose tumours have epidermal growth factor receptor (EGFR) exon\xa020 insertion mutations. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for locally advanced or metastatic NSCLC with EGFR exon\xa020 insertion mutations after platinum-based chemotherapy can include platinum-based chemotherapy again, immunotherapies, and docetaxel with or without nintedanib.\n\nIndirect comparisons using real-world evidence on immunotherapies and docetaxel with or without nintedanib, suggest that mobocertinib increases how long people live, and how long they have before their cancer gets worse. But this is uncertain because there is no direct comparison, and because of the way the real-world evidence was chosen and presented. So, the cost-effectiveness estimates are also uncertain.\n\nMobocertinib meets NICE's criteria to be considered a life-extending treatment at the end of life. Despite the uncertainty in the cost-effectiveness estimates, they are within what NICE considers an acceptable use of NHS resources for end of life treatments. So, mobocertinib is recommended.", 'Information about mobocertinib': "# Marketing authorisation indication\n\nMobocertinib (EXKIVITY, Takeda) 'as monotherapy is indicated for the treatment of adult patients with epidermal growth factor receptor (EGFR) exon\xa020 insertion mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received prior platinum-based chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for mobocertinib.\n\n# Price\n\nThe list price for mobocertinib is £7,751 per pack of 112\xa0capsules, each containing 40\xa0mg of the active ingredient (excluding VAT; BNF online, accessed October 2022).\n\nThe company has a commercial arrangement. This makes mobocertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## People with EGFR exon\xa020 insertion mutation-positive advanced NSCLC will welcome a new treatment option that is targeted and well tolerated\n\nThe clinical experts explained that epidermal growth factor receptor (EGFR) exon\xa020 insertion mutations are rare, and only seen in a few people with non-small-cell lung cancer (NSCLC). Compared with other EGFR mutations, they are more common in women, people from an East Asian family background and people who do not smoke. Exon\xa020 insertion mutations are also associated with poorer outcomes than other EGFR mutations. The patient experts explained that, in people with exon\xa020 insertion mutation-positive NSCLC, the condition has a significant effect on their quality of life, and that of their families and carers. The patient experts highlighted the need for targeted treatments that have a lower toxicity and better survival outcomes than current treatments. The clinical experts explained that there is no standard treatment for exon\xa020 insertion mutation-positive NSCLC (see section\xa03.2), and no treatment options that specifically target the mutations. The committee concluded that there is an unmet need for more effective treatment options that specifically target the exon\xa020 insertion mutations.\n\n# Comparators\n\n## EGFR tyrosine kinase inhibitors are not appropriate comparators\n\nThe clinical experts explained that there is no standard treatment pathway for people with exon\xa020 insertion mutation-positive NSCLC. Treatment choice depends on stage of disease, PD‑L1 status, and patient and clinician preference. Treatment options can include docetaxel with or without nintedanib, immunotherapy (such as atezolizumab, nivolumab or pembrolizumab) or best supportive care. Because there is no established standard treatment pathway, the company included a blended comparator arm in its submission. In its base case, the comparators were atezolizumab, and docetaxel with or without nintedanib. The clinical experts explained that EGFR tyrosine kinase inhibitors (TKIs) have limited efficacy when there are exon\xa020 insertion mutations. Because of this, they are rarely used in this population and are unlikely to represent standard care in the NHS. The NHS England Cancer Drugs Fund clinical lead (from here, the Cancer Drugs Fund lead) stated that EGFR TKI use is not considered routine practice in the NHS. The committee concluded that EGFR TKIs were not an appropriate comparator.\n\n## Using a blended comparator arm increases uncertainty\n\nThe company's approach compared mobocertinib with the average clinical effectiveness across all treatments in a blended comparator arm. The company explained that there was no robust way to define standard care (see section\xa03.2), making it unfeasible to identify a single treatment that would be displaced by mobocertinib. So, the most relevant comparator can only be accurately reflected by a blended comparator group, meaning that a full incremental analysis is not possible. The efficacy data for the blended comparator arm came from real-world evidence from 93\xa0people across multiple treatment arms. The treatments included chemotherapy (with or without monoclonal antibodies), immunotherapy with chemotherapy, immunotherapy and EGFR TKIs. The company explained that their choice of blended comparators reflected the treatments used in 2\xa0real-world evidence sources:\n\nUS cohort data from the Flatiron study\n\nretrospective cohort data from the German Chart Review.The committee noted that EGFR TKIs have limited efficacy in people with exon\xa020 insertion mutations (see section\xa03.2). The ERG explained that including an ineffective treatment option (that is, EGFR TKIs) in the blended comparator may have led to overestimating the comparative effectiveness of mobocertinib. Also, the company included costs for a different blend of treatments (see section\xa03.13). In its response to the consultation, the company did scenario analyses that excluded EGFR TKIs from the real-world data for the blended comparator arm. This reduced the incremental cost-effectiveness ratio (ICER). The company did not exclude EGFR TKIs from the real-world data in its base-case analysis. This was because it reduced the sample size of the population and because the clinical experts stated that the outcomes of the real-world evidence reflected the outcomes in UK clinical practice. The ERG noted that the results of the scenarios excluding people having EGFR TKIs from the real-world data were counterintuitive. It said that it would expect excluding EGFR TKIs to result in a decrease in incremental quality-adjusted life years (QALYs), given the change in hazard ratios presented in the company's submission. The ERG was unable to verify and reproduce these analyses because of the lack of detail and justification provided. But it suspected that the method of modelling survival may have been flawed. It stated that its preference would have been to exclude people having EGFR TKIs from the real-world data in its base-case analysis. But this was not done because of the counterintuitive results provided by the company. The committee concluded that the effect of excluding EGFR TKIs from the real-world data for the blended comparator arm was uncertain. It also concluded that uncertainty remained about mobocertinib's relative effectiveness compared with current treatments.\n\n# Clinical evidence\n\n## Mobocertinib is clinically effective, but the size of this benefit compared with current treatments is difficult to establish\n\nThe main evidence for mobocertinib came from the platinum pretreated cohort (n=114) in Study AP32788‑15‑101. This was a single-arm, open-label, multicentre, phase\xa01 and\xa02 trial. Results from November 2021 showed a median investigator-assessed progression-free survival of 7.33\xa0months (95% confidence interval [CI] 5.55\xa0to\xa08.84) and a median overall survival of 20.17\xa0months (95%\xa0CI 14.88\xa0to\xa025.26). The clinical experts considered these results to be clinically meaningful. Overall, the committee concluded that Study AP32788‑15‑101 showed clinically meaningful results for mobocertinib. But it thought that the lack of direct comparative evidence meant the size of benefit compared with current treatments was difficult to establish.\n\n## The approach used to identify real-world evidence for the blended comparator arm may not be robust and is associated with uncertainty\n\nThere was no comparator in Study AP32788‑15‑101 (see section\xa03.4). Also, no relevant trials were identified in the company's literature review of clinical trials and real-world studies comparing mobocertinib with the relevant comparators in people with EGFR exon\xa020 insertion mutations. So, the company did an adjusted indirect treatment comparison comparing mobocertinib with a blended comparator (see section\xa03.3) using real-world evidence. Because exon\xa020 insertion mutations affect the outcomes of people with NSCLC, the real-world evidence included was limited to people with NSCLC with these mutations. This evidence came from Flatiron and the German Chart Review (see section\xa03.3). The ERG highlighted that the clinical evidence may not have been generalisable because neither Study AP32788‑15‑101 nor the real-world evidence sources were from the UK. The company stated that, based on feedback from UK oncologists and health economists, it thought the evidence from the real-world evidence sources was generalisable to the UK. The ERG noted that the company did not provide a full, justified rationale for its choice of real-world evidence sources. Also, it was concerned that the literature had not been reviewed systematically. So, the company may have missed relevant sources. The committee noted that there may be additional relevant real-world evidence sources that were not identified by the company. To address this concern, the company provided a comparison of the baseline characteristics, index treatments and clinical efficacy outcomes between the pooled real-world evidence sources used in the blended comparator arm and Minchom et al. (2021). This study was used for NICE's technology appraisal guidance in development for amivantamab for treating EGFR exon 20 insertion mutation-positive advanced NSCLC after platinum-based chemotherapy. The company noted that, despite differences in baseline characteristics and index treatments between the sources of real-world evidence, there were no meaningful differences in outcomes. The committee noted that the company had chosen to only include the initial line of therapy after platinum-based chemotherapy in the Flatiron database. But, in Minchom et al., all lines of therapy after platinum-based chemotherapy were included. The company stated that this was to avoid double-counting and that their clinical experts had said the effect of previous lines of therapy was uncertain. Survival in people who went on to have subsequent lines of therapy may have been shorter because their condition was more advanced. But, also, their survival may have been longer because only the fittest individuals would go on to have subsequent treatments. The committee noted that it was surprised by the similarity in outcomes, given this difference in baseline characteristics. Also, the ERG noted that the company did not state how it identified Flatiron and the German chart review, or why they were chosen rather than other sources of real-world evidence. It emphasised that a systematic approach is the preferred way to identify real-world evidence. It explained that a direct comparison with Minchom et al. was not appropriate because this study was not identified systematically. The committee was concerned that the company had not provided enough information on how the sources were chosen from the pool of all potential data sources. It concluded that the approach to identifying real-world evidence to use in the blended comparator arm may not have been robust and was associated with uncertainty.\n\n## The way the company has used real-world evidence is associated with some areas of uncertainty and may bias the results\n\nThe committee noted that, in general, there are several key differences between real-world evidence and clinical trials. Specific to this appraisal, efficacy and safety endpoints were followed up regularly in Study AP32788‑15‑101, but there were no scheduled visits in routine care in the real-world evidence. Also, treatment monitoring and follow up on treatment adherence may have differed between Study AP32788‑15‑101 and routine care. This would have affected the efficacy and safety results. Progressed disease is less accurately captured in retrospective studies such as Flatiron and the German Chart Review than in prospective studies such as Study AP32788‑15‑101, in which people generally have closer monitoring. The company also highlighted that the definition of the index-line of treatment differed between the German Chart Review and Flatiron. In the German Chart Review, baseline characteristics were collected at diagnosis or study entry and not at the start of each treatment line. So, the data from routine care may have been subject to bias. After the first committee meeting, the company provided more information about differences in baseline data collection and index-line treatment definition between Study AP32788‑15‑101 and the real-world evidence sources. It noted that the small differences between timepoints for collection of baseline data and definition of index treatment were expected to have a minimal effect on comparability between the sources. The committee acknowledged the known limitations with real-world evidence. But it considered that it can be valuable for resolving gaps in knowledge when best-practice methods are applied, such as those described in the NICE real-world evidence framework. It also acknowledged the rarity of exon\xa020 insertion mutation-positive NSCLC and the lack of direct comparative efficacy data. This meant that the real-world evidence may have been the best available source of evidence for the comparator arm. At the first committee meeting, the committee was concerned that the company had not provided enough information on data provenance, accuracy and suitability, and had not explored the effect of missing data. To address these concerns, the company provided additional information on the real-world evidence sources used in the model. It provided completed DataSAT and RECORD‑PE real-world evidence checklists for both real-world evidence sources. It also did several scenario analyses:\n\nexploring the effect of excluding EGFR TKIs from the real-world data (see section\xa03.3)\n\nusing the sources of real-world evidence separately (rather than pooled).The company emphasised the strengths of the real-world evidence, including that it was mature, and that the baseline characteristics and efficacy outcomes between the 2\xa0studies, and cost-effectiveness results when using each study separately, were similar. The committee acknowledged the additional information provided by the company. Overall, the committee concluded that some areas of uncertainty remained and some of this uncertainty was currently unresolvable. It noted that the level of uncertainty could have been reduced if the company had shown that a systematic approach had been taken to selecting real-world evidence sources. The committee concluded that it would take this uncertainty into account in its decision making.\n\n# Indirect treatment comparison\n\n## The company's indirect comparison is acceptable for decision making, but using this is associated with uncertainty\n\nTo account for differences in populations between Study AP32788‑15‑101 and the real-world evidence sources, the company adjusted for key prognostic variables and baseline characteristics. These were identified before the analysis by a targeted review and an oncologist survey. These results were further validated by clinical experts. Five common prognostic factors were identified. The data was adjusted using an inverse probability of treatment weighting method. Because of missing data from Flatiron, only brain metastases, age and time since advanced diagnosis were included in the base-case adjustments. Eastern Cooperative Oncology Group (ECOG) performance status and number of lines of previous treatment were excluded. At the first committee meeting, the ERG suggested using the multiple imputation method to adjust for ECOG performance status. In response, the company provided scenario analyses:\n\nimputing missing data as ECOG performance status\xa00\n\nimputing missing data as ECOG performance status\xa01\n\nusing a complete case approach that excluded all people with missing data.These scenarios had a small effect on the ICER. The company stated that all people included in the real-world evidence sources had previously had platinum-based chemotherapy, followed by immunotherapy, chemotherapy or EGFR TKIs. This meant that they were likely to have an ECOG performance status of 0\xa0or\xa01, rather than of 2\xa0or higher (which indicates a poorer level of functioning). The Cancer Drugs Fund lead explained that, in England, most treatments for lung cancer are only commissioned for people with an ECOG performance status of 0\xa0or\xa01. But the committee noted that the Flatiron database is in the US. So, it was uncertain whether people with an ECOG performance status of 2\xa0or higher would be included in the relevant population in this database. The committee was also concerned that the company had been unable to adjust for number of previous lines of therapy between Study AP32788‑15‑101 and the real-world evidence sources. This was because the company had chosen to only include the initial line of therapy had after platinum-based chemotherapy in the Flatiron database (see section\xa03.5). The committee noted that about 60% of people included in Study AP32788‑15‑101 had had 2\xa0or more previous lines of treatment. So, it was concerned that lines of previous treatment had not been included as a prognostic factor in the indirect treatment comparison. It concluded that this increased uncertainty in the results. Also, at the first committee meeting, the ERG was concerned that the method of inclusion of prognostic factors was poorly justified, and that all possible confounding variables should have been included. In response, the company provided scenario analyses in which smoking status and gender were included in the inverse probability of treatment weighting. This reduced the ICER. The ERG noted that this suggested that the company's base-case approach of including prognostic factors in the indirect comparison was likely conservative. But the ERG noted that the company did not assess other factors that could have been included, such as race and type of previous therapy. The committee considered that the indirect treatment comparison was associated with uncertainty. It concluded that this was because of the risk of confounding noted by the ERG, and the potential evidence selection issues associated with the blended comparator data (see section\xa03.5 and section\xa03.6).\n\n## Results from the indirect treatment comparison show statistically significant improvements with mobocertinib, but are uncertain\n\nThe indirect comparison showed statistically significant improvements in overall survival and progression-free survival with mobocertinib compared with the blended comparator arm. This was evidenced by the pooled real-world evidence analysis from the November 2021 data cut (overall survival hazard ratio 0.56, 95%\xa0CI 0.39\xa0to\xa00.81; progression-free survival hazard ratio 0.54, 95%\xa0CI 0.36\xa0to\xa00.82). The ERG explained that the results of the analyses were associated with uncertainties. These included that they were limited by the number of covariates included for adjustment and that there were issues with the company's approach to comparing clinical trial and real-world data (see section\xa03.7). Overall, the committee concluded that the indirect treatment comparison showed a statistically significant improvement with mobocertinib compared with standard care, but that the exact level of improvement was uncertain.\n\n# Utility values in the economic model\n\n## There is uncertainty surrounding the most appropriate utility values to use in the economic model\n\nThe company mapped EQ‑5D‑5L data from Study AP32788‑15‑101 to EQ‑5D‑3L. The mapped EQ‑5D‑3L utility scores were analysed using a type of regression model. This model included baseline utility, progression status and ongoing treatment emergent adverse event (TEAE) status of grade\xa03 or more. In the base case, the company used health-state specific utilities without TEAEs, which were included separately. The ERG noted that the company's approach to selecting utility values was reasonable. But the ERG also noted that the utility values for progression-free and progressed disease were higher than what was used in past appraisals in NSCLC (that is, NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy and on nintedanib for previously treated locally advanced, metastatic or locally recurrent NSCLC). The exact utility values are considered confidential by the company and cannot be reported here. The company noted that using EQ‑5D data from a relevant clinical trial is in line with NICE's reference case. It also noted that its clinical experts had stated that utility values from non-mutationally driven NSCLC are not comparable with the population relevant for this appraisal. The committee noted that the utility values for both the progression-free survival and progressed-disease states were high compared with those for the general population and those used in past appraisals. It also noted that the difference between the utility values in the progression-free survival and progressed-disease states was smaller than has been seen in past appraisals. It noted that utility values in Study AP32788‑15‑101 were collected up until 30\xa0days after the end of treatment. It also noted that compliance dropped from greater than 95% at all points during the trial period to 62% at the end of treatment visit and to 52% 30\xa0days after last dose visit. So, the utility data collected in the trial only captured a short amount of time in the progressed-disease health state. The committee also considered that mobocertinib is an oral treatment and can be taken at home, which may present additional quality-of-life benefits compared with intravenous therapies (such as nivolumab). It concluded that there was uncertainty surrounding the most appropriate utility values to use in the economic model. It also concluded that the true utility values could fall somewhere between the utility values collected from Study AP32788‑15‑101 and the values from NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy.\n\n# Assumptions in the economic model\n\n## The company's model structure is suitable for decision making\n\nThe company used a partitioned survival model with 3\xa0mutually exclusive health states: progression-free survival, progressed disease and death. This approach allowed the company to use outcome data from the adjusted treatment comparison. It also enabled the clinical benefits of mobocertinib to be captured by reflecting the increased proportion of people expected to be alive or progression free over time. The committee agreed that the model structure was suitable for decision making.\n\n## The ERG's choice of survival curves are more plausible than the company's\n\nThe company fitted parametric models to the Kaplan–Meier curves for weighted overall survival, progression-free survival and time to treatment discontinuation (TTD) for the mobocertinib and blended comparator treatment arms. Across all outcomes, hazards were assumed to be proportional between treatment arms, and joint models were fitted with treatment as a covariate. In its original submission, the company fitted a joint generalised gamma distribution for overall survival and a joint exponential distribution for both progression-free survival and TTD. At the first committee meeting, the ERG disagreed with the company's choice of progression-free survival and TTD models. This was because the observed progression-free survival and TTD hazard functions (rate at which events occurred) were not constant over time. This contradicted the underlying properties of an exponential distribution, making the distribution unsuitable. The ERG also highlighted that the exponential distribution had the worst statistical fits compared with other distributions. It preferred the generalised gamma distribution for progression-free survival and the Gompertz distribution for TTD. In response to consultation, the company used a generalised gamma distribution for overall survival, progression-free survival and TTD. It explained that it preferred using the generalised gamma distribution for TTD in its base case because it aligned with the distribution used to model progression-free survival. The company noted that:\n\nUsing a Gompertz distribution for TTD led to a mismatch between the TTD and progression-free survival curves, in which the cancer continued to progress without treatment stopping, which lacked face validity.\n\nThere was little difference between statistical fit for the Gompertz and generalised gamma distributions.\n\nThe generalised gamma better aligned with clinical expert feedback suggesting no one would be having treatment by year\xa05.The company presented a scenario analysis using the Gompertz distribution for TTD, which increased the ICER. The ERG considered that the company did not provide enough new compelling justification on why the mismatch between TTD and progression-free survival distributions was a problem in this case. The committee retained its preference for the Gompertz distribution for TTD. It agreed that the ERG's choice of survival curves was more plausible than the company's choice of survival curves.\n\n## It is appropriate to exclude treatment effect waning from the modelling\n\nThe company's base case assumed that mobocertinib's treatment effect continued throughout the time horizon. The company explained that the survival data for mobocertinib was mature. Also, mobocertinib is usually given until progression and no stopping rules apply. The company assumed that any treatment effect waning would have been captured in the trial follow-up period. The ERG agreed with the company's approach. The committee noted that treatment effect waning has typically been applied in previous appraisals for immunotherapies when stopping rules have been applied. It also noted the limited impact of the treatment effect waning scenario done by the ERG. Based on this, the committee concluded that it was appropriate to exclude treatment effect waning from the modelling.\n\n## The mismatch of efficacy, cost and disutility increases uncertainty, but the company's approach to costs is conservative\n\nThe company included costs and disutility of adverse events for docetaxel with or without nintedanib, and atezolizumab in the blended comparator arm. Efficacy outcomes were included from other treatments, for example, EGFR TKIs. But EGFR TKIs were not considered to be appropriate comparators (see section\xa03.2), so the company excluded their costs and disutilities. The company also highlighted that atezolizumab's list price is the cheapest, and that it is the most frequently used immunotherapy. So, the exclusion of pembrolizumab and nivolumab was a conservative assumption. The ERG highlighted that only 8\xa0out of 93\xa0people in the pooled real-world evidence had had 1\xa0of the 3\xa0treatments in the blended comparator arm. This resulted in a mismatch between the treatments used in the real-world evidence that informed efficacy and the treatments that informed the cost and adverse events disutility in the model. The committee saw scenarios including the costs of EGFR TKIs and immunotherapies. It agreed that the company had taken a conservative approach by excluding the costs of EGFR TKIs and immunotherapy treatments. As previously noted by the committee (see section\xa03.2), including EGFR TKIs in the efficacy outcomes could have underestimated the comparator efficacy. The committee concluded that the mismatch of efficacy, and cost and disutility of adverse events data increased the uncertainty in the cost-effectiveness results. But it acknowledged that the company's approach to costs was conservative.\n\n# Costs in the economic model\n\n## Exon\xa020 insertion mutation testing costs should be included in the economic model\n\nIn line with section\xa05.9.1 of NICE's guide to the methods of technology appraisal, the NICE scope for mobocertinib states that the 'costs associated with diagnostic testing for EGFR in people with NSCLC who would not otherwise have been tested' should be modelled. The company did not include exon\xa020 insertion mutation testing in the economic modelling for mobocertinib. It explained that these costs were expected to be included in routine NHS testing. The Cancer Drugs Fund lead explained that the gold standard for detecting exon\xa020 insertion mutations is next generation sequencing. But the availability of this varies across the NHS. Many treatment centres use polymerase chain reaction (PCR) instead, which is expected to identify about 50% of people with exon\xa020 insertion mutation-positive NSCLC. Because of this, using mobocertinib (or other exon\xa020 insertion mutation targeted treatments) in the NHS would mean switching from current local PCR testing to next generation sequencing at Genomic Laboratory Hubs. This could result in a 50% increase in detecting people with exon\xa020 insertion mutation-positive NSCLC. But the Cancer Drugs Fund lead suggested that this increase may only be 33% because there is already some next generation sequencing testing being done. They explained that it would be appropriate to add a testing cost of £550 per person with exon\xa020 insertion mutation-positive NSCLC. This cost would account for a 2% incidence of exon\xa020 insertion mutations, and the standard cost of adding a mutation test onto a next generation sequencing panel of £34. The company presented scenario analyses including the cost of genomic testing in the mobocertinib arm only and in both treatment arms in the model. The ERG stated that if exon\xa020 insertion mutation testing is not embedded in NHS practice for people with NSCLC, then additional diagnostic testing would be applicable with the introduction of mobocertinib. The committee concluded that exon\xa020 insertion costs should be included in the mobocertinib arm of the economic model.\n\n# End of life\n\n## Mobocertinib meets the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that mobocertinib met the criteria for being a life-extending treatment for people with short life expectancy (normally less than 24\xa0months). Both the company's base case and the model using the committee's preferred assumptions predicted a mean and median overall survival with current standard care of substantially less than 24\xa0months. The mean overall survival for the blended comparator arm was 16.2\xa0months from the company's base-case model. Having considered the survival data from the real-world evidence, the committee concluded that mobocertinib met the end of life criterion for short life expectancy. The company's and ERG's modelling suggested that mobocertinib was associated with a gain in overall survival of substantially more than 3\xa0months. The company's base-case model showed a mean overall survival of 27.1\xa0months for mobocertinib, an increase of 10.8\xa0months. The committee noted the uncertainty in the real-world evidence and model estimates previously discussed (see section\xa03.8). It concluded that, despite the uncertainty in the size of the survival gain, mobocertinib met both of NICE's criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## Because of the uncertainty, the maximum acceptable ICER would be below £50,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. It recalled its conclusion from the first meeting that an acceptable ICER would be around £20,000 per QALY gained. But the committee also agreed that the end of life criteria applied to mobocertinib. When the end of life weighting was applied, the committee said that the maximum acceptable ICER would be substantially less than £50,000 per QALY gained. The committee acknowledged that, since the first committee meeting, the company had attempted to reduce the uncertainty around the use and selection of real-world evidence. But it noted the high level of outstanding uncertainty in the company's model, specifically:\n\nthe lack of direct comparative evidence\n\nthe lack of fully incremental analysis because of using a blended comparator\n\nthe effect of evidence selection issues because of the lack of a systematic approach to identifying real-world evidence sources\n\nthe potential for residual confounding in the indirect treatment comparison.The committee also took into account the lack of targeted treatment options available for this specific mutation, the emotional burden on people with EGFR exon\xa020 insertion mutation-positive NSCLC and their caregivers. It also heard that people with lung cancer may experience stigma, which could delay them seeking treatment. It noted the rarity of EGFR exon\xa020 insertion mutation-positive NSCLC and the difficulties this can create in generating evidence. The fact that mobocertinib met the end of life criteria in this indication was also considered. Taking these factors into account and the uncertainty that remained, the committee concluded that an acceptable ICER would need to be below the maximum acceptable ICER for end of life treatments (£50,000 per QALY gained) to be considered a cost-effective use of NHS resources.\n\n## The cost-effectiveness estimates are uncertain but are likely within what NICE considers to be an acceptable use of NHS resources\n\nThe company's updated base-case ICER for mobocertinib compared with the blended comparator arm was markedly below £50,000 per QALY gained. This was when confidential commercial arrangements for mobocertinib and all the comparators were included, so the exact ICERs cannot be reported here. The company's base case included the following assumptions, which were preferred by the committee:\n\nexcluding the costs of EGFR TKIs from the blended comparator arm (see section\xa03.13)\n\na joint generalised gamma model for overall survival and progression-free survival (see section\xa03.11)\n\nusing the individual patient weighting method for the indirect treatment comparison (see section\xa03.7)\n\nexcluding treatment waning (see section\xa03.12).The company's updated base case used a joint generalised gamma distribution for TTD. This differed from the committee's preferred approach, which was to use a joint Gompertz distribution for TTD (see section\xa03.11). The committee considered the scenario including its preferred assumptions using a joint Gompertz model for TTD and the additional testing costs for EGFR exon\xa020 insertion mutation testing. It noted that the ICER for this scenario was also below £50,000 per QALY gained. The exact ICERs are commercial in confidence and cannot be reported here. But the committee noted that there was uncertainty about the most appropriate utility values to use in the economic model and that the utility values from the company's trial lacked face validity (see section\xa03.9). It also noted that a scenario analysis using utility values from NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy produced an ICER slightly above £50,000 per QALY gained. But the committee also noted that some of the assumptions included in the company's base-case analysis were conservative, for example, excluding the costs of pembrolizumab and nivolumab in the blended comparator arm. The committee considered the uncertainty and the range in the cost-effectiveness estimates. But it agreed that the most plausible ICER was sufficiently below £50,000 per QALY gained to be considered an acceptable use of NHS resources.\n\n# Other factors\n\n## Mobocertinib is innovative but all benefits are captured in the analysis\n\nThe committee considered mobocertinib to be innovative because it represents a step-change in the treatment of exon\xa020 insertion mutation-positive NSCLC. The company did not present any evidence to suggest that there were additional benefits that were not captured in the QALY calculations. The committee considered the unmet need and the burden of stigma in its deliberations, and recognised that mobocertinib provides important benefits for people with exon\xa020 insertion mutation-positive NSCLC. But it did not consider that there were any additional benefits that had not been captured in the QALY calculations.\n\n## There are no equality issues relevant to the recommendations\n\nThe company explained that exon\xa020 insertion mutation-positive NSCLC is associated with a higher prevalence in people from an East Asian family background. Differences in prevalence cannot usually be resolved in a technology appraisal, although the committee can consider whether a specific equality issue has a significant impact on access to treatment. Also, the recommendation for mobocertinib is for the full population in the marketing authorisation. So, the committee agreed that its recommendations would not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no equality issues relevant to the recommendations.\n\n# Conclusion\n\n## Mobocertinib is recommended for routine use\n\nThe committee concluded that there was substantial uncertainty in the cost-effectiveness estimates. But it agreed that the most likely estimates are within what NICE considers a cost-effective use of NHS resources when the end of life modifier is applied. So, mobocertinib is recommended as an option for treating EGFR exon\xa020 insertion mutation-positive advanced NSCLC after platinum-based chemotherapy."}	https://www.nice.org.uk/guidance/ta855	Evidence-based recommendations on mobocertinib (EXKIVITY) for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy in adults.
d2374f1467b066b87bda96347a09b2628af34efa	nice	Upadacitinib for treating moderately to severely active ulcerative colitis	Upadacitinib for treating moderately to severely active ulcerative colitis Evidence-based recommendations on upadacitinib (Rinvoq) for treating moderately to severely active ulcerative colitis in adults. # Recommendations Upadacitinib is recommended, within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults: when conventional or biological treatment cannot be tolerated, or if the condition has not responded well enough or has stopped responding to these treatments, and if the company provides upadacitinib according to the commercial arrangement. Choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If patients and clinicians consider upadacitinib to be one of a range of suitable options, choose the least expensive treatment (taking into account drug administration costs, dose needed and frequency, and product price per dose). Why the committee made these recommendations Standard treatments for moderately to severely active ulcerative colitis after conventional treatments are biological treatments (adalimumab, golimumab, infliximab, ustekinumab or vedolizumab) or tofacitinib. Clinical trial evidence shows that upadacitinib is more effective than placebo for treating moderately to severely active ulcerative colitis. There is no direct evidence comparing upadacitinib with treatments that are offered after conventional treatment. Indirect comparison suggests that upadacitinib is likely to be at least as effective as the treatments it was compared with. The most likely cost-effectiveness estimates for upadacitinib compared with other treatments are within the range NICE normally considers an acceptable use of NHS resources. So, upadacitinib is recommended.# Information about upadacitinib # Marketing authorisation indication Upadacitinib (Rinvoq, AbbVie) is indicated for 'the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biological agent'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for upadacitinib. # Price The price per 28‑tablet pack is £805.56 for upadacitinib 15 mg and £1,281.54 for upadacitinib 30 mg (all prices excluding VAT; BNF online accessed October 2022). The estimated cost for 6 weeks of induction treatment (45 mg) is £3,131 based on list price (excluding VAT). The estimated cost of maintenance treatment is £10,472 at standard dose (15 mg) or £16,660 at high dose (30 mg) per person per year based on list price (excluding VAT). The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by AbbVie, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical management ## Treatment pathway Upadacitinib is a type of treatment called a Janus kinase (JAK) inhibitor. It has a marketing authorisation for treating moderately to severely active ulcerative colitis when conventional or biological treatment cannot be tolerated, or if the disease has not responded well enough or stopped responding to treatment. The committee noted that choice of treatment for ulcerative colitis is highly individualised based on a range of factors. The company's submission considered 2 subgroups: 'Biologic-naive' – people who have had a conventional treatment and their disease did not respond to it or they could not tolerate it, but they have not had a biological treatment (a tumour necrosis factor -alpha inhibitor, vedolizumab or ustekinumab) or tofacitinib (another JAK inhibitor). 'Biologic-experienced' – people who have had a conventional and biological treatment or tofacitinib, and their disease did not respond to it or they could not tolerate it. The committee acknowledged there are other non-biological treatments that have since been recommended for these populations and not considered in this evaluation, and there may be more in the future. The committee understood the treatment subgroup definitions but noted they may need reconsideration in the future to avoid clinical confusion. Patient and clinical experts noted that upadacitinib, as an oral treatment, offers additional benefit over some of the current treatment options because it can be taken at home. Clinical experts noted that some treatments are started in hospital because they need to be given intravenously. They suggested that upadacitinib is a step-change in managing moderately to severely active ulcerative colitis. They noted that because it performed well, it should not be reserved for after failure of biological treatment. The committee concluded that the company's categorisation based on biological treatment experience was appropriate. # Clinical evidence ## Data sources and generalisability The clinical-effectiveness evidence for upadacitinib comes from placebo-controlled, double-blind randomised controlled trials: Induction treatment: the U‑ACHIEVE (n=474) and U‑ACCOMPLISH (n=522) trials included people with moderately to severely active ulcerative colitis. They were randomised to have upadacitinib (45 mg once daily) or placebo. The primary outcome was clinical remission, measured using the adapted Mayo score. Secondary outcomes included endoscopic improvement and remission, clinical response (adapted Mayo score), histologic–endoscopic mucosal improvement, mucosal healing, lack of bowel urgency and abdominal pain. All outcomes were measured at 8‑weeks follow-up. People whose disease had an inadequate response at week 8 had a further 8 weeks of induction treatment. Maintenance treatment: the U‑ACHIEVE maintenance trial included 451 people whose disease clinically responded to upadacitinib in the induction trials. People took either upadacitinib (15 mg or 30 mg) or placebo, once daily. The primary outcome was clinical remission (adapted Mayo score) at week 52. Secondary outcomes included endoscopic improvement and remission, maintenance of clinical remission, corticosteroid-free clinical remission, histologic–endoscopic mucosal improvement, mucosal healing, lack of bowel urgency and abdominal pain. Clinical experts noted that these studies included people whose disease had not responded to therapies currently available in the NHS. The committee concluded that the trials are adequate and generalisable to UK clinical practice. ## Clinical effectiveness At the end of induction treatment, the rate of remission was statistically significantly higher in the upadacitinib 45 mg group than the placebo group (adjusted treatment difference compared with placebo of 22% and 29% in the 2 studies) for the overall population. Remission rates were consistent in the biologic-naive and biologic-exposed subgroups. At week 52 of the maintenance phase, a statistically significantly greater proportion of people who had upadacitinib were in remission compared with those who had placebo (adjusted treatment difference compared with placebo of 31% and 39% ). Remission rates were consistent in the biologic-naive and biologic-exposed subgroups. Clinical experts noted that the trials show upadacitinib will provide clinically meaningful benefits. The committee concluded that upadacitinib is more effective than placebo at inducing and maintaining remission. ## Safety profile In the induction trials, the most common adverse events with upadacitinib were creatine phosphokinase increase, acne and nasopharyngitis. In the maintenance trial these were nasopharyngitis, worsening of ulcerative colitis and creatine phosphokinase increase. Discontinuation from the trial because of adverse events was more common with placebo than with upadacitinib. There were no deaths in any trial. The committee was aware of the European Medicines Agency safety committee review of JAK inhibitors for inflammatory disorders (including upadacitinib for ulcerative colitis). This is because a clinical trial of tofacitinib in rheumatoid arthritis showed people with risk of heart disease were more likely to experience a major cardiovascular problem and had a higher risk of developing cancer with tofacitinib than TNF-alpha inhibitors. The company submitted a summary of the most recent data from a long-term extension study of upadacitinib (U‑ACTIVATE). No new safety risks were identified in people who completed maintenance treatment in U‑ACHIEVE and continued upadacitinib in the extension study. The committee concluded that based on the evidence presented, upadacitinib has an acceptable safety profile. # Indirect treatment comparison ## Company network meta-analyses Because there were no head-to-head studies, the company did network meta-analyses of 2 randomised placebo-controlled trials of upadacitinib (U‑ACHIEVE induction and maintenance, and U‑ACCOMPLISH induction) and 18 trials of comparators. The network meta-analyses for efficacy endpoints assessed clinical remission and clinical response in 2 subgroups: For the biologic-naive subgroup, the analysis estimated the relative efficacy of upadacitinib compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab. For the biologic-exposed subgroup, the analysis estimated the relative efficacy of upadacitinib compared with adalimumab, tofacitinib, ustekinumab and vedolizumab.The safety network meta-analysis assessed the rate of serious infection in the overall population during induction treatment with upadacitinib compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab. The EAG noted that the company's network meta-analyses had some unresolvable technical issues with an unclear impact that must be considered when interpreting the results: For all networks, the consistency assumption could not be tested formally. The results of the network meta-analysis for the maintenance phase were less reliable than those for the induction phase. The company and EAG preferred different approaches to generating the network meta-analyses results. The EAG was not satisfied with alternative approaches it explored and proposed that clinical opinion be sought on the plausibility of the results. The committee noted the wide credible intervals leading to uncertainty in the results. The company stated that its results were supported by evidence from 2 recently published network meta-analyses of treatment for moderate to severe ulcerative colitis (Burr et al. 2022; Lasa et al. 2022). Clinical experts agreed that these published analyses broadly reached the same conclusions as the company's analyses. They noted that the published analyses also included filgotinib and ozanimod, which were recently recommended for treating moderately to severely active ulcerative colitis (NICE's technology appraisal guidance on filgotinib and ozanimod). The committee noted that filgotinib and ozanimod have not yet been widely used in clinical practice and were not included as comparators in this appraisal. The committee concluded that the results of the company's network meta-analyses are plausible and appropriate for decision making. ## Results of network meta-analyses The company's network meta-analyses suggested that upadacitinib is as effective and sometimes more effective than comparators in the biologic-naive and biologic-exposed subgroups. The company considers the results confidential so they cannot be reported here. The company's safety network analysis suggested that upadacitinib has a low risk of serious infection. The committee concluded that upadacitinib was at least as effective as its comparators, and has a similar low risk of serious infection. # Economic model ## Company's modelling approach The company estimated the cost effectiveness of upadacitinib using a model with a hybrid structure (the induction phase was modelled using a decision tree and the maintenance phase was modelled using a Markov structure). The company provided cost-effectiveness estimates for the biologic-naive and biologic-exposed subgroups. The company's model structure was similar to those used in earlier ulcerative colitis technology appraisals. It included health states defined by remission and response without remission (in which people in the model had maintenance treatment with upadacitinib and comparators), active ulcerative colitis (with no biological drug treatment), and surgery and post-surgery. The company base case did not include a subsequent biological therapy. The EAG stated that it was not plausible for the company to assume that after having only 1 treatment people would move to an 'active ulcerative colitis' health state for the remaining duration of the model. Instead, in clinical practice, people would either be offered surgery within 12 months or other drug treatments. Clinical advisers to the EAG suggested these other medicines may include the treatment which previously gave the best symptom relief, even if the person's disease had not responded to it. The committee noted that the company's approach of not modelling further treatment after first-line treatment exaggerates the differences between treatments over a lifetime. The committee agreed that the company's model did not reflect NHS clinical practice. The committee added that it expects company submissions in future appraisals to reflect more up-to-date practice, recognising there are many treatments available for ulcerative colitis. This should include a structured decision-analytic model for ulcerative colitis that realistically represents what happens in NHS clinical practice. The committee concluded that the company's modelled treatment pathway did not reflect NHS clinical practice. ## EAG adjustment of the model The EAG preferred to adapt the company's model using an alternative health state, 'on subsequent treatment', after treatment failure in its base case. In this, people had a 'basket' of biologic treatments (the comparators). The committee noted that this alternative approach led to different costs and quality-adjusted life years (QALYs) being accrued. The EAG acknowledged that its own modelling approach had some limitations. It did not include surgery and it allowed for a more expensive second-line treatment option than might be used in clinical practice. But it did more closely reflect NHS practice than the company's approach. The committee highlighted that a preferable model would include likely sequences of treatment that are used in NHS practice, but acknowledged that it is unlikely that data exists to populate such a model. The committee agreed that neither treatment pathway reflected NHS practice but concluded that the EAG's simplified adjustment of the model was preferred for decision making. ## Use of trial-based utility estimates The company's utility values for remission, response without remission and active ulcerative colitis came from Woehl et al. (2008). The company noted that this was consistent with previous appraisals in ulcerative colitis. It suggested that utility values collected in real-world clinical practice (as done in Woehl et al. ) can provide more representative values of the population having treatment than those collected in clinical trials. The EAG preferred to use health state utility values from EQ‑5D data collected in the upadacitinib trials in its base case, in line with the NICE reference case. It noted that these utility estimates were mostly higher than in the source used by the company. The committee noted that the Woehl et al. (2008) data used by the company had been considered in previous ulcerative colitis appraisals but that the reliability of the utility estimates had also been a source of discussion. The committee noted that utility values for remission, response without remission, and active ulcerative colitis health states were collected in upadacitinib trials and therefore could have been used. The committee concluded that using the upadacitinib trial-based utility estimates is preferred. ## Maintenance dose assumption The committee recalled that upadacitinib maintenance treatment is 15 mg ('standard') or 30 mg ('high') daily dosing. The company and EAG agreed that, as was done for comparator drugs, it would be assumed that upadacitinib is prescribed in a 70:30 ratio of 'standard' to 'high' doses in the maintenance phase. The committee was concerned that this assumption was not based on evidence and that the true proportions of people who would have standard or high-dose levels of these treatments was uncertain. However, it noted that this assumption was consistent with the approach taken in NICE's technology appraisal guidance on ustekinumab. The committee reviewed alternative explorations of the ratio and noted these did not have a substantial impact on costs or effects. The committee concluded that some people have a high dose of maintenance treatment, but the proportion is uncertain. # Cost-effectiveness estimates ## Company and EAG cost-effectiveness estimates Fully incremental analyses were done on the company's and EAG's preferred base cases by prior biological treatment status. For the biologic-naive subgroup, the analyses compared upadacitinib with adalimumab, adalimumab biosimilar, golimumab, infliximab, infliximab biosimilar, tofacitinib, ustekinumab and vedolizumab. For the biologic-exposed subgroup, upadacitinib was compared with adalimumab, adalimumab biosimilar, tofacitinib, ustekinumab and vedolizumab. The committee recalled that there was some uncertainty associated with the results of the network meta-analyses (see section 3.5). It also recalled that neither the company's nor the EAG's model truly reflected NHS clinical practice but that the EAG's simplified approach was preferred (see section 3.8). The proportion of people who have high-dose maintenance treatment in clinical practice is also uncertain (see section 3.10). Looking at the cost-effectiveness results from the EAG's model, upadacitinib had the greatest net health benefit suggesting that it is a cost-effective use of NHS resources compared with existing NICE-recommended treatments. However, the committee noted that the differences between costs and QALYs were very small, and noted the uncertainties described above. The committee agreed it was likely that upadacitinib is a cost-effective use of NHS resources when conventional or biological treatments are not tolerated or are not working well enough. The committee concluded that upadacitinib is considered cost effective for treating moderately to severely active ulcerative colitis. # Other factors ## Choosing the most appropriate treatment The committee recalled that treatment of ulcerative colitis is highly individualised based on a range of factors. It also recalled that upadacitinib is likely to be a cost-effective use of NHS resources. But it noted that because the cost-effectiveness estimates were similar it could not consider it in preference to other options. This is because the value that each provides is uncertain and is likely to vary from case to case. It recalled that a range of treatments are already available for people with moderately to severely active ulcerative colitis, including some that have not yet been widely used in clinical practice (see section 3.5). The committee concluded that healthcare professionals should choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If patients and clinicians consider upadacitinib to be one of a range of suitable options, they should choose the least expensive treatment (taking into account drug administration costs, dose needed and frequency, and product price per dose). This may vary from person to person because of differences in how the drugs are taken and treatment schedules.	{'Recommendations': 'Upadacitinib is recommended, within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults:\n\nwhen conventional or biological treatment cannot be tolerated, or\n\nif the condition has not responded well enough or has stopped responding to these treatments, and\n\nif the company provides upadacitinib according to the commercial arrangement.\n\nChoose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If patients and clinicians consider upadacitinib to be one of a range of suitable options, choose the least expensive treatment (taking into account drug administration costs, dose needed and frequency, and product price per dose).\n\nWhy the committee made these recommendations\n\nStandard treatments for moderately to severely active ulcerative colitis after conventional treatments are biological treatments (adalimumab, golimumab, infliximab, ustekinumab or vedolizumab) or tofacitinib.\n\nClinical trial evidence shows that upadacitinib is more effective than placebo for treating moderately to severely active ulcerative colitis. There is no direct evidence comparing upadacitinib with treatments that are offered after conventional treatment. Indirect comparison suggests that upadacitinib is likely to be at least as effective as the treatments it was compared with.\n\nThe most likely cost-effectiveness estimates for upadacitinib compared with other treatments are within the range NICE normally considers an acceptable use of NHS resources. So, upadacitinib is recommended.', 'Information about upadacitinib': "# Marketing authorisation indication\n\nUpadacitinib (Rinvoq, AbbVie) is indicated for 'the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biological agent'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for upadacitinib.\n\n# Price\n\nThe price per 28‑tablet pack is £805.56 for upadacitinib 15\xa0mg and £1,281.54 for upadacitinib 30\xa0mg (all prices excluding VAT; BNF online accessed October\xa02022). The estimated cost for 6\xa0weeks of induction treatment (45\xa0mg) is £3,131 based on list price (excluding VAT). The estimated cost of maintenance treatment is £10,472 at standard dose (15\xa0mg) or £16,660 at high dose (30\xa0mg) per person per year based on list price (excluding VAT).\n\nThe company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by AbbVie, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## Treatment pathway\n\nUpadacitinib is a type of treatment called a Janus kinase (JAK) inhibitor. It has a marketing authorisation for treating moderately to severely active ulcerative colitis when conventional or biological treatment cannot be tolerated, or if the disease has not responded well enough or stopped responding to treatment. The committee noted that choice of treatment for ulcerative colitis is highly individualised based on a range of factors. The company's submission considered 2 subgroups:\n\n'Biologic-naive' – people who have had a conventional treatment and their disease did not respond to it or they could not tolerate it, but they have not had a biological treatment (a tumour necrosis factor [TNF]-alpha inhibitor, vedolizumab or ustekinumab) or tofacitinib (another JAK inhibitor).\n\n'Biologic-experienced' – people who have had a conventional and biological treatment or tofacitinib, and their disease did not respond to it or they could not tolerate it. The committee acknowledged there are other non-biological treatments that have since been recommended for these populations and not considered in this evaluation, and there may be more in the future. The committee understood the treatment subgroup definitions but noted they may need reconsideration in the future to avoid clinical confusion. Patient and clinical experts noted that upadacitinib, as an oral treatment, offers additional benefit over some of the current treatment options because it can be taken at home. Clinical experts noted that some treatments are started in hospital because they need to be given intravenously. They suggested that upadacitinib is a step-change in managing moderately to severely active ulcerative colitis. They noted that because it performed well, it should not be reserved for after failure of biological treatment. The committee concluded that the company's categorisation based on biological treatment experience was appropriate.\n\n# Clinical evidence\n\n## Data sources and generalisability\n\nThe clinical-effectiveness evidence for upadacitinib comes from placebo-controlled, double-blind randomised controlled trials:\n\nInduction treatment: the U‑ACHIEVE (n=474) and U‑ACCOMPLISH (n=522) trials included people with moderately to severely active ulcerative colitis. They were randomised to have upadacitinib (45\xa0mg once daily) or placebo. The primary outcome was clinical remission, measured using the adapted Mayo score. Secondary outcomes included endoscopic improvement and remission, clinical response (adapted Mayo score), histologic–endoscopic mucosal improvement, mucosal healing, lack of bowel urgency and abdominal pain. All outcomes were measured at 8‑weeks follow-up. People whose disease had an inadequate response at week\xa08 had a further 8\xa0weeks of induction treatment.\n\nMaintenance treatment: the U‑ACHIEVE maintenance trial included 451\xa0people whose disease clinically responded to upadacitinib in the induction trials. People took either upadacitinib (15\xa0mg or 30\xa0mg) or placebo, once daily. The primary outcome was clinical remission (adapted Mayo score) at week\xa052. Secondary outcomes included endoscopic improvement and remission, maintenance of clinical remission, corticosteroid-free clinical remission, histologic–endoscopic mucosal improvement, mucosal healing, lack of bowel urgency and abdominal pain. Clinical experts noted that these studies included people whose disease had not responded to therapies currently available in the NHS. The committee concluded that the trials are adequate and generalisable to UK clinical practice.\n\n## Clinical effectiveness\n\nAt the end of induction treatment, the rate of remission was statistically significantly higher in the upadacitinib 45\xa0mg group than the placebo group (adjusted treatment difference compared with placebo of 22% and 29% in the 2\xa0studies) for the overall population. Remission rates were consistent in the biologic-naive and biologic-exposed subgroups. At week\xa052 of the maintenance phase, a statistically significantly greater proportion of people who had upadacitinib were in remission compared with those who had placebo (adjusted treatment difference compared with placebo of 31% [15\xa0mg upadacitinib] and 39% [30\xa0mg upadacitinib]). Remission rates were consistent in the biologic-naive and biologic-exposed subgroups. Clinical experts noted that the trials show upadacitinib will provide clinically meaningful benefits. The committee concluded that upadacitinib is more effective than placebo at inducing and maintaining remission.\n\n## Safety profile\n\nIn the induction trials, the most common adverse events with upadacitinib were creatine phosphokinase increase, acne and nasopharyngitis. In the maintenance trial these were nasopharyngitis, worsening of ulcerative colitis and creatine phosphokinase increase. Discontinuation from the trial because of adverse events was more common with placebo than with upadacitinib. There were no deaths in any trial. The committee was aware of the European Medicines Agency safety committee review of JAK inhibitors for inflammatory disorders (including upadacitinib for ulcerative colitis). This is because a clinical trial of tofacitinib in rheumatoid arthritis showed people with risk of heart disease were more likely to experience a major cardiovascular problem and had a higher risk of developing cancer with tofacitinib than TNF-alpha inhibitors. The company submitted a summary of the most recent data from a long-term extension study of upadacitinib (U‑ACTIVATE). No new safety risks were identified in people who completed maintenance treatment in U‑ACHIEVE and continued upadacitinib in the extension study. The committee concluded that based on the evidence presented, upadacitinib has an acceptable safety profile.\n\n# Indirect treatment comparison\n\n## Company network meta-analyses\n\nBecause there were no head-to-head studies, the company did network meta-analyses of 2\xa0randomised placebo-controlled trials of upadacitinib (U‑ACHIEVE induction and maintenance, and U‑ACCOMPLISH induction) and 18 trials of comparators. The network meta-analyses for efficacy endpoints assessed clinical remission and clinical response in 2\xa0subgroups:\n\nFor the biologic-naive subgroup, the analysis estimated the relative efficacy of upadacitinib compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab.\n\nFor the biologic-exposed subgroup, the analysis estimated the relative efficacy of upadacitinib compared with adalimumab, tofacitinib, ustekinumab and vedolizumab.The safety network meta-analysis assessed the rate of serious infection in the overall population during induction treatment with upadacitinib compared with adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab. The EAG noted that the company's network meta-analyses had some unresolvable technical issues with an unclear impact that must be considered when interpreting the results:\n\nFor all networks, the consistency assumption could not be tested formally.\n\nThe results of the network meta-analysis for the maintenance phase were less reliable than those for the induction phase.\n\nThe company and EAG preferred different approaches to generating the network meta-analyses results. The EAG was not satisfied with alternative approaches it explored and proposed that clinical opinion be sought on the plausibility of the results. The committee noted the wide credible intervals leading to uncertainty in the results. The company stated that its results were supported by evidence from 2 recently published network meta-analyses of treatment for moderate to severe ulcerative colitis (Burr et al. 2022; Lasa et al. 2022). Clinical experts agreed that these published analyses broadly reached the same conclusions as the company's analyses. They noted that the published analyses also included filgotinib and ozanimod, which were recently recommended for treating moderately to severely active ulcerative colitis (NICE's technology appraisal guidance on filgotinib and ozanimod). The committee noted that filgotinib and ozanimod have not yet been widely used in clinical practice and were not included as comparators in this appraisal. The committee concluded that the results of the company's network meta-analyses are plausible and appropriate for decision making.\n\n## Results of network meta-analyses\n\nThe company's network meta-analyses suggested that upadacitinib is as effective and sometimes more effective than comparators in the biologic-naive and biologic-exposed subgroups. The company considers the results confidential so they cannot be reported here. The company's safety network analysis suggested that upadacitinib has a low risk of serious infection. The committee concluded that upadacitinib was at least as effective as its comparators, and has a similar low risk of serious infection.\n\n# Economic model\n\n## Company's modelling approach\n\nThe company estimated the cost effectiveness of upadacitinib using a model with a hybrid structure (the induction phase was modelled using a decision tree and the maintenance phase was modelled using a Markov structure). The company provided cost-effectiveness estimates for the biologic-naive and biologic-exposed subgroups. The company's model structure was similar to those used in earlier ulcerative colitis technology appraisals. It included health states defined by remission and response without remission (in which people in the model had maintenance treatment with upadacitinib and comparators), active ulcerative colitis (with no biological drug treatment), and surgery and post-surgery. The company base case did not include a subsequent biological therapy. The EAG stated that it was not plausible for the company to assume that after having only 1 treatment people would move to an 'active ulcerative colitis' health state for the remaining duration of the model. Instead, in clinical practice, people would either be offered surgery within 12\xa0months or other drug treatments. Clinical advisers to the EAG suggested these other medicines may include the treatment which previously gave the best symptom relief, even if the person's disease had not responded to it. The committee noted that the company's approach of not modelling further treatment after first-line treatment exaggerates the differences between treatments over a lifetime. The committee agreed that the company's model did not reflect NHS clinical practice. The committee added that it expects company submissions in future appraisals to reflect more up-to-date practice, recognising there are many treatments available for ulcerative colitis. This should include a structured decision-analytic model for ulcerative colitis that realistically represents what happens in NHS clinical practice. The committee concluded that the company's modelled treatment pathway did not reflect NHS clinical practice.\n\n## EAG adjustment of the model\n\nThe EAG preferred to adapt the company's model using an alternative health state, 'on subsequent treatment', after treatment failure in its base case. In this, people had a 'basket' of biologic treatments (the comparators). The committee noted that this alternative approach led to different costs and quality-adjusted life years (QALYs) being accrued. The EAG acknowledged that its own modelling approach had some limitations. It did not include surgery and it allowed for a more expensive second-line treatment option than might be used in clinical practice. But it did more closely reflect NHS practice than the company's approach. The committee highlighted that a preferable model would include likely sequences of treatment that are used in NHS practice, but acknowledged that it is unlikely that data exists to populate such a model. The committee agreed that neither treatment pathway reflected NHS practice but concluded that the EAG's simplified adjustment of the model was preferred for decision making.\n\n## Use of trial-based utility estimates\n\nThe company's utility values for remission, response without remission and active ulcerative colitis came from Woehl et al. (2008). The company noted that this was consistent with previous appraisals in ulcerative colitis. It suggested that utility values collected in real-world clinical practice (as done in Woehl et al. ) can provide more representative values of the population having treatment than those collected in clinical trials. The EAG preferred to use health state utility values from EQ‑5D data collected in the upadacitinib trials in its base case, in line with the NICE reference case. It noted that these utility estimates were mostly higher than in the source used by the company. The committee noted that the Woehl et al. (2008) data used by the company had been considered in previous ulcerative colitis appraisals but that the reliability of the utility estimates had also been a source of discussion. The committee noted that utility values for remission, response without remission, and active ulcerative colitis health states were collected in upadacitinib trials and therefore could have been used. The committee concluded that using the upadacitinib trial-based utility estimates is preferred.\n\n## Maintenance dose assumption\n\nThe committee recalled that upadacitinib maintenance treatment is 15\xa0mg ('standard') or 30\xa0mg ('high') daily dosing. The company and EAG agreed that, as was done for comparator drugs, it would be assumed that upadacitinib is prescribed in a 70:30 ratio of 'standard' to 'high' doses in the maintenance phase. The committee was concerned that this assumption was not based on evidence and that the true proportions of people who would have standard or high-dose levels of these treatments was uncertain. However, it noted that this assumption was consistent with the approach taken in NICE's technology appraisal guidance on ustekinumab. The committee reviewed alternative explorations of the ratio and noted these did not have a substantial impact on costs or effects. The committee concluded that some people have a high dose of maintenance treatment, but the proportion is uncertain.\n\n# Cost-effectiveness estimates\n\n## Company and EAG cost-effectiveness estimates\n\nFully incremental analyses were done on the company's and EAG's preferred base cases by prior biological treatment status. For the biologic-naive subgroup, the analyses compared upadacitinib with adalimumab, adalimumab biosimilar, golimumab, infliximab, infliximab biosimilar, tofacitinib, ustekinumab and vedolizumab. For the biologic-exposed subgroup, upadacitinib was compared with adalimumab, adalimumab biosimilar, tofacitinib, ustekinumab and vedolizumab. The committee recalled that there was some uncertainty associated with the results of the network meta-analyses (see section\xa03.5). It also recalled that neither the company's nor the EAG's model truly reflected NHS clinical practice but that the EAG's simplified approach was preferred (see section\xa03.8). The proportion of people who have high-dose maintenance treatment in clinical practice is also uncertain (see section\xa03.10). Looking at the cost-effectiveness results from the EAG's model, upadacitinib had the greatest net health benefit suggesting that it is a cost-effective use of NHS resources compared with existing NICE-recommended treatments. However, the committee noted that the differences between costs and QALYs were very small, and noted the uncertainties described above. The committee agreed it was likely that upadacitinib is a cost-effective use of NHS resources when conventional or biological treatments are not tolerated or are not working well enough. The committee concluded that upadacitinib is considered cost effective for treating moderately to severely active ulcerative colitis.\n\n# Other factors\n\n## Choosing the most appropriate treatment\n\nThe committee recalled that treatment of ulcerative colitis is highly individualised based on a range of factors. It also recalled that upadacitinib is likely to be a cost-effective use of NHS resources. But it noted that because the cost-effectiveness estimates were similar it could not consider it in preference to other options. This is because the value that each provides is uncertain and is likely to vary from case to case. It recalled that a range of treatments are already available for people with moderately to severely active ulcerative colitis, including some that have not yet been widely used in clinical practice (see section\xa03.5). The committee concluded that healthcare professionals should choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If patients and clinicians consider upadacitinib to be one of a range of suitable options, they should choose the least expensive treatment (taking into account drug administration costs, dose needed and frequency, and product price per dose). This may vary from person to person because of differences in how the drugs are taken and treatment schedules."}	https://www.nice.org.uk/guidance/ta856	Evidence-based recommendations on upadacitinib (Rinvoq) for treating moderately to severely active ulcerative colitis in adults.
900b808ba0f47926bddb4aeb149ac086c0d883cc	nice	Percutaneous image-guided cryoablation of peripheral neuroma for chronic pain	Percutaneous image-guided cryoablation of peripheral neuroma for chronic pain Evidence-based recommendations on percutaneous image-guided cryoablation of peripheral neuroma for chronic pain. This involves using a needle-like probe to freeze and destroy small parts of nerves in neuromas to stop the pain signals. # Recommendations Evidence on the safety and efficacy of percutaneous image-guided cryoablation of peripheral neuroma for chronic pain is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page. For Morton's neuroma, further research should preferably be in the form of randomised controlled trials and should report details of patient selection and the procedure, quality of life and pain reduction in the short and long term. For stump and other traumatic neuromas, further research could be in the form of case series.# The condition, current treatments and procedure # The condition Neuromas are thickenings of tissue around a nerve, which can happen after injuries to the nerve, such as a cut, a crushing injury, nerve compression or an excessive stretch. They are often associated with amputations. Peripheral neuromas affect nerves outside the brain and spinal cord that can carry pain signals between the brain and the rest of the body. This can cause chronic pain. A common type of neuroma is Morton's neuroma, which affects a nerve that lies between 2 metatarsal bones of the foot. It causes pain in the ball of the foot and sometimes the toes. # Current treatments Initial treatment for chronic pain caused by a peripheral neuroma may involve physical therapy, medication, or local anaesthetic and corticosteroid injections. NICE's guideline on neuropathic pain in adults describes pharmacological management in non‑specialist settings. Surgical options include decompression and nerve removal. For Morton's neuroma, conservative management includes measures such as soft pads or insoles to take pressure off the painful area of the foot, wearing shoes with plenty of room in the toes, weight loss and pain medication. If these measures do not work, non-surgical treatments include radiofrequency ablation and injection of corticosteroid or alcohol. If symptoms persist, the affected nerve can be surgically removed. # The procedure Image-guided cryoablation of a peripheral neuroma for chronic pain is a percutaneous treatment, which is usually done as an outpatient or day-case procedure under local anaesthesia. Using image guidance (MRI, CT or ultrasound), a needle-like probe is inserted through the skin and near to the neuroma. Inside the probe, gas flows from a high- to low-pressure chamber, creating an extremely cold temperature at the tip. The extreme cold causes reversible destruction of the nerve axon, which disrupts the pain signals. Unlike surgical or heat-mediated ablation, cryoablation does not disrupt the acellular epineurium or perineurium, which may allow eventual nerve regeneration. The time to total regeneration is related to the rate of axonal regrowth and the distance of the lesion from the end organ, so duration of symptomatic relief varies. The procedure can be repeated if necessary. The main aim of the procedure is to relieve pain but it can also reduce swelling associated with the neuroma.	{'Recommendations': "Evidence on the safety and efficacy of percutaneous image-guided cryoablation of peripheral neuroma for chronic pain is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFor Morton's neuroma, further research should preferably be in the form of randomised controlled trials and should report details of patient selection and the procedure, quality of life and pain reduction in the short and long term. For stump and other traumatic neuromas, further research could be in the form of case series.", 'The condition, current treatments and procedure': "# The condition\n\nNeuromas are thickenings of tissue around a nerve, which can happen after injuries to the nerve, such as a cut, a crushing injury, nerve compression or an excessive stretch. They are often associated with amputations. Peripheral neuromas affect nerves outside the brain and spinal cord that can carry pain signals between the brain and the rest of the body. This can cause chronic pain.\n\nA common type of neuroma is Morton's neuroma, which affects a nerve that lies between 2 metatarsal bones of the foot. It causes pain in the ball of the foot and sometimes the toes.\n\n# Current treatments\n\nInitial treatment for chronic pain caused by a peripheral neuroma may involve physical therapy, medication, or local anaesthetic and corticosteroid injections. NICE's guideline on neuropathic pain in adults describes pharmacological management in non‑specialist settings. Surgical options include decompression and nerve removal.\n\nFor Morton's neuroma, conservative management includes measures such as soft pads or insoles to take pressure off the painful area of the foot, wearing shoes with plenty of room in the toes, weight loss and pain medication. If these measures do not work, non-surgical treatments include radiofrequency ablation and injection of corticosteroid or alcohol. If symptoms persist, the affected nerve can be surgically removed.\n\n# The procedure\n\nImage-guided cryoablation of a peripheral neuroma for chronic pain is a percutaneous treatment, which is usually done as an outpatient or day-case procedure under local anaesthesia. Using image guidance (MRI, CT or ultrasound), a needle-like probe is inserted through the skin and near to the neuroma. Inside the probe, gas flows from a high- to low-pressure chamber, creating an extremely cold temperature at the tip. The extreme cold causes reversible destruction of the nerve axon, which disrupts the pain signals. Unlike surgical or heat-mediated ablation, cryoablation does not disrupt the acellular epineurium or perineurium, which may allow eventual nerve regeneration. The time to total regeneration is related to the rate of axonal regrowth and the distance of the lesion from the end organ, so duration of symptomatic relief varies. The procedure can be repeated if necessary.\n\nThe main aim of the procedure is to relieve pain but it can also reduce swelling associated with the neuroma."}	https://www.nice.org.uk/guidance/ipg747	Evidence-based recommendations on percutaneous image-guided cryoablation of peripheral neuroma for chronic pain. This involves using a needle-like probe to freeze and destroy small parts of nerves in neuromas to stop the pain signals.
c9c2b9d22cdcedb6ccf146caf6781f8e098f203b	nice	Thyroid cancer: assessment and management	Thyroid cancer: assessment and management This guideline covers diagnosis and management of thyroid cancer in people aged 16 and over. It aims to reduce variation in practice and increase the quality of care and survival for people with thyroid cancer. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Information and support ## Information for people with suspected thyroid cancer When providing information, follow the recommendations on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services and putting shared decision making into practice in NICE's guideline on shared decision making. Explain to people with suspected thyroid cancer: that not all lumps, nodules or swellings in the thyroid are cancer what the diagnostic pathway involves and what tests they may need. Advise people where to find reliable high-quality information and support after consultations, from sources such as national and local support groups, networks and information services. ## Information for people having surgery Offer people with suspected or confirmed thyroid cancer, and their family and carers if appropriate, written and verbal information on what hemithyroidectomy or total thyroidectomy involves. Explain the benefits and risks of treatment, including long-term implications such as: the effects of having part or all of your thyroid removed the potential for and possible consequences of: hypothyroidism and the subsequent need for lifelong thyroid hormone replacement the need for treatment for low parathyroid hormone voice change and swallowing disorders. ## Information for people with thyroid cancer When giving people with thyroid cancer their diagnosis, even for low-risk thyroid cancers, it is important to acknowledge that this is a cancer diagnosis and allow the person time to ask questions and be fully informed. Do not refer to thyroid cancer as a 'good cancer' because many people do not find this reassuring and it can cause them to feel that their diagnosis is unimportant. Consider further appointments if they will benefit a person's psychological wellbeing, even if they are not indicated for physical reasons. Give people with thyroid cancer, and their family and carers if appropriate, written and verbal information on: who their key worker is and who to contact for more information their thyroid cancer and its likely cure rate, effect on their life expectancy and likelihood of recurrence the role and function of the thyroid gland and the need for long-term monitoring of thyroid function how treatment may affect conception, pregnancy, breast feeding and fertility the risks, benefits and uncertainties of treatment and its potential effects on their quality of life, energy, weight and mood the roles of those involved in their treatment and follow up, and the composition of the multidisciplinary team where to get reliable further information. At follow up give people with thyroid cancer, and their family and carers if appropriate, information on: follow up and how it is likely to be done what thyroglobulin is, how it is measured and why lifelong thyroid hormone replacement lifelong monitoring of thyroid function when to seek advice from a healthcare professional, who that healthcare professional should be and how to contact them. ## Information for people having radioactive iodine Offer people with suspected or confirmed thyroid cancer, and their family and carers if appropriate, written and verbal information on the benefits, and short- and long-term risks of radioactive iodine (RAI). Explain that: the aim of RAI is to destroy any residual thyroid tissue, including tissue that may be malignant, and allows effective monitoring for recurrence by a blood test precautions may be needed when taking RAI which may temporarily affect conception, pregnancy, breast feeding and fertility although uncommon, there is the potential for dry mouth and salivary gland inflammation, both of which are temporary in most people there is a potential but very low risk of RAI causing new primary second cancers. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support . Full details of the evidence and the committee's discussion are in evidence review R: information, education and support needed by people with suspected and confirmed thyroid cancer, and their families and carers. Loading. Please wait. # Assessment and diagnosis See the recommendation on referral for suspected thyroid cancer in the NICE guideline on suspected cancer. ## Blood tests See the recommendations on thyroid function tests in the NICE guideline on thyroid disease. Do not use calcitonin testing to assess thyroid nodules unless there is a reason to suspect medullary thyroid cancer (MTC), such as a family history or a nodule with an appearance on ultrasound that suggests MTC. Do not routinely measure thyroid peroxidase antibody (TPO). Consider TPO measurement when interpreting indeterminate cytopathology. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on blood tests . Full details of the evidence and the committee's discussion are in evidence review B: indications for blood tests. Loading. Please wait. ## Ultrasound See the section on investigating thyroid enlargement in the NICE guideline on thyroid disease, and the recommendation on referral for suspected thyroid cancer in the NICE guideline on suspected cancer. Offer greyscale ultrasound with an established system for grading ultrasound appearance as the initial diagnostic test when investigating thyroid nodules for malignancy. See the recommendations on grading and reporting ultrasound findings when investigating thyroid enlargement in the NICE guideline on thyroid disease. Offer fine needle aspiration cytology (FNAC) to people who meet the threshold using an established system for grading ultrasound appearance. Consider FNAC or active surveillance for people who do not meet the threshold for FNAC on ultrasound grading alone if there are other reasons for clinical concern. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on ultrasound . Full details of the evidence and the committee's discussion are in evidence review A: ultrasound accuracy and threshold of nodule size and classification. Loading. Please wait. ## FNAC testing See the recommendation on using ultrasound guidance when performing FNAC in the NICE guideline on thyroid disease. Use liquid-based cytology, direct smear or both when processing FNAC samples. Use the Royal College of Pathologists modification of the British Thyroid Association (BTA) reporting system to report cytology results. Consider rapid on-site evaluation of FNAC adequacy rates to improve the diagnostic yield of samples if the Thy1 (inadequate) rate for the centre or individual clinicians is higher than 15% (when Thy1c is excluded). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on performing and reporting FNAC . Full details of the evidence and the committee's discussion are in evidence review D: diagnostic accuracy of fine needle aspiration cytology. Loading. Please wait. ## Management and further sampling after initial FNAC Use the initial FNAC results to determine further management and sampling options, as shown in table 1. Initial fine-needle aspiration cytology result Management and further sampling Thy1 (inadequate) Offer repeat sampling Consider core-needle biopsy (CNB) or fine-needle aspiration cytology (FNAC) with rapid on-site evaluation (ROSE) as the first choice Consider FNAC alone if ROSE is unavailable and CNB is unavailable or inappropriate Consider diagnostic hemithyroidectomy if the repeat sample is also Thy1 Thy1c (cystic lesion) Offer repeat sampling with FNAC Consider diagnostic hemithyroidectomy if the repeat sample is also Thy1c and the ultrasound appearances are concerning Thy2 and Thy2c (benign) Consider repeat ultrasound Offer repeat sampling with FNAC if the second ultrasound also reaches the threshold for FNAC Consider CNB as an alternative to FNAC Discharge people if there is no evidence of malignancy after all investigations are complete, unless there are other reasons for clinical concern Thy3a (atypia, neoplasia possible) Offer repeat sampling Consider CNB (or FNAC if CNB unavailable or inappropriate) Consider diagnostic hemithyroidectomy or active surveillance if repeated samples are still Thy3a Thy3f (suggesting follicular neoplasm) Consider diagnostic hemithyroidectomy Thy4 (suspicion of malignancy) and Thy5 (malignant) Offer diagnostic hemithyroidectomy, or treatment with therapeutic hemithyroidectomy or total thyroidectomy For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on management and further sampling after initial FNAC . Full details of the evidence and the committee's discussion are in evidence review E: efficacy of repeat FNAC, active surveillance or discharge and evidence review F: molecular testing. Loading. Please wait. ## Radioisotope scans Do not routinely use radioisotope scans for the initial diagnosis of thyroid cancer. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on radioisotope scans . Full details of the evidence and the committee's discussion are in evidence review C: radioisotope scans. Loading. Please wait. ## Imaging for further staging Do not routinely use cross-sectional imaging (CT or MRI) in people with T1 or T2 disease and no other indications. Consider cross-sectional imaging (CT of neck and chest, or MRI of neck and CT of chest) for people with thyroid cancer that is T3 or T4, any N1 or M1 thyroid cancer or other clinical suspicion of metastases. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on imaging for further staging . Full details of the evidence and the committee's discussion are in evidence review G: imaging for further staging. Loading. Please wait. # Initial treatment of differentiated thyroid cancer ## Surgery and active surveillance for primary tumours When discussing surgical options with a person with differentiated thyroid cancer, take into account their preferences, comorbidities and all the available evidence regarding their tumour. Offer hemithyroidectomy or total thyroidectomy to people with differentiated thyroid tumours larger than 1 cm or multifocal disease (T1a to T2N0M0). Offer total thyroidectomy to people who have: a T3 or T4 stage primary tumour regional lymph node involvement (N1) adverse pathological features distant metastatic disease (M1). Offer completion thyroidectomy to people who have had a hemithyroidectomy if it is indicated on review of the histological features of the initial specimen. Consider hemithyroidectomy or active surveillance for people with a solitary microcarcinoma (T1a) without evidence of nodal involvement. ## Surgery for nodal disease Offer a compartment-orientated lateral neck dissection for people with structural nodal disease in the lateral neck. Consider a prophylactic ipsilateral central neck dissection when doing the compartment-orientated lateral neck dissection for people with structural nodal disease in the lateral neck. Offer a compartment-orientated central neck dissection for people with structural nodal disease in the central neck. Do not offer prophylactic central or lateral neck dissection (except in the circumstances in recommendation 1.3.7). ## Surgery during pregnancy Consider deferring surgery until after pregnancy, taking into account: the risk of delaying surgery the risk to the pregnancy the rate of disease progression.The obstetrician, surgeon and endocrinologist should discuss these factors and a joint decision should be reached in discussion with the pregnant woman. When surgery cannot be delayed until after pregnancy, it should be done during the second trimester if possible. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgery and active surveillance for primary tumours . Full details of the evidence and the committee's discussion are in evidence review H: initial treatments for differentiated thyroid cancer. Loading. Please wait. ## Thyrotropin alfa Offer thyrotropin alfa for pretherapeutic stimulation for people with thyroid cancer (including those with distant metastases; see recommendation 1.3.13) who are having RAI ablation. In December 2022 this use of thyrotropin alfa as a treatment for thyroid cancer in people with distant metastases was off-label. See NICE's information on prescribing medicines. Use thyrotropin alfa with caution in people with thyroid cancer who have brain or spinal metastases, because there is a risk of clinically significant tumour flare. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on thyrotropin alfa . Full details of the evidence and the committee's discussion are in evidence review I: thyrotropin alfa. Loading. Please wait. ## RAI for initial ablation Offer RAI to people who have had a total or completion thyroidectomy based on the criteria in the recommendation on offering total thyroidectomy in the section on surgery and active surveillance for primary tumours. Do not offer RAI to people with T1a or T1b tumours including those with multifocal disease, unless there are adverse features, regional lymph node involvement, or evidence of other metastatic disease. Consider RAI for people with T2 disease who have had a total or completion thyroidectomy, but whose disease does not show any of the features in the recommendation on offering total thyroidectomy in the section on surgery and active surveillance for primary tumours. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on RAI for initial ablation . Full details of the evidence and the committee's discussion are in evidence review J: radioactive iodine versus no radioactive iodine. Loading. Please wait. ## RAI activity for initial ablation Consider RAI with an activity for initial ablation of 3.7 GBq for people with high-risk features such as T4, N1b or M1 disease or aggressive subtypes, or people for whom multiple ablations should be avoided because they have one or more of the following characteristics: significant comorbidities such as cardiovascular disease mobility issues complex social concerns. Offer RAI with an activity for initial ablation of 1.1 GBq to people who are not having 3.7 GBq. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on RAI activity . Full details of the evidence and the committee's discussion are in evidence review K: activity of radioactive iodine after thyroidectomy. Loading. Please wait. ## External beam radiotherapy Consider external beam radiotherapy (EBRT) if there is macroscopic disease after surgery or local disease that is unlikely to be controlled with RAI. Consider EBRT for symptom control for people receiving palliative care. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on external beam radiotherapy . Full details of the evidence and the committee's discussion are in evidence review L: external beam radiotherapy versus no external beam radiotherapy. Loading. Please wait. # Ongoing treatment with thyroid stimulating hormone suppression for differentiated thyroid cancer ## When to offer thyroid stimulating hormone suppression Do not offer thyroid stimulating hormone (TSH) suppression to people who: do not meet the threshold for RAI (see the section on RAI for initial ablation) have significant comorbidities that mean low TSH levels should be avoided. Offer thyroid hormone at doses that will suppress TSH to below 0.1 mIU/litre, to people who have had total or completion thyroidectomy and RAI. TSH suppression should be continued until follow-up review at 9 to 12 months after initial treatment has been completed. ## Assessing and managing response to TSH suppression Use dynamic risk stratification to determine further management at 9 to 12 months after completion of initial RAI ablation, as follows: Reduce TSH suppression to achieve a TSH level of between 0.3 mIU/litre and 2.0 mIU/litre and continue this for life in people with an excellent response to treatment. Continue TSH suppression to achieve a TSH level of between 0.1 mIU/litre and 0.5 mIU/litre in people who have an intermediate response to initial treatment. Continue to suppress TSH to less than 0.1 mIU/litre in people who have biochemical or structural evidence of persistent or recurrent disease. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on thyroid stimulating hormone suppression . Full details of the evidence and the committee's discussion are in evidence review M: TSH suppression versus no TSH suppression. Loading. Please wait. ## Long-term duration of TSH suppression Offer a review to people who have had ongoing TSH suppression for more than 10 years. Decide whether the TSH suppression can be reduced after an individualised assessment of risks and benefits, and explain that: lifelong suppression is not necessary unless they have high-risk or metastatic disease reducing TSH suppression may lower the risk of developing bone and cardiac problems. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on long-term duration of TSH suppression . Full details of the evidence and the committee's discussion are in evidence review N: duration of TSH suppression. Loading. Please wait. # Post-thyroidectomy monitoring of differentiated thyroid cancer ## Measuring thyroglobulin and thyroglobulin antibodies Be aware that: the presence of thyroglobulin antibodies, above the laboratory threshold, can interfere with the measurement of thyroglobulin levels detectable thyroglobulin levels in people without thyroglobulin antibodies suggest the presence of either residual thyroid tissue or residual or recurrent thyroid cancer. Offer thyroglobulin measurement alongside measurement of thyroglobulin antibodies in people with differentiated thyroid cancer who have had total or completion thyroidectomy and RAI. Measure at: - to 6-month intervals in the first 2 years after RAI ablation and - to 12-month intervals thereafter. Consider further investigations if a person has had total thyroidectomy and RAI, and: has detectable thyroglobulin levels without thyroglobulin antibodies investigations have not shown recurrent or residual cancer in the presence of detectable thyroglobulin without thyroglobulin antibodies, and now the thyroglobulin levels without thyroglobulin antibodies are rising. Consider further investigations if a person has had a total thyroidectomy without RAI and has rising thyroglobulin levels without thyroglobulin antibodies. Do not routinely measure thyroglobulin levels in people who have not had total or completion thyroidectomy. Consider further investigation when thyroglobulin antibodies are first detected above the laboratory threshold or at any point if the levels of thyroglobulin or thyroglobulin antibodies are rising. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on measuring thyroglobulin and thyroglobulin antibodies . Full details of the evidence and the committee's discussion are in evidence review O: measurement of thyroglobulin. Loading. Please wait. ## Stimulated thyroglobulin and highly sensitive thyroglobulin testing Consider either a stimulated thyroglobulin test or highly sensitive thyroglobulin test if thyroglobulin is undetectable on a standard assay in people who have had a total or completion thyroidectomy and RAI, and have no evidence of structural persistent disease. Consider the following if using a stimulated thyroglobulin test: less frequent follow up, where appropriate, and more relaxed TSH suppression if stimulated thyroglobulin is below 1 microgram/litre (low risk) continuing TSH suppression if stimulated thyroglobulin is between 1 microgram/litre and 10 microgram/litre (indeterminate risk) further investigations and treatment if stimulated thyroglobulin is 10 microgram/litre or more and there is no resectable disease. Consider the following if using a highly sensitive assay that can detect thyroglobulin levels lower than 0.2 microgram/litre: less frequent follow up, where appropriate, and more relaxed TSH suppression if the thyroglobulin level is lower than 0.2 microgram/litre stimulated thyroglobulin, which can be helpful in separating people into lower- and higher-risk groups if the thyroglobulin level is between 0.2 microgram/litre and 1 microgram/litre. Use caution when interpreting results in the presence of thyroglobulin antibodies because they may cause false-positive or negative findings. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on stimulated thyroglobulin and highly sensitive thyroglobulin testing . Full details of the evidence and the committee's discussion are in evidence review P: stimulated or highly sensitive thyroglobulin assays. Loading. Please wait. # Follow up of differentiated thyroid cancer Do not routinely follow up people with thyroid cancer who have a solitary microcarcinoma (T1a) that has been surgically removed. Consider an ultrasound at 6 to 12 months initially then annual clinical follow up for up to 5 years for people with T1a (m) or T1b stage or greater thyroid cancer, who have had a hemithyroidectomy or total thyroidectomy without RAI. Consider a risk-stratified approach to follow up for any person who has had total or completion thyroidectomy and RAI, as shown in table 2. Risk group Follow up Low risk (no evidence of disease on imaging and thyroglobulin of less than 0.2 microgram/litre, or stimulated thyroglobulin of less than 1 microgram/litre) Consider (at least annually) follow up of 2 to 5 years with thyroglobulin testing Use ultrasound if needed Medium risk (thyroglobulin between 0.2 and 1.0 microgram/litre, or stimulated thyroglobulin of between 1 and 10 microgram/litre) Consider (at least annually) 5 to 10 years follow up with thyroglobulin testing Use ultrasound if needed High risk (thyroglobulin of greater than 1.0 microgram/litre, or stimulated thyroglobulin of greater than 10 microgram/litre) Consider (at least annually) 10 years follow up with thyroglobulin testing Use ultrasound if needed Anyone with biochemical or structural evidence of disease Consider (at least annually) lifelong follow up with thyroglobulin testing Use ultrasound if needed Discuss at the multidisciplinary team meeting any person who has had a total or completion thyroidectomy and RAI and has evidence of structural persistent disease. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow up . Full details of the evidence and the committee's discussion are in evidence review Q: length and frequency of follow up. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## Active surveillance Active surveillance involves monitoring the person's thyroid cancer with periodic appointments that include investigations such as blood tests and ultrasound. The duration and frequency of further appointments and investigations should be a clinical decision that considers the risks for the person. ## Completion thyroidectomy A completion thyroidectomy relates to when someone who has had a hemithyroidectomy has the rest of their thyroid gland removed. In this guideline, recommendations related to treatment and monitoring for total thyroidectomy also apply to people who have had a completion thyroidectomy. ## Dynamic risk stratification Following initial risk assessment at diagnosis, the risk of recurrence is re-assessed at follow up by evaluating the person's response to treatment. This re-evaluation of risk constitutes a 'dynamic risk stratification' allowing the follow-up strategy to be modified according to risk. This is an established system and the response to treatment is based on measurement of serum thyroglobulin Tg (and anti‑thyroglobulin antibody TgAb) and ultrasound imaging. ## Radioactive iodine A radioactive form of iodine used to treat thyroid cancer by killing thyroid cells and thyroid cancer cells after surgery. It is usually taken in a capsule or liquid. ## Thyroid cytology specimens This guideline uses the Royal College of Pathologists guidance on the reporting of thyroid cytology specimens published in 2016 (see table 3) for recommendations related to reporting FNAC results. Thy category Description Thy1 Inadequate or non-diagnostic Thy1: inadequate Thy1c: cystic lesion Thy2 Benign or non-neoplastic Thy3 Indeterminate or neoplasm possible Thy3A: neoplasm possible (atypical features) Thy3F: follicular neoplasm Thy4 Suspicious of malignancy Thy5 Malignant ## TNM classification This guideline uses the tumour, node, metastasis (TNM) classification developed by the Union for International Cancer Control (UICC) to describe the stage of the cancer. Please refer to the TNM Classification of Malignant Tumours, 8th Edition for further information.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Molecular tests In fine-needle aspiration cytology (FNAC) samples that are adequate but cannot differentiate between benign and malignant samples, what is the clinical and cost effectiveness of molecular testing for thyroid cancer? For a short explanation of why the committee made this recommendation for research, see the rationale section on management and further sampling after initial FNAC . Full details of the evidence and the committee's discussion are in evidence review F: molecular testing. Loading. Please wait. ## Duration of follow up What is the clinical and cost effectiveness for different durations of follow up for people with differentiated thyroid cancer who have been treated? For a short explanation of why the committee made this recommendation for research, see the rationale section on follow up . Full details of the evidence and the committee's discussion are in evidence review Q: length and frequency of follow up. Loading. Please wait. ## Active surveillance compared with surgery For people with stage 1 differentiated thyroid cancer, what is the clinical and cost effectiveness of active surveillance compared with surgery? For a short explanation of why the committee made this recommendation for research, see the rationale section on surgery and active surveillance for primary tumours . Full details of the evidence and the committee's discussion are in evidence review H: initial treatments for differentiated thyroid cancer. Loading. Please wait. ## Duration of thyroid stimulating hormone suppression For people with differentiated thyroid cancer who have had surgery and radioactive iodine (RAI), what is the optimal duration of thyroid stimulating hormone suppression? For a short explanation of why the committee made this recommendation for research, see the rationale section on long-term duration of TSH suppression . Full details of the evidence and the committee's discussion are in evidence review N: duration of TSH suppression. Loading. Please wait. # Other recommendations for research ## Radioactive iodine What is the clinical and cost effectiveness of RAI after total or completion thyroidectomy for people with T2 disease and no adverse pathological features? For a short explanation of why the committee made this recommendation for research, see the rationale section on RAI for initial ablation . Full details of the evidence and the committee's discussion are in evidence review J: radioactive iodine versus no radioactive iodine. Loading. Please wait. ## Thyroid peroxidase antibody testing For people with indeterminate cytopathology, what is the clinical and cost effectiveness of thyroid peroxidase antibody testing? For a short explanation of why the committee made this recommendation for research, see the rationale section on thyroid peroxidase antibody testing . Full details of the evidence and the committee's discussion are in evidence review B: indications for blood tests. Loading. Please wait. ## Imaging for further staging For people with differentiated thyroid cancer who have initial ultrasound evidence of extensive local spread (T2N1), what is the clinical and cost effectiveness of CT, MRI or F-18 FDG PET-CT scanning, with or without ultrasound, as part of a further staging strategy? For a short explanation of why the committee made this recommendation for research, see the rationale section on imaging for further staging . Full details of the evidence and the committee's discussion are in evidence review G: imaging for further staging. Loading. Please wait. ## External beam radiotherapy compared with usual care What is the clinical and cost effectiveness of external beam radiotherapy for people with residual or recurrent thyroid cancer? For a short explanation of why the committee made this recommendation for research, see the rationale section on external beam radiotherapy . Full details of the evidence and the committee's discussion are in evidence review L: external beam radiotherapy versus no external beam radiotherapy. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Information and support Recommendations 1.1.1 to 1.1.10 ## Why the committee made the recommendations The committee agreed that the NICE guidelines on patient experience in adult NHS services and shared decision making give important advice on enabling people to participate in their care. The committee agreed that it is important to give information on what to expect with investigations and treatments, and to deliver it at an appropriate time to support people in managing their condition. The committee were aware that people often look for information themselves and therefore it is important to direct them to sources that are good quality and reliable. The committee also agreed it is important to explain to people with signs of thyroid cancer that not all swellings are cancerous and what any investigations may entail. This included the implications of surgery on thyroid function and what the consequences are. Evidence showed that telling people with thyroid cancer that it is a 'good cancer', was generally not reassuring. It caused them to feel that the diagnosis was being dismissed as unimportant and, as a result, they felt undeserving of seeking support. Therefore, the committee recommended that healthcare professionals should avoid telling people they have a 'good cancer'. Instead, they should give the person time to acknowledge they have cancer and to ask any questions. For some people this may mean further appointments are beneficial. The committee agreed that a lot of people with newly diagnosed thyroid cancer might not know what the thyroid gland does. Therefore, it is important to give them information on the thyroid gland, how their condition will be managed, any consequences of treatment and the long-term follow-up requirements. ## How the recommendations might affect practice Giving people information and support and including further appointments for some people, is current practice. Therefore, the recommendations are unlikely to have a big impact. Return to recommendations # Blood tests Recommendations 1.2.2 to 1.2.5 ## Why the committee made the recommendations The very early part of the pathway for suspected thyroid cancer is covered in other NICE guidance. NICE's guideline on suspected cancer covers when to refer people with an unexplained thyroid lump and NICE's guideline on thyroid disease covers the initial tests to use when investigating suspected thyroid dysfunction or thyroid enlargement. For this guideline, the committee looked at additional blood tests that could be used for the diagnosis of thyroid cancer. The committee made recommendations in this area based on consensus because no evidence was identified. The committee discussed the high rate of false positives from calcitonin testing, which can cause serious harm from unnecessary treatments. For example, the committee were aware of evidence that suggested that borderline raised calcitonin can be caused by Hashimoto's disease or certain drugs. This can in turn cause over‑treatment and high levels of morbidity. The false positives may cause a particularly low positive-predictive value because of the relative rarity of medullary thyroid cancer (MTC), with only 100 to 150 new cases per year in the UK. The committee therefore agreed that for most people it would be more useful and less harmful not to use calcitonin testing. Instead, other methods of assessment should be used, such as fine-needle aspiration cytology (FNAC). However, the committee agreed that there were some people for whom the benefits of calcitonin testing might outweigh its harms. This would include people at higher risk of MTC, for whom the risks of false negatives would outweigh the risks of false positives at a population level. This includes people with a family history of MTC; those with multiple endocrine neoplasms; those with suspected MTC or MTC diagnosed by cytopathology, core biopsy, or other histopathology; and people with C-cell hyperplasia. Therefore, a recommendation was made that calcitonin should not be tested routinely unless there are prior reasons to suspect MTC. The committee discussed from their experience how results from thyroid peroxidase antibody (TPO) tests can facilitate interpretation of FNAC results. For example, if the FNAC result is suggestive of benign thyroiditis, then a positive TPO test may help to confirm this. A positive TPO test may also allow an indeterminate result to be downgraded to benign. Therefore, the committee agreed that TPO should be used to facilitate interpretation in cases where the FNAC result is uncertain. However, where there is little uncertainty about the FNAC result, the committee did not think the benefits of TPO testing justified its use. Therefore, the recommendation was made that TPO should not be routinely measured but could be considered when there was indeterminate cytopathology. Given the uncertainty in this area the committee also made a recommendation for research on thyroid peroxidase antibody testing. ## How the recommendations might affect practice The recommendation to not offer calcitonin testing unless MTC is suspected largely reflects current practice in the UK. It also represents a targeted use of NHS resources due to the rarity of MTC and high cost of the test. The recommendation on TPO may lead to an additional use of resources but was considered important to avoid unnecessary surgeries in people with benign nodules and indeterminate cytopathology (for example, people with Hashimoto's disease). It is therefore expected to lead to fewer unnecessary thyroidectomies and ultimately improve the efficiency of the NHS. Return to recommendations # Ultrasound Recommendations 1.2.6 to 1.2.10 ## Why the committee made the recommendations After considering the diagnostic accuracy evidence, the committee eliminated all index tests that had sensitivity and specificity benchmarks below 0.9 and 0.5, respectively. These were the minimum pre-hoc standards for first-line diagnostic tests. Given that there was evidence for simpler techniques, such as greyscale ultrasound, the committee also excluded techniques that were impractical, unsuitable for most people or invasive. This included elastography and contrast enhanced ultrasound. The committee also considered a simple combination of greyscale characteristics and a doppler test that used blood-velocity measurement. However, evidence for both tests was taken from single studies, which raised questions of representativeness, and the doppler test had imprecision in the sensitivity result. The only index tests remaining that fulfilled all criteria of accuracy and clinical appropriateness were the ordinal scales of greyscale characteristics. Therefore, the committee recommended that greyscale ultrasound should be offered as the initial test. The data available did not provide evidence to suggest one system for grading ultrasound was better than another. Therefore, the committee agreed with the recommendation in the NICE guideline on thyroid disease that the decision to do FNAC should be made using an established system for grading ultrasound. The committee were also aware that none of the established systems have perfect sensitivity. Therefore, some people with malignancy might 'slip through the net' and not receive further investigation. So, another recommendation was made that people whose results do not meet the threshold could still have further investigations with FNAC or active surveillance if there are still clinical concerns. Overall, the committee agreed with the recommendations on investigating thyroid enlargement in the NICE guideline on thyroid disease. They discussed the importance of using a classification system that considers: echogenicity microcalcifications border shape in transverse plane internal vascularity and lymphadenopathy. They also agreed that reports of ultrasound findings should: specify which grading system has been used for the assessment include information on the characteristics of the nodule provide an overall assessment of malignancy confirm that both lobes have been assessed and document assessment of cervical lymph nodes. This can help improve diagnosis by ensuring all the data is available to clinicians when assessing the person. ## How the recommendations might affect practice Recommending an established system for grading ultrasound appearance is not expected to affect current practice significantly. This is because the recommendation does not state which system to use and therefore it is unlikely to persuade clinicians to adopt a new system. Instituting FNAC or active surveillance for people who do not meet the threshold for FNAC or who have small nodules does not represent a change to current practice. Return to recommendations # Performing and reporting FNAC Recommendations 1.2.11 to 1.2.14 ## Why the committee made the recommendations The committee recommended that FNAC should be offered with either liquid-based cytology, direct smear or both. They agreed that the evidence did not show that one technique was better than the other. Current practice varies with some centres using one technique and others using both. The committee agreed that the Royal College of Pathologists modification of the BTA reporting system (RCPath BTA) is widely used in the UK. Therefore, they made a recommendation, based on consensus, to use the RCPath BTA reporting system. An estimation of the data from the evidence review suggested that rapid on-site evaluation (ROSE) reduced non-diagnostic results by 55%. It is likely to be cost effective when offered where there is a concerningly high inadequacy rate. The Royal College of Pathologists notes that an inadequacy rate of more than 15% (excluding Thy1c) is problematic. Therefore, the committee agreed that centres or individual clinicians with high inadequacy rates might benefit from ROSE if this is implemented and routinely used. Thy1c was excluded from the threshold because it would not benefit from ROSE. This is because Thy1c indicates a non-diagnostic for cystic lesion which is not operator- or technique-dependent. ## How the recommendations might affect practice Although direct smear is commonly used with FNAC, liquid-based cytology is less commonly used in smaller centres. If a centre adopts liquid-based cytology, then some changes in training and provision of equipment may be needed. However, most large centres already use liquid-based cytology and some centres use both as part of a quality assurance process to get better results. The overall impact on practice is likely to be small. Use of ROSE, specifically for centres or individual clinicians with high inadequacy rates, was thought to represent a change in practice. It would require auditing the adequacy rates of samples and personnel would be needed to provide such services. However, it likely represents a cost-effective use of NHS resources if used where there is a concerningly high inadequacy rate, particularly those with a medium or high volume of FNACs. The committee also agreed it may be beneficial in all centres with a high inadequacy rate. Furthermore, a persistent, low inadequacy rate of FNAC (with or without ROSE) may be achieved due to the training provided by cytopathologists, thus improving the diagnostic efficiency of the NHS in the long‑term. Return to recommendations # Management and further sampling after initial FNAC Recommendation 1.2.15 ## Why the committee made the recommendation For people who have an inadequate (Thy1) FNAC results, the committee recommended that sampling should be repeated. This was because an unsatisfactory aspirate is often a random technical failure that might not be repeated. The preferred approach for repeat sampling is a core-needle biopsy (CNB) or FNAC with ROSE. This was because the diagnostic clinical review of FNAC and CNB, and the studies informing the health economic model, found that CNB and FNAC with ROSE are more accurate than repeat FNAC and associated with a lower rate of unsatisfactory results. The committee recommended that, in some cases, FNAC alone could be performed instead. For example, if CNB and ROSE are not available locally, or if the nodule is near a blood vessel that would make the use of CNB with large needles inappropriate. Should this further test still be Thy1, then the committee thought the best way to determine malignancy is by diagnostic hemithyroidectomy. For people with a cystic lesion (Thy1c), FNAC should be repeated. This is because neither CNB or FNAC with ROSE were considered useful for non-diagnostic cystic samples. If the second FNAC is also Thy1c and the initial ultrasound appearances are concerning, then the committee agreed that a diagnostic hemithyroidectomy should be considered to establish the diagnosis. To optimise the sensitivity of FNAC testing, which was fractionally below the target of 0.95, the committee recommended repeating tests that are benign (Thy2 or Thy2c). In the first instance, the committee agreed that repeating ultrasound should be considered. If this still produces a suspicious result, then the next step would be to repeat the FNAC. CNB could be considered as an alternative to repeating FNAC, because although it is invasive and more expensive than FNAC, it can extract more material. Benign FNAC tests should be repeated because sampling error can sometimes cause false negatives. Therefore, if the initial Thy2 result was caused by sampling error, a repeat test is likely to return a positive result but, if it was not, the repeated test will also be Thy2. The committee therefore recommended that people who have had repeated investigations, and there is no evidence of malignancy after these are complete, can be discharged unless there are other clinical concerns. The committee made a repeat sampling recommendation for people with Thy3a results. The preferred approach is CNB, which reflects the findings of the economic evaluation and clinical review. A consider recommendation was made, because in some cases a Thy3a sample may suggest a follicular lesion, which would not benefit from repeat sampling with CNB. FNAC is recommended as an alternative when CNB is unavailable or inappropriate. In case of a further Thy3a results, a recommendation was made to use diagnostic hemithyroidectomy or active surveillance. For people with Thy3f results, the committee recommended that diagnostic hemithyroidectomy be considered. This reflected the committee's view that repeat sampling with FNAC or CNB is less useful after a suspected follicular lesion (Thy3f) and that diagnostic hemithyroidectomy is justified by the high risk of malignancy in this group (around 30%). There were also concerns that, if not followed up with surgery, final diagnosis after Thy3f could take longer. This would delay treatment for a potentially malignant tumour, create uncertainty for the person, and in some centres lead to a longer delay than is allowed by NHS cancer targets. Although the committee agreed that this is current practice, a consider recommendation was made. This reflects the uncertainty in the evidence and the committee agreed that there may be some cases, for instance in older people with severe comorbidities, where a hemithyroidectomy for a Thy3f may not be appropriate. For people with Thy4 or Thy5 cytology, the committee recommended diagnostic or therapeutic hemithyroidectomy, or total thyroidectomy. The recommendation that people in these groups should be sent straight to surgery was based on evidence that the groups would contain a significant proportion of people with malignancy. The economic model suggested that molecular testing could be cost effective in certain cytologies, particularly after a suspected follicular lesion (Thy3f), which would not benefit from repeat sampling. However, molecular tests are not widely available in the NHS and are mostly produced outside the UK. The committee agreed that molecular tests could help reduce the number of unnecessary diagnostic hemithyroidectomies in people with indeterminate FNAC results and made a recommendation for research for molecular tests. ## How the recommendation might affect practice The recommendation to offer CNB or FNAC with ROSE after a non-diagnostic Thy1 cytology result is considered a change from current practice. Some centres could have preference for, or availability of, only one of the two techniques, so the recommendation ensures flexibility in the management of Thy1. In centres where neither technique is available, the implementation of CNB or FNAC with ROSE could require additional resources for training and resourcing in the short term. However, the reduction of non-adequate cytologies, repeat sampling and unnecessary surgeries is expected to offset the initial investments. The recommendation to consider repeat ultrasound and repeat FNAC with Thy2 reflects current practice and it is not expected to have an impact on NHS resources. The recommendations to repeat sampling with CNB after a Thy3a cytology is a significant change from current practice. FNAC has generally been the preferred method for repeat sampling in the NHS, so some changes in training for biomedical scientists, radiologists and pathologists and provision of equipment in centres where CNB is rarely offered or not available are expected. However, as shown in the health economic analysis, this is likely a cost-effective use of NHS resources, which would reduce unnecessary diagnostic surgeries and improve efficiency. The recommendations to offer diagnostic hemithyroidectomy to people with Thy3f and either diagnostic or therapeutic surgery to people with Thy4 and Thy5, reflect the current approach and are not likely to have an impact on practice or resources. Return to recommendation # Radioisotope scans Recommendation 1.2.16 ## Why the committee made the recommendation In the absence of evidence from the review, the committee formed a recommendation by consensus. The committee agreed that there is a potential harm from radioisotope scans and, based on clinical experience, agreed that they are no more accurate than FNAC. Therefore, the benefits of radioisotope scans would normally not outweigh the harms and they would not be considered. However, the committee did not have enough evidence to recommend that radioisotope scans should never be used. Therefore, the word 'routinely' was used to indicate that they might be useful in very rare and specific circumstances, although the committee did not provide examples. This was because any such examples would be extremely context-dependent and would not demonstrate the complexity of such decision making. The committee agreed that there may be value in using radioisotope scans when assessing recurrent thyroid cancer, however this was not part of this review question. Therefore, this recommendation relates to the initial diagnosis of thyroid cancer. ## How the recommendation might affect practice The recommendation largely reflects current practice because radioisotope scans are only used rarely, and it is therefore not expected to have a significant effect on practice. Return to recommendation # Imaging for further staging Recommendations 1.2.17 and 1.2.18 ## Why the committee made the recommendations In the absence of evidence, the committee used consensus to form the recommendations. The committee agreed that for people with T1 or T2 thyroid cancer and no other indications, cross-sectional imaging is not needed. The ultrasound results obtained when the thyroid was first assessed should provide enough detail for further staging. Other indications that would suggest cross‑sectional imaging may be useful, include signs of metastases or a suspicious symptom such as a cough. This decision was based on the agreement that ultrasound would be sensitive enough to pick up the relatively superficial structural lesions that might occur in most of this group. It was also agreed that the potential harms of deeper imaging techniques would not be outweighed by the benefits in this group. For example, CT carries radiation risks, particularly to younger people, and some people find the experience of MRI distressing. For people at even higher levels of risk, such as those with T3 or T4 thyroid cancer, or with any local spread to nodes or distant metastases, cross-sectional imaging techniques should be considered, as well as the initial ultrasound, to help define the stage of cancer. The committee agreed that cross-sectional imaging would be useful either before surgery, to help inform the procedure, or after surgery, to inform subsequent management. However, the committee noted that clinicians would need to balance the benefit of additional information gained from CT contrast, against the potential need to delay RAI as a result of having a CT scan. ## How the recommendations might affect practice The impact of the recommendations on practice is expected to be small, because the recommendations reflect current practice. Return to recommendations # Surgery and active surveillance for primary tumours Recommendations 1.3.1 to 1.3.11 ## Why the committee made the recommendations Evidence from the randomised control trial (RCT) showed total thyroidectomy led to less cancer recurrence than hemithyroidectomy. Weighing up the benefits and harms, using this evidence and their experience, the committee agreed that total thyroidectomy should be recommended over hemithyroidectomy if there are definite indications for postoperative radioactive iodine (RAI), such as a large primary tumour or bilateral disease. This is because definite indications for postoperative RAI suggest that the risk of recurrence is high enough that the benefits of total thyroidectomy outweigh its potential harms. However, where the risk of recurrence is lower, the committee agreed that a hemithyroidectomy would be as beneficial and potentially less harmful, and might also allow people to maintain normal thyroid function. The committee also agreed that, although a hemithyroidectomy might be chosen, some people might need a completion thyroidectomy later if it is indicated by a histological review or during later surveillance. No randomised evidence was found for active surveillance. Observational evidence showed that surgery led to lower overall mortality compared with active surveillance in people with stage 1 disease. However, the committee were aware of the lack of adjustment for likely confounding by comorbidity. In this population there were no other outcomes reported and so it was difficult to establish a full picture of benefits and harms. In contrast, observational evidence from adults with cytologically confirmed papillary thyroid microcarcinoma favoured active surveillance over hemithyroidectomy. This was because people on active surveillance had fewer surgical scar problems, neuromuscular symptoms, throat and mouth symptoms and loss of interest in sex. However, measurements of other quality of life outcomes were largely inconclusive. The committee agreed that the evidence base suggested that active surveillance should not be used for most people with thyroid cancer. Instead, it should only be considered for people who have a small (less than 1 cm) solitary microcarcinoma, with the person's preferences taken into account after a full discussion. This was because, in the committee's experience, there is a low risk of the tumour adversely affecting the person's quality of life. Therefore the committee made a recommendation to consider either hemithyroidectomy or active surveillance for people with a microcarcinoma. Given the lack of RCT evidence and low quality of the observational data for active surveillance, the committee also made a recommendation for research comparing active surveillance with surgery. No evidence was found for treatment of existing nodal disease, and so the committee drew upon their clinical experience to form recommendations. The committee agreed that any nodal disease should be dealt with at the time of the total thyroidectomy. Despite the lack of evidence, the committee agreed that a strong 'offer' recommendation was justified because it is in the best interests of the person to ensure no cancerous material is left behind. Leaving it in situ is likely to mean the person would have to have an additional invasive procedure, and also there would be additional cost to the NHS. The committee also noted that there were no alternative procedures to those recommended. Therefore the committee agreed that if nodal disease is present in the lateral neck, a compartment-orientated lateral neck dissection should be offered, and, if nodal disease is present only in the central neck, a compartment-orientated central neck dissection should be offered. They also discussed that carrying out an ipsilateral central neck dissection at the same time may also benefit the person. Because the cancer has already spread to the neck and surgery of the neck is already being performed, carrying out this procedure at the same time may help avoid future surgery. This is a 'consider' recommendation because it was not based on evidence and the procedure is prophylactic and not for the removal of known cancer. RCT evidence suggested that people who have had a total thyroidectomy and prophylactic central compartment lymph node dissection (PCCND) needed fewer additional RAI treatments but had a higher risk of permanent hypoparathyroidism. Evidence was inconclusive in terms of recurrent laryngeal nerve palsy. Overall, the committee thought that the benefits from having fewer additional ablations were outweighed by the risks of permanent hypoparathyroidism. Therefore, in conjunction with the limited and poor-quality evidence, the committee agreed that PCCND should not be offered. No evidence was found for prophylactic lateral lymph node dissection, but the committee agreed that, while the benefits would be similar, the harms would exceed those observed for central lymph node dissection. Therefore, the committee agreed that prophylactic lateral lymph node dissection should also not be offered. Finally, the committee agreed that there could be risks to the foetus if operating on pregnant women, although the risks are unclear. The concern in the first trimester is largely about preventing birth defects from the anaesthetic drugs. The concern in the later trimesters is about loss of the pregnancy. Therefore the committee agreed that it would be better to defer any surgical treatment until after pregnancy. However, they also noted that in the rare event of there being clinical or radiological evidence of progression (local invasion or regional disease development) then surgery should be done during the second trimester if possible. The committee recommended that a joint decision should be reached with the mother about whether to defer surgery during pregnancy, after a discussion by the obstetrician, surgeon and endocrinologist. ## How the recommendations might affect practice The committee agreed that the recommendations were unlikely to change current practice. Return to recommendations # Thyrotropin alfa Recommendations 1.3.12 and 1.3.13 ## Why the committee made the recommendations Evidence showed that thyrotropin alfa (also known as recombinant human thyroid stimulating hormone) had short-term benefits over RAI with thyroid hormone withdrawal (THW) and did not demonstrate any harms. The relative benefits from thyrotropin alfa were improved quality of life, wellbeing, social, emotional and general function and reduced fatigue. The committee also agreed that thyrotropin alfa is better tolerated than THW. Economic evidence showed mixed results when thyrotropin alfa was compared with THW. Three studies showed thyrotropin alfa to be either cost effective or to dominate THW. One study, based on the latest evidence, found thyrotropin alfa not to be cost effective. Therefore the committee agreed to take into account some original analysis that found a cost per quality-adjusted life year of thyrotropin alfa between £20,000 and £30,000. Overall, the committee agreed that thyrotropin alfa should be offered to everyone. They noted that some people might be harmed by THW. People vulnerable to the detrimental effects of THW include those with psychiatric or mental health conditions, cardiac conditions, older-age, chronic kidney disease and a higher risk of falls. The committee made a strong recommendation, because they agreed a weaker recommendation would be inappropriate when the aim is to avoid direct harm. The committee also agreed that thyrotropin alfa is better than THW for those who are not 'lower stage', or people for whom THW was not contraindicated. Thyrotropin alfa enables people to return to normal activities within 2 or 3 days of treatment, whereas THW is taken for 4 to 6 weeks before treatment with RAI, and people typically need to take at least 2 to 3 weeks off work. This means that THW was also considered to disadvantage those from lower socioeconomic groups, in whom a loss of earnings could adversely affect their quality of life, and those who have caring responsibility for children or the elderly. Unpaid carers may also struggle to find or afford someone to do their role while they are unable to do normal activities. The committee also discussed the harms associated with THW and noted that the person will become acutely hypothyroid. This means they may experience mood changes such as anxiety, depression, lethargy and difficulty concentrating. This is particularly important for people with pre-existing mental health problems. The committee acknowledged that in most people the harm caused by THW is temporary. However, they agreed that the degree of short-term harm was so great that a change in practice to THW could not be recommended without clear and certain evidence of THW being cost effective. Because thyrotropin alfa is an established and accepted current practice, a change in practice could disrupt RAI treatment. The committee noted that the preparation with thyrotropin alfa ensures flexibility for periods of RAI shortage, whereas THW could cause disruption and harm to people if providers are not able to offer the treatment at the end of the withdrawing period. Therefore, taking these factors into account, the committee made a recommendation for thyrotropin alfa. In December 2022, using thyrotropin alfa as a treatment for thyroid cancer in people with distant metastases was an off-label use. However, the committee agreed that in their experience thyrotropin alfa still offered benefits to people with distant metastases if carefully managed because it avoided a short-term reduction in their quality of life. Finally, any rise in TSH has the theoretical risk of causing flare of thyroid cancer. Due to the sharp rise and high levels of TSH following treatment with thyrotropin alfa, particular caution should be taken. This is of most concern in people with metastases in the brain or spine. The committee agreed that in these cases thyrotropin alfa can still be used by giving pre-treatment steroids or external beam radiotherapy (EBRT). ## How the recommendations might affect practice The committee noted that using thyrotropin alfa has become standard practice, so the recommendation is not expected to have any impact on current practice. Return to recommendations # RAI for initial ablation Recommendations 1.3.14 to 1.3.16 ## Why the committee made the recommendations In the absence of evidence, the committee made a consensus recommendation that RAI should be offered after a total or completion thyroidectomy, if a person has a primary tumour at stage T3 or T4, regional lymph node involvement, pathological findings associated with a poor prognosis (including multifocal disease), or evidence of distant metastases. This recommendation is strong because there was consensus that, based on clinical experience, the benefits would significantly outweigh any harms for people who fulfil these criteria. The committee were also aware that trials that are currently ongoing do not cover people in these groups. There was also agreement that RAI should not be offered for T1a or T1b tumours after thyroidectomy, unless there are adverse features such as prognostically poor histological subtypes or an R1 resection margin. This decision was based on evidence that there was no difference in outcome and a consensus that the harms from RAI might outweigh the benefits unless adverse prognostic features or evidence of metastatic disease are present. Having defined the situations in which RAI would and would not be offered, the committee agreed that a recommendation to consider RAI for clinical presentations that fit neither of the former recommendations would be appropriate. On balance they agreed that RAI would be of benefit for this group, and they made a consider recommendation. Given the uncertainty, a recommendation for research was made to address the clinical and cost effectiveness of RAI after total or completion thyroidectomy for people with T2 disease and no adverse pathological features. The committee agreed that this is important to establish the precise balance of benefits and harms so that appropriate clinical decisions can be made. ## How the recommendations might affect practice There are currently variations in how RAI is used in practice. However, this is gradually reducing, particularly for people considered to be at intermediate risk of thyroid cancer recurrence. By defining 3 distinct sets of clinical presentations, the recommendations offer new clarity on when RAI should and should not be offered, and when it should be considered. They are therefore likely to change practice leading to a more transparent decision-making process. Return to recommendations # RAI activity for initial ablation Recommendations 1.3.17 and 1.3.18 ## Why the committee made the recommendations The evidence suggested that higher activity RAI only provides a small benefit to a small number of people. The committee agreed that given the legal requirement to minimise radiation exposure (The Ionising Radiation Regulations, 2017), this did not warrant giving higher activity RAI to everyone. Therefore the committee recommended that most people should have RAI with an activity for initial ablation of 1.1 GBq. However, the committee recognised that some people in high-risk groups should be considered for RAI with an activity of 3.7 GBq for their initial ablation. High-risk groups include people with advanced or aggressive disease and people with significant comorbidities such as cardiovascular disease, mobility issues or complex social concerns, who should therefore avoid multiple ablations. For these people, the benefits of more complete ablation after a single exposure would probably outweigh the harms of higher activity RAI. The committee therefore recommended that these high-risk groups could have higher activity RAI. ## How the recommendations might affect practice The committee agreed that the evidence supports current practice, where lower activity RAI is generally preferred to high activity. It is likely that the recommendation would further increase the number of people having lower activity RAI instead of high activity, which would reduce NHS costs and potentially prevent second malignancies caused by radiation exposure. Return to recommendations # External beam radiotherapy Recommendations 1.3.19 and 1.3.20 ## Why the committee made the recommendations The committee discussed the benefits and risks of EBRT. They agreed that it is only used in a small subgroup of people with thyroid cancer when there is no alternative treatment. In people with well-differentiated thyroid cancer there was evidence that EBRT reduced recurrence and prevented local disease progression. There was also evidence of increased death at 10 years. However, the committee agreed that despite this observational evidence adjusting for confounders, there was still likely to be some residual confounding within the analysis. In their experience, the committee agreed that EBRT showed benefit without increased mortality. Although they acknowledged that mortality is likely to be higher in people selected for EBRT because of the advanced nature of their disease. Therefore the committee decided that EBRT should be carefully considered on a person-by-person basis that minimises risk and maximises benefit. The committee agreed that people with macroscopic disease or histological appearances that may indicate more aggressive disease, and people with tumours that have not taken up RAI, may benefit most from EBRT. This is because their tumours would not usually respond well to other treatments. Similarly, the committee agreed that EBRT may benefit people who are having palliative care, in whom cancer metastases or local residual disease can cause symptoms such as ulceration due to skin invasion, pressure symptoms or pain. The committee therefore recommended that EBRT should be considered in these cases. Overall, the committee agreed that the observational evidence was of low quality, but suggested that EBRT can provide benefit by reducing recurrence and local progression. However, they did not believe the mortality data reflected their experience and, given their view that the observational data was likely to be biased, they also made a recommendation for research for an RCT for EBRT. ## How the recommendations might affect practice Less than 5% of people with well-differentiated thyroid cancer currently have EBRT. The recommendation is unlikely to increase workload or referrals and therefore the resource impact should be minimal or non-existent. It is possible that the recommendations will lead to a more careful and appropriate selection of people for EBRT, reducing both the costs of EBRT use and of avoidable adverse effects. Return to recommendations # Thyroid stimulating hormone suppression Recommendations 1.4.1 to 1.4.4 ## Why the committee made the recommendations The evidence suggested that thyroid stimulating hormone (TSH) suppression with thyroid hormone reduces cancer recurrence and mortality when compared with no TSH suppression. However, this evidence was from a single, small study graded as very low quality. There was also no accompanying evidence that assessed potential harms or risks associated with TSH suppression, such as osteoporosis or cardiac complications. Because the evidence base was weak, and lacked information on harms, the committee decided to form recommendations largely through consensus. The recommendations reflect current practice. It was agreed that people who do not need RAI, should not be offered TSH suppression. In this group, the risks of recurrence, spread or mortality were believed to be so low that TSH suppression would benefit only a very small number of people. Given that the adverse effects on bone and cardiac health would affect a far greater proportion, it was agreed that the balance of benefits and harms strongly indicated avoidance of TSH suppression in this group. In contrast, the committee agreed that the situation would be different for people who have had total or completion thyroidectomy and RAI. These treatments are only given when the perceived risks of recurrence, spread or mortality are higher. For these people, the balance of benefits and harms shifts towards an overall benefit from TSH suppression. Therefore for such people TSH suppression may be offered to maintain TSH levels below 0.1 mIU/litre. After starting treatment, the person's response to the suppression should be monitored. After 9 to 12 months, if they have an excellent response to treatment, suppression can be reduced to achieve a TSH level of between 0.3 IU/litre and 2.0 IU/litre. If there is an intermediate response, suppression should be continued to achieve a TSH level of between 0.1 IU/litre and 0.5 IU/litre. This is on the basis that initial treatments and TSH suppression have probably eliminated the cancer and that further high levels of suppression could do more harm than good. However, if their response has been poor, they should continue to receive high levels of suppression. This is because the potential harms from the uncontrolled disease outweigh the harms of TSH. The committee agreed that achieving the target TSH levels may not be possible in all people but should be for most. ## How the recommendations might affect practice The recommendations to avoid TSH suppression in low-risk cancers might change practice. Avoidance of inappropriate TSH suppression would be expected to reduce long-term adverse effects. This would in turn have a favourable effect on resources, because most thyroid cancers diagnosed at present are low risk. Return to recommendations # Long-term duration of TSH suppression Recommendation 1.4.5 ## Why the committee made the recommendations There was no evidence found for the optimal duration of TSH suppression. Previously, people would have TSH suppression indefinitely. However, with regular monitoring and risk assessment, this is no longer the case. Now TSH suppression is stopped if the perceived risk from TSH suppression outweighs the likely benefit in preventing cancer recurrence. The recommendations reflect that change in practice by highlighting the importance of an individualised assessment of risks and benefits. The committee also emphasised that some people may not want to suddenly stop or reduce TSH suppression because of the anxiety related with such a change. Therefore people on TSH suppression for more than 10 years should have a clinical review to assess their ongoing treatment, as well as the risks and benefits of TSH suppression. In the past, people with thyroid cancer would have been told that TSH suppression is for life. However, the current thinking is that this not usually necessary. The committee agreed that it was important to explain this to people with thyroid cancer and reassure them that they will still be monitored if their suppression is relaxed. Because of the lack of evidence, a recommendation for research was also made on the duration of TSH suppression. ## How the recommendations might affect practice The recommendations reflect current practice and so are not likely to have an impact on practice or resources. Return to recommendation # Measuring thyroglobulin and thyroglobulin antibodies Recommendations 1.5.1 to 1.5.6 ## Why the committee made the recommendations In the absence of evidence, recommendations were made by consensus. The committee discussed how measuring thyroglobulin antibodies alongside thyroglobulin was important because the presence of thyroglobulin antibodies can affect thyroglobulin levels. This can increase the number of false positive or false negative results. They also noted that detectable thyroglobulin levels in people without thyroglobulin antibodies suggests the presence of either residual thyroid tissue or residual or recurrent thyroid malignancy. They agreed that the harms of thyroglobulin measurement, such as false positives leading to over investigation, did not outweigh the clinical benefits from early detection of recurrence or progression. In the absence of a feasible alternative method for measuring recurrence, the committee recommended measurement of thyroglobulin following a total or completion thyroidectomy with RAI. Frequency of thyroglobulin measurement was recommended, in line with current practice, at 3- to 6-month intervals for the first 2 years, followed by 6- to 12-month intervals after that. The committee agreed that if thyroglobulin antibodies are not detected, then thyroglobulin levels can be interpreted at face value. In such a case, this initial evidence of recurrence from thyroglobulin testing should lead to further investigations, either to confirm or refute recurrence. They also recommended that people who have previously been cleared of having recurrence after a thyroglobulin test, but now have rising thyroglobulin levels, should also have further investigations for recurrence. This is because the rise in thyroglobulin levels might be a 'new' sign of recurrence that requires investigation. Further investigations could include neck ultrasound, CT scan of neck and chest or MRI scan of the neck. The choice often depends on local availability, and a prior knowledge of what happened with the patient in assessing where in the body recurrence is most likely to be. The committee noted that there may be some cases where a person has had a total thyroidectomy without RAI. However, there may be additional factors that suggest more detailed follow up is needed. In these circumstances, the clinician may have decided to measure thyroglobulin as part of the follow up. If the person's levels rise, then further investigations should be considered. A detectable level of thyroglobulin that is not rising is not usually an indication for further investigations as often there will be a small amount of residual thyroid tissue following total thyroidectomy without RAI. For people who have not had a total thyroidectomy, there would rarely be a need to measure thyroglobulin levels and interpretation of results can be difficult. This is because the person would still have functioning thyroid. Therefore the committee recommended that thyroglobulin levels should not be routinely measured. The committee also considered the more complex scenario of what should happen if thyroglobulin antibodies are detected above the laboratory threshold. Initially, the clinician would be expected to investigate how the assay might be affected by antibodies, and if it might cause an increase or decrease in measured thyroglobulin levels. This would influence how the thyroglobulin levels are interpreted and, if there was enough uncertainty, prompt a move to other investigations to confirm or refute recurrence. It was also agreed that there should be further investigations if, at a later point, either the thyroglobulin levels or thyroglobulin antibodies start to rise. This was because each of these scenarios could, directly or indirectly, indicate recurrence. Therefore the committee made a recommendation to consider further investigation in the presence of thyroglobulin antibodies when they are first detected or at any point if thyroglobulin or thyroglobulin antibody levels are rising. ## How the recommendations might affect practice The committee did not think that the recommendations would have an impact on current practice, because the recommendations reflect current and established practice. Return to recommendations # Stimulated thyroglobulin and highly sensitive thyroglobulin testing Recommendations 1.5.7 to 1.5.10 ## Why the committee made the recommendations The committee agreed to form recommendations by consensus because no evidence was available from the literature. When thyroglobulin is undetectable on a standard assay, the committee agreed that further investigation should be considered with either a stimulated or highly sensitive thyroglobulin assay. They also suggested strategies for what to do depending on the results obtained from using each method. When using stimulated thyroglobulin, there were 3 levels of response suggested. A reading of below 1 microgram/litre was considered low risk, and led to the recommendation that follow up and TSH suppression could be relaxed. A reading of between 1 microgram/litre and 10 microgram/litre was considered an indeterminate response, and led to the recommendation to consider continuation of TSH suppression. Finally, a reading of 10 microgram/litre or more led to a recommendation to consider further investigations and treatment. The type of treatment would depend on what the further investigations revealed. This gradation of actions, from a relaxation to a strengthening of vigilance, was based on the changing perception of recurrence risk associated with the stimulated thyroglobulin measurements. When using a highly sensitive assay that can detect thyroglobulin levels lower than 0.2 microgram/litre, there were 2 levels of response suggested. A reading of below 0.2 microgram/litre was considered low risk and led to the recommendation that follow up and TSH suppression could be relaxed. A reading of between 0.2 microgram/litre and 1.0 microgram/litre led to a recommendation to consider stimulated thyroglobulin, which can be helpful in separating people into lower- and higher-risk categories. If a person was shown to be at medium risk on stimulated thyroglobulin, this would suggest continuing with the same strategy and not relaxing TSH suppression. But, if they were at high risk, this would indicate the consideration of further investigations and treatment. With all these recommendations, the committee stressed that the presence of anti-thyroglobulin antibodies can distort both stimulated and highly sensitive thyroglobulin measurements, and caution should therefore be used when interpreting results in this situation. ## How the recommendations might affect practice The impact of the recommendations on practice is expected to be small, because the recommendations reflect current practice. Return to recommendations # Follow up Recommendations 1.6.1 to 1.6.4 ## Why the committee made the recommendations The available evidence on follow-up strategy included people with very early-stage thyroid cancer. The committee agreed that the evidence was therefore not representative of much of the population, so they used consensus to make the recommendations. They agreed the strategy should be set according to the severity of disease and the treatment given. For people with T1a disease that has been surgically removed with no local (N0) or distant (M0) spread, the committee agreed that the risks of further spread or recurrence were so low that the harms of further follow up would outweigh any benefits. Such harms include the anxiety caused by the investigations and the radiation risks of some forms of detection. For people with thyroid cancer that is stage T1a(m), T1b or greater, and who have had a hemithyroidectomy or total thyroidectomy without RAI, an ultrasound at 6 to 12 months was recommended, followed by an annual clinical follow up for 5 years. This group was regarded as having a small but real risk of recurrence and spread. Therefore the benefits of follow up, such as better prognosis resulting from early detection and treatment, starts to outweigh the previously outlined harms. The timing of the initial follow up was based on current practice. The frequency was based on the committee's understanding of how quickly recurrences and spread may occur. They also considered at what point it tends to be safe to assume that further problems are unlikely, provided no recurrence or spread has yet occurred. The committee agreed that the need for ultrasound at these annual clinical follow ups would need to be decided on a case-by-case basis. The committee also acknowledged that there may occasionally be instances when it is appropriate to measure thyroglobulin in those cases, but detectable thyroglobulin alone did not indicate recurrence of cancer. The trend in thyroglobulin over several measurements was therefore considered more useful in these people. For people who have had both a total or completion thyroidectomy and RAI, the duration and frequency of follow up was based on the assumed level of risk and response to treatment. Low risk was defined as no evidence of disease on imaging and a thyroglobulin level of less than 0.2 microgram/litre (or a stimulated thyroglobulin level of less than 1 microgram/litre). Medium risk was defined as thyroglobulin between 0.2 microgram/litre and 1.0 microgram/litre, or stimulated thyroglobulin of between 1 microgram/litre and 10 microgram/litre. High risk was defined as thyroglobulin of greater than 1.0 microgram/litre, or stimulated thyroglobulin of greater than 10 microgram/litre. The annual frequencies were again based on the committee's understanding of how quickly recurrences and spread may occur. The committee acknowledged that, while annual follow up is recommended, there may be cases in which more frequent follow up is needed. The increasing duration of total follow up with the level of presumed risk was based on the committee's experience that late recurrence and spread increases with risk. Therefore more prolonged vigilance is needed, and the benefit outweighs any potential harms from follow up, such as anxiety about radiation. For anyone at the highest levels of risk, with persistent biochemical or structural disease, there is the potential for disease progression. Therefore the committee recommended that follow up should occur annually for an indefinite period, and potentially for life. Finally, the committee discussed how thyroglobulin measurement is designed to identify recurrence that may not yet be structurally evident. Therefore if structural recurrence is detected in people who have been treated with total or completion thyroidectomy and RAI, further thyroglobulin measurement is unnecessary. Such people should be discussed in the multidisciplinary team meeting with the surgeon. There was no evidence for how long people should be followed up, so the committee set minimum periods and wrote a recommendation for research on the duration of follow up. ## How the recommendations might affect practice The impact of the recommendations on practice is expected to be small, because the recommendations reflect current practice. Return to recommendations# Context Cancer of the thyroid, a small gland at the base of the neck, is uncommon and can occur at any age. It is most often diagnosed in people from their 20s through to their 60s. Almost all thyroid cancers (about 97%) are differentiated and have a good prognosis. When deaths do occur, they tend to arise from the spread of the cancer to the bones or lungs. There has been an increase of over 150% in the incidence of thyroid cancer in the UK over the past 30 years. It is unclear if this is because of more effective diagnosis or more people developing thyroid cancer. The rise in incidence has not been matched by a rise in mortality, but raises questions about assessment for people with suspected thyroid cancer and about appropriate treatment. There is particular uncertainty about the management of nodules of small and intermediate size and classification, and practice varies internationally. Thyroid cancer is usually treated by partial (hemi-) or total thyroidectomy, sometimes followed by radioactive iodine. Since thyroid cancer can occur in young adults and has a good prognosis, many who have this surgery will spend most of their lives without a thyroid gland. The long-term implications of this include lifelong treatment with replacement thyroid hormone, and possible complications such as hypoparathyroidism and vocal cord palsy. Internationally, very small thyroid tumours are sometimes managed with active surveillance. Once thyroid cancer has been treated, there is still a chance it might recur. Recurrence is uncommon in well-differentiated cancers, but it can be more serious than the original occurrence. There are questions about the risk of recurrence and how this risk should be translated into a long-term follow-up strategy.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information and support\n\n## Information for people with suspected thyroid cancer\n\nWhen providing information, follow the recommendations on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services and putting shared decision making into practice in NICE's guideline on shared decision making.\n\nExplain to people with suspected thyroid cancer:\n\nthat not all lumps, nodules or swellings in the thyroid are cancer\n\nwhat the diagnostic pathway involves and what tests they may need.\n\nAdvise people where to find reliable high-quality information and support after consultations, from sources such as national and local support groups, networks and information services.\n\n## Information for people having surgery\n\nOffer people with suspected or confirmed thyroid cancer, and their family and carers if appropriate, written and verbal information on what hemithyroidectomy or total thyroidectomy involves. Explain the benefits and risks of treatment, including long-term implications such as:\n\nthe effects of having part or all of your thyroid removed\n\nthe potential for and possible consequences of:\n\n\n\nhypothyroidism and the subsequent need for lifelong thyroid hormone replacement\n\nthe need for treatment for low parathyroid hormone\n\nvoice change and swallowing disorders.\n\n\n\n## Information for people with thyroid cancer\n\nWhen giving people with thyroid cancer their diagnosis, even for low-risk thyroid cancers, it is important to acknowledge that this is a cancer diagnosis and allow the person time to ask questions and be fully informed.\n\nDo not refer to thyroid cancer as a 'good cancer' because many people do not find this reassuring and it can cause them to feel that their diagnosis is unimportant.\n\nConsider further appointments if they will benefit a person's psychological wellbeing, even if they are not indicated for physical reasons.\n\nGive people with thyroid cancer, and their family and carers if appropriate, written and verbal information on:\n\nwho their key worker is and who to contact for more information\n\ntheir thyroid cancer and its likely cure rate, effect on their life expectancy and likelihood of recurrence\n\nthe role and function of the thyroid gland and the need for long-term monitoring of thyroid function\n\nhow treatment may affect conception, pregnancy, breast feeding and fertility\n\nthe risks, benefits and uncertainties of treatment and its potential effects on their quality of life, energy, weight and mood\n\nthe roles of those involved in their treatment and follow up, and the composition of the multidisciplinary team\n\nwhere to get reliable further information.\n\nAt follow up give people with thyroid cancer, and their family and carers if appropriate, information on:\n\nfollow up and how it is likely to be done\n\nwhat thyroglobulin is, how it is measured and why\n\nlifelong thyroid hormone replacement\n\nlifelong monitoring of thyroid function\n\nwhen to seek advice from a healthcare professional, who that healthcare professional should be and how to contact them.\n\n## Information for people having radioactive iodine\n\nOffer people with suspected or confirmed thyroid cancer, and their family and carers if appropriate, written and verbal information on the benefits, and short- and long-term risks of radioactive iodine (RAI). Explain that:\n\nthe aim of RAI is to destroy any residual thyroid tissue, including tissue that may be malignant, and allows effective monitoring for recurrence by a blood test\n\nprecautions may be needed when taking RAI which may temporarily affect conception, pregnancy, breast feeding and fertility\n\nalthough uncommon, there is the potential for dry mouth and salivary gland inflammation, both of which are temporary in most people\n\nthere is a potential but very low risk of RAI causing new primary second cancers.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: information, education and support needed by people with suspected and confirmed thyroid cancer, and their families and carers.\n\nLoading. Please wait.\n\n# Assessment and diagnosis\n\nSee the recommendation on referral for suspected thyroid cancer in the NICE guideline on suspected cancer.\n\n## Blood tests\n\nSee the recommendations on thyroid function tests in the NICE guideline on thyroid disease.\n\nDo not use calcitonin testing to assess thyroid nodules unless there is a reason to suspect medullary thyroid cancer (MTC), such as a family history or a nodule with an appearance on ultrasound that suggests MTC.\n\nDo not routinely measure thyroid peroxidase antibody (TPO).\n\nConsider TPO measurement when interpreting indeterminate cytopathology.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on blood tests\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: indications for blood tests.\n\nLoading. Please wait.\n\n## Ultrasound\n\nSee the section on investigating thyroid enlargement in the NICE guideline on thyroid disease, and the recommendation on referral for suspected thyroid cancer in the NICE guideline on suspected cancer.\n\nOffer greyscale ultrasound with an established system for grading ultrasound appearance as the initial diagnostic test when investigating thyroid nodules for malignancy.\n\nSee the recommendations on grading and reporting ultrasound findings when investigating thyroid enlargement in the NICE guideline on thyroid disease.\n\nOffer fine needle aspiration cytology (FNAC) to people who meet the threshold using an established system for grading ultrasound appearance.\n\nConsider FNAC or active surveillance for people who do not meet the threshold for FNAC on ultrasound grading alone if there are other reasons for clinical concern.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on ultrasound\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: ultrasound accuracy and threshold of nodule size and classification.\n\nLoading. Please wait.\n\n## FNAC testing\n\nSee the recommendation on using ultrasound guidance when performing FNAC in the NICE guideline on thyroid disease.\n\nUse liquid-based cytology, direct smear or both when processing FNAC samples.\n\nUse the Royal College of Pathologists modification of the British Thyroid Association (BTA) reporting system to report cytology results.\n\nConsider rapid on-site evaluation of FNAC adequacy rates to improve the diagnostic yield of samples if the Thy1 (inadequate) rate for the centre or individual clinicians is higher than 15% (when Thy1c is excluded).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on performing and reporting FNAC\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: diagnostic accuracy of fine needle aspiration cytology.\n\nLoading. Please wait.\n\n## Management and further sampling after initial FNAC\n\nUse the initial FNAC results to determine further management and sampling options, as shown in table 1.\n\nInitial fine-needle aspiration cytology result\n\nManagement and further sampling\n\nThy1 (inadequate)\n\nOffer repeat sampling\n\nConsider core-needle biopsy (CNB) or fine-needle aspiration cytology (FNAC) with rapid on-site evaluation (ROSE) as the first choice\n\nConsider FNAC alone if ROSE is unavailable and CNB is unavailable or inappropriate\n\nConsider diagnostic hemithyroidectomy if the repeat sample is also Thy1\n\nThy1c (cystic lesion)\n\nOffer repeat sampling with FNAC\n\nConsider diagnostic hemithyroidectomy if the repeat sample is also Thy1c and the ultrasound appearances are concerning\n\nThy2 and Thy2c (benign)\n\nConsider repeat ultrasound\n\nOffer repeat sampling with FNAC if the second ultrasound also reaches the threshold for FNAC\n\nConsider CNB as an alternative to FNAC\n\nDischarge people if there is no evidence of malignancy after all investigations are complete, unless there are other reasons for clinical concern\n\nThy3a (atypia, neoplasia possible)\n\nOffer repeat sampling\n\nConsider CNB (or FNAC if CNB unavailable or inappropriate)\n\nConsider diagnostic hemithyroidectomy or active surveillance if repeated samples are still Thy3a\n\nThy3f (suggesting follicular neoplasm)\n\nConsider diagnostic hemithyroidectomy\n\nThy4 (suspicion of malignancy) and Thy5 (malignant)\n\nOffer diagnostic hemithyroidectomy, or treatment with therapeutic hemithyroidectomy or total thyroidectomy\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on management and further sampling after initial FNAC\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: efficacy of repeat FNAC, active surveillance or discharge and evidence review F: molecular testing.\n\nLoading. Please wait.\n\n## Radioisotope scans\n\nDo not routinely use radioisotope scans for the initial diagnosis of thyroid cancer.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on radioisotope scans\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: radioisotope scans.\n\nLoading. Please wait.\n\n## Imaging for further staging\n\nDo not routinely use cross-sectional imaging (CT or MRI) in people with T1 or T2 disease and no other indications.\n\nConsider cross-sectional imaging (CT of neck and chest, or MRI of neck and CT of chest) for people with thyroid cancer that is T3 or T4, any N1 or M1 thyroid cancer or other clinical suspicion of metastases.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on imaging for further staging\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: imaging for further staging.\n\nLoading. Please wait.\n\n# Initial treatment of differentiated thyroid cancer\n\n## Surgery and active surveillance for primary tumours\n\nWhen discussing surgical options with a person with differentiated thyroid cancer, take into account their preferences, comorbidities and all the available evidence regarding their tumour.\n\nOffer hemithyroidectomy or total thyroidectomy to people with differentiated thyroid tumours larger than 1\xa0cm or multifocal disease (T1a\xa0[m] to T2N0M0).\n\nOffer total thyroidectomy to people who have:\n\na T3 or T4 stage primary tumour\n\nregional lymph node involvement (N1)\n\nadverse pathological features\n\ndistant metastatic disease (M1).\n\nOffer completion thyroidectomy to people who have had a hemithyroidectomy if it is indicated on review of the histological features of the initial specimen.\n\nConsider hemithyroidectomy or active surveillance for people with a solitary microcarcinoma (T1a) without evidence of nodal involvement.\n\n## Surgery for nodal disease\n\nOffer a compartment-orientated lateral neck dissection for people with structural nodal disease in the lateral neck.\n\nConsider a prophylactic ipsilateral central neck dissection when doing the compartment-orientated lateral neck dissection for people with structural nodal disease in the lateral neck.\n\nOffer a compartment-orientated central neck dissection for people with structural nodal disease in the central neck.\n\nDo not offer prophylactic central or lateral neck dissection (except in the circumstances in recommendation 1.3.7).\n\n## Surgery during pregnancy\n\nConsider deferring surgery until after pregnancy, taking into account:\n\nthe risk of delaying surgery\n\nthe risk to the pregnancy\n\nthe rate of disease progression.The obstetrician, surgeon and endocrinologist should discuss these factors and a joint decision should be reached in discussion with the pregnant woman.\n\nWhen surgery cannot be delayed until after pregnancy, it should be done during the second trimester if possible.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgery and active surveillance for primary tumours\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: initial treatments for differentiated thyroid cancer.\n\nLoading. Please wait.\n\n## Thyrotropin alfa\n\nOffer thyrotropin alfa for pretherapeutic stimulation for people with thyroid cancer (including those with distant metastases; see recommendation 1.3.13) who are having RAI ablation. In December\xa02022 this use of thyrotropin alfa as a treatment for thyroid cancer in people with distant metastases was off-label. See NICE's information on prescribing medicines.\n\nUse thyrotropin alfa with caution in people with thyroid cancer who have brain or spinal metastases, because there is a risk of clinically significant tumour flare.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on thyrotropin alfa\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: thyrotropin alfa.\n\nLoading. Please wait.\n\n## RAI for initial ablation\n\nOffer RAI to people who have had a total or completion thyroidectomy based on the criteria in the recommendation on offering total thyroidectomy in the section on surgery and active surveillance for primary tumours.\n\nDo not offer RAI to people with T1a or T1b tumours including those with multifocal disease, unless there are adverse features, regional lymph node involvement, or evidence of other metastatic disease.\n\nConsider RAI for people with T2 disease who have had a total or completion thyroidectomy, but whose disease does not show any of the features in the recommendation on offering total thyroidectomy in the section on surgery and active surveillance for primary tumours.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on RAI for initial ablation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: radioactive iodine versus no radioactive iodine.\n\nLoading. Please wait.\n\n## RAI activity for initial ablation\n\nConsider RAI with an activity for initial ablation of 3.7\xa0GBq for people with high-risk features such as T4, N1b or M1 disease or aggressive subtypes, or people for whom multiple ablations should be avoided because they have one or more of the following characteristics:\n\nsignificant comorbidities such as cardiovascular disease\n\nmobility issues\n\ncomplex social concerns.\n\nOffer RAI with an activity for initial ablation of 1.1\xa0GBq to people who are not having 3.7\xa0GBq.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on RAI activity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: activity of radioactive iodine after thyroidectomy.\n\nLoading. Please wait.\n\n## External beam radiotherapy\n\nConsider external beam radiotherapy (EBRT) if there is macroscopic disease after surgery or local disease that is unlikely to be controlled with RAI.\n\nConsider EBRT for symptom control for people receiving palliative care.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on external beam radiotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: external beam radiotherapy versus no external beam radiotherapy.\n\nLoading. Please wait.\n\n# Ongoing treatment with thyroid stimulating hormone suppression for differentiated thyroid cancer\n\n## When to offer thyroid stimulating hormone suppression\n\nDo not offer thyroid stimulating hormone (TSH) suppression to people who:\n\ndo not meet the threshold for RAI (see the section on RAI for initial ablation)\n\nhave significant comorbidities that mean low TSH levels should be avoided.\n\nOffer thyroid hormone at doses that will suppress TSH to below 0.1\xa0mIU/litre, to people who have had total or completion thyroidectomy and RAI. TSH suppression should be continued until follow-up review at 9\xa0to 12\xa0months after initial treatment has been completed.\n\n## Assessing and managing response to TSH suppression\n\nUse dynamic risk stratification to determine further management at 9\xa0to\xa012\xa0months after completion of initial RAI ablation, as follows:\n\nReduce TSH suppression to achieve a TSH level of between 0.3\xa0mIU/litre and 2.0\xa0mIU/litre and continue this for life in people with an excellent response to treatment.\n\nContinue TSH suppression to achieve a TSH level of between 0.1\xa0mIU/litre and 0.5\xa0mIU/litre in people who have an intermediate response to initial treatment.\n\nContinue to suppress TSH to less than 0.1\xa0mIU/litre in people who have biochemical or structural evidence of persistent or recurrent disease.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on thyroid stimulating hormone suppression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: TSH suppression versus no TSH suppression.\n\nLoading. Please wait.\n\n## Long-term duration of TSH suppression\n\nOffer a review to people who have had ongoing TSH suppression for more than 10\xa0years. Decide whether the TSH suppression can be reduced after an individualised assessment of risks and benefits, and explain that:\n\nlifelong suppression is not necessary unless they have high-risk or metastatic disease\n\nreducing TSH suppression may lower the risk of developing bone and cardiac problems.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on long-term duration of TSH suppression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: duration of TSH suppression.\n\nLoading. Please wait.\n\n# Post-thyroidectomy monitoring of differentiated thyroid cancer\n\n## Measuring thyroglobulin and thyroglobulin antibodies\n\nBe aware that:\n\nthe presence of thyroglobulin antibodies, above the laboratory threshold, can interfere with the measurement of thyroglobulin levels\n\ndetectable thyroglobulin levels in people without thyroglobulin antibodies suggest the presence of either residual thyroid tissue or residual or recurrent thyroid cancer.\n\nOffer thyroglobulin measurement alongside measurement of thyroglobulin antibodies in people with differentiated thyroid cancer who have had total or completion thyroidectomy and RAI. Measure at:\n\n- to 6-month intervals in the first 2\xa0years after RAI ablation and\n\n- to 12-month intervals thereafter.\n\nConsider further investigations if a person has had total thyroidectomy and RAI, and:\n\nhas detectable thyroglobulin levels without thyroglobulin antibodies\n\ninvestigations have not shown recurrent or residual cancer in the presence of detectable thyroglobulin without thyroglobulin antibodies, and now the thyroglobulin levels without thyroglobulin antibodies are rising.\n\nConsider further investigations if a person has had a total thyroidectomy without RAI and has rising thyroglobulin levels without thyroglobulin antibodies.\n\nDo not routinely measure thyroglobulin levels in people who have not had total or completion thyroidectomy.\n\nConsider further investigation when thyroglobulin antibodies are first detected above the laboratory threshold or at any point if the levels of thyroglobulin or thyroglobulin antibodies are rising.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on measuring thyroglobulin and thyroglobulin antibodies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: measurement of thyroglobulin.\n\nLoading. Please wait.\n\n## Stimulated thyroglobulin and highly sensitive thyroglobulin testing\n\nConsider either a stimulated thyroglobulin test or highly sensitive thyroglobulin test if thyroglobulin is undetectable on a standard assay in people who have had a total or completion thyroidectomy and RAI, and have no evidence of structural persistent disease.\n\nConsider the following if using a stimulated thyroglobulin test:\n\nless frequent follow up, where appropriate, and more relaxed TSH suppression if stimulated thyroglobulin is below 1\xa0microgram/litre (low risk)\n\ncontinuing TSH suppression if stimulated thyroglobulin is between 1\xa0microgram/litre and 10\xa0microgram/litre (indeterminate risk)\n\nfurther investigations and treatment if stimulated thyroglobulin is 10\xa0microgram/litre or more and there is no resectable disease.\n\nConsider the following if using a highly sensitive assay that can detect thyroglobulin levels lower than 0.2\xa0microgram/litre:\n\nless frequent follow up, where appropriate, and more relaxed TSH suppression if the thyroglobulin level is lower than 0.2\xa0microgram/litre\n\nstimulated thyroglobulin, which can be helpful in separating people into lower- and higher-risk groups if the thyroglobulin level is between 0.2\xa0microgram/litre and 1\xa0microgram/litre.\n\nUse caution when interpreting results in the presence of thyroglobulin antibodies because they may cause false-positive or negative findings.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on stimulated thyroglobulin and highly sensitive thyroglobulin testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0P: stimulated or highly sensitive thyroglobulin assays.\n\nLoading. Please wait.\n\n# Follow up of differentiated thyroid cancer\n\nDo not routinely follow up people with thyroid cancer who have a solitary microcarcinoma (T1a) that has been surgically removed.\n\nConsider an ultrasound at 6\xa0to 12\xa0months initially then annual clinical follow up for up to 5\xa0years for people with T1a (m) or T1b stage or greater thyroid cancer, who have had a hemithyroidectomy or total thyroidectomy without RAI.\n\nConsider a risk-stratified approach to follow up for any person who has had total or completion thyroidectomy and RAI, as shown in table 2.\n\nRisk group\n\nFollow up\n\nLow risk (no evidence of disease on imaging and thyroglobulin of less than 0.2\xa0microgram/litre, or stimulated thyroglobulin of less than 1\xa0microgram/litre)\n\nConsider (at least annually) follow up of 2 to 5\xa0years with thyroglobulin testing\n\nUse ultrasound if needed\n\nMedium risk (thyroglobulin between 0.2 and 1.0\xa0microgram/litre, or stimulated thyroglobulin of between 1\xa0and 10 microgram/litre)\n\nConsider (at least annually) 5 to 10\xa0years follow up with thyroglobulin testing\n\nUse ultrasound if needed\n\nHigh risk (thyroglobulin of greater than 1.0\xa0microgram/litre, or stimulated thyroglobulin of greater than 10\xa0microgram/litre)\n\nConsider (at least annually) 10\xa0years follow up with thyroglobulin testing\n\nUse ultrasound if needed\n\nAnyone with biochemical or structural evidence of disease\n\nConsider (at least annually) lifelong follow up with thyroglobulin testing\n\nUse ultrasound if needed\n\nDiscuss at the multidisciplinary team meeting any person who has had a total or completion thyroidectomy and RAI and has evidence of structural persistent disease.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow up\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0Q: length and frequency of follow up.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Active surveillance\n\nActive surveillance involves monitoring the person's thyroid cancer with periodic appointments that include investigations such as blood tests and ultrasound. The duration and frequency of further appointments and investigations should be a clinical decision that considers the risks for the person.\n\n## Completion thyroidectomy\n\nA completion thyroidectomy relates to when someone who has had a hemithyroidectomy has the rest of their thyroid gland removed. In this guideline, recommendations related to treatment and monitoring for total thyroidectomy also apply to people who have had a completion thyroidectomy.\n\n## Dynamic risk stratification\n\nFollowing initial risk assessment at diagnosis, the risk of recurrence is re-assessed at follow up by evaluating the person's response to treatment. This re-evaluation of risk constitutes a 'dynamic risk stratification' allowing the follow-up strategy to be modified according to risk. This is an established system and the response to treatment is based on measurement of serum thyroglobulin Tg (and anti‑thyroglobulin antibody TgAb) and ultrasound imaging.\n\n## Radioactive iodine\n\nA radioactive form of iodine used to treat thyroid cancer by killing thyroid cells and thyroid cancer cells after surgery. It is usually taken in a capsule or liquid.\n\n## Thyroid cytology specimens\n\nThis guideline uses the Royal College of Pathologists guidance on the reporting of thyroid cytology specimens published in 2016 (see table 3) for recommendations related to reporting FNAC results.\n\nThy category\n\nDescription\n\nThy1\n\nInadequate or non-diagnostic\n\nThy1: inadequate\n\nThy1c: cystic lesion\n\nThy2\n\nBenign or non-neoplastic\n\nThy3\n\nIndeterminate or neoplasm possible\n\nThy3A: neoplasm possible (atypical features)\n\nThy3F: follicular neoplasm\n\nThy4\n\nSuspicious of malignancy\n\nThy5\n\nMalignant\n\n## TNM classification\n\nThis guideline uses the tumour, node, metastasis (TNM) classification developed by the Union for International Cancer Control (UICC) to describe the stage of the cancer. Please refer to the TNM Classification of Malignant Tumours, 8th Edition for further information.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Molecular tests\n\nIn fine-needle aspiration cytology (FNAC) samples that are adequate but cannot differentiate between benign and malignant samples, what is the clinical and cost effectiveness of molecular testing for thyroid cancer?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on management and further sampling after initial FNAC\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: molecular testing.\n\nLoading. Please wait.\n\n## Duration of follow up\n\nWhat is the clinical and cost effectiveness for different durations of follow up for people with differentiated thyroid cancer who have been treated?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on follow up\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0Q: length and frequency of follow up.\n\nLoading. Please wait.\n\n## Active surveillance compared with surgery\n\nFor people with stage\xa01 differentiated thyroid cancer, what is the clinical and cost effectiveness of active surveillance compared with surgery?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on surgery and active surveillance for primary tumours\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: initial treatments for differentiated thyroid cancer.\n\nLoading. Please wait.\n\n## Duration of thyroid stimulating hormone suppression\n\nFor people with differentiated thyroid cancer who have had surgery and radioactive iodine (RAI), what is the optimal duration of thyroid stimulating hormone suppression?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on long-term duration of TSH suppression\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: duration of TSH suppression.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Radioactive iodine\n\nWhat is the clinical and cost effectiveness of RAI after total or completion thyroidectomy for people with T2 disease and no adverse pathological features?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on RAI for initial ablation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: radioactive iodine versus no radioactive iodine.\n\nLoading. Please wait.\n\n## Thyroid peroxidase antibody testing\n\nFor people with indeterminate cytopathology, what is the clinical and cost effectiveness of thyroid peroxidase antibody testing?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on thyroid peroxidase antibody testing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: indications for blood tests.\n\nLoading. Please wait.\n\n## Imaging for further staging\n\nFor people with differentiated thyroid cancer who have initial ultrasound evidence of extensive local spread (T2N1), what is the clinical and cost effectiveness of CT, MRI or F-18 FDG PET-CT scanning, with or without ultrasound, as part of a further staging strategy?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on imaging for further staging\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: imaging for further staging.\n\nLoading. Please wait.\n\n## External beam radiotherapy compared with usual care\n\nWhat is the clinical and cost effectiveness of external beam radiotherapy for people with residual or recurrent thyroid cancer?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on external beam radiotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: external beam radiotherapy versus no external beam radiotherapy.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Information and support\n\nRecommendations 1.1.1 to 1.1.10\n\n## Why the committee made the recommendations\n\nThe committee agreed that the NICE guidelines on patient experience in adult NHS services and shared decision making give important advice on enabling people to participate in their care.\n\nThe committee agreed that it is important to give information on what to expect with investigations and treatments, and to deliver it at an appropriate time to support people in managing their condition. The committee were aware that people often look for information themselves and therefore it is important to direct them to sources that are good quality and reliable.\n\nThe committee also agreed it is important to explain to people with signs of thyroid cancer that not all swellings are cancerous and what any investigations may entail. This included the implications of surgery on thyroid function and what the consequences are.\n\nEvidence showed that telling people with thyroid cancer that it is a 'good cancer', was generally not reassuring. It caused them to feel that the diagnosis was being dismissed as unimportant and, as a result, they felt undeserving of seeking support. Therefore, the committee recommended that healthcare professionals should avoid telling people they have a 'good cancer'. Instead, they should give the person time to acknowledge they have cancer and to ask any questions. For some people this may mean further appointments are beneficial.\n\nThe committee agreed that a lot of people with newly diagnosed thyroid cancer might not know what the thyroid gland does. Therefore, it is important to give them information on the thyroid gland, how their condition will be managed, any consequences of treatment and the long-term follow-up requirements.\n\n## How the recommendations might affect practice\n\nGiving people information and support and including further appointments for some people, is current practice. Therefore, the recommendations are unlikely to have a big impact.\n\nReturn to recommendations\n\n# Blood tests\n\nRecommendations 1.2.2 to 1.2.5\n\n## Why the committee made the recommendations\n\nThe very early part of the pathway for suspected thyroid cancer is covered in other NICE guidance. NICE's guideline on suspected cancer covers when to refer people with an unexplained thyroid lump and NICE's guideline on thyroid disease covers the initial tests to use when investigating suspected thyroid dysfunction or thyroid enlargement. For this guideline, the committee looked at additional blood tests that could be used for the diagnosis of thyroid cancer. The committee made recommendations in this area based on consensus because no evidence was identified.\n\nThe committee discussed the high rate of false positives from calcitonin testing, which can cause serious harm from unnecessary treatments. For example, the committee were aware of evidence that suggested that borderline raised calcitonin can be caused by Hashimoto's disease or certain drugs. This can in turn cause over‑treatment and high levels of morbidity. The false positives may cause a particularly low positive-predictive value because of the relative rarity of medullary thyroid cancer (MTC), with only 100 to 150 new cases per year in the UK. The committee therefore agreed that for most people it would be more useful and less harmful not to use calcitonin testing. Instead, other methods of assessment should be used, such as fine-needle aspiration cytology (FNAC).\n\nHowever, the committee agreed that there were some people for whom the benefits of calcitonin testing might outweigh its harms. This would include people at higher risk of MTC, for whom the risks of false negatives would outweigh the risks of false positives at a population level. This includes people with a family history of MTC; those with multiple endocrine neoplasms; those with suspected MTC or MTC diagnosed by cytopathology, core biopsy, or other histopathology; and people with C-cell hyperplasia.\n\nTherefore, a recommendation was made that calcitonin should not be tested routinely unless there are prior reasons to suspect MTC.\n\nThe committee discussed from their experience how results from thyroid peroxidase antibody (TPO) tests can facilitate interpretation of FNAC results. For example, if the FNAC result is suggestive of benign thyroiditis, then a positive TPO test may help to confirm this. A positive TPO test may also allow an indeterminate result to be downgraded to benign. Therefore, the committee agreed that TPO should be used to facilitate interpretation in cases where the FNAC result is uncertain. However, where there is little uncertainty about the FNAC result, the committee did not think the benefits of TPO testing justified its use. Therefore, the recommendation was made that TPO should not be routinely measured but could be considered when there was indeterminate cytopathology. Given the uncertainty in this area the committee also made a recommendation for research on thyroid peroxidase antibody testing.\n\n## How the recommendations might affect practice\n\nThe recommendation to not offer calcitonin testing unless MTC is suspected largely reflects current practice in the UK. It also represents a targeted use of NHS resources due to the rarity of MTC and high cost of the test. The recommendation on TPO may lead to an additional use of resources but was considered important to avoid unnecessary surgeries in people with benign nodules and indeterminate cytopathology (for example, people with Hashimoto's disease). It is therefore expected to lead to fewer unnecessary thyroidectomies and ultimately improve the efficiency of the NHS.\n\nReturn to recommendations\n\n# Ultrasound\n\nRecommendations 1.2.6 to 1.2.10\n\n## Why the committee made the recommendations\n\nAfter considering the diagnostic accuracy evidence, the committee eliminated all index tests that had sensitivity and specificity benchmarks below 0.9 and 0.5, respectively. These were the minimum pre-hoc standards for first-line diagnostic tests. Given that there was evidence for simpler techniques, such as greyscale ultrasound, the committee also excluded techniques that were impractical, unsuitable for most people or invasive. This included elastography and contrast enhanced ultrasound. The committee also considered a simple combination of greyscale characteristics and a doppler test that used blood-velocity measurement. However, evidence for both tests was taken from single studies, which raised questions of representativeness, and the doppler test had imprecision in the sensitivity result. The only index tests remaining that fulfilled all criteria of accuracy and clinical appropriateness were the ordinal scales of greyscale characteristics. Therefore, the committee recommended that greyscale ultrasound should be offered as the initial test. The data available did not provide evidence to suggest one system for grading ultrasound was better than another. Therefore, the committee agreed with the recommendation in the NICE guideline on thyroid disease that the decision to do FNAC should be made using an established system for grading ultrasound.\n\nThe committee were also aware that none of the established systems have perfect sensitivity. Therefore, some people with malignancy might 'slip through the net' and not receive further investigation. So, another recommendation was made that people whose results do not meet the threshold could still have further investigations with FNAC or active surveillance if there are still clinical concerns.\n\nOverall, the committee agreed with the recommendations on investigating thyroid enlargement in the NICE guideline on thyroid disease. They discussed the importance of using a classification system that considers:\n\nechogenicity\n\nmicrocalcifications\n\nborder\n\nshape in transverse plane\n\ninternal vascularity and\n\nlymphadenopathy.\n\nThey also agreed that reports of ultrasound findings should:\n\nspecify which grading system has been used for the assessment\n\ninclude information on the characteristics of the nodule\n\nprovide an overall assessment of malignancy\n\nconfirm that both lobes have been assessed and\n\ndocument assessment of cervical lymph nodes.\n\nThis can help improve diagnosis by ensuring all the data is available to clinicians when assessing the person.\n\n## How the recommendations might affect practice\n\nRecommending an established system for grading ultrasound appearance is not expected to affect current practice significantly. This is because the recommendation does not state which system to use and therefore it is unlikely to persuade clinicians to adopt a new system.\n\nInstituting FNAC or active surveillance for people who do not meet the threshold for FNAC or who have small nodules does not represent a change to current practice.\n\nReturn to recommendations\n\n# Performing and reporting FNAC\n\nRecommendations 1.2.11 to 1.2.14\n\n## Why the committee made the recommendations\n\nThe committee recommended that FNAC should be offered with either liquid-based cytology, direct smear or both. They agreed that the evidence did not show that one technique was better than the other. Current practice varies with some centres using one technique and others using both. The committee agreed that the Royal College of Pathologists modification of the BTA reporting system (RCPath BTA) is widely used in the UK. Therefore, they made a recommendation, based on consensus, to use the RCPath BTA reporting system.\n\nAn estimation of the data from the evidence review suggested that rapid on-site evaluation (ROSE) reduced non-diagnostic results by 55%. It is likely to be cost effective when offered where there is a concerningly high inadequacy rate. The Royal College of Pathologists notes that an inadequacy rate of more than 15% (excluding Thy1c) is problematic. Therefore, the committee agreed that centres or individual clinicians with high inadequacy rates might benefit from ROSE if this is implemented and routinely used. Thy1c was excluded from the threshold because it would not benefit from ROSE. This is because Thy1c indicates a non-diagnostic for cystic lesion which is not operator- or technique-dependent.\n\n## How the recommendations might affect practice\n\nAlthough direct smear is commonly used with FNAC, liquid-based cytology is less commonly used in smaller centres. If a centre adopts liquid-based cytology, then some changes in training and provision of equipment may be needed. However, most large centres already use liquid-based cytology and some centres use both as part of a quality assurance process to get better results. The overall impact on practice is likely to be small.\n\nUse of ROSE, specifically for centres or individual clinicians with high inadequacy rates, was thought to represent a change in practice. It would require auditing the adequacy rates of samples and personnel would be needed to provide such services. However, it likely represents a cost-effective use of NHS resources if used where there is a concerningly high inadequacy rate, particularly those with a medium or high volume of FNACs. The committee also agreed it may be beneficial in all centres with a high inadequacy rate. Furthermore, a persistent, low inadequacy rate of FNAC (with or without ROSE) may be achieved due to the training provided by cytopathologists, thus improving the diagnostic efficiency of the NHS in the long‑term.\n\nReturn to recommendations\n\n# Management and further sampling after initial FNAC\n\nRecommendation 1.2.15\n\n## Why the committee made the recommendation\n\nFor people who have an inadequate (Thy1) FNAC results, the committee recommended that sampling should be repeated. This was because an unsatisfactory aspirate is often a random technical failure that might not be repeated. The preferred approach for repeat sampling is a core-needle biopsy (CNB) or FNAC with ROSE. This was because the diagnostic clinical review of FNAC and CNB, and the studies informing the health economic model, found that CNB and FNAC with ROSE are more accurate than repeat FNAC and associated with a lower rate of unsatisfactory results. The committee recommended that, in some cases, FNAC alone could be performed instead. For example, if CNB and ROSE are not available locally, or if the nodule is near a blood vessel that would make the use of CNB with large needles inappropriate. Should this further test still be Thy1, then the committee thought the best way to determine malignancy is by diagnostic hemithyroidectomy.\n\nFor people with a cystic lesion (Thy1c), FNAC should be repeated. This is because neither CNB or FNAC with ROSE were considered useful for non-diagnostic cystic samples. If the second FNAC is also Thy1c and the initial ultrasound appearances are concerning, then the committee agreed that a diagnostic hemithyroidectomy should be considered to establish the diagnosis.\n\nTo optimise the sensitivity of FNAC testing, which was fractionally below the target of 0.95, the committee recommended repeating tests that are benign (Thy2 or Thy2c). In the first instance, the committee agreed that repeating ultrasound should be considered. If this still produces a suspicious result, then the next step would be to repeat the FNAC. CNB could be considered as an alternative to repeating FNAC, because although it is invasive and more expensive than FNAC, it can extract more material. Benign FNAC tests should be repeated because sampling error can sometimes cause false negatives. Therefore, if the initial Thy2 result was caused by sampling error, a repeat test is likely to return a positive result but, if it was not, the repeated test will also be Thy2. The committee therefore recommended that people who have had repeated investigations, and there is no evidence of malignancy after these are complete, can be discharged unless there are other clinical concerns.\n\nThe committee made a repeat sampling recommendation for people with Thy3a results. The preferred approach is CNB, which reflects the findings of the economic evaluation and clinical review. A consider recommendation was made, because in some cases a Thy3a sample may suggest a follicular lesion, which would not benefit from repeat sampling with CNB. FNAC is recommended as an alternative when CNB is unavailable or inappropriate. In case of a further Thy3a results, a recommendation was made to use diagnostic hemithyroidectomy or active surveillance.\n\nFor people with Thy3f results, the committee recommended that diagnostic hemithyroidectomy be considered. This reflected the committee's view that repeat sampling with FNAC or CNB is less useful after a suspected follicular lesion (Thy3f) and that diagnostic hemithyroidectomy is justified by the high risk of malignancy in this group (around 30%). There were also concerns that, if not followed up with surgery, final diagnosis after Thy3f could take longer. This would delay treatment for a potentially malignant tumour, create uncertainty for the person, and in some centres lead to a longer delay than is allowed by NHS cancer targets. Although the committee agreed that this is current practice, a consider recommendation was made. This reflects the uncertainty in the evidence and the committee agreed that there may be some cases, for instance in older people with severe comorbidities, where a hemithyroidectomy for a Thy3f may not be appropriate.\n\nFor people with Thy4 or Thy5 cytology, the committee recommended diagnostic or therapeutic hemithyroidectomy, or total thyroidectomy. The recommendation that people in these groups should be sent straight to surgery was based on evidence that the groups would contain a significant proportion of people with malignancy.\n\nThe economic model suggested that molecular testing could be cost effective in certain cytologies, particularly after a suspected follicular lesion (Thy3f), which would not benefit from repeat sampling. However, molecular tests are not widely available in the NHS and are mostly produced outside the UK. The committee agreed that molecular tests could help reduce the number of unnecessary diagnostic hemithyroidectomies in people with indeterminate FNAC results and made a recommendation for research for molecular tests.\n\n## How the recommendation might affect practice\n\nThe recommendation to offer CNB or FNAC with ROSE after a non-diagnostic Thy1 cytology result is considered a change from current practice. Some centres could have preference for, or availability of, only one of the two techniques, so the recommendation ensures flexibility in the management of Thy1. In centres where neither technique is available, the implementation of CNB or FNAC with ROSE could require additional resources for training and resourcing in the short term. However, the reduction of non-adequate cytologies, repeat sampling and unnecessary surgeries is expected to offset the initial investments.\n\nThe recommendation to consider repeat ultrasound and repeat FNAC with Thy2 reflects current practice and it is not expected to have an impact on NHS resources.\n\nThe recommendations to repeat sampling with CNB after a Thy3a cytology is a significant change from current practice. FNAC has generally been the preferred method for repeat sampling in the NHS, so some changes in training for biomedical scientists, radiologists and pathologists and provision of equipment in centres where CNB is rarely offered or not available are expected. However, as shown in the health economic analysis, this is likely a cost-effective use of NHS resources, which would reduce unnecessary diagnostic surgeries and improve efficiency.\n\nThe recommendations to offer diagnostic hemithyroidectomy to people with Thy3f and either diagnostic or therapeutic surgery to people with Thy4 and Thy5, reflect the current approach and are not likely to have an impact on practice or resources.\n\nReturn to recommendation\n\n# Radioisotope scans\n\nRecommendation 1.2.16\n\n## Why the committee made the recommendation\n\nIn the absence of evidence from the review, the committee formed a recommendation by consensus. The committee agreed that there is a potential harm from radioisotope scans and, based on clinical experience, agreed that they are no more accurate than FNAC. Therefore, the benefits of radioisotope scans would normally not outweigh the harms and they would not be considered.\n\nHowever, the committee did not have enough evidence to recommend that radioisotope scans should never be used. Therefore, the word 'routinely' was used to indicate that they might be useful in very rare and specific circumstances, although the committee did not provide examples. This was because any such examples would be extremely context-dependent and would not demonstrate the complexity of such decision making.\n\nThe committee agreed that there may be value in using radioisotope scans when assessing recurrent thyroid cancer, however this was not part of this review question. Therefore, this recommendation relates to the initial diagnosis of thyroid cancer.\n\n## How the recommendation might affect practice\n\nThe recommendation largely reflects current practice because radioisotope scans are only used rarely, and it is therefore not expected to have a significant effect on practice.\n\nReturn to recommendation\n\n# Imaging for further staging\n\nRecommendations 1.2.17 and 1.2.18\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, the committee used consensus to form the recommendations. The committee agreed that for people with T1 or T2 thyroid cancer and no other indications, cross-sectional imaging is not needed. The ultrasound results obtained when the thyroid was first assessed should provide enough detail for further staging. Other indications that would suggest cross‑sectional imaging may be useful, include signs of metastases or a suspicious symptom such as a cough. This decision was based on the agreement that ultrasound would be sensitive enough to pick up the relatively superficial structural lesions that might occur in most of this group. It was also agreed that the potential harms of deeper imaging techniques would not be outweighed by the benefits in this group. For example, CT carries radiation risks, particularly to younger people, and some people find the experience of MRI distressing.\n\nFor people at even higher levels of risk, such as those with T3 or T4 thyroid cancer, or with any local spread to nodes or distant metastases, cross-sectional imaging techniques should be considered, as well as the initial ultrasound, to help define the stage of cancer.\n\nThe committee agreed that cross-sectional imaging would be useful either before surgery, to help inform the procedure, or after surgery, to inform subsequent management. However, the committee noted that clinicians would need to balance the benefit of additional information gained from CT contrast, against the potential need to delay RAI as a result of having a CT scan.\n\n## How the recommendations might affect practice\n\nThe impact of the recommendations on practice is expected to be small, because the recommendations reflect current practice.\n\nReturn to recommendations\n\n# Surgery and active surveillance for primary tumours\n\nRecommendations 1.3.1 to 1.3.11\n\n## Why the committee made the recommendations\n\nEvidence from the randomised control trial (RCT) showed total thyroidectomy led to less cancer recurrence than hemithyroidectomy. Weighing up the benefits and harms, using this evidence and their experience, the committee agreed that total thyroidectomy should be recommended over hemithyroidectomy if there are definite indications for postoperative radioactive iodine (RAI), such as a large primary tumour or bilateral disease. This is because definite indications for postoperative RAI suggest that the risk of recurrence is high enough that the benefits of total thyroidectomy outweigh its potential harms. However, where the risk of recurrence is lower, the committee agreed that a hemithyroidectomy would be as beneficial and potentially less harmful, and might also allow people to maintain normal thyroid function. The committee also agreed that, although a hemithyroidectomy might be chosen, some people might need a completion thyroidectomy later if it is indicated by a histological review or during later surveillance.\n\nNo randomised evidence was found for active surveillance. Observational evidence showed that surgery led to lower overall mortality compared with active surveillance in people with stage\xa01 disease. However, the committee were aware of the lack of adjustment for likely confounding by comorbidity. In this population there were no other outcomes reported and so it was difficult to establish a full picture of benefits and harms.\n\nIn contrast, observational evidence from adults with cytologically confirmed papillary thyroid microcarcinoma favoured active surveillance over hemithyroidectomy. This was because people on active surveillance had fewer surgical scar problems, neuromuscular symptoms, throat and mouth symptoms and loss of interest in sex. However, measurements of other quality of life outcomes were largely inconclusive.\n\nThe committee agreed that the evidence base suggested that active surveillance should not be used for most people with thyroid cancer. Instead, it should only be considered for people who have a small (less than 1\xa0cm) solitary microcarcinoma, with the person's preferences taken into account after a full discussion. This was because, in the committee's experience, there is a low risk of the tumour adversely affecting the person's quality of life. Therefore the committee made a recommendation to consider either hemithyroidectomy or active surveillance for people with a microcarcinoma.\n\nGiven the lack of RCT evidence and low quality of the observational data for active surveillance, the committee also made a recommendation for research comparing active surveillance with surgery.\n\nNo evidence was found for treatment of existing nodal disease, and so the committee drew upon their clinical experience to form recommendations. The committee agreed that any nodal disease should be dealt with at the time of the total thyroidectomy. Despite the lack of evidence, the committee agreed that a strong 'offer' recommendation was justified because it is in the best interests of the person to ensure no cancerous material is left behind. Leaving it in situ is likely to mean the person would have to have an additional invasive procedure, and also there would be additional cost to the NHS. The committee also noted that there were no alternative procedures to those recommended. Therefore the committee agreed that if nodal disease is present in the lateral neck, a compartment-orientated lateral neck dissection should be offered, and, if nodal disease is present only in the central neck, a compartment-orientated central neck dissection should be offered. They also discussed that carrying out an ipsilateral central neck dissection at the same time may also benefit the person. Because the cancer has already spread to the neck and surgery of the neck is already being performed, carrying out this procedure at the same time may help avoid future surgery. This is a 'consider' recommendation because it was not based on evidence and the procedure is prophylactic and not for the removal of known cancer.\n\nRCT evidence suggested that people who have had a total thyroidectomy and prophylactic central compartment lymph node dissection (PCCND) needed fewer additional RAI treatments but had a higher risk of permanent hypoparathyroidism. Evidence was inconclusive in terms of recurrent laryngeal nerve palsy. Overall, the committee thought that the benefits from having fewer additional ablations were outweighed by the risks of permanent hypoparathyroidism. Therefore, in conjunction with the limited and poor-quality evidence, the committee agreed that PCCND should not be offered. No evidence was found for prophylactic lateral lymph node dissection, but the committee agreed that, while the benefits would be similar, the harms would exceed those observed for central lymph node dissection. Therefore, the committee agreed that prophylactic lateral lymph node dissection should also not be offered.\n\nFinally, the committee agreed that there could be risks to the foetus if operating on pregnant women, although the risks are unclear. The concern in the first trimester is largely about preventing birth defects from the anaesthetic drugs. The concern in the later trimesters is about loss of the pregnancy. Therefore the committee agreed that it would be better to defer any surgical treatment until after pregnancy. However, they also noted that in the rare event of there being clinical or radiological evidence of progression (local invasion or regional disease development) then surgery should be done during the second trimester if possible. The committee recommended that a joint decision should be reached with the mother about whether to defer surgery during pregnancy, after a discussion by the obstetrician, surgeon and endocrinologist.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the recommendations were unlikely to change current practice.\n\nReturn to recommendations\n\n# Thyrotropin alfa\n\nRecommendations 1.3.12 and 1.3.13\n\n## Why the committee made the recommendations\n\nEvidence showed that thyrotropin alfa (also known as recombinant human thyroid stimulating hormone) had short-term benefits over RAI with thyroid hormone withdrawal (THW) and did not demonstrate any harms. The relative benefits from thyrotropin alfa were improved quality of life, wellbeing, social, emotional and general function and reduced fatigue. The committee also agreed that thyrotropin alfa is better tolerated than THW.\n\nEconomic evidence showed mixed results when thyrotropin alfa was compared with THW. Three studies showed thyrotropin alfa to be either cost effective or to dominate THW. One study, based on the latest evidence, found thyrotropin alfa not to be cost effective. Therefore the committee agreed to take into account some original analysis that found a cost per quality-adjusted life year of thyrotropin alfa between £20,000 and £30,000.\n\nOverall, the committee agreed that thyrotropin alfa should be offered to everyone. They noted that some people might be harmed by THW. People vulnerable to the detrimental effects of THW include those with psychiatric or mental health conditions, cardiac conditions, older-age, chronic kidney disease and a higher risk of falls. The committee made a strong recommendation, because they agreed a weaker recommendation would be inappropriate when the aim is to avoid direct harm.\n\nThe committee also agreed that thyrotropin alfa is better than THW for those who are not 'lower stage', or people for whom THW was not contraindicated. Thyrotropin alfa enables people to return to normal activities within 2 or 3\xa0days of treatment, whereas THW is taken for 4 to 6\xa0weeks before treatment with RAI, and people typically need to take at least 2 to 3\xa0weeks off work. This means that THW was also considered to disadvantage those from lower socioeconomic groups, in whom a loss of earnings could adversely affect their quality of life, and those who have caring responsibility for children or the elderly. Unpaid carers may also struggle to find or afford someone to do their role while they are unable to do normal activities.\n\nThe committee also discussed the harms associated with THW and noted that the person will become acutely hypothyroid. This means they may experience mood changes such as anxiety, depression, lethargy and difficulty concentrating. This is particularly important for people with pre-existing mental health problems. The committee acknowledged that in most people the harm caused by THW is temporary. However, they agreed that the degree of short-term harm was so great that a change in practice to THW could not be recommended without clear and certain evidence of THW being cost effective.\n\nBecause thyrotropin alfa is an established and accepted current practice, a change in practice could disrupt RAI treatment. The committee noted that the preparation with thyrotropin alfa ensures flexibility for periods of RAI shortage, whereas THW could cause disruption and harm to people if providers are not able to offer the treatment at the end of the withdrawing period. Therefore, taking these factors into account, the committee made a recommendation for thyrotropin alfa.\n\nIn December 2022, using thyrotropin alfa as a treatment for thyroid cancer in people with distant metastases was an off-label use. However, the committee agreed that in their experience thyrotropin alfa still offered benefits to people with distant metastases if carefully managed because it avoided a short-term reduction in their quality of life.\n\nFinally, any rise in TSH has the theoretical risk of causing flare of thyroid cancer. Due to the sharp rise and high levels of TSH following treatment with thyrotropin alfa, particular caution should be taken. This is of most concern in people with metastases in the brain or spine. The committee agreed that in these cases thyrotropin alfa can still be used by giving pre-treatment steroids or external beam radiotherapy (EBRT).\n\n## How the recommendations might affect practice\n\nThe committee noted that using thyrotropin alfa has become standard practice, so the recommendation is not expected to have any impact on current practice.\n\nReturn to recommendations\n\n# RAI for initial ablation\n\nRecommendations 1.3.14 to 1.3.16\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, the committee made a consensus recommendation that RAI should be offered after a total or completion thyroidectomy, if a person has a primary tumour at stage T3 or T4, regional lymph node involvement, pathological findings associated with a poor prognosis (including multifocal disease), or evidence of distant metastases. This recommendation is strong because there was consensus that, based on clinical experience, the benefits would significantly outweigh any harms for people who fulfil these criteria. The committee were also aware that trials that are currently ongoing do not cover people in these groups.\n\nThere was also agreement that RAI should not be offered for T1a or T1b tumours after thyroidectomy, unless there are adverse features such as prognostically poor histological subtypes or an R1 resection margin. This decision was based on evidence that there was no difference in outcome and a consensus that the harms from RAI might outweigh the benefits unless adverse prognostic features or evidence of metastatic disease are present.\n\nHaving defined the situations in which RAI would and would not be offered, the committee agreed that a recommendation to consider RAI for clinical presentations that fit neither of the former recommendations would be appropriate. On balance they agreed that RAI would be of benefit for this group, and they made a consider recommendation. Given the uncertainty, a recommendation for research was made to address the clinical and cost effectiveness of RAI after total or completion thyroidectomy for people with T2 disease and no adverse pathological features. The committee agreed that this is important to establish the precise balance of benefits and harms so that appropriate clinical decisions can be made.\n\n## How the recommendations might affect practice\n\nThere are currently variations in how RAI is used in practice. However, this is gradually reducing, particularly for people considered to be at intermediate risk of thyroid cancer recurrence. By defining 3 distinct sets of clinical presentations, the recommendations offer new clarity on when RAI should and should not be offered, and when it should be considered. They are therefore likely to change practice leading to a more transparent decision-making process.\n\nReturn to recommendations\n\n# RAI activity for initial ablation\n\nRecommendations 1.3.17 and 1.3.18\n\n## Why the committee made the recommendations\n\nThe evidence suggested that higher activity RAI only provides a small benefit to a small number of people. The committee agreed that given the legal requirement to minimise radiation exposure (The Ionising Radiation [Medical Exposure] Regulations, 2017), this did not warrant giving higher activity RAI to everyone. Therefore the committee recommended that most people should have RAI with an activity for initial ablation of 1.1\xa0GBq.\n\nHowever, the committee recognised that some people in high-risk groups should be considered for RAI with an activity of 3.7 GBq for their initial ablation. High-risk groups include people with advanced or aggressive disease and people with significant comorbidities such as cardiovascular disease, mobility issues or complex social concerns, who should therefore avoid multiple ablations. For these people, the benefits of more complete ablation after a single exposure would probably outweigh the harms of higher activity RAI. The committee therefore recommended that these high-risk groups could have higher activity RAI.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the evidence supports current practice, where lower activity RAI is generally preferred to high activity. It is likely that the recommendation would further increase the number of people having lower activity RAI instead of high activity, which would reduce NHS costs and potentially prevent second malignancies caused by radiation exposure.\n\nReturn to recommendations\n\n# External beam radiotherapy\n\nRecommendations 1.3.19 and 1.3.20\n\n## Why the committee made the recommendations\n\nThe committee discussed the benefits and risks of EBRT. They agreed that it is only used in a small subgroup of people with thyroid cancer when there is no alternative treatment. In people with well-differentiated thyroid cancer there was evidence that EBRT reduced recurrence and prevented local disease progression. There was also evidence of increased death at 10\xa0years. However, the committee agreed that despite this observational evidence adjusting for confounders, there was still likely to be some residual confounding within the analysis. In their experience, the committee agreed that EBRT showed benefit without increased mortality. Although they acknowledged that mortality is likely to be higher in people selected for EBRT because of the advanced nature of their disease. Therefore the committee decided that EBRT should be carefully considered on a person-by-person basis that minimises risk and maximises benefit. The committee agreed that people with macroscopic disease or histological appearances that may indicate more aggressive disease, and people with tumours that have not taken up RAI, may benefit most from EBRT. This is because their tumours would not usually respond well to other treatments.\n\nSimilarly, the committee agreed that EBRT may benefit people who are having palliative care, in whom cancer metastases or local residual disease can cause symptoms such as ulceration due to skin invasion, pressure symptoms or pain. The committee therefore recommended that EBRT should be considered in these cases.\n\nOverall, the committee agreed that the observational evidence was of low quality, but suggested that EBRT can provide benefit by reducing recurrence and local progression. However, they did not believe the mortality data reflected their experience and, given their view that the observational data was likely to be biased, they also made a recommendation for research for an RCT for EBRT.\n\n## How the recommendations might affect practice\n\nLess than 5% of people with well-differentiated thyroid cancer currently have EBRT. The recommendation is unlikely to increase workload or referrals and therefore the resource impact should be minimal or non-existent. It is possible that the recommendations will lead to a more careful and appropriate selection of people for EBRT, reducing both the costs of EBRT use and of avoidable adverse effects.\n\nReturn to recommendations\n\n# Thyroid stimulating hormone suppression\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nThe evidence suggested that thyroid stimulating hormone (TSH) suppression with thyroid hormone reduces cancer recurrence and mortality when compared with no TSH suppression. However, this evidence was from a single, small study graded as very low quality. There was also no accompanying evidence that assessed potential harms or risks associated with TSH suppression, such as osteoporosis or cardiac complications. Because the evidence base was weak, and lacked information on harms, the committee decided to form recommendations largely through consensus. The recommendations reflect current practice.\n\nIt was agreed that people who do not need RAI, should not be offered TSH suppression. In this group, the risks of recurrence, spread or mortality were believed to be so low that TSH suppression would benefit only a very small number of people. Given that the adverse effects on bone and cardiac health would affect a far greater proportion, it was agreed that the balance of benefits and harms strongly indicated avoidance of TSH suppression in this group.\n\nIn contrast, the committee agreed that the situation would be different for people who have had total or completion thyroidectomy and RAI. These treatments are only given when the perceived risks of recurrence, spread or mortality are higher. For these people, the balance of benefits and harms shifts towards an overall benefit from TSH suppression. Therefore for such people TSH suppression may be offered to maintain TSH levels below 0.1\xa0mIU/litre.\n\nAfter starting treatment, the person's response to the suppression should be monitored. After 9 to 12\xa0months, if they have an excellent response to treatment, suppression can be reduced to achieve a TSH level of between 0.3\xa0IU/litre and 2.0\xa0IU/litre. If there is an intermediate response, suppression should be continued to achieve a TSH level of between 0.1\xa0IU/litre and 0.5 IU/litre. This is on the basis that initial treatments and TSH suppression have probably eliminated the cancer and that further high levels of suppression could do more harm than good. However, if their response has been poor, they should continue to receive high levels of suppression. This is because the potential harms from the uncontrolled disease outweigh the harms of TSH. The committee agreed that achieving the target TSH levels may not be possible in all people but should be for most.\n\n## How the recommendations might affect practice\n\nThe recommendations to avoid TSH suppression in low-risk cancers might change practice. Avoidance of inappropriate TSH suppression would be expected to reduce long-term adverse effects. This would in turn have a favourable effect on resources, because most thyroid cancers diagnosed at present are low risk.\n\nReturn to recommendations\n\n# Long-term duration of TSH suppression\n\nRecommendation 1.4.5\n\n## Why the committee made the recommendations\n\nThere was no evidence found for the optimal duration of TSH suppression. Previously, people would have TSH suppression indefinitely. However, with regular monitoring and risk assessment, this is no longer the case. Now TSH suppression is stopped if the perceived risk from TSH suppression outweighs the likely benefit in preventing cancer recurrence. The recommendations reflect that change in practice by highlighting the importance of an individualised assessment of risks and benefits. The committee also emphasised that some people may not want to suddenly stop or reduce TSH suppression because of the anxiety related with such a change. Therefore people on TSH suppression for more than 10\xa0years should have a clinical review to assess their ongoing treatment, as well as the risks and benefits of TSH suppression.\n\nIn the past, people with thyroid cancer would have been told that TSH suppression is for life. However, the current thinking is that this not usually necessary. The committee agreed that it was important to explain this to people with thyroid cancer and reassure them that they will still be monitored if their suppression is relaxed.\n\nBecause of the lack of evidence, a recommendation for research was also made on the duration of TSH suppression.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice and so are not likely to have an impact on practice or resources.\n\nReturn to recommendation\n\n# Measuring thyroglobulin and thyroglobulin antibodies\n\nRecommendations 1.5.1 to 1.5.6\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, recommendations were made by consensus. The committee discussed how measuring thyroglobulin antibodies alongside thyroglobulin was important because the presence of thyroglobulin antibodies can affect thyroglobulin levels. This can increase the number of false positive or false negative results. They also noted that detectable thyroglobulin levels in people without thyroglobulin antibodies suggests the presence of either residual thyroid tissue or residual or recurrent thyroid malignancy. They agreed that the harms of thyroglobulin measurement, such as false positives leading to over investigation, did not outweigh the clinical benefits from early detection of recurrence or progression. In the absence of a feasible alternative method for measuring recurrence, the committee recommended measurement of thyroglobulin following a total or completion thyroidectomy with RAI. Frequency of thyroglobulin measurement was recommended, in line with current practice, at 3- to 6-month intervals for the first 2\xa0years, followed by 6- to 12-month intervals after that.\n\nThe committee agreed that if thyroglobulin antibodies are not detected, then thyroglobulin levels can be interpreted at face value. In such a case, this initial evidence of recurrence from thyroglobulin testing should lead to further investigations, either to confirm or refute recurrence. They also recommended that people who have previously been cleared of having recurrence after a thyroglobulin test, but now have rising thyroglobulin levels, should also have further investigations for recurrence. This is because the rise in thyroglobulin levels might be a 'new' sign of recurrence that requires investigation. Further investigations could include neck ultrasound, CT scan of neck and chest or MRI scan of the neck. The choice often depends on local availability, and a prior knowledge of what happened with the patient in assessing where in the body recurrence is most likely to be.\n\nThe committee noted that there may be some cases where a person has had a total thyroidectomy without RAI. However, there may be additional factors that suggest more detailed follow up is needed. In these circumstances, the clinician may have decided to measure thyroglobulin as part of the follow\xa0up. If the person's levels rise, then further investigations should be considered. A detectable level of thyroglobulin that is not rising is not usually an indication for further investigations as often there will be a small amount of residual thyroid tissue following total thyroidectomy without RAI.\n\nFor people who have not had a total thyroidectomy, there would rarely be a need to measure thyroglobulin levels and interpretation of results can be difficult. This is because the person would still have functioning thyroid. Therefore the committee recommended that thyroglobulin levels should not be routinely measured.\n\nThe committee also considered the more complex scenario of what should happen if thyroglobulin antibodies are detected above the laboratory threshold. Initially, the clinician would be expected to investigate how the assay might be affected by antibodies, and if it might cause an increase or decrease in measured thyroglobulin levels. This would influence how the thyroglobulin levels are interpreted and, if there was enough uncertainty, prompt a move to other investigations to confirm or refute recurrence. It was also agreed that there should be further investigations if, at a later point, either the thyroglobulin levels or thyroglobulin antibodies start to rise. This was because each of these scenarios could, directly or indirectly, indicate recurrence. Therefore the committee made a recommendation to consider further investigation in the presence of thyroglobulin antibodies when they are first detected or at any point if thyroglobulin or thyroglobulin antibody levels are rising.\n\n## How the recommendations might affect practice\n\nThe committee did not think that the recommendations would have an impact on current practice, because the recommendations reflect current and established practice.\n\nReturn to recommendations\n\n# Stimulated thyroglobulin and highly sensitive thyroglobulin testing\n\nRecommendations 1.5.7 to 1.5.10\n\n## Why the committee made the recommendations\n\nThe committee agreed to form recommendations by consensus because no evidence was available from the literature. When thyroglobulin is undetectable on a standard assay, the committee agreed that further investigation should be considered with either a stimulated or highly sensitive thyroglobulin assay. They also suggested strategies for what to do depending on the results obtained from using each method.\n\nWhen using stimulated thyroglobulin, there were 3 levels of response suggested. A reading of below 1\xa0microgram/litre was considered low risk, and led to the recommendation that follow up and TSH suppression could be relaxed. A reading of between 1\xa0microgram/litre and 10\xa0microgram/litre was considered an indeterminate response, and led to the recommendation to consider continuation of TSH suppression. Finally, a reading of 10\xa0microgram/litre or more led to a recommendation to consider further investigations and treatment. The type of treatment would depend on what the further investigations revealed. This gradation of actions, from a relaxation to a strengthening of vigilance, was based on the changing perception of recurrence risk associated with the stimulated thyroglobulin measurements.\n\nWhen using a highly sensitive assay that can detect thyroglobulin levels lower than 0.2\xa0microgram/litre, there were 2\xa0levels of response suggested. A reading of below 0.2\xa0microgram/litre was considered low risk and led to the recommendation that follow up and TSH suppression could be relaxed. A reading of between 0.2\xa0microgram/litre and 1.0\xa0microgram/litre led to a recommendation to consider stimulated thyroglobulin, which can be helpful in separating people into lower- and higher-risk categories. If a person was shown to be at medium risk on stimulated thyroglobulin, this would suggest continuing with the same strategy and not relaxing TSH suppression. But, if they were at high risk, this would indicate the consideration of further investigations and treatment.\n\nWith all these recommendations, the committee stressed that the presence of anti-thyroglobulin antibodies can distort both stimulated and highly sensitive thyroglobulin measurements, and caution should therefore be used when interpreting results in this situation.\n\n## How the recommendations might affect practice\n\nThe impact of the recommendations on practice is expected to be small, because the recommendations reflect current practice.\n\nReturn to recommendations\n\n# Follow up\n\nRecommendations 1.6.1 to 1.6.4\n\n## Why the committee made the recommendations\n\nThe available evidence on follow-up strategy included people with very early-stage thyroid cancer. The committee agreed that the evidence was therefore not representative of much of the population, so they used consensus to make the recommendations. They agreed the strategy should be set according to the severity of disease and the treatment given. For people with T1a disease that has been surgically removed with no local (N0) or distant (M0) spread, the committee agreed that the risks of further spread or recurrence were so low that the harms of further follow up would outweigh any benefits. Such harms include the anxiety caused by the investigations and the radiation risks of some forms of detection.\n\nFor people with thyroid cancer that is stage T1a(m), T1b or greater, and who have had a hemithyroidectomy or total thyroidectomy without RAI, an ultrasound at 6\xa0to 12\xa0months was recommended, followed by an annual clinical follow up for 5\xa0years. This group was regarded as having a small but real risk of recurrence and spread. Therefore the benefits of follow up, such as better prognosis resulting from early detection and treatment, starts to outweigh the previously outlined harms. The timing of the initial follow up was based on current practice. The frequency was based on the committee's understanding of how quickly recurrences and spread may occur. They also considered at what point it tends to be safe to assume that further problems are unlikely, provided no recurrence or spread has yet occurred. The committee agreed that the need for ultrasound at these annual clinical follow ups would need to be decided on a case-by-case basis. The committee also acknowledged that there may occasionally be instances when it is appropriate to measure thyroglobulin in those cases, but detectable thyroglobulin alone did not indicate recurrence of cancer. The trend in thyroglobulin over several measurements was therefore considered more useful in these people.\n\nFor people who have had both a total or completion thyroidectomy and RAI, the duration and frequency of follow up was based on the assumed level of risk and response to treatment. Low risk was defined as no evidence of disease on imaging and a thyroglobulin level of less than 0.2\xa0microgram/litre (or a stimulated thyroglobulin level of less than 1\xa0microgram/litre). Medium risk was defined as thyroglobulin between 0.2\xa0microgram/litre and 1.0\xa0microgram/litre, or stimulated thyroglobulin of between 1\xa0microgram/litre and 10\xa0microgram/litre. High risk was defined as thyroglobulin of greater than 1.0\xa0microgram/litre, or stimulated thyroglobulin of greater than 10\xa0microgram/litre. The annual frequencies were again based on the committee's understanding of how quickly recurrences and spread may occur. The committee acknowledged that, while annual follow up is recommended, there may be cases in which more frequent follow up is needed. The increasing duration of total follow up with the level of presumed risk was based on the committee's experience that late recurrence and spread increases with risk. Therefore more prolonged vigilance is needed, and the benefit outweighs any potential harms from follow up, such as anxiety about radiation.\n\nFor anyone at the highest levels of risk, with persistent biochemical or structural disease, there is the potential for disease progression. Therefore the committee recommended that follow up should occur annually for an indefinite period, and potentially for life. Finally, the committee discussed how thyroglobulin measurement is designed to identify recurrence that may not yet be structurally evident. Therefore if structural recurrence is detected in people who have been treated with total or completion thyroidectomy and RAI, further thyroglobulin measurement is unnecessary. Such people should be discussed in the multidisciplinary team meeting with the surgeon.\n\nThere was no evidence for how long people should be followed up, so the committee set minimum periods and wrote a recommendation for research on the duration of follow\xa0up.\n\n## How the recommendations might affect practice\n\nThe impact of the recommendations on practice is expected to be small, because the recommendations reflect current practice.\n\nReturn to recommendations", 'Context': 'Cancer of the thyroid, a small gland at the base of the neck, is uncommon and can occur at any age. It is most often diagnosed in people from their 20s through to their 60s. Almost all thyroid cancers (about 97%) are differentiated and have a good prognosis. When deaths do occur, they tend to arise from the spread of the cancer to the bones or lungs. There has been an increase of over 150% in the incidence of thyroid cancer in the UK over the past 30\xa0years. It is unclear if this is because of more effective diagnosis or more people developing thyroid cancer. The rise in incidence has not been matched by a rise in mortality, but raises questions about assessment for people with suspected thyroid cancer and about appropriate treatment.\n\nThere is particular uncertainty about the management of nodules of small and intermediate size and classification, and practice varies internationally.\n\nThyroid cancer is usually treated by partial (hemi-) or total thyroidectomy, sometimes followed by radioactive iodine. Since thyroid cancer can occur in young adults and has a good prognosis, many who have this surgery will spend most of their lives without a thyroid gland. The long-term implications of this include lifelong treatment with replacement thyroid hormone, and possible complications such as hypoparathyroidism and vocal cord palsy. Internationally, very small thyroid tumours are sometimes managed with active surveillance.\n\nOnce thyroid cancer has been treated, there is still a chance it might recur. Recurrence is uncommon in well-differentiated cancers, but it can be more serious than the original occurrence. There are questions about the risk of recurrence and how this risk should be translated into a long-term follow-up strategy.'}	https://www.nice.org.uk/guidance/ng230	This guideline covers diagnosis and management of thyroid cancer in people aged 16 and over. It aims to reduce variation in practice and increase the quality of care and survival for people with thyroid cancer.
cdd725ef34b4159d602b9e1fabd3861776d3da21	nice	Avatrombopag for treating primary chronic immune thrombocytopenia	Avatrombopag for treating primary chronic immune thrombocytopenia Evidence-based recommendations on avatrombopag (Doptelet) for treating primary chronic immune thrombocytopenia in adults. # Recommendations Avatrombopag is recommended, within its marketing authorisation, as an option for treating primary chronic immune thrombocytopenia (ITP) refractory to other treatments (for example, corticosteroids, immunoglobulins) in adults. It is only recommended if the company provides it according to the commercial arrangement. Why the committee made these recommendations Current treatment for newly diagnosed primary chronic ITP usually includes corticosteroids and immunoglobulins. This is followed by thrombopoietin receptor agonists (TPO‑RAs). Avatrombopag is another TPO‑RA. Clinical trial evidence shows that avatrombopag is more effective than placebo at increasing the number of platelets in the blood (cells that help the blood to clot) to a level that meaningfully reduces the risk of bleeding. Avatrombopag may be as effective as other TPO‑RAs, but it has only been compared with them indirectly, which is uncertain. There are also uncertainties with some assumptions in the economic modelling. Despite this, avatrombopag is likely to provide benefit for people who have primary chronic ITP. Also, the cost-effectiveness estimates are below what NICE normally considers an acceptable use of NHS resources. So, avatrombopag is recommended.# Information about avatrombopag # Marketing authorisation indication Avatrombopag (Doptelet, Swedish Orphan Biovitrum) is 'indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e.g., corticosteroids or immunoglobulins)'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for avatrombopag. # Price The list price of a 10‑tablet pack of avatrombopag 20 mg is £640.00 (excluding VAT; BNF online, accessed June 2022). The company has a commercial arrangement. This makes avatrombopag available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Swedish Orphan Biovitrum, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Immune thrombocytopenia (ITP) is an autoimmune condition that is chronic in most affected adults ITP is characterised by a platelet count less than 100×109 per litre. This reduced platelet count is caused by abnormally high platelet destruction and reduced platelet production. ITP is a rare condition. About 3,000 to 4,000 adults in the UK are estimated to have ITP at any one time. To make a diagnosis, any other possible causes of thrombocytopenia, including impaired bone marrow, need to be excluded. Most diagnosed cases in adults progress to chronic ITP that may be difficult to control. Symptoms include fatigue, spontaneous bruising and regular bleeding episodes. The patient experts highlighted that the fatigue can be debilitating, reducing cognitive function and making it difficult to focus. The fatigue also often contributes towards increased bruising. This is because reduced coordination related to the fatigue may cause people to bump into things more often. Bleeding episodes can range from minor bleeds to severe, life-threatening haemorrhages. The patient experts emphasised the effect ITP has on mental as well as physical health. This is because many people with ITP worry about maintaining high enough platelet levels to prevent bleeding episodes. Treatment for ITP is usually introduced when the platelet count drops below 30×109 per litre. Current treatments include corticosteroids, immunoglobulins, thrombopoietin receptor agonists (TPO‑RAs) and immunosuppressants such as rituximab. The patient and clinical experts highlighted that the current treatments have disadvantages, including unpleasant and potentially harmful side effects, and the need for dietary changes. They emphasised a need for another treatment option that offered more normality for those affected by ITP. The committee concluded that ITP is a chronic condition that significantly affects the lives of those affected by it. ## People with chronic ITP would welcome new treatment options that maintain platelet counts at a level that prevents bleeds ITP is a burden to people with the condition, as well as their families and carers. This burden is often linked to the unpredictable nature of the condition and the side effects of treatment. Also, some people with ITP need to inject some treatments themselves, so need to plan their life around injection dates, and ensure safe storage and administration of these treatments. The patient experts highlighted that this could affect everyday life. Self-injecting can also cause increased anxiety. One patient expert described how they still had stress about injecting 5 years into treatment. Also, soreness and bruising can occur at the injection site, particularly in people whose platelet counts are low. There is an oral TPO‑RA, but this can cause side effects including chronic gastrointestinal issues and increased risk of blood clots. It can also be affected by diet, and people taking it may need to restrict what foods they eat, and when they eat them. Both the patient and clinical experts highlighted that this has a large effect on everyday life, adherence to treatment and effectiveness. Some treatments for ITP also cause immunosuppression, which increases the risk of infection. One patient expert explained that they had had 22 infections in an 18‑month period when taking an immunosuppressant for ITP. Infections can cause a drop in platelet count, which may need hospitalisation and rescue therapy if uncontrolled. Both the patient and clinical experts agreed that avatrombopag, an oral treatment with no dietary restrictions and no immunosuppression would be an advance in ITP treatment in the UK. They also agreed it could improve quality of life for people with ITP by increasing platelet count without being a difficult treatment to take. The committee agreed that a new treatment option for maintaining platelet counts would be welcomed by people with ITP. # Treatment pathway and comparators ## The company's positioning of avatrombopag in the treatment pathway is appropriate The company's positioning of avatrombopag was aligned with avatrombopag's marketing authorisation, that is, for treating primary chronic ITP in adults refractory to other treatments. When someone is diagnosed with ITP, they have an 'initial' treatment that includes corticosteroids, immunoglobulins or both. The clinical experts explained that TPO‑RAs would not be used before corticosteroids and immunoglobulins but would be used if this initial treatment failed. The committee concluded that avatrombopag is likely to be used after initial treatment of newly diagnosed chronic ITP. It agreed that the company's positioning of avatrombopag in the treatment pathway was appropriate. ## The relevant comparators for avatrombopag are other TPO-RAs In its submission, the company considered other TPO‑RAs (eltrombopag and romiplostim) to be the only appropriate comparators for avatrombopag. The company's rationale for this was that: TPO‑RAs are considered to be well-established standard care for ITP it would be inappropriate to consider rituximab or surgical splenectomy as the comparators given the availability of 2 other TPO‑RAs.The ERG agreed that the company's positioning of avatrombopag was reasonable. But it highlighted uncertainty around the variations in rituximab use in clinical practice. The committee queried at what point in the treatment pathway TPO‑RAs are prescribed in the NHS. The clinical experts explained that, while care is individualised to people with ITP, clinicians generally use TPO‑RAs before rituximab. They also explained that, before the COVID‑19 pandemic, rituximab's use varied across the UK. But international guidance changes have caused a shift in practice to use TPO‑RAs first after initial treatment has failed. This is because rituximab can suppress the immune system. They also confirmed that clinicians rarely offer splenectomy in the first year of diagnosis and do not consider it as an alternative to TPO‑RAs. The committee concluded that eltrombopag and romiplostim were the appropriate comparators for avatrombopag. # Clinical effectiveness ## The population of Study 302 may represent the likely NHS population, but there are uncertainties The key clinical evidence for avatrombopag came from 1 clinical trial, Study 302, and its 72‑week open-label extension. Study 302 was a 26‑week, phase 3, multicentre, randomised, double-blind, parallel-group trial of avatrombopag compared with placebo. The company also submitted clinical evidence from 2 open-label clinical trials: Study 305, a discontinued phase 3, multicentre, randomised, double-blind, parallel-group trial of avatrombopag compared with eltrombopag CL‑003, a 28‑day, phase 2, double-blind, randomised, controlled trial of avatrombopag compared with placebo, and CL‑004, a 6‑month rollover study for people who completed CL‑003.The company only included Study 302 data in the economic model because it considered that it contained robust comparative data on key efficacy and safety outcomes. It stated that the results of the other studies largely supported the safety and efficacy profile of avatrombopag. But it did not think it was appropriate to include the data from these studies in the economic model. The ERG noted that, although Study 302 did not have a UK site, the baseline characteristics of its population would likely be applicable and relevant to an NHS population. But the committee noted that the trial's population may have been younger than the NHS population. The clinical experts explained that they would not expect the response to avatrombopag to be age specific. But more fatal bleeds and infection events may happen in older people, which the clinical experts thought may not have been fully captured in the trial. The committee also noted that 72% of the avatrombopag group were women compared with 47% in the placebo group. There were also people in the trial who had had a splenectomy, which would normally be done after treatment with avatrombopag. Neither the ERG nor the clinical experts thought that this would have had a meaningful effect on the trial results. The committee concluded that the population in Study 302 may represent the NHS population but that there were uncertainties in the study population's baseline characteristics. It took this into account in its decision making. ## The clinical trials of avatrombopag has recruitment and attrition issues, resulting in a limited evidence base There were 49 people in Study 302, 32 in the avatrombopag group and 17 in the placebo group. Twenty two people on avatrombopag completed the trial, while 7 stopped because of inadequate treatment effects and 3 stopped for other reasons. One person on placebo completed the trial, while 15 stopped because of inadequate treatment effects and 1 stopped for other reasons. The clinical experts explained that it is difficult to have a true 'placebo' group for chronic ITP treatments. This is because people in a placebo group would not be expected to stay in a trial if they had extremely low platelets and bleeding episodes. This led to limitations when estimating the durable platelet response rate in the placebo group over the course of Study 302. The ERG was concerned with the robustness of the efficacy and safety data from Study 302 because of the imbalanced drop-out between the avatrombopag and placebo groups. During the first committee meeting, it highlighted that this also affected the results of the company's network meta-analysis (NMA) that indirectly compared avatrombopag with other TPO‑RAs (see section 3.9) and used durable platelet response rate as the outcome. This was because the durable platelet response rate was a key outcome assessed in the NMA presented to the first committee meeting. The committee was aware that Study 305 was stopped early, and that the results of this study were not included in the economic model. It questioned why it was stopped early. The company explained that the trial protocol for Study 305 mandated unpleasant screening and monitoring procedures for people in the trial, and this contributed to recruitment challenges. It also commented that the trial started when eltrombopag was approved and became commercially available. It thought that people may have been reluctant to enrol and be randomised to avatrombopag, a non-approved treatment. So, the trial was stopped before durable platelet response rate could be measured. But the company thought that data from the study could have been used to provide information on other outcomes, including bleeding episodes. At the first committee meeting, the committee had concerns around the limitations of Study 302. In response, the company stated that there was a growing evidence base and clinical experience of using avatrombopag. It also stated that the efficacy of avatrombopag has been shown in randomised controlled trials and real-world settings. The committee understood that there was a limited evidence base for the clinical efficacy of avatrombopag because of recruitment and attrition issues in the clinical trials. ## Avatrombopag may improve cumulative platelet response and durable platelet response rate, but the clinical evidence is highly uncertain The primary outcome of Study 302 was the median cumulative number of weeks of platelet response, measured over 26 weeks. A platelet response was defined as 50×109 per litre or more. Evidence suggested that the median cumulative number of weeks of platelet response was 12.4 weeks with avatrombopag and 0 weeks with placebo (p<0.0001). Other outcomes measured included: secondary: proportion of people with a platelet response without rescue therapy at day 8 (avatrombopag 65.6%, placebo 0%; p<0.0001) proportion of people with a reduction in concomitant ITP medication (avatrombopag 33.3%, placebo 0%; p=0.13) exploratory: durable platelet response rate, that is, the proportion of people who had a platelet response for 6 or more of the last 8 weeks of treatment (avatrombopag 34.4%, placebo 0%; p=0.009) incidence of any grade of bleeding (avatrombopag 43.8%, placebo 52.9%; p=0.54) use of rescue therapy (avatrombopag 21.9%, placebo 11.8%; p=0.47). The ERG noted that the evidence suggested that, compared with placebo, avatrombopag improved the median cumulative number of weeks of platelet response over 26 weeks and the durable platelet response rate. But it highlighted that the interpretation of the evidence was difficult because of the high drop-out in the placebo group. The committee commented that a platelet response without any form of treatment is improbable. It noted the statistically significant difference in proportion of people with a platelet response without rescue therapy at day 8 between avatrombopag and placebo. It contrasted this with the relatively smaller difference between the 2 groups for the outcome of incidence of bleeds. It questioned what the most clinically meaningful outcomes for assessing clinical effectiveness would be. The clinical experts explained that time spent above a platelet count threshold is a clinically meaningful outcome, but this can be difficult to reach because ITP is variable. They thought that a platelet count of 30×109 per litre or more could usually be taken as a response in practice. But they added that a platelet count of 50×109 per litre or more indicates a clinically meaningful response. The company explained that sometimes a platelet count of 20×109 per litre or more reduces bleeding risk and that there could be bleeding with a count of 50×109 per litre or more. So, the company thought that the proportion of people with a platelet count of 50×109 per litre or more without rescue therapy at day 8 could not be a reliable indicator for incidence of bleeds. It thought this was particularly so, given the imbalanced drop-out and follow-up times of the 2 groups in Study 302. The committee was aware that results on long-term durable platelet response rate were not recorded in another trial, Study 305. This was because the trial was stopped before they could be measured. The committee concluded that the evidence from Study 302 suggested that avatrombopag improved cumulative platelet response and the durable platelet response rate, but that this was highly uncertain. ## The frequency of adverse reactions is broadly similar between avatrombopag and placebo In Study 302, the incidence of adverse reactions was compared between the avatrombopag and placebo groups at 26 weeks. Because of the imbalanced treatment durations between these groups (mean 22.8 weeks for avatrombopag compared with mean 8.9 weeks for placebo), the ERG adjusted the treatment duration times to allow a fair comparison. The adjusted analysis suggested that the frequencies of adverse reactions were broadly similar (avatrombopag 4.3%, placebo 6.6%; p value not reported). The ERG noted that higher adverse-reaction incidence rates were seen in Study 305 and CL‑003/004. But the incidence rates for the avatrombopag and comparator groups in these studies were largely similar. The committee highlighted that the small number of people in Study 302 meant that only adverse reactions occurring in more than 10% to 20% would have been identified. It concluded that, within the limitations of the data, the frequency of adverse reactions was broadly similar between avatrombopag and placebo. # NMA using durable platelet response rate as the outcome ## The ERG's continuity correction method proportional to sample size may be appropriate, but there are uncertainties The company presented a series of NMAs to the first committee meeting because there was no direct comparison available. These NMAs compared avatrombopag's efficacy and safety with other TPO‑RAs (eltrombopag and romiplostim), fostamatinib and placebo. The ERG highlighted that fostamatinib was included unnecessarily because it was not included in the final scope as a comparator and is not recommended by NICE. The ERG did not consider it in its own analysis. A frequentist approach using fixed effect models was considered appropriate by both the company and ERG after the technical engagement before the first committee meeting. The NMAs were done for 6 outcomes, including: binary outcomes, reported as odds ratios (ORs): proportion of people with a durable platelet response (durable platelet response rate) proportion of people with reduced concomitant ITP medications incidence rate ratio outcomes: any bleeding episodes bleeding episodes with World Health Organization bleeding assessment score grades 2 to 4 need for rescue therapy any adverse events.The NMA for durable platelet response rate was done despite it not being the primary outcome of Study 302. The company stated that this was because it was the only platelet response outcome that could provide meaningful comparative effectiveness data between avatrombopag, and eltrombopag and romiplostim. During its first meeting, the committee's discussion focused on the durable platelet response rate NMA because it was the only outcome that informed the company's model. The committee understood that the company had chosen durable platelet response rate as the outcome for the feasibility of this NMA because all trials assessed it in a similar way. It noted that 2 other trials included in the NMA for this outcome had zero event or response in its placebo group because of early drop-out or no response. So, the company adjusted the zero events or response in placebo groups to calculate the ORs. Its first continuity correction attempt resulted in an OR of 102.80 (95% credible interval 3.87 to 2,796,448) for avatrombopag compared with placebo. The ERG pointed out that this estimate lacked face validity compared with the evidence from Study 302. It also noted that the company did not provide any detail on how it had corrected for zero events in placebo groups. The ERG preferred another continuity correction method. This involved adding 0.5 to both event and non-event cells in each treatment group to OR. It resulted in an OR of 18.72 (95% CrI 1.02 to 340) for avatrombopag compared with placebo using Study 302 as an example. During technical engagement, the company argued that this approach by the ERG was not appropriate. This was because people were randomised into placebo (n=17) and treatment groups (n=32) in a 1 to 2 proportion in Study 302. The company considered that the ERG's approach introduced directional bias and made the OR highly uncertain. In response to the ERG's critique at technical engagement, the company revised its correction method. It did this by adding an adjustment value to each treatment group proportional to the sample size of the trial, but only to event cells. The company stated that this method was based on Sweeting et al. (2004). When there was a zero event or response cell in the placebo group, an adjustment value of 0.35 (17 of 49) was added to the placebo events cell but subtracted from placebo no-events cell. Also, an adjustment value of 0.65 (32 of 49) was added to any avatrombopag events cell but subtracted from an avatrombopag no-events cell. This was done to maintain the original number of people in each treatment group (17 in the placebo group and 32 in the avatrombopag group). This correction method resulted in an OR of 27.49 (95% confidence interval 0.88 to 855.90) for avatrombopag compared with placebo. The ERG acknowledged that Sweeting et al. suggested an option of correcting zero events or response by adding adjustment values proportional to the sample size to the cells. But it thought that the company had implemented the method incorrectly. This was because, according to Sweeting et al., any adjustments must be applied to both event and no-event cells. This then increases the total number of people in each group as well. So, the ERG did a study-specific sensitivity analysis that correctly implemented the adjustment method suggested by Sweeting et al. As a result, when there was a zero events or response cell in the placebo group, an adjustment value of 0.35 (17 of 49) was added to both events and no-events cells for the placebo group. Also, an adjustment value of 0.65 (32 of 49) was added to both events and no-events cells in the avatrombopag group. This resulted in an OR of 26.91 (95% CI 0.87 to 835.27). During the first committee meeting, the company stated that it agreed with the ERG's sensitivity analysis. The committee considered that any correction should have been done across both events and no events and would ideally have been weighted according to sample size. It concluded that the proportional to sample size approach used in the ERG's sensitivity analysis may have been appropriate for correcting zero events in placebo groups. But it considered that any correction methods would have been associated with a high level of uncertainty when assessing avatrombopag's clinical effectiveness relative to other TPO‑RAs. The committee took this into account in its decision making. # NMA using mean platelet count as a continuous outcome ## An alternative NMA with mean platelet count as a continuous outcome is needed The committee noted the uncertainties associated with the clinical evidence from Study 302 during its first meeting because of the: high attrition in the placebo group (see section 3.6) uncertainties associated with the correction of zero events involved in the NMA analysis on the outcome of durable platelet response rate (see sections 3.9 and 3.10).The committee was aware that a durable platelet response would be unlikely with placebo. This would have made it challenging to compare treatments that had been compared with placebo for this outcome, regardless of the approach taken to adjust for the zero events. The committee was aware that the company's NMA results on the outcome of 'any bleeding events' suggested that avatrombopag may be associated with a lower risk of bleeding compared with placebo (OR 0.32, 95% CI 0.16 to 0.61), eltrombopag (OR 0.43, 95% CI 0.22 to 0.84) or romiplostim (OR 0.39, 95% CI 0.18 to 0.85). But durable platelet response rate was the only outcome that informed the model. The committee was aware that there is an alternative way of exploring avatrombopag's clinical effectiveness relative to other TPO‑RAs, while avoiding the issue of zero events or response in placebo groups. This was to assess mean platelet count as a continuous outcome and transform the resulting estimates into response probabilities for the economic model using an appropriate distributional assumption. Given the uncertainties in the NMA for durable platelet response rate, the committee requested to see the results of an NMA with mean platelet count as a continuous outcome. ## The alternative NMA with mean platelet count as a continuous outcome does not resolve all the uncertainties After the first committee meeting, the company provided an additional NMA comparing avatrombopag's efficacy with other TPO‑RAs (eltrombopag and romiplostim). The outcome was change in mean platelet count from baseline at 25 to 26 weeks. This outcome, along with a distributional assumption, was used to derive the probability of avatrombopag, eltrombopag and romiplostim achieving a platelet count over 30×109 per litre or 50×109 per litre. The company used a Bayesian approach for this NMA, in both a fixed and random effects model. Results showed that avatrombopag was associated with a greater improvement in mean platelet count from baseline compared with placebo: 56.73 (95% CrI 30.62 to 83.13). But there was no difference between avatrombopag and eltrombopag: 1.30 (95% CrI, -27.57 to 30.24), or romiplostim: 10.46, (95% CrI -18.93 to 39.92). The additional analysis also showed that the probability for reaching a 30×109 per litre or a 50×109 per litre platelet count threshold was almost 100% for all treatments compared. Both the company and ERG highlighted the limitations associated with this additional NMA. The company noted the issue around mean change estimates having to be derived from median values for comparators. It also noted the high level of drop-out in the placebo group of Study 302, with only 1 person left at the end of 26‑week follow up. The ERG was particularly concerned with the last observation carried forward (LOCF) method the company had used to input missing data from the placebo group. It pointed out that LOCF was a less conservative approach to replace missing values compared with what had been done in the original NMA by zero correction methods. Also, the last recorded trial observation might have been made when the person was still on treatment and before the loss of efficacy or adverse events. So, it may have overestimated the efficacy of treatment compared with data at later timepoints. The ERG considered that the company should have explored the other more conservative missing data replacement methods. It continued that the company did not provide sufficient justifications for choosing the change in mean platelet count from baseline as the outcome for this additional NMA. This was because there were alternative outcomes that could have been explored. These included, for example, assessing the continuous outcome accounting for multiple timepoints, or adjusting for baseline imbalances. Other uncertainties associated with this additional NMA and noted by the ERG included: The mean platelet count fluctuated over time, but the company chose the 26‑week follow-up timepoint for this analysis. This provided a limited view of the treatment response over time compared with the original NMA analysis using durable platelet response rate as the outcome. The results of this additional NMA markedly differed from the NMA presented to the first committee meeting in terms of ranking efficacy of TPO‑RAs.The company explained that it had chosen change in mean platelet count from baseline as the continuous outcome for this additional NMA and LOCF to input missing data because of time and resource reasons. Also, it chose the timepoint at 26‑week follow up because this was consistent with the timepoint at which the durable platelet response rate was measured in the trial. It continued that, although the ranking efficacy of TPO‑RAs differed between the 2 analyses, both suggested that avatrombopag had the highest probabilities of being the best treatment. Given the high uncertainties, the ERG considered that this additional NMA did not resolve the uncertainties associated with avatrombopag's clinical effectiveness relative to other TPO‑RAs. It noted that durable platelet response rate may be a more appropriate outcome for measuring treatment response to avatrombopag, as supported by its clinical expert. The committee noted that this additional NMA was requested in the hope to validate the NMA results with durable platelet rate as the outcome. This was because of the uncertainties associated with the zero correction methods in the company's original NMA (see section 3.10). The committee understood that this additional NMA was also subject to high uncertainties. This was because of the limitations in the evidence from Study 302, and the company's choice of change in mean platelet count from baseline as the continuous outcome. It is aware that durable platelet response rate is commonly used for assessing treatment response and has been used in previous appraisals for ITP. It agreed that the additional NMA did not resolve the uncertainties in the evidence, and it took this into account in its decision making. # Avatrombopag's clinical effectiveness relative to other TPO-RAs ## Avatrombopag's treatment effect on durable platelet response rate may be similar to other TPO-RAs, but there are high uncertainties The committee discussed the uncertainties associated with the 2 NMAs presented by the company. It recalled its discussions on whether durable platelet response would be likely with placebo (see section 3.6 and section 3.7). It was aware of the limitations in the evidence from both Study 302 and the 2 NMAs given the high attrition rate on the placebo arm. It noted that the outcome on durable platelet response rate may be more appropriate for assessing avatrombopag's treatment effect and informing the model. But the committee noted the considerable challenges when interpreting the results of the NMAs because there were exceptionally wide credible intervals and a high level of uncertainty in the results as a consequence. So, it was difficult for the committee to accept avatrombopag's superiority over other TPO‑RAs. The committee was aware that avatrombopag is an oral treatment and associated with less dietary restrictions compared with the other oral treatment available for ITP (see section 3.2). Considering the challenges with the evidence generation, the committee concluded that, on balance, avatrombopag's treatment effect on durable platelet response rate may be broadly similar to other TPO‑RAs. But it noted that there are high uncertainties. The committee took this into account in its decision making. # Economic model ## The company's economic model structure is appropriate for decision making The economic model was a Markov cohort model consisting of 4 mutually exclusive health states: 'active treatment' (up to 24 weeks waiting for a response), 'responder', 'no treatment no response' (watch and wait) and 'death'. People began in the 'active treatment' state with a platelet count of less than 30×109 per litre and remained there until their response status was determined. People moved to the 'responder' state if their platelet count increased to more than 50×109 per litre. There, they continued active treatment. People stopped active treatment and moved to the 'no treatment no response' state if their platelet count did not increase above 50×109 per litre while on active treatment. 'Responders' could also stop treatment and move to the 'no treatment no response' state if relapse occurred. People in the 'no treatment no response' state restarted active treatment if a bleeding episode occurred, or if there was a need for rescue therapy. At this point, they had an alternative active treatment from their first-line treatment option. People could move into the 'death' state from any of the other model states. Each model cycle lasted 4 weeks, with a time horizon of 56 years representing a lifetime horizon. The ERG considered the model structure to be broadly representative of ITP, and appropriate for modelling the effect of TPO‑RAs. The clinical experts noted that people with a low platelet count would typically have active treatment. But they explained that this is not the only factor considered when determining treatment. But the platelet response threshold of 50×109 per litre is widely used to define treatment response and has been used in previous NICE technology appraisals for ITP. The committee concluded that the economic model structure was appropriate for decision making. ## The 12-week timeframe for assessing non-response might be appropriate but there are uncertainties The company used durable platelet response rate to measure the clinical effectiveness of avatrombopag. During the first committee meeting, the company took a pragmatic approach and assumed a 24‑week timeframe to assess response to TPO‑RA treatments in the model based on Study 302. The ERG noted that, according to the summaries of product characteristics for TPO‑RAs, treatment should be stopped if there is no response within 4 weeks of prescribing the maximum dose. The clinical experts explained that they would expect to assess response over a period of 8 to 12 weeks rather than 24 weeks. They anticipated that the time taken to titrate an oral treatment would be 4 to 8 weeks, followed by 4 weeks at maximum dose to determine response. They also noted that choice of TPO‑RA could affect this. For example, romiplostim has 10 dosing levels so it can take longer to titrate and to determine response to its maximum dose. The committee queried the effect on the cost-effectiveness analysis of changing this timeframe. The ERG explained that the 24‑week was a relatively short timeframe because the model considered a lifetime horizon. It thought that this may have been the reason why its scenario analysis with an 8‑week timeframe had a small effect on the cost-effectiveness results. The committee considered that the 24‑week timeframe to assess response did not reflect clinical practice. After the first committee meeting, the company updated its base case to reflect a 12‑week timeframe for assessing response to treatment in the model. The company stated that it had updated this to be in line with the ERG's base case after the technical engagement and before the first committee meeting. The ERG clarified that its base case presented at the first committee meeting did not use a 12‑week timeframe. It noted that it was considered unlikely that people would remain on avatrombopag for 24 weeks if there was no response. But it explained that either an 8‑week or 12‑week time frame would not align with the definition of durable platelet rate used in the model. This was defined as a platelet response equal or larger than 50×109 per litre for at least 6 of the last 8 weeks of treatment. But the ERG updated the model to use a 12‑week timeframe for assessing response after the first committee meeting. It noted that this had a minor effect on the cost-effective estimates. The committee agreed with this and understood that the 12‑week timeframe was closer to clinical practice, but it noted the uncertainties associated with its use in the model. It concluded that the 12‑week timeframe for assessing non-response might be appropriate but there were uncertainties. ## The company's approach to modelling subsequent treatments is acceptable The company used a mixed treatment approach to model subsequent lines of treatment in the model. These included other TPO‑RAs and non-TPO‑RAs but did not consider treatment sequencing of TPO‑RAs. As a result, response rates for subsequent lines may have been higher than for first-line treatment in the company's model (see section 3.17). The company did not consider that assessing treatment sequencing in the model was plausible from a clinical perspective. This was because it considered that avatrombopag and other TPO‑RAs had similar efficacy, safety, and long-term treatment durations. Also, avatrombopag would be considered for use in people who are suitable for other TPO‑RAs. The ERG disagreed with the company. It stated that a comprehensive assessment of fixed treatment sequences, weighted according to treatment pathways in UK clinical practice, would have more appropriately reflected treatment variability. The ERG did a scenario analysis simulating sequences of treatment options. It noted that, when compared with sequences without avatrombopag, sequences including avatrombopag appeared to provide similar value for money as avatrombopag compared with other TPO‑RAs in the single-line model. But this assumed identical treatment durations among TPO‑RAs. The clinical experts explained that treatment for ITP is highly individualised in practice because the condition is variable. Also, there is no fixed treatment sequence that is followed in clinical practice. People with ITP are also able to switch between TPO‑RAs if their condition stops responding or they become intolerant to a specific one. The committee acknowledged that it was difficult to determine fixed treatment sequences for ITP. It concluded that the company's approach to modelling subsequent treatments was acceptable. ## Defining response differently between TPO-RAs and non-TPO-RAs leads to uncertainties in the model The company defined response for TPO‑RAs as durable platelet response rate (see section 3.7). But it defined the response for non-TPO‑RAs based on NICE's technology appraisal guidance on romiplostim for treating chronic ITP. This definition combined data on efficacy from different studies and took a weighted average. The subsequent lines of treatments that included a mix of TPO‑RAs and non-TPO‑RAs had mixed treatment response definitions. The ERG noted that the response rates used in subsequent lines of treatment for non-TPO‑RAs were high relative to the response rates used in the model for TPO‑RAs. The company explained that, because subsequent lines of treatment included treatments unlicensed for ITP, there was a lack of published evidence for durable platelet response rate for non-TPO‑RAs. But avatrombopag, eltrombopag and romiplostim all had a similar definition of durable platelet response rate (platelet response over 50×109 per litre for at least 6 of the last 8 weeks of treatment). The company also explained that its approach of using different definitions for TPO‑RAs and non-TPO‑RAs could have underestimated the response associated with avatrombopag. But it pointed out that a similar approach had been taken in previous NICE technology appraisals. The ERG highlighted that, in fact, the previous appraisals only included non-TPO‑RAs at subsequent lines, which was different to the company's model. The ERG also noted that it was unclear whether this approach was conservative for avatrombopag. The committee considered that similar definitions for response for TPO‑RAs and non-TPO‑RAs would have been preferrable. But it was also aware that this was not possible given the lack of evidence for non-TPO‑RAs. It concluded that having different definitions for responses for TPO‑RAs and non-TPO‑RAs led to uncertainties in the model. It took this into account in its decision making. ## The same treatment duration of 109 cycles for all TPO-RAs in the long term may be appropriate but there are uncertainties The company assumed long-term treatment duration to be 109 model cycles (436 weeks, or about 8.4 years) for all TPO‑RAs. It assumed the constant stopping rate to be 0.9% per 4‑week model cycle. The company took these estimates from Lee et al. (2013). This fitted a survival curve to: romiplostim data based on a phase 3, placebo-controlled, 24‑week trial and a follow-on, open-label extension of up to 6.0 years eltrombopag data based on results from the open-label EXTEND trial of up to 5.5 years.The company estimated a mean treatment duration of 393 cycles for romiplostim and 109 cycles for eltrombopag, based on data from Lee et al. The ERG highlighted that the difference in mean times on treatment between eltrombopag and romiplostim suggested that there was a difference in treatment durations and stopping rates between TPO‑RAs. During technical engagement, the company provided the results from a survey that it did among 9 clinicians in the UK. It explained that the results supported similar long-term treatment duration between TPO‑RAs. The clinical experts noted that 109 cycles is already a long time for people to be on treatments, so 393 cycles would be unrealistic. They noted that TPO‑RAs may have similar treatment durations and stopping rates, but that some people might stay longer on oral treatment options with less dietary restrictions. The committee noted that about 31% (10 of 32) of people stopped avatrombopag in Study 302. This would equate to about 1.7% per month stopping avatrombopag during its 72‑week extension period. The clinical experts explained that sometimes people stop treatments because their condition becomes stable. The committee was aware the company's approach of using stopping rates from Lee et al. represented a departure from the approach taken by NICE's technology appraisal guidance on romiplostim and eltrombopag. These appraisals modelled time on treatment using patient-level data from the pivotal trials. The company explained that the estimates from Lee et al. were based on longer trial periods (up to 6.0 years for romiplostim and 5.5 years for eltrombopag) than Study 302 (26 weeks plus a 72‑week extension). During its first meeting, the committee considered that treatment duration might be similar between TPO‑RAs. But it requested more scenario analyses to enable it to compare what the company assumed in the model, including: estimated treatment duration based on modelling stopping rates from Study 302 a scenario using the empirical data from the extension of Study 302.The company provided these scenario analyses after the first committee meeting. It fitted a log-normal distribution to the Kaplan–Meier data from the trial and its extension. This resulted in an average treatment duration of 57 cycles (229 weeks or 4.4 years) based on Study 302 alone, and 633 cycles (2,531 weeks or 48 years) with the extension. The company stated that the treatment duration of 109 cycles used in the model was based on long-term trials for the comparators. So, it would be more appropriate to include the extension of Study 302 when determining treatment duration. The ERG explained that the company's approach of analysing data from Study 302 was reasonable because it was similar to that used in Lee et al. But the ERG highlighted that only a few people were at risk in the extension (less than 10 people at risk in 1 year). These small numbers at risk were extrapolated into the longer term, resulting in an average treatment duration of about 48 years for avatrombopag. This was clinically unlikely giving the starting age of 45 years in the model. The company explained that this new extrapolation was presented to confirm that avatrombopag's treatment duration could be as long as other TPO‑RAs. It explained that its original treatment duration of 109 cycles remained unchanged in its base case. The committee noted the uncertainties. On balance, it considered that it was likely that TPO‑RAs would have similar treatment durations in the long term. It concluded that a long-term treatment duration of 109 model cycles for all TPO‑RAs was appropriate for decision making. # Resource use and costing in the economic model ## It is appropriate to cost bleeding episodes based on NHS reference costs using the weighted average In its original submission, the company stratified rescue therapy events into bleed related and non-bleed related. But it nested bleed-related rescue therapies within bleeding episodes. The company also commissioned independent market research to inform the resource use associated with non-minor bleeding episodes. Resources used included hospital stays, diagnostic imaging, blood test and therapeutic interventions. The ERG preferred to cost rescue therapies and bleed-specific unit costs independently. It noted that the company's bleed-specific unit costs informed by its market research data were much higher than those based on NHS reference costs, and those applied in NICE's technology appraisal guidance on romiplostim and eltrombopag. The ERG also noted that there was no clear reporting of which bleed-specific costs were excluded from NHS reference costs and how using the market research captured these alleged omissions. It explained that, because bleed-related rescue therapies were nested within bleeding episodes, the bleed-specific costs were also difficult to interpret. The company aligned its approach to costing to that of the ERG's by modelling bleeding episodes and rescue therapies independently after the technical engagement, except for bleed-specific unit costs. The company took the midpoint between the NHS reference costs and its market research data to represent bleed-specific unit costs and presented it to the first committee meeting. The ERG remained concerned because the company's market research data for bleed-specific unit costs may still have included the costs of rescue therapies. It highlighted that taking this midpoint suggested that bleed-specific costs may not be independent from the costs of rescue therapy, and that this midpoint was still difficult to interpret. The committee noted that there was a lack of detail on the methods of the company's market research. The committee considered that the ERG's approach of using the NHS reference costs would have been appropriate. But the committee recognised that there might be additional resources not covered by the NHS reference costs. So, it requested to see the detailed methods of the company's market research, and how the company derived the bleed-specific unit costs from its qualitative survey questions. After the first committee meeting, the company provided further details on the methods of it market research. It did not use costs from this market research but updated its analyses using NHS reference costs for bleed-specific unit costs in the model. This was in line with the ERG's approach. But the company's bleed-specific unit costs were based on the highest unit cost for the different types of bleeds, rather the weighted average as done by the ERG. The company justified this because duration of different bleeds in people with ITP tend to be longer than the general population. It also explained that this was because additional time is usually needed to increase the person's platelet count and to stabilise the bleed, and bleeds in these people tend to be more severe. The committee questioned where this information had come from. The company explained that it had sought further advice from UK clinicians. But it acknowledged that it was reliant on clinical opinion and there was no published evidence to support these claims. The ERG explained that the company's approach may be reasonable. But it noted that the company's selection of highest unit costs for each type of bleed deviated from methods used in previous appraisals for ITP. Given the uncertainties in the evidence and the model, the committee concluded that the ERG's approach of using the weighted average costs for bleed-specific unit costs was preferrable. # Cost-effectiveness estimates ## Uncertainties remain in the clinical evidence and in the company's modelling assumptions The committee noted that unresolved uncertainties remained in the company's evidence base and model assumptions, including: the recruitment and attrition issues with avatrombopag studies (see section 3.6 and section 3.7) the results from the NMA on durable platelet response rate (see sections 3.9 and 3.10) the different definitions of response between TPO‑RAs and non-TPO‑RAs (see section 3.17) the long-term treatment duration (see section 3.18) the company's approach to costing bleeding episodes in the model (see section 3.19) probabilistic sensitivity analyses were only conducted for pairwise comparisons because of how the company's model was designed. ## Avatrombopag is likely to be cost effective for primary chronic ITP in adults NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratio (ICER). The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. At the first committee meeting, the committee concluded that the true ICER was not known because of the uncertainties in the clinical evidence provided and in the modelling. The company attempted to reduce these uncertainties by providing updated analyses. In addition, the company provided a comparison of the net cost to the NHS that showed avatrombopag had a cost similar to or lower than its comparators. When the company updated its base case after the first committee meeting, the ICER was below what NICE normally considers an acceptable use of NHS resources. Because of confidential commercial arrangements for avatrombopag and comparator treatments, the cost-effectiveness results cannot be reported here. Scenario analyses exploring other areas of uncertainty did not increase the ICER above an acceptable use of NHS resources. There was further assurance provided with the comparison of costs. So, the committee considered that avatrombopag is cost effective for primary chronic ITP in adults. ## It is unclear whether there are additional benefits of avatrombopag not captured in the model There were no equality issues identified for avatrombopag. The company considers avatrombopag to be innovative because it will offer an additional effective treatment choice to those with chronic ITP. More treatment options are needed because people with ITP can experience loss of response or adverse events with current treatment options. The company also highlighted that there may be uncaptured benefits with avatrombopag because it is an oral treatment and can be taken without the need for dietary restrictions. This might improve treatment adherence. The patient experts emphasised the importance of having the choice of a treatment such as avatrombopag because anxiety around injecting is common, and maintaining dietary restrictions is burdensome. The company also noted that, unlike eltrombopag, avatrombopag does not cause hepatoxicity. This means that less monitoring is needed, and that it can be used for people with ITP who also have liver disease. The committee concluded there might be additional benefits with avatrombopag. But, given the uncertainties in the evidence and in the model (see section 3.20), it was unclear whether there were any not captured in the cost-effectiveness analysis. # Conclusion ## Avatrombopag is recommended as an option for treating primary chronic ITP in adults Avatrombopag is recommended for use in the NHS as an option for treating primary chronic ITP in adults. The cost-effectiveness estimates for people with ITP were uncertain because of uncertainties within the clinical evidence and in the modelling. But they were highly likely to be below what is considered an acceptable use of NHS resources.	{'Recommendations': 'Avatrombopag is recommended, within its marketing authorisation, as an option for treating primary chronic immune thrombocytopenia (ITP) refractory to other treatments (for example, corticosteroids, immunoglobulins) in adults. It is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for newly diagnosed primary chronic ITP usually includes corticosteroids and immunoglobulins. This is followed by thrombopoietin receptor agonists (TPO‑RAs). Avatrombopag is another TPO‑RA.\n\nClinical trial evidence shows that avatrombopag is more effective than placebo at increasing the number of platelets in the blood (cells that help the blood to clot) to a level that meaningfully reduces the risk of bleeding. Avatrombopag may be as effective as other TPO‑RAs, but it has only been compared with them indirectly, which is uncertain.\n\nThere are also uncertainties with some assumptions in the economic modelling. Despite this, avatrombopag is likely to provide benefit for people who have primary chronic ITP. Also, the cost-effectiveness estimates are below what NICE normally considers an acceptable use of NHS resources. So, avatrombopag is recommended.', 'Information about avatrombopag': "# Marketing authorisation indication\n\nAvatrombopag (Doptelet, Swedish Orphan Biovitrum) is 'indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e.g., corticosteroids or immunoglobulins)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for avatrombopag.\n\n# Price\n\nThe list price of a 10‑tablet pack of avatrombopag 20\xa0mg is £640.00 (excluding VAT; BNF online, accessed June 2022).\n\nThe company has a commercial arrangement. This makes avatrombopag available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Swedish Orphan Biovitrum, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Immune thrombocytopenia (ITP) is an autoimmune condition that is chronic in most affected adults\n\nITP is characterised by a platelet count less than 100×109 per litre. This reduced platelet count is caused by abnormally high platelet destruction and reduced platelet production. ITP is a rare condition. About 3,000 to 4,000 adults in the UK are estimated to have ITP at any one time. To make a diagnosis, any other possible causes of thrombocytopenia, including impaired bone marrow, need to be excluded. Most diagnosed cases in adults progress to chronic ITP that may be difficult to control. Symptoms include fatigue, spontaneous bruising and regular bleeding episodes. The patient experts highlighted that the fatigue can be debilitating, reducing cognitive function and making it difficult to focus. The fatigue also often contributes towards increased bruising. This is because reduced coordination related to the fatigue may cause people to bump into things more often. Bleeding episodes can range from minor bleeds to severe, life-threatening haemorrhages. The patient experts emphasised the effect ITP has on mental as well as physical health. This is because many people with ITP worry about maintaining high enough platelet levels to prevent bleeding episodes. Treatment for ITP is usually introduced when the platelet count drops below 30×109 per litre. Current treatments include corticosteroids, immunoglobulins, thrombopoietin receptor agonists (TPO‑RAs) and immunosuppressants such as rituximab. The patient and clinical experts highlighted that the current treatments have disadvantages, including unpleasant and potentially harmful side effects, and the need for dietary changes. They emphasised a need for another treatment option that offered more normality for those affected by ITP. The committee concluded that ITP is a chronic condition that significantly affects the lives of those affected by it.\n\n## People with chronic ITP would welcome new treatment options that maintain platelet counts at a level that prevents bleeds\n\nITP is a burden to people with the condition, as well as their families and carers. This burden is often linked to the unpredictable nature of the condition and the side effects of treatment. Also, some people with ITP need to inject some treatments themselves, so need to plan their life around injection dates, and ensure safe storage and administration of these treatments. The patient experts highlighted that this could affect everyday life. Self-injecting can also cause increased anxiety. One patient expert described how they still had stress about injecting 5\xa0years into treatment. Also, soreness and bruising can occur at the injection site, particularly in people whose platelet counts are low. There is an oral TPO‑RA, but this can cause side effects including chronic gastrointestinal issues and increased risk of blood clots. It can also be affected by diet, and people taking it may need to restrict what foods they eat, and when they eat them. Both the patient and clinical experts highlighted that this has a large effect on everyday life, adherence to treatment and effectiveness. Some treatments for ITP also cause immunosuppression, which increases the risk of infection. One patient expert explained that they had had 22\xa0infections in an 18‑month period when taking an immunosuppressant for ITP. Infections can cause a drop in platelet count, which may need hospitalisation and rescue therapy if uncontrolled. Both the patient and clinical experts agreed that avatrombopag, an oral treatment with no dietary restrictions and no immunosuppression would be an advance in ITP treatment in the UK. They also agreed it could improve quality of life for people with ITP by increasing platelet count without being a difficult treatment to take. The committee agreed that a new treatment option for maintaining platelet counts would be welcomed by people with ITP.\n\n# Treatment pathway and comparators\n\n## The company's positioning of avatrombopag in the treatment pathway is appropriate\n\nThe company's positioning of avatrombopag was aligned with avatrombopag's marketing authorisation, that is, for treating primary chronic ITP in adults refractory to other treatments. When someone is diagnosed with ITP, they have an 'initial' treatment that includes corticosteroids, immunoglobulins or both. The clinical experts explained that TPO‑RAs would not be used before corticosteroids and immunoglobulins but would be used if this initial treatment failed. The committee concluded that avatrombopag is likely to be used after initial treatment of newly diagnosed chronic ITP. It agreed that the company's positioning of avatrombopag in the treatment pathway was appropriate.\n\n## The relevant comparators for avatrombopag are other TPO-RAs\n\nIn its submission, the company considered other TPO‑RAs (eltrombopag and romiplostim) to be the only appropriate comparators for avatrombopag. The company's rationale for this was that:\n\nTPO‑RAs are considered to be well-established standard care for ITP\n\nit would be inappropriate to consider rituximab or surgical splenectomy as the comparators given the availability of 2\xa0other TPO‑RAs.The ERG agreed that the company's positioning of avatrombopag was reasonable. But it highlighted uncertainty around the variations in rituximab use in clinical practice. The committee queried at what point in the treatment pathway TPO‑RAs are prescribed in the NHS. The clinical experts explained that, while care is individualised to people with ITP, clinicians generally use TPO‑RAs before rituximab. They also explained that, before the COVID‑19 pandemic, rituximab's use varied across the UK. But international guidance changes have caused a shift in practice to use TPO‑RAs first after initial treatment has failed. This is because rituximab can suppress the immune system. They also confirmed that clinicians rarely offer splenectomy in the first year of diagnosis and do not consider it as an alternative to TPO‑RAs. The committee concluded that eltrombopag and romiplostim were the appropriate comparators for avatrombopag.\n\n# Clinical effectiveness\n\n## The population of Study\xa0302 may represent the likely NHS population, but there are uncertainties\n\nThe key clinical evidence for avatrombopag came from 1\xa0clinical trial, Study\xa0302, and its 72‑week open-label extension. Study\xa0302 was a 26‑week, phase\xa03, multicentre, randomised, double-blind, parallel-group trial of avatrombopag compared with placebo. The company also submitted clinical evidence from 2\xa0open-label clinical trials:\n\nStudy\xa0305, a discontinued phase\xa03, multicentre, randomised, double-blind, parallel-group trial of avatrombopag compared with eltrombopag\n\nCL‑003, a 28‑day, phase\xa02, double-blind, randomised, controlled trial of avatrombopag compared with placebo, and CL‑004, a 6‑month rollover study for people who completed CL‑003.The company only included Study\xa0302 data in the economic model because it considered that it contained robust comparative data on key efficacy and safety outcomes. It stated that the results of the other studies largely supported the safety and efficacy profile of avatrombopag. But it did not think it was appropriate to include the data from these studies in the economic model. The ERG noted that, although Study\xa0302 did not have a UK site, the baseline characteristics of its population would likely be applicable and relevant to an NHS population. But the committee noted that the trial's population may have been younger than the NHS population. The clinical experts explained that they would not expect the response to avatrombopag to be age specific. But more fatal bleeds and infection events may happen in older people, which the clinical experts thought may not have been fully captured in the trial. The committee also noted that 72% of the avatrombopag group were women compared with 47% in the placebo group. There were also people in the trial who had had a splenectomy, which would normally be done after treatment with avatrombopag. Neither the ERG nor the clinical experts thought that this would have had a meaningful effect on the trial results. The committee concluded that the population in Study\xa0302 may represent the NHS population but that there were uncertainties in the study population's baseline characteristics. It took this into account in its decision making.\n\n## The clinical trials of avatrombopag has recruitment and attrition issues, resulting in a limited evidence base\n\nThere were 49\xa0people in Study\xa0302, 32\xa0in the avatrombopag group and 17\xa0in the placebo group. Twenty two\xa0people on avatrombopag completed the trial, while 7\xa0stopped because of inadequate treatment effects and 3\xa0stopped for other reasons. One\xa0person on placebo completed the trial, while 15\xa0stopped because of inadequate treatment effects and 1\xa0stopped for other reasons. The clinical experts explained that it is difficult to have a true 'placebo' group for chronic ITP treatments. This is because people in a placebo group would not be expected to stay in a trial if they had extremely low platelets and bleeding episodes. This led to limitations when estimating the durable platelet response rate in the placebo group over the course of Study\xa0302. The ERG was concerned with the robustness of the efficacy and safety data from Study\xa0302 because of the imbalanced drop-out between the avatrombopag and placebo groups. During the first committee meeting, it highlighted that this also affected the results of the company's network meta-analysis (NMA) that indirectly compared avatrombopag with other TPO‑RAs (see section\xa03.9) and used durable platelet response rate as the outcome. This was because the durable platelet response rate was a key outcome assessed in the NMA presented to the first committee meeting. The committee was aware that Study\xa0305 was stopped early, and that the results of this study were not included in the economic model. It questioned why it was stopped early. The company explained that the trial protocol for Study\xa0305 mandated unpleasant screening and monitoring procedures for people in the trial, and this contributed to recruitment challenges. It also commented that the trial started when eltrombopag was approved and became commercially available. It thought that people may have been reluctant to enrol and be randomised to avatrombopag, a non-approved treatment. So, the trial was stopped before durable platelet response rate could be measured. But the company thought that data from the study could have been used to provide information on other outcomes, including bleeding episodes. At the first committee meeting, the committee had concerns around the limitations of Study\xa0302. In response, the company stated that there was a growing evidence base and clinical experience of using avatrombopag. It also stated that the efficacy of avatrombopag has been shown in randomised controlled trials and real-world settings. The committee understood that there was a limited evidence base for the clinical efficacy of avatrombopag because of recruitment and attrition issues in the clinical trials.\n\n## Avatrombopag may improve cumulative platelet response and durable platelet response rate, but the clinical evidence is highly uncertain\n\nThe primary outcome of Study\xa0302 was the median cumulative number of weeks of platelet response, measured over 26\xa0weeks. A platelet response was defined as 50×109 per litre or more. Evidence suggested that the median cumulative number of weeks of platelet response was 12.4\xa0weeks with avatrombopag and 0\xa0weeks with placebo (p<0.0001). Other outcomes measured included:\n\nsecondary:\n\n\n\nproportion of people with a platelet response without rescue therapy at day\xa08 (avatrombopag\xa065.6%, placebo\xa00%; p<0.0001)\n\nproportion of people with a reduction in concomitant ITP medication (avatrombopag\xa033.3%, placebo\xa00%; p=0.13)\n\n\n\nexploratory:\n\n\n\ndurable platelet response rate, that is, the proportion of people who had a platelet response for 6\xa0or more of the last 8\xa0weeks of treatment (avatrombopag\xa034.4%, placebo\xa00%; p=0.009)\n\nincidence of any grade of bleeding (avatrombopag\xa043.8%, placebo\xa052.9%; p=0.54)\n\nuse of rescue therapy (avatrombopag\xa021.9%, placebo\xa011.8%; p=0.47). The ERG noted that the evidence suggested that, compared with placebo, avatrombopag improved the median cumulative number of weeks of platelet response over 26\xa0weeks and the durable platelet response rate. But it highlighted that the interpretation of the evidence was difficult because of the high drop-out in the placebo group. The committee commented that a platelet response without any form of treatment is improbable. It noted the statistically significant difference in proportion of people with a platelet response without rescue therapy at day\xa08 between avatrombopag and placebo. It contrasted this with the relatively smaller difference between the 2\xa0groups for the outcome of incidence of bleeds. It questioned what the most clinically meaningful outcomes for assessing clinical effectiveness would be. The clinical experts explained that time spent above a platelet count threshold is a clinically meaningful outcome, but this can be difficult to reach because ITP is variable. They thought that a platelet count of 30×109 per litre or more could usually be taken as a response in practice. But they added that a platelet count of 50×109 per litre or more indicates a clinically meaningful response. The company explained that sometimes a platelet count of 20×109 per litre or more reduces bleeding risk and that there could be bleeding with a count of 50×109 per litre or more. So, the company thought that the proportion of people with a platelet count of 50×109 per litre or more without rescue therapy at day\xa08 could not be a reliable indicator for incidence of bleeds. It thought this was particularly so, given the imbalanced drop-out and follow-up times of the 2\xa0groups in Study\xa0302. The committee was aware that results on long-term durable platelet response rate were not recorded in another trial, Study\xa0305. This was because the trial was stopped before they could be measured. The committee concluded that the evidence from Study\xa0302 suggested that avatrombopag improved cumulative platelet response and the durable platelet response rate, but that this was highly uncertain.\n\n\n\n## The frequency of adverse reactions is broadly similar between avatrombopag and placebo\n\nIn Study\xa0302, the incidence of adverse reactions was compared between the avatrombopag and placebo groups at 26\xa0weeks. Because of the imbalanced treatment durations between these groups (mean 22.8\xa0weeks for avatrombopag compared with mean 8.9\xa0weeks for placebo), the ERG adjusted the treatment duration times to allow a fair comparison. The adjusted analysis suggested that the frequencies of adverse reactions were broadly similar (avatrombopag\xa04.3%, placebo\xa06.6%; p\xa0value not reported). The ERG noted that higher adverse-reaction incidence rates were seen in Study\xa0305 and CL‑003/004. But the incidence rates for the avatrombopag and comparator groups in these studies were largely similar. The committee highlighted that the small number of people in Study\xa0302 meant that only adverse reactions occurring in more than 10% to 20% would have been identified. It concluded that, within the limitations of the data, the frequency of adverse reactions was broadly similar between avatrombopag and placebo.\n\n# NMA using durable platelet response rate as the outcome\n\n## The ERG's continuity correction method proportional to sample size may be appropriate, but there are uncertainties\n\nThe company presented a series of NMAs to the first committee meeting because there was no direct comparison available. These NMAs compared avatrombopag's efficacy and safety with other TPO‑RAs (eltrombopag and romiplostim), fostamatinib and placebo. The ERG highlighted that fostamatinib was included unnecessarily because it was not included in the final scope as a comparator and is not recommended by NICE. The ERG did not consider it in its own analysis. A frequentist approach using fixed effect models was considered appropriate by both the company and ERG after the technical engagement before the first committee meeting. The NMAs were done for 6\xa0outcomes, including:\n\nbinary outcomes, reported as odds ratios (ORs):\n\n\n\nproportion of people with a durable platelet response (durable platelet response rate)\n\nproportion of people with reduced concomitant ITP medications\n\n\n\nincidence rate ratio outcomes:\n\n\n\nany bleeding episodes\n\nbleeding episodes with World Health Organization bleeding assessment score grades\xa02 to\xa04\n\nneed for rescue therapy\n\nany adverse events.The NMA for durable platelet response rate was done despite it not being the primary outcome of Study\xa0302. The company stated that this was because it was the only platelet response outcome that could provide meaningful comparative effectiveness data between avatrombopag, and eltrombopag and romiplostim. During its first meeting, the committee's discussion focused on the durable platelet response rate NMA because it was the only outcome that informed the company's model. The committee understood that the company had chosen durable platelet response rate as the outcome for the feasibility of this NMA because all trials assessed it in a similar way. It noted that 2\xa0other trials included in the NMA for this outcome had zero event or response in its placebo group because of early drop-out or no response. So, the company adjusted the zero events or response in placebo groups to calculate the ORs. Its first continuity correction attempt resulted in an OR of 102.80 (95% credible interval [CrI] 3.87 to 2,796,448) for avatrombopag compared with placebo. The ERG pointed out that this estimate lacked face validity compared with the evidence from Study\xa0302. It also noted that the company did not provide any detail on how it had corrected for zero events in placebo groups. The ERG preferred another continuity correction method. This involved adding 0.5 to both event and non-event cells in each treatment group to OR. It resulted in an OR of 18.72 (95%\xa0CrI 1.02 to 340) for avatrombopag compared with placebo using Study\xa0302 as an example. During technical engagement, the company argued that this approach by the ERG was not appropriate. This was because people were randomised into placebo (n=17) and treatment groups (n=32) in a 1\xa0to 2\xa0proportion in Study\xa0302. The company considered that the ERG's approach introduced directional bias and made the OR highly uncertain.\n\n\n\nIn response to the ERG's critique at technical engagement, the company revised its correction method. It did this by adding an adjustment value to each treatment group proportional to the sample size of the trial, but only to event cells. The company stated that this method was based on Sweeting et al. (2004). When there was a zero event or response cell in the placebo group, an adjustment value of\xa00.35 (17\xa0of\xa049) was added to the placebo events cell but subtracted from placebo no-events cell. Also, an adjustment value of\xa00.65 (32\xa0of\xa049) was added to any avatrombopag events cell but subtracted from an avatrombopag no-events cell. This was done to maintain the original number of people in each treatment group (17\xa0in the placebo group and 32\xa0in the avatrombopag group). This correction method resulted in an OR of 27.49 (95% confidence interval [CI] 0.88 to 855.90) for avatrombopag compared with placebo. The ERG acknowledged that Sweeting et al. suggested an option of correcting zero events or response by adding adjustment values proportional to the sample size to the cells. But it thought that the company had implemented the method incorrectly. This was because, according to Sweeting et al., any adjustments must be applied to both event and no-event cells. This then increases the total number of people in each group as well. So, the ERG did a study-specific sensitivity analysis that correctly implemented the adjustment method suggested by Sweeting et al. As a result, when there was a zero events or response cell in the placebo group, an adjustment value of\xa00.35 (17\xa0of\xa049) was added to both events and no-events cells for the placebo group. Also, an adjustment value of\xa00.65 (32\xa0of\xa049) was added to both events and no-events cells in the avatrombopag group. This resulted in an OR of 26.91 (95%\xa0CI 0.87 to 835.27). During the first committee meeting, the company stated that it agreed with the ERG's sensitivity analysis. The committee considered that any correction should have been done across both events and no events and would ideally have been weighted according to sample size. It concluded that the proportional to sample size approach used in the ERG's sensitivity analysis may have been appropriate for correcting zero events in placebo groups. But it considered that any correction methods would have been associated with a high level of uncertainty when assessing avatrombopag's clinical effectiveness relative to other TPO‑RAs. The committee took this into account in its decision making.\n\n# NMA using mean platelet count as a continuous outcome\n\n## An alternative NMA with mean platelet count as a continuous outcome is needed\n\nThe committee noted the uncertainties associated with the clinical evidence from Study\xa0302 during its first meeting because of the:\n\nhigh attrition in the placebo group (see section\xa03.6)\n\nuncertainties associated with the correction of zero events involved in the NMA analysis on the outcome of durable platelet response rate (see sections\xa03.9 and 3.10).The committee was aware that a durable platelet response would be unlikely with placebo. This would have made it challenging to compare treatments that had been compared with placebo for this outcome, regardless of the approach taken to adjust for the zero events. The committee was aware that the company's NMA results on the outcome of 'any bleeding events' suggested that avatrombopag may be associated with a lower risk of bleeding compared with placebo (OR\xa00.32, 95%\xa0CI 0.16 to 0.61), eltrombopag (OR\xa00.43, 95%\xa0CI 0.22 to 0.84) or romiplostim (OR\xa00.39, 95%\xa0CI 0.18 to 0.85). But durable platelet response rate was the only outcome that informed the model. The committee was aware that there is an alternative way of exploring avatrombopag's clinical effectiveness relative to other TPO‑RAs, while avoiding the issue of zero events or response in placebo groups. This was to assess mean platelet count as a continuous outcome and transform the resulting estimates into response probabilities for the economic model using an appropriate distributional assumption. Given the uncertainties in the NMA for durable platelet response rate, the committee requested to see the results of an NMA with mean platelet count as a continuous outcome.\n\n## The alternative NMA with mean platelet count as a continuous outcome does not resolve all the uncertainties\n\nAfter the first committee meeting, the company provided an additional NMA comparing avatrombopag's efficacy with other TPO‑RAs (eltrombopag and romiplostim). The outcome was change in mean platelet count from baseline at 25\xa0to 26\xa0weeks. This outcome, along with a distributional assumption, was used to derive the probability of avatrombopag, eltrombopag and romiplostim achieving a platelet count over 30×109 per litre or 50×109 per litre. The company used a Bayesian approach for this NMA, in both a fixed and random effects model. Results showed that avatrombopag was associated with a greater improvement in mean platelet count from baseline compared with placebo: 56.73 (95%\xa0CrI 30.62\xa0to\xa083.13). But there was no difference between avatrombopag and eltrombopag: 1.30 (95%\xa0CrI, -27.57\xa0to\xa030.24), or romiplostim: 10.46, (95%\xa0CrI -18.93\xa0to\xa039.92). The additional analysis also showed that the probability for reaching a 30×109 per litre or a 50×109 per litre platelet count threshold was almost 100% for all treatments compared. Both the company and ERG highlighted the limitations associated with this additional NMA. The company noted the issue around mean change estimates having to be derived from median values for comparators. It also noted the high level of drop-out in the placebo group of Study\xa0302, with only 1\xa0person left at the end of 26‑week follow up. The ERG was particularly concerned with the last observation carried forward (LOCF) method the company had used to input missing data from the placebo group. It pointed out that LOCF was a less conservative approach to replace missing values compared with what had been done in the original NMA by zero correction methods. Also, the last recorded trial observation might have been made when the person was still on treatment and before the loss of efficacy or adverse events. So, it may have overestimated the efficacy of treatment compared with data at later timepoints. The ERG considered that the company should have explored the other more conservative missing data replacement methods. It continued that the company did not provide sufficient justifications for choosing the change in mean platelet count from baseline as the outcome for this additional NMA. This was because there were alternative outcomes that could have been explored. These included, for example, assessing the continuous outcome accounting for multiple timepoints, or adjusting for baseline imbalances. Other uncertainties associated with this additional NMA and noted by the ERG included:\n\nThe mean platelet count fluctuated over time, but the company chose the 26‑week follow-up timepoint for this analysis. This provided a limited view of the treatment response over time compared with the original NMA analysis using durable platelet response rate as the outcome.\n\nThe results of this additional NMA markedly differed from the NMA presented to the first committee meeting in terms of ranking efficacy of TPO‑RAs.The company explained that it had chosen change in mean platelet count from baseline as the continuous outcome for this additional NMA and LOCF to input missing data because of time and resource reasons. Also, it chose the timepoint at 26‑week follow up because this was consistent with the timepoint at which the durable platelet response rate was measured in the trial. It continued that, although the ranking efficacy of TPO‑RAs differed between the 2\xa0analyses, both suggested that avatrombopag had the highest probabilities of being the best treatment. Given the high uncertainties, the ERG considered that this additional NMA did not resolve the uncertainties associated with avatrombopag's clinical effectiveness relative to other TPO‑RAs. It noted that durable platelet response rate may be a more appropriate outcome for measuring treatment response to avatrombopag, as supported by its clinical expert. The committee noted that this additional NMA was requested in the hope to validate the NMA results with durable platelet rate as the outcome. This was because of the uncertainties associated with the zero correction methods in the company's original NMA (see section\xa03.10). The committee understood that this additional NMA was also subject to high uncertainties. This was because of the limitations in the evidence from Study\xa0302, and the company's choice of change in mean platelet count from baseline as the continuous outcome. It is aware that durable platelet response rate is commonly used for assessing treatment response and has been used in previous appraisals for ITP. It agreed that the additional NMA did not resolve the uncertainties in the evidence, and it took this into account in its decision making.\n\n# Avatrombopag's clinical effectiveness relative to other TPO-RAs\n\n## Avatrombopag's treatment effect on durable platelet response rate may be similar to other TPO-RAs, but there are high uncertainties\n\nThe committee discussed the uncertainties associated with the 2\xa0NMAs presented by the company. It recalled its discussions on whether durable platelet response would be likely with placebo (see section\xa03.6 and section\xa03.7). It was aware of the limitations in the evidence from both Study\xa0302 and the 2\xa0NMAs given the high attrition rate on the placebo arm. It noted that the outcome on durable platelet response rate may be more appropriate for assessing avatrombopag's treatment effect and informing the model. But the committee noted the considerable challenges when interpreting the results of the NMAs because there were exceptionally wide credible intervals and a high level of uncertainty in the results as a consequence. So, it was difficult for the committee to accept avatrombopag's superiority over other TPO‑RAs. The committee was aware that avatrombopag is an oral treatment and associated with less dietary restrictions compared with the other oral treatment available for ITP (see section\xa03.2). Considering the challenges with the evidence generation, the committee concluded that, on balance, avatrombopag's treatment effect on durable platelet response rate may be broadly similar to other TPO‑RAs. But it noted that there are high uncertainties. The committee took this into account in its decision making.\n\n# Economic model\n\n## The company's economic model structure is appropriate for decision making\n\nThe economic model was a Markov cohort model consisting of 4\xa0mutually exclusive health states: 'active treatment' (up to 24\xa0weeks waiting for a response), 'responder', 'no treatment no response' (watch and wait) and 'death'. People began in the 'active treatment' state with a platelet count of less than 30×109 per litre and remained there until their response status was determined. People moved to the 'responder' state if their platelet count increased to more than 50×109 per litre. There, they continued active treatment. People stopped active treatment and moved to the 'no treatment no response' state if their platelet count did not increase above 50×109 per litre while on active treatment. 'Responders' could also stop treatment and move to the 'no treatment no response' state if relapse occurred. People in the 'no treatment no response' state restarted active treatment if a bleeding episode occurred, or if there was a need for rescue therapy. At this point, they had an alternative active treatment from their first-line treatment option. People could move into the 'death' state from any of the other model states. Each model cycle lasted 4\xa0weeks, with a time horizon of 56\xa0years representing a lifetime horizon. The ERG considered the model structure to be broadly representative of ITP, and appropriate for modelling the effect of TPO‑RAs. The clinical experts noted that people with a low platelet count would typically have active treatment. But they explained that this is not the only factor considered when determining treatment. But the platelet response threshold of 50×109 per litre is widely used to define treatment response and has been used in previous NICE technology appraisals for ITP. The committee concluded that the economic model structure was appropriate for decision making.\n\n## The 12-week timeframe for assessing non-response might be appropriate but there are uncertainties\n\nThe company used durable platelet response rate to measure the clinical effectiveness of avatrombopag. During the first committee meeting, the company took a pragmatic approach and assumed a 24‑week timeframe to assess response to TPO‑RA treatments in the model based on Study\xa0302. The ERG noted that, according to the summaries of product characteristics for TPO‑RAs, treatment should be stopped if there is no response within 4\xa0weeks of prescribing the maximum dose. The clinical experts explained that they would expect to assess response over a period of 8\xa0to 12\xa0weeks rather than 24\xa0weeks. They anticipated that the time taken to titrate an oral treatment would be 4\xa0to 8\xa0weeks, followed by 4\xa0weeks at maximum dose to determine response. They also noted that choice of TPO‑RA could affect this. For example, romiplostim has 10\xa0dosing levels so it can take longer to titrate and to determine response to its maximum dose. The committee queried the effect on the cost-effectiveness analysis of changing this timeframe. The ERG explained that the 24‑week was a relatively short timeframe because the model considered a lifetime horizon. It thought that this may have been the reason why its scenario analysis with an 8‑week timeframe had a small effect on the cost-effectiveness results. The committee considered that the 24‑week timeframe to assess response did not reflect clinical practice. After the first committee meeting, the company updated its base case to reflect a 12‑week timeframe for assessing response to treatment in the model. The company stated that it had updated this to be in line with the ERG's base case after the technical engagement and before the first committee meeting. The ERG clarified that its base case presented at the first committee meeting did not use a 12‑week timeframe. It noted that it was considered unlikely that people would remain on avatrombopag for 24\xa0weeks if there was no response. But it explained that either an 8‑week or 12‑week time frame would not align with the definition of durable platelet rate used in the model. This was defined as a platelet response equal or larger than 50×109 per litre for at least 6\xa0of the last 8\xa0weeks of treatment. But the ERG updated the model to use a 12‑week timeframe for assessing response after the first committee meeting. It noted that this had a minor effect on the cost-effective estimates. The committee agreed with this and understood that the 12‑week timeframe was closer to clinical practice, but it noted the uncertainties associated with its use in the model. It concluded that the 12‑week timeframe for assessing non-response might be appropriate but there were uncertainties.\n\n## The company's approach to modelling subsequent treatments is acceptable\n\nThe company used a mixed treatment approach to model subsequent lines of treatment in the model. These included other TPO‑RAs and non-TPO‑RAs but did not consider treatment sequencing of TPO‑RAs. As a result, response rates for subsequent lines may have been higher than for first-line treatment in the company's model (see section\xa03.17). The company did not consider that assessing treatment sequencing in the model was plausible from a clinical perspective. This was because it considered that avatrombopag and other TPO‑RAs had similar efficacy, safety, and long-term treatment durations. Also, avatrombopag would be considered for use in people who are suitable for other TPO‑RAs. The ERG disagreed with the company. It stated that a comprehensive assessment of fixed treatment sequences, weighted according to treatment pathways in UK clinical practice, would have more appropriately reflected treatment variability. The ERG did a scenario analysis simulating sequences of treatment options. It noted that, when compared with sequences without avatrombopag, sequences including avatrombopag appeared to provide similar value for money as avatrombopag compared with other TPO‑RAs in the single-line model. But this assumed identical treatment durations among TPO‑RAs. The clinical experts explained that treatment for ITP is highly individualised in practice because the condition is variable. Also, there is no fixed treatment sequence that is followed in clinical practice. People with ITP are also able to switch between TPO‑RAs if their condition stops responding or they become intolerant to a specific one. The committee acknowledged that it was difficult to determine fixed treatment sequences for ITP. It concluded that the company's approach to modelling subsequent treatments was acceptable.\n\n## Defining response differently between TPO-RAs and non-TPO-RAs leads to uncertainties in the model\n\nThe company defined response for TPO‑RAs as durable platelet response rate (see section\xa03.7). But it defined the response for non-TPO‑RAs based on NICE's technology appraisal guidance on romiplostim for treating chronic ITP. This definition combined data on efficacy from different studies and took a weighted average. The subsequent lines of treatments that included a mix of TPO‑RAs and non-TPO‑RAs had mixed treatment response definitions. The ERG noted that the response rates used in subsequent lines of treatment for non-TPO‑RAs were high relative to the response rates used in the model for TPO‑RAs. The company explained that, because subsequent lines of treatment included treatments unlicensed for ITP, there was a lack of published evidence for durable platelet response rate for non-TPO‑RAs. But avatrombopag, eltrombopag and romiplostim all had a similar definition of durable platelet response rate (platelet response over 50×109 per litre for at least 6\xa0of the last 8\xa0weeks of treatment). The company also explained that its approach of using different definitions for TPO‑RAs and non-TPO‑RAs could have underestimated the response associated with avatrombopag. But it pointed out that a similar approach had been taken in previous NICE technology appraisals. The ERG highlighted that, in fact, the previous appraisals only included non-TPO‑RAs at subsequent lines, which was different to the company's model. The ERG also noted that it was unclear whether this approach was conservative for avatrombopag. The committee considered that similar definitions for response for TPO‑RAs and non-TPO‑RAs would have been preferrable. But it was also aware that this was not possible given the lack of evidence for non-TPO‑RAs. It concluded that having different definitions for responses for TPO‑RAs and non-TPO‑RAs led to uncertainties in the model. It took this into account in its decision making.\n\n## The same treatment duration of 109 cycles for all TPO-RAs in the long term may be appropriate but there are uncertainties\n\nThe company assumed long-term treatment duration to be 109\xa0model cycles (436\xa0weeks, or about 8.4\xa0years) for all TPO‑RAs. It assumed the constant stopping rate to be 0.9% per 4‑week model cycle. The company took these estimates from Lee et al. (2013). This fitted a survival curve to:\n\nromiplostim data based on a phase\xa03, placebo-controlled, 24‑week trial and a follow-on, open-label extension of up to 6.0\xa0years\n\neltrombopag data based on results from the open-label EXTEND trial of up to 5.5\xa0years.The company estimated a mean treatment duration of 393\xa0cycles for romiplostim and 109\xa0cycles for eltrombopag, based on data from Lee et al. The ERG highlighted that the difference in mean times on treatment between eltrombopag and romiplostim suggested that there was a difference in treatment durations and stopping rates between TPO‑RAs. During technical engagement, the company provided the results from a survey that it did among 9\xa0clinicians in the UK. It explained that the results supported similar long-term treatment duration between TPO‑RAs. The clinical experts noted that 109\xa0cycles is already a long time for people to be on treatments, so 393\xa0cycles would be unrealistic. They noted that TPO‑RAs may have similar treatment durations and stopping rates, but that some people might stay longer on oral treatment options with less dietary restrictions. The committee noted that about 31% (10\xa0of\xa032) of people stopped avatrombopag in Study\xa0302. This would equate to about 1.7% per month stopping avatrombopag during its 72‑week extension period. The clinical experts explained that sometimes people stop treatments because their condition becomes stable. The committee was aware the company's approach of using stopping rates from Lee et al. represented a departure from the approach taken by NICE's technology appraisal guidance on romiplostim and eltrombopag. These appraisals modelled time on treatment using patient-level data from the pivotal trials. The company explained that the estimates from Lee et al. were based on longer trial periods (up to 6.0\xa0years for romiplostim and 5.5\xa0years for eltrombopag) than Study\xa0302 (26\xa0weeks plus a 72‑week extension). During its first meeting, the committee considered that treatment duration might be similar between TPO‑RAs. But it requested more scenario analyses to enable it to compare what the company assumed in the model, including:\n\nestimated treatment duration based on modelling stopping rates from Study\xa0302\n\na scenario using the empirical data from the extension of Study\xa0302.The company provided these scenario analyses after the first committee meeting. It fitted a log-normal distribution to the Kaplan–Meier data from the trial and its extension. This resulted in an average treatment duration of 57\xa0cycles (229\xa0weeks or 4.4\xa0years) based on Study\xa0302 alone, and 633\xa0cycles (2,531\xa0weeks or 48\xa0years) with the extension. The company stated that the treatment duration of 109\xa0cycles used in the model was based on long-term trials for the comparators. So, it would be more appropriate to include the extension of Study\xa0302 when determining treatment duration. The ERG explained that the company's approach of analysing data from Study\xa0302 was reasonable because it was similar to that used in Lee et al. But the ERG highlighted that only a few people were at risk in the extension (less than 10\xa0people at risk in 1\xa0year). These small numbers at risk were extrapolated into the longer term, resulting in an average treatment duration of about 48\xa0years for avatrombopag. This was clinically unlikely giving the starting age of 45\xa0years in the model. The company explained that this new extrapolation was presented to confirm that avatrombopag's treatment duration could be as long as other TPO‑RAs. It explained that its original treatment duration of 109\xa0cycles remained unchanged in its base case. The committee noted the uncertainties. On balance, it considered that it was likely that TPO‑RAs would have similar treatment durations in the long term. It concluded that a long-term treatment duration of 109\xa0model cycles for all TPO‑RAs was appropriate for decision making.\n\n# Resource use and costing in the economic model\n\n## It is appropriate to cost bleeding episodes based on NHS reference costs using the weighted average\n\nIn its original submission, the company stratified rescue therapy events into bleed related and non-bleed related. But it nested bleed-related rescue therapies within bleeding episodes. The company also commissioned independent market research to inform the resource use associated with non-minor bleeding episodes. Resources used included hospital stays, diagnostic imaging, blood test and therapeutic interventions. The ERG preferred to cost rescue therapies and bleed-specific unit costs independently. It noted that the company's bleed-specific unit costs informed by its market research data were much higher than those based on NHS reference costs, and those applied in NICE's technology appraisal guidance on romiplostim and eltrombopag. The ERG also noted that there was no clear reporting of which bleed-specific costs were excluded from NHS reference costs and how using the market research captured these alleged omissions. It explained that, because bleed-related rescue therapies were nested within bleeding episodes, the bleed-specific costs were also difficult to interpret. The company aligned its approach to costing to that of the ERG's by modelling bleeding episodes and rescue therapies independently after the technical engagement, except for bleed-specific unit costs. The company took the midpoint between the NHS reference costs and its market research data to represent bleed-specific unit costs and presented it to the first committee meeting. The ERG remained concerned because the company's market research data for bleed-specific unit costs may still have included the costs of rescue therapies. It highlighted that taking this midpoint suggested that bleed-specific costs may not be independent from the costs of rescue therapy, and that this midpoint was still difficult to interpret. The committee noted that there was a lack of detail on the methods of the company's market research. The committee considered that the ERG's approach of using the NHS reference costs would have been appropriate. But the committee recognised that there might be additional resources not covered by the NHS reference costs. So, it requested to see the detailed methods of the company's market research, and how the company derived the bleed-specific unit costs from its qualitative survey questions. After the first committee meeting, the company provided further details on the methods of it market research. It did not use costs from this market research but updated its analyses using NHS reference costs for bleed-specific unit costs in the model. This was in line with the ERG's approach. But the company's bleed-specific unit costs were based on the highest unit cost for the different types of bleeds, rather the weighted average as done by the ERG. The company justified this because duration of different bleeds in people with ITP tend to be longer than the general population. It also explained that this was because additional time is usually needed to increase the person's platelet count and to stabilise the bleed, and bleeds in these people tend to be more severe. The committee questioned where this information had come from. The company explained that it had sought further advice from UK clinicians. But it acknowledged that it was reliant on clinical opinion and there was no published evidence to support these claims. The ERG explained that the company's approach may be reasonable. But it noted that the company's selection of highest unit costs for each type of bleed deviated from methods used in previous appraisals for ITP. Given the uncertainties in the evidence and the model, the committee concluded that the ERG's approach of using the weighted average costs for bleed-specific unit costs was preferrable.\n\n# Cost-effectiveness estimates\n\n## Uncertainties remain in the clinical evidence and in the company's modelling assumptions\n\nThe committee noted that unresolved uncertainties remained in the company's evidence base and model assumptions, including:\n\nthe recruitment and attrition issues with avatrombopag studies (see section\xa03.6 and section\xa03.7)\n\nthe results from the NMA on durable platelet response rate (see sections\xa03.9 and 3.10)\n\nthe different definitions of response between TPO‑RAs and non-TPO‑RAs (see section\xa03.17)\n\nthe long-term treatment duration (see section\xa03.18)\n\nthe company's approach to costing bleeding episodes in the model (see section\xa03.19)\n\nprobabilistic sensitivity analyses were only conducted for pairwise comparisons because of how the company's model was designed.\n\n## Avatrombopag is likely to be cost effective for primary chronic ITP in adults\n\nNICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratio (ICER). The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. At the first committee meeting, the committee concluded that the true ICER was not known because of the uncertainties in the clinical evidence provided and in the modelling. The company attempted to reduce these uncertainties by providing updated analyses. In addition, the company provided a comparison of the net cost to the NHS that showed avatrombopag had a cost similar to or lower than its comparators. When the company updated its base case after the first committee meeting, the ICER was below what NICE normally considers an acceptable use of NHS resources. Because of confidential commercial arrangements for avatrombopag and comparator treatments, the cost-effectiveness results cannot be reported here. Scenario analyses exploring other areas of uncertainty did not increase the ICER above an acceptable use of NHS resources. There was further assurance provided with the comparison of costs. So, the committee considered that avatrombopag is cost effective for primary chronic ITP in adults.\n\n## It is unclear whether there are additional benefits of avatrombopag not captured in the model\n\nThere were no equality issues identified for avatrombopag. The company considers avatrombopag to be innovative because it will offer an additional effective treatment choice to those with chronic ITP. More treatment options are needed because people with ITP can experience loss of response or adverse events with current treatment options. The company also highlighted that there may be uncaptured benefits with avatrombopag because it is an oral treatment and can be taken without the need for dietary restrictions. This might improve treatment adherence. The patient experts emphasised the importance of having the choice of a treatment such as avatrombopag because anxiety around injecting is common, and maintaining dietary restrictions is burdensome. The company also noted that, unlike eltrombopag, avatrombopag does not cause hepatoxicity. This means that less monitoring is needed, and that it can be used for people with ITP who also have liver disease. The committee concluded there might be additional benefits with avatrombopag. But, given the uncertainties in the evidence and in the model (see section\xa03.20), it was unclear whether there were any not captured in the cost-effectiveness analysis.\n\n# Conclusion\n\n## Avatrombopag is recommended as an option for treating primary chronic ITP in adults\n\nAvatrombopag is recommended for use in the NHS as an option for treating primary chronic ITP in adults. The cost-effectiveness estimates for people with ITP were uncertain because of uncertainties within the clinical evidence and in the modelling. But they were highly likely to be below what is considered an acceptable use of NHS resources."}	https://www.nice.org.uk/guidance/ta853	Evidence-based recommendations on avatrombopag (Doptelet) for treating primary chronic immune thrombocytopenia in adults.
8c2ea9254674a3c27ecbdc60c706a4840b438723	nice	Cabozantinib for previously treated advanced hepatocellular carcinoma	Cabozantinib for previously treated advanced hepatocellular carcinoma Evidence-based recommendations on cabozantinib (Cabometyx) for advanced hepatocellular carcinoma in adults who have had sorafenib. # Recommendations Cabozantinib is recommended as an option for treating advanced hepatocellular carcinoma (HCC) in adults who have had sorafenib, only if: they have Child–Pugh grade A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and the company provides it according to the commercial arrangement. This recommendation is not intended to affect treatment with cabozantinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Current treatment for advanced HCC in adults who have had sorafenib is regorafenib. Cabozantinib is an alternative for these people. Clinical trial evidence shows that cabozantinib is effective for treating advanced HCC compared with placebo. But cabozantinib has not been compared directly with regorafenib. The results of indirect comparisons suggest that cabozantinib is likely to be similarly effective to regorafenib, although this is not certain. The most plausible cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Because of this, and because there are few treatment options for people with advanced HCC who have tried sorafenib, cabozantinib is recommended.# Information about cabozantinib # Marketing authorisation indication Cabozantinib (Cabometyx, Ipsen) is indicated for 'the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for cabozantinib. # Price The list price of cabozantinib is £5,143 for a 30‑tablet pack of 20 mg, 40 mg or 60 mg tablets (excluding VAT; BNF online accessed October 2022). The company has a commercial arrangement. This makes cabozantinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Ipsen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need and treatment pathway ## HCC has a substantial impact on the quality of life of patients and carers Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage. Symptoms of HCC include weakness, deep fatigue, nausea, abdominal pain, ascites, and hepatic encephalopathy. Patient experts described how the physical symptoms of HCC can affect everyday life, making basic functions like eating, speaking, writing and even staying awake difficult. Aside from physical symptoms, people with HCC often experience depression from the poor prognosis. The patient experts explained that people with advanced HCC live with uncertainty, hopelessness and often stigma and isolation because of the perception of liver cancer. They described how the physical symptoms and the psychological impact of HCC can also have a considerable impact on the quality of life of families and carers. The committee concluded that HCC has a substantial impact on the quality of life of people with the condition, and their families and carers. ## Regorafenib is the relevant comparator for people with Child–Pugh grade A liver impairment and an ECOG status of 0 to 1 The company proposed that cabozantinib would be used in the same position as regorafenib in the treatment pathway. That is, as a second-line or third-line systemic therapy after progression on or intolerance to sorafenib. The NICE technology appraisal guidance on regorafenib for previously treated advanced HCC recommends it only for people who have Child–Pugh grade A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The company positioned cabozantinib at the same position and in the same population as regorafenib. This is because the clinical trial evidence is relatively limited for cabozantinib in people with advanced HCC with more severe liver disease or a poorer performance status. The clinical experts agreed with the company's proposed positioning of cabozantinib and explained that in clinical practice atezolizumab plus bevacizumab, lenvatinib and sorafenib are used as first-line systemic therapies. After first-line atezolizumab plus bevacizumab, lenvatinib and sorafenib can be used second line, with regorafenib available as a third-line option if someone has previously had sorafenib. For those treated with sorafenib first line, regorafenib can be used second line. So, the committee concluded that the company's proposed positioning in the treatment pathway was appropriate, and regorafenib was the relevant comparator. ## People with HCC whose disease has progressed on, or who are intolerant to, sorafenib would welcome a new treatment option The patient and clinical experts said that if people's disease has progressed on sorafenib, or if they cannot tolerate it, there are limited treatment options. Only regorafenib is available. They said a new treatment option would be welcomed. Clinical experts also said that cabozantinib may be an option for a broader group of people than regorafenib, which was only evaluated in a sorafenib-tolerant population. They explained that regorafenib is generally only used if sorafenib was tolerated, whereas cabozantinib could be used for people who could not tolerate sorafenib. The committee concluded that cabozantinib would offer a new treatment for people with limited options. # Clinical evidence ## Cabozantinib is clinically effective compared with placebo The clinical effectiveness evidence was based on CELESTIAL, a randomised, double-blind trial that compared cabozantinib plus best supportive care with placebo plus best supportive care. CELESTIAL included people with HCC who had had 1 or 2 treatments already, and who had had sorafenib (whether they tolerated it or not). People also had to have an ECOG performance status of 0 or 1 and Child–Pugh grade A. The primary outcome was overall survival. Secondary outcomes included progression-free survival and objective response rate. At a median follow up of 22.9 months, the median overall survival in the cabozantinib arm was 10.2 months, compared with 8.0 months in the placebo arm (hazard ratio 0.76, 95% confidence interval 0.63 to 0.92). The median progression-free survival was 5.2 months, compared with 1.9 months in the placebo arm (hazard ratio 0.44, 95% CI 0.36 to 0.52). The committee concluded that cabozantinib was clinically effective compared with placebo. ## The anchored MAIC analyses are likely to be more robust than the unanchored MAIC but all analyses have limitations Because there was no direct head-to-head evidence for cabozantinib compared with regorafenib, the company provided a series of indirect treatment comparisons. The indirect treatment comparisons used the Bucher approach and matching-adjusted indirect comparison (MAIC). Data for cabozantinib was from the CELESTIAL trial. Data for regorafenib was from the RESORCE trial, a randomised, double-blind trial of regorafenib plus best supportive care compared with placebo plus best supportive care. The relative treatment effect of cabozantinib compared with regorafenib was estimated for overall survival and progression-free survival. The company acknowledged that population differences between the CELESTIAL and RESORCE trials introduced bias into the Bucher analysis, so it had to do the MAICs. The ERG agreed and said that the Bucher approach does not provide robust results because of the observed cross-trial differences. So, the committee discussion focused on the 3 MAIC approaches presented by the company: anchored MAIC with constant hazard ratio anchored MAIC with time-varying hazard ratio unanchored MAIC.The MAICs used a second-line population from CELESTIAL. Indirect treatment comparisons in the third-line population were not possible because the RESORCE trial was restricted to second line. The ERG noted that each of the MAICs had limitations, but from a methodological perspective, the preferred option was the anchored MAIC analyses. This was because the unanchored MAIC relies on the strongest assumptions and is likely the least robust. Specifically, the unanchored MAIC relies on the assumption that all prognostic factors and treatment effect modifiers are accounted for, an assumption that is rarely met. Also, the unanchored MAIC is limited because trial randomisation is not preserved. The ERG also said that the proportional hazards assumption in the MAIC with a constant hazard ratio was not met. This meant that the MAIC with time-varying hazard ratios may be preferred from a purely methodological point of view. But it added that from a clinical point of view the MAIC with constant hazard ratios may be the better option because the extrapolation for overall survival based on that MAIC was the one most consistent with the 4‑year overall survival prediction from its clinical advisers. Before the committee meeting, the company said that the anchored MAIC with constant hazard ratios was its preferred option because the underlying assumptions were more likely to be met compared with the unanchored MAIC. But during the meeting the company noted the limitations of the anchored MAICs, including concerns about the comparability of the placebo arms across both trials. The company clarified the limitations with all of the options and said that all 3 options should be considered because of the uncertainty associated with all of the methods. The committee acknowledged the limitations with all 3 MAICs but it agreed that the anchored MAICs are likely to be more robust because the underlying assumptions are more likely to be met. ## The MAICs suggest no clear difference in efficacy between cabozantinib and regorafenib, but the results should be interpreted with caution The committee noted that the anchored MAICs showed a non-statistically significant progression-free survival benefit for cabozantinib and a non-statistically significant overall survival benefit for regorafenib. The anchored MAIC analysis with constant hazard ratios produced hazard ratios of 1.09 (95% CI 0.73 to 1.62) for overall survival and 0.80 (95% CI 0.55 to 1.15) for progression-free survival. The anchored MAIC analysis with time-varying hazard ratios produced time-varying hazard ratios of: more than 1.0 for overall survival (95% CI includes a time-varying hazard ratio of 1.0) less than 1.0 for progression-free survival (95% CI includes a time-varying hazard ratio of 1.0).The non-statistically significant results from the anchored MAICs were supported by clinical experts, who said that they believed that cabozantinib and regorafenib had broadly similar efficacy. The committee concluded that the MAIC analyses show no clear evidence of any difference in efficacy between cabozantinib and regorafenib but that the results should be interpreted with caution because of the limitations outlined in section 3.5. # Economic model ## It is uncertain whether cabozantinib would result in higher healthcare management costs than regorafenib The company's model assumed equivalent healthcare management costs in the progression-free health state for cabozantinib and regorafenib. This was based on the company's clinical expert opinion, which was that clinicians are experienced in handling generic tyrosine kinase inhibitor toxicities, and that cabozantinib's tolerability issues can be managed. The ERG preferred to include additional monitoring costs, based on the views of its clinical advisers that cabozantinib has a comparatively worse toxicity profile than regorafenib. This was supported by the comparison of safety outcomes from the MAICs. Only the odds ratio for diarrhoea was statistically significant in favour of regorafenib but the point estimate odds ratios for hypertension, elevated aspartate transaminase, fatigue and palmar-plantar erythrodysaesthesia syndrome were also above 1 (in favour of regorafenib). The odds ratio for elevated bilirubin was in favour of cabozantinib but was not statistically significant. The ERG provided an alternative scenario that included the cost of 0.5 additional oncologist visits per month (0.46 visits per 28‑day model cycle). The ERG commented that in the CELESTIAL trial there was a potentially clinically meaningful difference in favour of placebo for health-related quality of life when measured using the EQ‑5D. The company acknowledged that the EQ‑5D data from RESORCE does not suggest a significant difference between regorafenib and placebo. But it said that the EQ‑5D questionnaire in RESORCE was completed on the first day of each treatment cycle, when someone had not had treatment for a week. This may have affected responses. Clinical experts said that the toxicity profiles for regorafenib and cabozantinib seem broadly consistent. The committee concluded that it was uncertain if cabozantinib would result in additional monitoring costs compared with regorafenib, but it would consider both the company's and ERG's scenarios in its decision making. ## Including drug wastage costs in the economic model is appropriate The company's base case analyses assumed that packs of treatment can be split so that every tablet prescribed is taken, so they did not include wastage costs. This assumption advantages the cabozantinib group because the relative dose intensity is much lower for cabozantinib than for regorafenib (61% compared with 90%, respectively). The ERG noted that there may be some wastage because people can progress or die before completing a pack of treatment. The ERG provided an alternative scenario consistent with previous appraisals in HCC, in which the costs of 7 days' worth of treatment in both treatment groups (adjusted for relative dose intensity) was included. A clinical expert said that dose adjustments are usually made quickly; normally after 2 weeks of treatment, so wastage is likely to be minimised. The committee noted that including drug wastage costs as per the ERG's scenario was not a key driver of cost effectiveness but was likely to reflect clinical practice. # Cost-effectiveness estimates ## Cabozantinib is a cost-effective use of NHS resources for advanced HCC after treatment with sorafenib The committee agreed that its preferred approach to modelling would: Use scenarios that use the anchored MAIC with constant hazard ratios and scenarios that use the anchored MAIC with time-varying hazard ratios (see section 3.5). Include scenarios in which healthcare management costs in the progression-free health state are equivalent for cabozantinib and regorafenib, and scenarios that include the cost of 0.5 additional oncologist visits per month for cabozantinib (see section 3.7). Include treatment wastage costs (see section 3.9). The committee also accepted the ERG analyses, which included corrections of minor errors, a general population mortality constraint and age-adjusted utilities. Using the committee's preferred assumptions and including the confidential discounts for cabozantinib and regorafenib, cabozantinib was associated with fewer quality-adjusted life years (QALYs) and overall lower costs than regorafenib in all scenarios. The scenario using the anchored MAIC with constant hazard ratios and equivalent healthcare management costs in the progression-free health state produced the most favourable results. The scenario using the anchored MAIC with time-varying hazard ratios and the cost of 0.5 additional oncologist visits per month for cabozantinib produced the least favourable results. The committee acknowledged that the true costs and QALYs were likely to be in between the 2 scenarios. The exact savings, net health benefits and incremental cost-effectiveness ratios (ICERs) are commercial in confidence and cannot be reported here. The committee was aware that, when an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment is. The committee considered the limited treatment options after sorafenib, particularly for people unable to tolerate it. It took the net health benefits and the ICERs into account. It noted that the QALY losses were sufficiently small for the anchored MAICs (less than 0.1, or roughly equivalent to 1 month in perfect health) and the south-west quadrant ICERs per QALY lost were high enough to consider cabozantinib a cost-effective use of NHS resources. The exact QALYs are commercial in confidence and cannot be reported here. The committee concluded that cabozantinib can be considered cost effective for treating advanced HCC in people who have previously had sorafenib. # Other factors ## There are no equality issues relevant to the recommendations The patient expert said that liver disease and liver cancer disproportionally affect the poorest in society, and many people with liver cancer come from disadvantaged backgrounds. Differences in prevalence and patient population cannot usually be resolved in a technology appraisal, although the committee can consider whether a specific equality issue has a significant impact on access to treatments it recommends. The committee concluded that this was not the case for its recommendations about cabozantinib. # Conclusion ## Cabozantinib is recommended for people with advanced HCC who have previously had sorafenib The committee acknowledged the need for more treatment options in advanced HCC. It took account of the commercial discounts for cabozantinib and regorafenib. In the committee's preferred analyses, cabozantinib was considered a cost-effective use of NHS resources compared with regorafenib. So, cabozantinib is recommended as a treatment option for people with advanced HCC who have had sorafenib and who have Child–Pugh grade A liver impairment and an ECOG performance status of 0 or 1.	{'Recommendations': 'Cabozantinib is recommended as an option for treating advanced hepatocellular carcinoma (HCC) in adults who have had sorafenib, only if:\n\nthey have Child–Pugh grade\xa0A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and\n\nthe company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with cabozantinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for advanced HCC in adults who have had sorafenib is regorafenib. Cabozantinib is an alternative for these people.\n\nClinical trial evidence shows that cabozantinib is effective for treating advanced HCC compared with placebo. But cabozantinib has not been compared directly with regorafenib. The results of indirect comparisons suggest that cabozantinib is likely to be similarly effective to regorafenib, although this is not certain.\n\nThe most plausible cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Because of this, and because there are few treatment options for people with advanced HCC who have tried sorafenib, cabozantinib is recommended.', 'Information about cabozantinib': "# Marketing authorisation indication\n\nCabozantinib (Cabometyx, Ipsen) is indicated for 'the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for cabozantinib.\n\n# Price\n\nThe list price of cabozantinib is £5,143 for a 30‑tablet pack of 20\xa0mg, 40\xa0mg or 60\xa0mg tablets (excluding VAT; BNF online accessed October\xa02022). The company has a commercial arrangement. This makes cabozantinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Ipsen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## HCC has a substantial impact on the quality of life of patients and carers\n\nHepatocellular carcinoma (HCC) is often diagnosed at an advanced stage. Symptoms of HCC include weakness, deep fatigue, nausea, abdominal pain, ascites, and hepatic encephalopathy. Patient experts described how the physical symptoms of HCC can affect everyday life, making basic functions like eating, speaking, writing and even staying awake difficult. Aside from physical symptoms, people with HCC often experience depression from the poor prognosis. The patient experts explained that people with advanced HCC live with uncertainty, hopelessness and often stigma and isolation because of the perception of liver cancer. They described how the physical symptoms and the psychological impact of HCC can also have a considerable impact on the quality of life of families and carers. The committee concluded that HCC has a substantial impact on the quality of life of people with the condition, and their families and carers.\n\n## Regorafenib is the relevant comparator for people with Child–Pugh grade\xa0A liver impairment and an ECOG status of 0 to 1\n\nThe company proposed that cabozantinib would be used in the same position as regorafenib in the treatment pathway. That is, as a second-line or third-line systemic therapy after progression on or intolerance to sorafenib. The NICE technology appraisal guidance on regorafenib for previously treated advanced HCC recommends it only for people who have Child–Pugh grade\xa0A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The company positioned cabozantinib at the same position and in the same population as regorafenib. This is because the clinical trial evidence is relatively limited for cabozantinib in people with advanced HCC with more severe liver disease or a poorer performance status. The clinical experts agreed with the company's proposed positioning of cabozantinib and explained that in clinical practice atezolizumab plus bevacizumab, lenvatinib and sorafenib are used as first-line systemic therapies. After first-line atezolizumab plus bevacizumab, lenvatinib and sorafenib can be used second line, with regorafenib available as a third-line option if someone has previously had sorafenib. For those treated with sorafenib first line, regorafenib can be used second line. So, the committee concluded that the company's proposed positioning in the treatment pathway was appropriate, and regorafenib was the relevant comparator.\n\n## People with HCC whose disease has progressed on, or who are intolerant to, sorafenib would welcome a new treatment option\n\nThe patient and clinical experts said that if people's disease has progressed on sorafenib, or if they cannot tolerate it, there are limited treatment options. Only regorafenib is available. They said a new treatment option would be welcomed. Clinical experts also said that cabozantinib may be an option for a broader group of people than regorafenib, which was only evaluated in a sorafenib-tolerant population. They explained that regorafenib is generally only used if sorafenib was tolerated, whereas cabozantinib could be used for people who could not tolerate sorafenib. The committee concluded that cabozantinib would offer a new treatment for people with limited options.\n\n# Clinical evidence\n\n## Cabozantinib is clinically effective compared with placebo\n\nThe clinical effectiveness evidence was based on CELESTIAL, a randomised, double-blind trial that compared cabozantinib plus best supportive care with placebo plus best supportive care. CELESTIAL included people with HCC who had had 1 or 2 treatments already, and who had had sorafenib (whether they tolerated it or not). People also had to have an ECOG performance status of 0 or 1 and Child–Pugh grade\xa0A. The primary outcome was overall survival. Secondary outcomes included progression-free survival and objective response rate. At a median follow up of 22.9\xa0months, the median overall survival in the cabozantinib arm was 10.2\xa0months, compared with 8.0\xa0months in the placebo arm (hazard ratio 0.76, 95% confidence interval [CI] 0.63 to 0.92). The median progression-free survival was 5.2\xa0months, compared with 1.9\xa0months in the placebo arm (hazard ratio 0.44, 95% CI 0.36 to 0.52). The committee concluded that cabozantinib was clinically effective compared with placebo.\n\n## The anchored MAIC analyses are likely to be more robust than the unanchored MAIC but all analyses have limitations\n\nBecause there was no direct head-to-head evidence for cabozantinib compared with regorafenib, the company provided a series of indirect treatment comparisons. The indirect treatment comparisons used the Bucher approach and matching-adjusted indirect comparison (MAIC). Data for cabozantinib was from the CELESTIAL trial. Data for regorafenib was from the RESORCE trial, a randomised, double-blind trial of regorafenib plus best supportive care compared with placebo plus best supportive care. The relative treatment effect of cabozantinib compared with regorafenib was estimated for overall survival and progression-free survival. The company acknowledged that population differences between the CELESTIAL and RESORCE trials introduced bias into the Bucher analysis, so it had to do the MAICs. The ERG agreed and said that the Bucher approach does not provide robust results because of the observed cross-trial differences. So, the committee discussion focused on the 3 MAIC approaches presented by the company:\n\nanchored MAIC with constant hazard ratio\n\nanchored MAIC with time-varying hazard ratio\n\nunanchored MAIC.The MAICs used a second-line population from CELESTIAL. Indirect treatment comparisons in the third-line population were not possible because the RESORCE trial was restricted to second line. The ERG noted that each of the MAICs had limitations, but from a methodological perspective, the preferred option was the anchored MAIC analyses. This was because the unanchored MAIC relies on the strongest assumptions and is likely the least robust. Specifically, the unanchored MAIC relies on the assumption that all prognostic factors and treatment effect modifiers are accounted for, an assumption that is rarely met. Also, the unanchored MAIC is limited because trial randomisation is not preserved. The ERG also said that the proportional hazards assumption in the MAIC with a constant hazard ratio was not met. This meant that the MAIC with time-varying hazard ratios may be preferred from a purely methodological point of view. But it added that from a clinical point of view the MAIC with constant hazard ratios may be the better option because the extrapolation for overall survival based on that MAIC was the one most consistent with the 4‑year overall survival prediction from its clinical advisers. Before the committee meeting, the company said that the anchored MAIC with constant hazard ratios was its preferred option because the underlying assumptions were more likely to be met compared with the unanchored MAIC. But during the meeting the company noted the limitations of the anchored MAICs, including concerns about the comparability of the placebo arms across both trials. The company clarified the limitations with all of the options and said that all 3 options should be considered because of the uncertainty associated with all of the methods. The committee acknowledged the limitations with all 3 MAICs but it agreed that the anchored MAICs are likely to be more robust because the underlying assumptions are more likely to be met.\n\n## The MAICs suggest no clear difference in efficacy between cabozantinib and regorafenib, but the results should be interpreted with caution\n\nThe committee noted that the anchored MAICs showed a non-statistically significant progression-free survival benefit for cabozantinib and a non-statistically significant overall survival benefit for regorafenib. The anchored MAIC analysis with constant hazard ratios produced hazard ratios of 1.09 (95% CI 0.73 to 1.62) for overall survival and 0.80 (95% CI 0.55 to 1.15) for progression-free survival. The anchored MAIC analysis with time-varying hazard ratios produced time-varying hazard ratios of:\n\nmore than 1.0 for overall survival (95% CI includes a time-varying hazard ratio of 1.0)\n\nless than 1.0 for progression-free survival (95% CI includes a time-varying hazard ratio of 1.0).The non-statistically significant results from the anchored MAICs were supported by clinical experts, who said that they believed that cabozantinib and regorafenib had broadly similar efficacy. The committee concluded that the MAIC analyses show no clear evidence of any difference in efficacy between cabozantinib and regorafenib but that the results should be interpreted with caution because of the limitations outlined in section 3.5.\n\n# Economic model\n\n## It is uncertain whether cabozantinib would result in higher healthcare management costs than regorafenib\n\nThe company's model assumed equivalent healthcare management costs in the progression-free health state for cabozantinib and regorafenib. This was based on the company's clinical expert opinion, which was that clinicians are experienced in handling generic tyrosine kinase inhibitor toxicities, and that cabozantinib's tolerability issues can be managed. The ERG preferred to include additional monitoring costs, based on the views of its clinical advisers that cabozantinib has a comparatively worse toxicity profile than regorafenib. This was supported by the comparison of safety outcomes from the MAICs. Only the odds ratio for diarrhoea was statistically significant in favour of regorafenib but the point estimate odds ratios for hypertension, elevated aspartate transaminase, fatigue and palmar-plantar erythrodysaesthesia syndrome were also above 1 (in favour of regorafenib). The odds ratio for elevated bilirubin was in favour of cabozantinib but was not statistically significant. The ERG provided an alternative scenario that included the cost of 0.5 additional oncologist visits per month (0.46 visits per 28‑day model cycle).\n\nThe ERG commented that in the CELESTIAL trial there was a potentially clinically meaningful difference in favour of placebo for health-related quality of life when measured using the EQ‑5D. The company acknowledged that the EQ‑5D data from RESORCE does not suggest a significant difference between regorafenib and placebo. But it said that the EQ‑5D questionnaire in RESORCE was completed on the first day of each treatment cycle, when someone had not had treatment for a week. This may have affected responses. Clinical experts said that the toxicity profiles for regorafenib and cabozantinib seem broadly consistent. The committee concluded that it was uncertain if cabozantinib would result in additional monitoring costs compared with regorafenib, but it would consider both the company's and ERG's scenarios in its decision making.\n\n## Including drug wastage costs in the economic model is appropriate\n\nThe company's base case analyses assumed that packs of treatment can be split so that every tablet prescribed is taken, so they did not include wastage costs. This assumption advantages the cabozantinib group because the relative dose intensity is much lower for cabozantinib than for regorafenib (61% compared with 90%, respectively). The ERG noted that there may be some wastage because people can progress or die before completing a pack of treatment. The ERG provided an alternative scenario consistent with previous appraisals in HCC, in which the costs of 7\xa0days' worth of treatment in both treatment groups (adjusted for relative dose intensity) was included. A clinical expert said that dose adjustments are usually made quickly; normally after 2\xa0weeks of treatment, so wastage is likely to be minimised. The committee noted that including drug wastage costs as per the ERG's scenario was not a key driver of cost effectiveness but was likely to reflect clinical practice.\n\n# Cost-effectiveness estimates\n\n## Cabozantinib is a cost-effective use of NHS resources for advanced HCC after treatment with sorafenib\n\nThe committee agreed that its preferred approach to modelling would:\n\nUse scenarios that use the anchored MAIC with constant hazard ratios and scenarios that use the anchored MAIC with time-varying hazard ratios (see section 3.5).\n\nInclude scenarios in which healthcare management costs in the progression-free health state are equivalent for cabozantinib and regorafenib, and scenarios that include the cost of 0.5 additional oncologist visits per month for cabozantinib (see section 3.7).\n\nInclude treatment wastage costs (see section 3.9).\n\nThe committee also accepted the ERG analyses, which included corrections of minor errors, a general population mortality constraint and age-adjusted utilities. Using the committee's preferred assumptions and including the confidential discounts for cabozantinib and regorafenib, cabozantinib was associated with fewer quality-adjusted life years (QALYs) and overall lower costs than regorafenib in all scenarios. The scenario using the anchored MAIC with constant hazard ratios and equivalent healthcare management costs in the progression-free health state produced the most favourable results. The scenario using the anchored MAIC with time-varying hazard ratios and the cost of 0.5 additional oncologist visits per month for cabozantinib produced the least favourable results. The committee acknowledged that the true costs and QALYs were likely to be in between the 2 scenarios. The exact savings, net health benefits and incremental cost-effectiveness ratios (ICERs) are commercial in confidence and cannot be reported here. The committee was aware that, when an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment is. The committee considered the limited treatment options after sorafenib, particularly for people unable to tolerate it. It took the net health benefits and the ICERs into account. It noted that the QALY losses were sufficiently small for the anchored MAICs (less than 0.1, or roughly equivalent to 1\xa0month in perfect health) and the south-west quadrant ICERs per QALY lost were high enough to consider cabozantinib a cost-effective use of NHS resources. The exact QALYs are commercial in confidence and cannot be reported here. The committee concluded that cabozantinib can be considered cost effective for treating advanced HCC in people who have previously had sorafenib.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe patient expert said that liver disease and liver cancer disproportionally affect the poorest in society, and many people with liver cancer come from disadvantaged backgrounds. Differences in prevalence and patient population cannot usually be resolved in a technology appraisal, although the committee can consider whether a specific equality issue has a significant impact on access to treatments it recommends. The committee concluded that this was not the case for its recommendations about cabozantinib.\n\n# Conclusion\n\n## Cabozantinib is recommended for people with advanced HCC who have previously had sorafenib\n\nThe committee acknowledged the need for more treatment options in advanced HCC. It took account of the commercial discounts for cabozantinib and regorafenib. In the committee's preferred analyses, cabozantinib was considered a cost-effective use of NHS resources compared with regorafenib. So, cabozantinib is recommended as a treatment option for people with advanced HCC who have had sorafenib and who have Child–Pugh grade\xa0A liver impairment and an ECOG performance status of 0 or 1."}	https://www.nice.org.uk/guidance/ta849	Evidence-based recommendations on cabozantinib (Cabometyx) for advanced hepatocellular carcinoma in adults who have had sorafenib.
a5bd7e7d10c44c322b2bb11a6c15519fa4a8f554	nice	Amivantamab for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy	Amivantamab for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy Evidence-based recommendations on amivantamab (Rybrevant) for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy in adults. # Recommendations Amivantamab is not recommended, within its marketing authorisation, for treating locally advanced or metastatic non-small-cell lung cancer (NSCLC) after platinum-based chemotherapy in adults whose tumours have epidermal growth factor receptor (EGFR) exon 20 insertion mutations. This recommendation is not intended to affect treatment with amivantamab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Current treatment for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations after platinum-based chemotherapy can include platinum-based chemotherapy again, immunotherapies, and docetaxel with or without nintedanib. Indirect comparisons using real-world evidence on immunotherapies, platinum-based chemotherapy, and docetaxel with or without nintedanib, suggest that amivantamab increases how long people live, and how long they have before their cancer gets worse. But this is uncertain because there is no direct comparison, and because of the way the real-world evidence was chosen and presented. So, the cost-effectiveness estimates are also uncertain. Amivantamab meets NICE's criteria to be considered a life-extending treatment at the end of life. But, even taking this into account, the most plausible cost-effectiveness estimates are higher than what NICE usually considers an acceptable use of NHS resources. So, amivantamab is not recommended for routine use. Collecting more data would not resolve the uncertainties, so it is not recommended for use in the Cancer Drugs Fund.# Information about amivantamab # Marketing authorisation indication Amivantamab (Rybrevant, Janssen) is indicated for the 'treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) Exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for amivantamab. # Price The list price for amivantamab is £1,079 per 50 mg vial (excluding VAT; BNF online, accessed October 2022). The company has a commercial arrangement, which would have applied if the technology had been recommended.# Committee discussion The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical management ## People with EGFR exon 20 insertion mutation-positive advanced NSCLC will welcome a new treatment option that is targeted and well tolerated The clinical experts explained that epidermal growth factor receptor (EGFR) exon 20 insertion mutations are rare and only seen in a few people with non-small-cell lung cancer (NSCLC). Compared with other EGFR mutations, they are more common in women, people from an East Asian family background and people who do not smoke. Exon 20 insertion mutations are also associated with poorer outcomes than other EGFR mutations. The patient experts explained that, in people with exon 20 insertion mutation-positive NSCLC, the condition has a significant effect on their quality of life, and that of their families and carers. The patient experts highlighted the need for targeted treatments that have a lower toxicity and improved survival outcomes than current treatments. The clinical experts explained that there is no standard treatment for exon 20 insertion mutation-positive NSCLC (see section 3.2) and no treatment options that specifically target the mutations. The committee concluded that there is an unmet need for more effective treatment options that specifically target the exon 20 insertion mutations. # Comparators ## EGFR tyrosine kinase inhibitors are not appropriate comparators The clinical experts explained that there is no standard treatment pathway for people with exon 20 insertion mutation-positive NSCLC. Treatment choice depends on stage of disease, PD‑L1 status, and patient and clinician preference. Treatment options can include docetaxel with or without nintedanib, immunotherapy (such as atezolizumab, nivolumab or pembrolizumab) or best supportive care. Because there is no established standard treatment pathway, the company included a blended comparator arm in its submission. The company's original base case included immunotherapy treatments, EGFR tyrosine kinase inhibitors (TKIs), platinum-based chemotherapy and non-platinum-based chemotherapy. The company explained that its choice of blended comparators reflected the treatments used in 2 real-world evidence sources: a US cohort that included pooled data from Flatiron Health Spotlight, ConcertAI and COTA data sources routinely collected population-level data from the National Cancer Registration and Analysis Service (NCRAS) in England.The clinical experts explained that EGFR TKIs have limited efficacy when there are exon 20 insertion mutations. Because of this, they are rarely used in this population and are unlikely to represent standard care in the NHS. The ERG noted that including an ineffective treatment option (that is, EGFR TKIs) in the blended comparator arm may have led to overestimating the comparative efficacy of amivantamab. But scenario analyses excluding EGFR TKIs from the blended comparator arm had a limited effect on overall survival, progression-free survival and time to next treatment estimates. The committee noted that the NCRAS data included use of EGFR TKIs. But this was from a very small population and so may not have reflected the broader NHS population (the population size is considered confidential by the company and cannot be reported here). The NHS England Cancer Drugs Fund clinical lead (from here, Cancer Drugs Fund lead) stated that EGFR‑TKI use is not considered routine practice in the NHS. Considering the limitations of the available real-world evidence from England and the input from the clinical experts, the committee concluded that EGFR TKIs were not an appropriate comparator. After consultation, the company's updated base case removed EGFR TKIs as a comparator. ## Using a blended comparator arm increases uncertainty The company's approach compared amivantamab with the average clinical effectiveness across all treatments in a blended comparator arm. The company explained that there was no robust way to define standard care (see section 3.2), making it unfeasible to identify a single treatment that would be displaced by amivantamab. So, the most relevant comparator can only be accurately reflected by a blended comparator group, meaning that a fully incremental analysis is not possible. The committee noted that the company's approach meant that amivantamab was compared with the average clinical effectiveness across all treatments in the blended comparator group. It concluded that this substantially increased the uncertainty of the comparator-arm evidence. # Clinical evidence ## Amivantamab is clinically effective, but the size of this benefit compared with current treatments is difficult to establish The main evidence for amivantamab came from CHRYSALIS, a single-arm, open-label, phase 1b trial. Results from March 2021 showed a median progression-free survival of 6.74 months (95% confidence interval 5.45 to 9.66) and a median overall survival of 22.77 months (95% CI 17.48 to not estimated). Overall survival results from March 2022 were also available but are considered confidential by the company and cannot be reported here. The clinical experts considered these results to be clinically meaningful. The ERG highlighted that a smaller population (n=114) was used for the CHRYSALIS efficacy analyses than for the safety population (n=153) analyses. It noted that this may have exaggerated the treatment benefits of amivantamab. During technical engagement, the company explained that a larger safety population was used to gather safety data from as large a group as possible. The company also submitted safety analyses for the smaller (n=114) population to show that similar adverse events were reported in both populations. The company said that it did not provide updated efficacy analyses from the larger (n=153) population. This was because not all people in the safety population had had at least 3 disease assessments, so were not eligible to be included in the efficacy analysis set. Overall, the committee concluded that CHRYSALIS showed clinically meaningful results for amivantamab. But it thought that the lack of direct comparative evidence meant the size of this benefit compared with current treatments was difficult to establish. ## The approach used to identify real-world evidence for the blended comparator arm may not be robust and is associated with uncertainty There was no comparator in CHRYSALIS (see section 3.4), and no relevant trials were identified in a systematic literature review comparing amivantamab with the relevant comparators. So, the company did an adjusted treatment comparison comparing amivantamab with a blended comparator (see section 3.2) using real-world evidence. Because exon 20 insertion mutations affect the outcomes of people with NSCLC, the real-world evidence included was limited to people with NSCLC with these mutations. Two sources were identified: pooled US real-world evidence (used in the company's base case) and evidence from the NCRAS in England (used in scenario analyses). The company explained that the US real-world evidence was chosen for the base case because: -f its substantially larger sample size clinical experts considered the evidence to be generalisable to clinical practice in England (sample sizes are considered confidential by the company and so cannot be reported here).In addition, the US real-world evidence included data on progression-free survival, time to next treatment, overall survival and overall response rate outcomes. In contrast, the NCRAS evidence only provided data on time to next treatment and overall survival. The ERG agreed that, because of the larger sample size and because it included data on more outcomes, it was appropriate to use the US real-world evidence in the base case. But the ERG noted that the company did not provide a full, justified rationale for its choice of real-world evidence sources. Also, it was concerned that the real-world evidence sources had not been reviewed systematically. So, the company may have missed relevant sources. The committee concluded that, of the 2 data sources included, the pooled US real-world evidence may have been the best source of evidence. But it was concerned that the company had not provided enough information on how the sources were chosen from the pool of all potential data sources. It concluded that the approach to identifying real-world evidence to use in the blended comparator arm may not have been robust and was associated with uncertainty. ## The way the company has used real-world evidence is associated with some areas of uncertainty and may bias the results The committee noted that, in general, there are several key differences between real-world evidence and clinical trials. Specific to this appraisal, efficacy and safety endpoints were followed up regularly in CHRYSALIS, but there were no scheduled visits in routine care in the real-world evidence. Also, treatment monitoring and follow up on treatment adherence may have differed between CHRYSALIS and routine care. This would have affected the efficacy and safety results. Progressed disease is less accurately captured in retrospective studies (such as from the US real-world evidence) than in prospective studies in which people generally have closer monitoring and specific criteria are applied. The committee considered that, despite these known limitations with real-world evidence, it can be valuable for resolving gaps in knowledge when best-practice methods are applied, such as those described in the NICE real-world evidence framework. It also acknowledged the rarity of exon 20 insertion mutation-positive NSCLC and the lack of direct comparative efficacy data. This meant that the real-world evidence may have been the best available source of evidence for the comparator arm. At the first committee meeting, the committee was concerned that the company had not provided enough information on data provenance, accuracy and suitability, and had not explored the effect of missing data. To address these concerns, the company provided additional information on the real-world evidence sources used in the model. It provided a completed DataSAT real-world evidence checklist and did sensitivity analyses to assess the effect of missing data. Outcomes for each of the 3 US real-world evidence sources were provided individually, including the hazard ratios for overall survival, progression-free survival and time to next treatment. The ERG noted that the pooled-analysis results were conservative when compared with the individual results of the sensitivity analyses and were generally consistent across the 3 datasets. The company also provided further information on the eligibility criteria and baseline characteristics across the 3 US real-world evidence sources. The ERG noted some differences in the care settings and baseline characteristics between data sources. It also noted some potential selection bias in the eligibility criteria. The committee acknowledged the additional information provided by the company and agreed that it had reduced some areas of uncertainty, such as the effect of missing data. But there were some remaining gaps in the information and analyses provided by the company. Overall, the committee concluded that some areas of uncertainty remained and some of this uncertainty was currently unresolvable. It noted that the level of uncertainty could have been reduced if the company had shown that a systematic approach had been taken to selecting real-world evidence sources. The committee concluded that this uncertainty may have biased the results in the modelling. # Indirect treatment comparison ## The company's indirect comparison is suitable for decision making, but using this is associated with uncertainty To account for differences in populations between CHRYSALIS and the real-world evidence sources, the company adjusted for key prognostic variables and baseline characteristics. These were identified before the analysis by a systematic literature review and validated by clinical experts. For the US real-world evidence, data was adjusted using inverse probability weighting (IPW). The company explained that IPW was not suitable for the NCRAS evidence because of its small sample size, so it used covariate adjustment instead. Because of data availability, 8 covariates could be adjusted for in the US real-world evidence, and 7 could be adjusted for in the NCRAS evidence. The covariates adjusted for are considered confidential by the company and so cannot be described here. The ERG explained that the company's methods of adjustment appeared robust, but were limited by the covariates chosen for adjustment. Because of this, there may have been residual confounding. Also, although using IPW appeared acceptable, alternative forms of adjustment such as propensity score matching could have been applied to the US real-world evidence. The ERG noted that propensity score matching did not improve the balance between covariates compared with the IPW method. The committee concluded that the indirect comparison using IPW for adjustment was suitable for decision making. But it also noted that the indirect treatment comparison was associated with uncertainty. This was because of the potential residual confounding noted by the ERG, and the potential evidence issues associated with the blended comparator data (see section 3.5). ## Results from the indirect treatment comparison show statistically significant improvements with amivantamab, but are uncertain The indirect comparisons showed statistically significant improvements in overall survival and progression-free survival with amivantamab compared with the blended comparator arm when the US real-world evidence was used. The committee noted that scenario analyses using the NCRAS evidence for the comparator arm increased the treatment effect of amivantamab. The exact results of the indirect treatment comparison are considered confidential by the company and so cannot be reported here. The ERG explained that the results of the analyses were associated with uncertainties. These included that they were limited by the number of covariates included for adjustment and that there were issues with the company's approach to comparing clinical trial and real-world data (see section 3.7). Overall, the committee concluded that the indirect treatment comparison showed statistically significant improvements with amivantamab compared with standard care, but that the exact level of improvement was uncertain. # Utility values in the economic model ## It is acceptable to use utility values from past appraisals In its base case, the company took utility values for the progression-free survival state (0.713) and the post-progression state (0.569) from NICE's technology appraisal guidance on nivolumab for advanced NSCLC after chemotherapy. The company explained that it had some data on quality of life from CHRYSALIS. But it did not use this in the model because the number of EQ‑5D‑5L responses from CHRYSALIS was low at time of data cut-off. It also explained that the clinical experts it consulted considered the population in NICE's technology appraisal guidance on nivolumab was appropriate to use in place of the amivantamab population. The company explained that EQ‑5D‑5L data from CHRYSALIS was only collected for a limited number of people, and only for the progression-free survival state. The committee noted that there may have been differences between the CHRYSALIS population and the population in NICE's technology appraisal guidance on nivolumab. It also noted that using robust quality-of-life data from CHRYSALIS would have been preferrable, but that it would accept the company's preferred utility values instead. Overall, the committee concluded that, because of the limitations of the available CHRYSALIS EQ‑5D‑5L data, the company's base-case approach to utilities was acceptable. # Assumptions in the economic model ## The company's model structure is suitable for decision making The company used a partitioned survival model with 3 mutually exclusive health states: progression-free survival, progressed disease and death. This approach allowed the company to use outcome data from the adjusted treatment comparison. It also enabled the clinical benefits of amivantamab to be captured by reflecting the increased proportion of people expected to be alive or progression free over time. The committee agreed that the model structure was suitable for decision making. ## It is appropriate to use parametric modelling for survival in the blended comparator arm The company used Kaplan–Meier curves directly to represent survival outcomes for the blended comparator arm, and argued that this was appropriate because of the maturity of the data. The ERG explained that because follow up occurs at specific intervals, Kaplan–Meier curves have a 'stepped' nature. This means that at each measurement, all people who have died or whose condition has progressed will leave the health state at once. The ERG explained that this may introduce bias into the modelling of survival outcomes for the blended comparator arm, and considered it more appropriate to use parametric modelling. The ERG's base case used a Weibull curve to represent overall survival and a log-logistic curve to represent progression-free survival in the blended comparator arm. At technical engagement, the company did scenario analyses using parametric modelling to represent the blended comparator arm. The company explained that these scenarios had a minimal effect on the model results. NICE Decision Support Unit Technical Support Document 14 states 'parametric models are likely to represent the preferred method for incorporating survival data into health economic models in the majority of cases'. Based on this, the committee concluded that it was more appropriate to use parametric modelling to represent survival in the blended comparator arm. ## It is appropriate to base time on treatment on time to treatment discontinuation data from CHRYSALIS The company's base case modelled time to treatment discontinuation (TTD) based on the duration of progression-free survival. The company explained that this was because people having amivantamab would be expected to stop treatment at progression, as per the marketing authorisation. It also explained that, because of closer monitoring, progression during CHRYSALIS was likely to have been detected earlier than it would be in clinical practice. This could mean that the base-case approach underestimated the benefits of amivantamab. The committee noted that the costs may also have been underestimated compared with clinical practice. The company noted that TTD data was not available from the real-world evidence that was used for the comparator arm. Because of this, it considered that using TTD for amivantamab, but progression-free survival for the comparator arm, would be a conservative approach. The ERG noted that treatment duration with amivantamab in CHRYSALIS was longer than progression-free survival. So, it considered that the company's approach removed the costs of amivantamab used after progression from the modelling without removing any benefits from continuing to use it. One of the clinical experts suggested that people may continue having amivantamab after radiological disease progression if the clinician thinks they are still benefitting from it. This would be for about 2 to 3 months, although this will vary widely. The committee noted this was consistent with the difference between median TTD and median progression-free survival from the modelling. The Cancer Drugs Fund lead said that there was justification for using a different approach between the amivantamab and comparator arms. This is because chemotherapy has a different risk-benefit profile to amivantamab, so clinicians may apply a different threshold for when to stop treatment and may stop closer to disease progression. The committee considered NICE's recent technology appraisals in NSCLC (such as NICE's technology appraisal guidance on tepotinib for treating advanced NSCLC). It noted that most had used TTD data, rather than progression-free survival. Overall, the committee considered that: the duration of modelled costs and benefits of amivantamab should have been aligned amivantamab's use in the trial reflected its likely use in clinical practice it may be more likely that, in clinical practice, the comparator treatments are stopped on disease progression.So, the committee concluded that using TTD data from CHRYSALIS was appropriate for estimating the time on treatment. ## It is appropriate to extrapolate the TTD data using the Gompertz curve The ERG explained that its approach was to use the CHRYSALIS TTD data, with an exponential curve applied to model time on treatment. This was because the exponential curve had the best statistical fit. During consultation, the company said that statistical fit was not the only consideration when selecting the most appropriate curve. It noted that the Gompertz curve also had a good fit to the data, especially at the start of the Kaplan–Meier curve where there is more patient data available. It added that the Gompertz curve was more aligned with the hazard curve for TTD, where hazards decreased initially before increasing from around month 5. The company provided a scenario analysis using the CHRYSALIS TTD data, with the Gompertz curve applied. The committee recalled its discussion from the first committee meeting, when it thought that the exponential curve was the more appropriate curve to select. Taking into consideration the additional information provided by the company, the committee acknowledged that both Gompertz and exponential curves had good visual fits to the CHRYSALIS data. It also noted the importance of considering how the hazard function aligned with the trial data. It concluded that selecting the Gompertz curve for modelling the time to TTD was appropriate for estimating the time on treatment in the base case. But it noted that scenario analyses using the exponential curve should also be considered in its decision making. ## It is appropriate to exclude treatment-effect waning from the modelling The company's base case assumed that the amivantamab treatment effect is continued throughout the time horizon. The company said that people with exon 20 insertion mutation-positive NSCLC have poor prognosis with a short life expectancy. So, treatment-effect waning is unlikely to be seen. Also, if there is treatment waning, it would be highly unlikely to have a clinically meaningful effect because of the short time periods over which it could occur. The company highlighted that overall survival data showed that treatment benefit was maintained at follow up. Also, clinician input confirmed that outcomes at 2 years and 5 years were aligned with their expectations. The ERG considered that there was limited evidence to support a lifelong treatment effect of amivantamab. At technical engagement, the company provided a scenario in which it applied linear treatment waning from 3 years after amivantamab treatment was stopped until efficacy was equal to that of the blended comparator arm. The company explained that this was consistent with the approach taken in NICE's technology appraisal guidance on nivolumab. One of the clinical experts considered amivantamab's treatment effect is likely to be somewhere between that of existing oral EGFR TKIs (which provide little benefit after progression) and immunotherapies (which may provide long-term benefit). The committee noted that waning has typically been applied in previous appraisals for immunotherapies when stopping rules have been applied. It also noted the limited impact of the treatment-effect waning scenario done by the company. Based on this, the committee concluded that it was appropriate to exclude treatment-effect waning from the modelling. # Costs in the economic model ## Exon 20 insertion mutation testing costs should be included in the economic model In line with section 5.9.1 of NICE's guide to the methods of technology appraisal, the NICE scope for amivantamab states that the 'costs associated with diagnostic testing in people with NSCLC who would not otherwise have been tested should be included' in modelling. The company did not include exon 20 insertion mutation testing in its base case. It explained that these costs were expected to be included in routine NHS testing. The Cancer Drugs Fund lead explained that the gold standard for detecting exon 20 insertion mutations is next generation sequencing. But the availability of this varies across the NHS. Many treatment centres use polymerase chain reaction (PCR) instead, which is expected to identify about 50% of people with exon 20 insertion mutation-positive NSCLC. Because of this, using amivantamab (or other exon 20 insertion mutation targeted treatments) in the NHS would mean switching from current local PCR testing to next generation sequencing at Genomic Laboratory Hubs. This could result in a 50% increase in detecting exon 20 insertion mutation-positive NSCLC. But the Cancer Drugs Fund lead suggested that this increase may only be 33% because there is already some next generation sequencing testing being done. They explained that it would be appropriate to add a testing cost of £550 per person with exon 20 insertion mutation-positive NSCLC. This cost would account for a 2% incidence of exon 20 insertion mutations and the standard cost of adding a mutation test onto a next generation sequencing panel of £34. At the request of the committee, the company provided a scenario that included the mutation testing costs. The committee concluded that exon 20 insertion costs should be included in the amivantamab arm of the economic model. # End of life ## Amivantamab meets the criteria to be considered a life-extending treatment at the end of life The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that amivantamab met the criteria for being a life-extending treatment for people with short life expectancy (normally less than 24 months). Both the company's base case and the model using the committee's preferred assumptions predicted a mean and median overall survival with current standard care of substantially less than 24 months (the exact values are considered confidential by the company and cannot be reported here). Having considered the survival data from the US real-world evidence, the committee concluded that amivantamab met the end of life criterion for short life expectancy. The company's and ERG's modelling suggested that amivantamab was associated with a gain in overall survival of substantially more than 3 months (the exact values are considered confidential by the company and cannot be reported here). The committee noted the uncertainty in the real-world evidence and model estimates previously discussed (see section 3.6, section 3.7 and section 3.8). It concluded that, despite the uncertainty, amivantamab met both of NICE's criteria to be considered a life-extending treatment at the end of life. # Cost-effectiveness results ## Because of the uncertainty, an acceptable ICER would be below £50,000 per QALY gained NICE's guide to the methods of technology appraisal notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. It recalled its conclusion from the first meeting that an acceptable ICER would be around £20,000 per QALY gained. But the committee also agreed that the end of life criteria applied to amivantamab. When the end of life weighting was applied, the committee said that the maximum acceptable ICER would be substantially less than £50,000 per QALY gained. The committee acknowledged that, since the first committee meeting, the company had attempted to reduce the uncertainty around the use and selection of real-world evidence. But it noted the high level of outstanding uncertainty in the company's model, specifically: the lack of direct comparative evidence the effect of evidence selection issues because of the lack of systematic identification of real-world evidence sources the potential for residual confounding in the indirect treatment comparison the potential effect of selection bias because of differences in the eligibility criteria for the real-world evidence sources the lack of a fully incremental analysis because of using a blended comparator.The committee also took into account the lack of targeted treatment options available for this specific mutation and the emotional burden on people with EGFR exon 20 insertion mutation-positive NSCLC and their caregivers. It also heard that people with lung cancer may experience stigma, which could delay them seeking treatment. It noted the rarity of EGFR exon 20 insertion mutation-positive NSCLC and the difficulties this can create in generating evidence. The fact that amivantamab met the end of life criteria in this indication was also considered. Taking these factors into account and the uncertainty that remained, the committee concluded that an acceptable ICER would need to be below the maximum acceptable ICER for end of life treatments (£50,000 per QALY gained). ## The most plausible ICER is above £50,000 per QALY gained The company's updated base-case deterministic and probabilistic ICERs for amivantamab compared with the blended comparator arm were around £50,000 per QALY gained. This was when confidential commercial arrangements for amivantamab and all the comparators were included, so the exact ICERs cannot be reported here. The company's base case included the following assumptions, which were preferred by the committee: excluding EGFR TKIs from the blended comparator arm (see section 3.2) using the IPW method for the indirect treatment comparison (see section 3.7) using utility values from NICE's technology appraisal guidance on nivolumab (see section 3.9) using parametric modelling to represent survival in the blended comparator arm (see section 3.11) excluding treatment waning (see section 3.14).But, for modelling time on treatment, the company's updated base case used the progression-free survival data from CHRYSALIS (see section 3.12). This differed from the committee's preferred approach, which was to use TTD data with the Gompertz curve applied (see section 3.13). The committee began by considering scenarios that included the additional costs for EGFR exon 20 insertion mutation testing (see section 3.15). It noted that these ICERs were all above £50,000 per QALY gained. So, both the company's and the ERG's preferred methods for modelling time on treatment gave ICERs that were above the maximum possible ICER once testing costs were included. But the committee's preferred approach increased the ICER substantially. The committee also noted the remaining uncertainty in the cost-effectiveness estimates and concluded that it could not recommend amivantamab for routine use. # Cancer Drugs Fund ## Amivantamab does not meet the criteria to be included in the Cancer Drugs Fund Having concluded that amivantamab could not be recommended for routine use, the committee then considered whether it could be recommended for treating exon 20 insertion mutation-positive NSCLC in the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company thought that the Cancer Drugs Fund would allow observational data collection on baseline characteristics, overall survival, TTD and subsequent therapies through the Systemic Anti-Cancer Therapy dataset. It also suggested that the Cancer Drugs Fund would allow data from NCRAS to be linked to other datasets, to increase the sample size of the real-world evidence available from NHS clinical practice. The company suggested that this may resolve the uncertainties with the US real-world evidence. The committee recalled that the main uncertainties in this appraisal related to the limitations of the company's approach to existing real-world evidence (including the real-world evidence selection issues to identifying real-world evidence sources; see section 3.5). The Cancer Drugs Fund lead said that, because CHRYSALIS was mature, making amivantamab available in the Cancer Drugs Fund would not generate data that would resolve the main uncertainties. They suggested that it may be difficult to get relevant additional data from the NCRAS that would increase the sample size of the retrospective real-world evidence available from NHS clinical practice. The committee recalled that the most plausible ICER was above £50,000 per QALY gained and noted the remaining uncertainty around this ICER. The committee concluded that it is unlikely that Cancer Drugs Fund data collection would reduce the uncertainties and improve the cost-effectiveness estimate for amivantamab. So, amivantamab could not be recommended for use in the Cancer Drugs Fund. # Other factors ## Amivantamab is innovative but all benefits are captured in the analysis The committee considered amivantamab to be innovative because it represents a step-change in the treatment of exon 20 insertion mutation-positive NSCLC. The company considered that there were additional benefits of amivantamab that were not captured within the model. It suggested that improvements in the aspects of daily life most valued by people with lung cancer and their caregivers were not intrinsically captured in the QALY framework. These aspects include being able to maintain independence, 'feeling normal' and having hope for the future. The company also noted that EGFR-positive NSCLC is associated with significant stigma because of being associated with smoking behaviours. This is despite this population having a larger proportion of people who are never-smokers, relative to other lung cancers. This stigma can result in a delay in diagnosis, which places a higher value on treatments for cancer at an advanced stage. The committee recognised that there is stigma associated with a lung cancer diagnosis and that the prognosis for people with EGFR-positive NSCLC is poor. It considered principle 9 of the principles that guide the development of NICE guidance and standards. This states that the committee should take into account that 'stigma may affect people's behaviour in a way that changes the effectiveness of an intervention and routine quality-of-life assessments may not capture the benefits of treatment'. No evidence of this was provided in this appraisal, nor of how treatment with amivantamab would relieve the stigma of a lung cancer diagnosis. It acknowledged the significant unmet need for these people because of a lack of targeted treatment options being available for this specific mutation. The committee also recognised the significant emotional burden that a diagnosis of EGFR-positive NSCLC has on both people with lung cancer and their caregivers. It thought that many of the benefits highlighted by the company, such as maintaining usual activities, would typically be captured with the EQ‑5D tool that underpins the QALY calculations. It noted that the poor prognosis and lack of treatment options were reflected by the end of life weighting being applied (see section 3.16). The committee accepted that amivantamab provides important benefits for people with exon 20 insertion mutation-positive NSCLC. It considered the unmet need and the burden of stigma in its deliberations. But the committee did not consider that there were any additional benefits that had not been captured in the QALY calculations. ## There are no equality issues relevant to the recommendations The company explained that exon 20 insertion mutation NSCLC is associated with people who have never smoked and has a higher prevalence in people from an East Asian family background. It also noted that lung cancer is often associated with stigma, which may result in a delay in seeking diagnosis and treatments. This may mean initial treatment options are not effective. The company considered that this stigma may be greater in people who have never smoked and people with an East Asian family background. The committee appreciated that differences in prevalence cannot usually be resolved in a technology appraisal, although it can consider whether a specific equality issue has a significant impact on access to treatment. The committee noted that there was no evidence suggesting an increase in stigma in people protected by equality legislation. Also, the recommendation for amivantamab is for the full population in the marketing authorisation. So, the committee agreed that its recommendation would not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no equality issues relevant to the recommendations. # Conclusion ## Amivantamab is not recommended The committee concluded that amivantamab is not recommended for treating EGFR exon 20 insertion mutation-positive NSCLC after platinum-based chemotherapy. The committee considered the uncertainty and the range in the cost-effectiveness estimates. It noted that the most plausible ICER was above the range considered to be a cost-effective use of NHS resources when the end of life modifier was applied.	{'Recommendations': "Amivantamab is not recommended, within its marketing authorisation, for treating locally advanced or metastatic non-small-cell lung cancer (NSCLC) after platinum-based chemotherapy in adults whose tumours have epidermal growth factor receptor (EGFR) exon\xa020 insertion mutations.\n\nThis recommendation is not intended to affect treatment with amivantamab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for locally advanced or metastatic NSCLC with EGFR exon\xa020 insertion mutations after platinum-based chemotherapy can include platinum-based chemotherapy again, immunotherapies, and docetaxel with or without nintedanib.\n\nIndirect comparisons using real-world evidence on immunotherapies, platinum-based chemotherapy, and docetaxel with or without nintedanib, suggest that amivantamab increases how long people live, and how long they have before their cancer gets worse. But this is uncertain because there is no direct comparison, and because of the way the real-world evidence was chosen and presented. So, the cost-effectiveness estimates are also uncertain.\n\nAmivantamab meets NICE's criteria to be considered a life-extending treatment at the end of life. But, even taking this into account, the most plausible cost-effectiveness estimates are higher than what NICE usually considers an acceptable use of NHS resources. So, amivantamab is not recommended for routine use. Collecting more data would not resolve the uncertainties, so it is not recommended for use in the Cancer Drugs Fund.", 'Information about amivantamab': "# Marketing authorisation indication\n\nAmivantamab (Rybrevant, Janssen) is indicated for the 'treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) Exon\xa020 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for amivantamab.\n\n# Price\n\nThe list price for amivantamab is £1,079 per 50\xa0mg vial (excluding VAT; BNF online, accessed October\xa02022).\n\nThe company has a commercial arrangement, which would have applied if the technology had been recommended.", 'Committee discussion': "The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## People with EGFR exon 20 insertion mutation-positive advanced NSCLC will welcome a new treatment option that is targeted and well tolerated\n\nThe clinical experts explained that epidermal growth factor receptor (EGFR) exon\xa020 insertion mutations are rare and only seen in a few people with non-small-cell lung cancer (NSCLC). Compared with other EGFR mutations, they are more common in women, people from an East Asian family background and people who do not smoke. Exon\xa020 insertion mutations are also associated with poorer outcomes than other EGFR mutations. The patient experts explained that, in people with exon\xa020 insertion mutation-positive NSCLC, the condition has a significant effect on their quality of life, and that of their families and carers. The patient experts highlighted the need for targeted treatments that have a lower toxicity and improved survival outcomes than current treatments. The clinical experts explained that there is no standard treatment for exon\xa020 insertion mutation-positive NSCLC (see section\xa03.2) and no treatment options that specifically target the mutations. The committee concluded that there is an unmet need for more effective treatment options that specifically target the exon\xa020 insertion mutations.\n\n# Comparators\n\n## EGFR tyrosine kinase inhibitors are not appropriate comparators\n\nThe clinical experts explained that there is no standard treatment pathway for people with exon\xa020 insertion mutation-positive NSCLC. Treatment choice depends on stage of disease, PD‑L1 status, and patient and clinician preference. Treatment options can include docetaxel with or without nintedanib, immunotherapy (such as atezolizumab, nivolumab or pembrolizumab) or best supportive care. Because there is no established standard treatment pathway, the company included a blended comparator arm in its submission. The company's original base case included immunotherapy treatments, EGFR tyrosine kinase inhibitors (TKIs), platinum-based chemotherapy and non-platinum-based chemotherapy. The company explained that its choice of blended comparators reflected the treatments used in 2\xa0real-world evidence sources:\n\na US cohort that included pooled data from Flatiron Health Spotlight, ConcertAI and COTA data sources\n\nroutinely collected population-level data from the National Cancer Registration and Analysis Service (NCRAS) in England.The clinical experts explained that EGFR TKIs have limited efficacy when there are exon\xa020 insertion mutations. Because of this, they are rarely used in this population and are unlikely to represent standard care in the NHS. The ERG noted that including an ineffective treatment option (that is, EGFR TKIs) in the blended comparator arm may have led to overestimating the comparative efficacy of amivantamab. But scenario analyses excluding EGFR TKIs from the blended comparator arm had a limited effect on overall survival, progression-free survival and time to next treatment estimates. The committee noted that the NCRAS data included use of EGFR TKIs. But this was from a very small population and so may not have reflected the broader NHS population (the population size is considered confidential by the company and cannot be reported here). The NHS England Cancer Drugs Fund clinical lead (from here, Cancer Drugs Fund lead) stated that EGFR‑TKI use is not considered routine practice in the NHS. Considering the limitations of the available real-world evidence from England and the input from the clinical experts, the committee concluded that EGFR TKIs were not an appropriate comparator. After consultation, the company's updated base case removed EGFR TKIs as a comparator.\n\n## Using a blended comparator arm increases uncertainty\n\nThe company's approach compared amivantamab with the average clinical effectiveness across all treatments in a blended comparator arm. The company explained that there was no robust way to define standard care (see section\xa03.2), making it unfeasible to identify a single treatment that would be displaced by amivantamab. So, the most relevant comparator can only be accurately reflected by a blended comparator group, meaning that a fully incremental analysis is not possible. The committee noted that the company's approach meant that amivantamab was compared with the average clinical effectiveness across all treatments in the blended comparator group. It concluded that this substantially increased the uncertainty of the comparator-arm evidence.\n\n# Clinical evidence\n\n## Amivantamab is clinically effective, but the size of this benefit compared with current treatments is difficult to establish\n\nThe main evidence for amivantamab came from CHRYSALIS, a single-arm, open-label, phase\xa01b trial. Results from March\xa02021 showed a median progression-free survival of 6.74\xa0months (95% confidence interval [CI] 5.45\xa0to\xa09.66) and a median overall survival of 22.77\xa0months (95%\xa0CI 17.48\xa0to not estimated). Overall survival results from March\xa02022 were also available but are considered confidential by the company and cannot be reported here. The clinical experts considered these results to be clinically meaningful. The ERG highlighted that a smaller population (n=114) was used for the CHRYSALIS efficacy analyses than for the safety population (n=153) analyses. It noted that this may have exaggerated the treatment benefits of amivantamab. During technical engagement, the company explained that a larger safety population was used to gather safety data from as large a group as possible. The company also submitted safety analyses for the smaller (n=114) population to show that similar adverse events were reported in both populations. The company said that it did not provide updated efficacy analyses from the larger (n=153) population. This was because not all people in the safety population had had at least 3\xa0disease assessments, so were not eligible to be included in the efficacy analysis set. Overall, the committee concluded that CHRYSALIS showed clinically meaningful results for amivantamab. But it thought that the lack of direct comparative evidence meant the size of this benefit compared with current treatments was difficult to establish.\n\n## The approach used to identify real-world evidence for the blended comparator arm may not be robust and is associated with uncertainty\n\nThere was no comparator in CHRYSALIS (see section\xa03.4), and no relevant trials were identified in a systematic literature review comparing amivantamab with the relevant comparators. So, the company did an adjusted treatment comparison comparing amivantamab with a blended comparator (see section\xa03.2) using real-world evidence. Because exon\xa020 insertion mutations affect the outcomes of people with NSCLC, the real-world evidence included was limited to people with NSCLC with these mutations. Two sources were identified: pooled US real-world evidence (used in the company's base case) and evidence from the NCRAS in England (used in scenario analyses). The company explained that the US real-world evidence was chosen for the base case because:\n\nof its substantially larger sample size\n\nclinical experts considered the evidence to be generalisable to clinical practice in England (sample sizes are considered confidential by the company and so cannot be reported here).In addition, the US real-world evidence included data on progression-free survival, time to next treatment, overall survival and overall response rate outcomes. In contrast, the NCRAS evidence only provided data on time to next treatment and overall survival. The ERG agreed that, because of the larger sample size and because it included data on more outcomes, it was appropriate to use the US real-world evidence in the base case. But the ERG noted that the company did not provide a full, justified rationale for its choice of real-world evidence sources. Also, it was concerned that the real-world evidence sources had not been reviewed systematically. So, the company may have missed relevant sources. The committee concluded that, of the 2\xa0data sources included, the pooled US real-world evidence may have been the best source of evidence. But it was concerned that the company had not provided enough information on how the sources were chosen from the pool of all potential data sources. It concluded that the approach to identifying real-world evidence to use in the blended comparator arm may not have been robust and was associated with uncertainty.\n\n## The way the company has used real-world evidence is associated with some areas of uncertainty and may bias the results\n\nThe committee noted that, in general, there are several key differences between real-world evidence and clinical trials. Specific to this appraisal, efficacy and safety endpoints were followed up regularly in CHRYSALIS, but there were no scheduled visits in routine care in the real-world evidence. Also, treatment monitoring and follow up on treatment adherence may have differed between CHRYSALIS and routine care. This would have affected the efficacy and safety results. Progressed disease is less accurately captured in retrospective studies (such as from the US real-world evidence) than in prospective studies in which people generally have closer monitoring and specific criteria are applied. The committee considered that, despite these known limitations with real-world evidence, it can be valuable for resolving gaps in knowledge when best-practice methods are applied, such as those described in the NICE real-world evidence framework. It also acknowledged the rarity of exon\xa020 insertion mutation-positive NSCLC and the lack of direct comparative efficacy data. This meant that the real-world evidence may have been the best available source of evidence for the comparator arm. At the first committee meeting, the committee was concerned that the company had not provided enough information on data provenance, accuracy and suitability, and had not explored the effect of missing data. To address these concerns, the company provided additional information on the real-world evidence sources used in the model. It provided a completed DataSAT real-world evidence checklist and did sensitivity analyses to assess the effect of missing data. Outcomes for each of the 3\xa0US real-world evidence sources were provided individually, including the hazard ratios for overall survival, progression-free survival and time to next treatment. The ERG noted that the pooled-analysis results were conservative when compared with the individual results of the sensitivity analyses and were generally consistent across the 3\xa0datasets. The company also provided further information on the eligibility criteria and baseline characteristics across the 3\xa0US real-world evidence sources. The ERG noted some differences in the care settings and baseline characteristics between data sources. It also noted some potential selection bias in the eligibility criteria. The committee acknowledged the additional information provided by the company and agreed that it had reduced some areas of uncertainty, such as the effect of missing data. But there were some remaining gaps in the information and analyses provided by the company. Overall, the committee concluded that some areas of uncertainty remained and some of this uncertainty was currently unresolvable. It noted that the level of uncertainty could have been reduced if the company had shown that a systematic approach had been taken to selecting real-world evidence sources. The committee concluded that this uncertainty may have biased the results in the modelling.\n\n# Indirect treatment comparison\n\n## The company's indirect comparison is suitable for decision making, but using this is associated with uncertainty\n\nTo account for differences in populations between CHRYSALIS and the real-world evidence sources, the company adjusted for key prognostic variables and baseline characteristics. These were identified before the analysis by a systematic literature review and validated by clinical experts. For the US real-world evidence, data was adjusted using inverse probability weighting (IPW). The company explained that IPW was not suitable for the NCRAS evidence because of its small sample size, so it used covariate adjustment instead. Because of data availability, 8\xa0covariates could be adjusted for in the US real-world evidence, and 7\xa0could be adjusted for in the NCRAS evidence. The covariates adjusted for are considered confidential by the company and so cannot be described here. The ERG explained that the company's methods of adjustment appeared robust, but were limited by the covariates chosen for adjustment. Because of this, there may have been residual confounding. Also, although using IPW appeared acceptable, alternative forms of adjustment such as propensity score matching could have been applied to the US real-world evidence. The ERG noted that propensity score matching did not improve the balance between covariates compared with the IPW method. The committee concluded that the indirect comparison using IPW for adjustment was suitable for decision making. But it also noted that the indirect treatment comparison was associated with uncertainty. This was because of the potential residual confounding noted by the ERG, and the potential evidence issues associated with the blended comparator data (see section\xa03.5).\n\n## Results from the indirect treatment comparison show statistically significant improvements with amivantamab, but are uncertain\n\nThe indirect comparisons showed statistically significant improvements in overall survival and progression-free survival with amivantamab compared with the blended comparator arm when the US real-world evidence was used. The committee noted that scenario analyses using the NCRAS evidence for the comparator arm increased the treatment effect of amivantamab. The exact results of the indirect treatment comparison are considered confidential by the company and so cannot be reported here. The ERG explained that the results of the analyses were associated with uncertainties. These included that they were limited by the number of covariates included for adjustment and that there were issues with the company's approach to comparing clinical trial and real-world data (see section\xa03.7). Overall, the committee concluded that the indirect treatment comparison showed statistically significant improvements with amivantamab compared with standard care, but that the exact level of improvement was uncertain.\n\n# Utility values in the economic model\n\n## It is acceptable to use utility values from past appraisals\n\nIn its base case, the company took utility values for the progression-free survival state (0.713) and the post-progression state (0.569) from NICE's technology appraisal guidance on nivolumab for advanced NSCLC after chemotherapy. The company explained that it had some data on quality of life from CHRYSALIS. But it did not use this in the model because the number of EQ‑5D‑5L responses from CHRYSALIS was low at time of data cut-off. It also explained that the clinical experts it consulted considered the population in NICE's technology appraisal guidance on nivolumab was appropriate to use in place of the amivantamab population. The company explained that EQ‑5D‑5L data from CHRYSALIS was only collected for a limited number of people, and only for the progression-free survival state. The committee noted that there may have been differences between the CHRYSALIS population and the population in NICE's technology appraisal guidance on nivolumab. It also noted that using robust quality-of-life data from CHRYSALIS would have been preferrable, but that it would accept the company's preferred utility values instead. Overall, the committee concluded that, because of the limitations of the available CHRYSALIS EQ‑5D‑5L data, the company's base-case approach to utilities was acceptable.\n\n# Assumptions in the economic model\n\n## The company's model structure is suitable for decision making\n\nThe company used a partitioned survival model with 3\xa0mutually exclusive health states: progression-free survival, progressed disease and death. This approach allowed the company to use outcome data from the adjusted treatment comparison. It also enabled the clinical benefits of amivantamab to be captured by reflecting the increased proportion of people expected to be alive or progression free over time. The committee agreed that the model structure was suitable for decision making.\n\n## It is appropriate to use parametric modelling for survival in the blended comparator arm\n\nThe company used Kaplan–Meier curves directly to represent survival outcomes for the blended comparator arm, and argued that this was appropriate because of the maturity of the data. The ERG explained that because follow up occurs at specific intervals, Kaplan–Meier curves have a 'stepped' nature. This means that at each measurement, all people who have died or whose condition has progressed will leave the health state at once. The ERG explained that this may introduce bias into the modelling of survival outcomes for the blended comparator arm, and considered it more appropriate to use parametric modelling. The ERG's base case used a Weibull curve to represent overall survival and a log-logistic curve to represent progression-free survival in the blended comparator arm. At technical engagement, the company did scenario analyses using parametric modelling to represent the blended comparator arm. The company explained that these scenarios had a minimal effect on the model results. NICE Decision Support Unit Technical Support Document 14 states 'parametric models are likely to represent the preferred method for incorporating survival data into health economic models in the majority of cases'. Based on this, the committee concluded that it was more appropriate to use parametric modelling to represent survival in the blended comparator arm.\n\n## It is appropriate to base time on treatment on time to treatment discontinuation data from CHRYSALIS\n\nThe company's base case modelled time to treatment discontinuation (TTD) based on the duration of progression-free survival. The company explained that this was because people having amivantamab would be expected to stop treatment at progression, as per the marketing authorisation. It also explained that, because of closer monitoring, progression during CHRYSALIS was likely to have been detected earlier than it would be in clinical practice. This could mean that the base-case approach underestimated the benefits of amivantamab. The committee noted that the costs may also have been underestimated compared with clinical practice. The company noted that TTD data was not available from the real-world evidence that was used for the comparator arm. Because of this, it considered that using TTD for amivantamab, but progression-free survival for the comparator arm, would be a conservative approach. The ERG noted that treatment duration with amivantamab in CHRYSALIS was longer than progression-free survival. So, it considered that the company's approach removed the costs of amivantamab used after progression from the modelling without removing any benefits from continuing to use it. One of the clinical experts suggested that people may continue having amivantamab after radiological disease progression if the clinician thinks they are still benefitting from it. This would be for about 2\xa0to 3\xa0months, although this will vary widely. The committee noted this was consistent with the difference between median TTD and median progression-free survival from the modelling. The Cancer Drugs Fund lead said that there was justification for using a different approach between the amivantamab and comparator arms. This is because chemotherapy has a different risk-benefit profile to amivantamab, so clinicians may apply a different threshold for when to stop treatment and may stop closer to disease progression. The committee considered NICE's recent technology appraisals in NSCLC (such as NICE's technology appraisal guidance on tepotinib for treating advanced NSCLC). It noted that most had used TTD data, rather than progression-free survival. Overall, the committee considered that:\n\nthe duration of modelled costs and benefits of amivantamab should have been aligned\n\namivantamab's use in the trial reflected its likely use in clinical practice\n\nit may be more likely that, in clinical practice, the comparator treatments are stopped on disease progression.So, the committee concluded that using TTD data from CHRYSALIS was appropriate for estimating the time on treatment.\n\n## It is appropriate to extrapolate the TTD data using the Gompertz curve\n\nThe ERG explained that its approach was to use the CHRYSALIS TTD data, with an exponential curve applied to model time on treatment. This was because the exponential curve had the best statistical fit. During consultation, the company said that statistical fit was not the only consideration when selecting the most appropriate curve. It noted that the Gompertz curve also had a good fit to the data, especially at the start of the Kaplan–Meier curve where there is more patient data available. It added that the Gompertz curve was more aligned with the hazard curve for TTD, where hazards decreased initially before increasing from around month\xa05. The company provided a scenario analysis using the CHRYSALIS TTD data, with the Gompertz curve applied. The committee recalled its discussion from the first committee meeting, when it thought that the exponential curve was the more appropriate curve to select. Taking into consideration the additional information provided by the company, the committee acknowledged that both Gompertz and exponential curves had good visual fits to the CHRYSALIS data. It also noted the importance of considering how the hazard function aligned with the trial data. It concluded that selecting the Gompertz curve for modelling the time to TTD was appropriate for estimating the time on treatment in the base case. But it noted that scenario analyses using the exponential curve should also be considered in its decision making.\n\n## It is appropriate to exclude treatment-effect waning from the modelling\n\nThe company's base case assumed that the amivantamab treatment effect is continued throughout the time horizon. The company said that people with exon\xa020 insertion mutation-positive NSCLC have poor prognosis with a short life expectancy. So, treatment-effect waning is unlikely to be seen. Also, if there is treatment waning, it would be highly unlikely to have a clinically meaningful effect because of the short time periods over which it could occur. The company highlighted that overall survival data showed that treatment benefit was maintained at follow up. Also, clinician input confirmed that outcomes at 2\xa0years and 5\xa0years were aligned with their expectations. The ERG considered that there was limited evidence to support a lifelong treatment effect of amivantamab. At technical engagement, the company provided a scenario in which it applied linear treatment waning from 3\xa0years after amivantamab treatment was stopped until efficacy was equal to that of the blended comparator arm. The company explained that this was consistent with the approach taken in NICE's technology appraisal guidance on nivolumab. One of the clinical experts considered amivantamab's treatment effect is likely to be somewhere between that of existing oral EGFR TKIs (which provide little benefit after progression) and immunotherapies (which may provide long-term benefit). The committee noted that waning has typically been applied in previous appraisals for immunotherapies when stopping rules have been applied. It also noted the limited impact of the treatment-effect waning scenario done by the company. Based on this, the committee concluded that it was appropriate to exclude treatment-effect waning from the modelling.\n\n# Costs in the economic model\n\n## Exon 20 insertion mutation testing costs should be included in the economic model\n\nIn line with section\xa05.9.1 of NICE's guide to the methods of technology appraisal, the NICE scope for amivantamab states that the 'costs associated with diagnostic testing in people with NSCLC who would not otherwise have been tested should be included' in modelling. The company did not include exon\xa020 insertion mutation testing in its base case. It explained that these costs were expected to be included in routine NHS testing. The Cancer Drugs Fund lead explained that the gold standard for detecting exon\xa020 insertion mutations is next generation sequencing. But the availability of this varies across the NHS. Many treatment centres use polymerase chain reaction (PCR) instead, which is expected to identify about 50% of people with exon\xa020 insertion mutation-positive NSCLC. Because of this, using amivantamab (or other exon\xa020 insertion mutation targeted treatments) in the NHS would mean switching from current local PCR testing to next generation sequencing at Genomic Laboratory Hubs. This could result in a 50% increase in detecting exon\xa020 insertion mutation-positive NSCLC. But the Cancer Drugs Fund lead suggested that this increase may only be 33% because there is already some next generation sequencing testing being done. They explained that it would be appropriate to add a testing cost of £550 per person with exon\xa020 insertion mutation-positive NSCLC. This cost would account for a 2% incidence of exon\xa020 insertion mutations and the standard cost of adding a mutation test onto a next generation sequencing panel of £34. At the request of the committee, the company provided a scenario that included the mutation testing costs. The committee concluded that exon\xa020 insertion costs should be included in the amivantamab arm of the economic model.\n\n# End of life\n\n## Amivantamab meets the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that amivantamab met the criteria for being a life-extending treatment for people with short life expectancy (normally less than 24\xa0months). Both the company's base case and the model using the committee's preferred assumptions predicted a mean and median overall survival with current standard care of substantially less than 24\xa0months (the exact values are considered confidential by the company and cannot be reported here). Having considered the survival data from the US real-world evidence, the committee concluded that amivantamab met the end of life criterion for short life expectancy. The company's and ERG's modelling suggested that amivantamab was associated with a gain in overall survival of substantially more than 3\xa0months (the exact values are considered confidential by the company and cannot be reported here). The committee noted the uncertainty in the real-world evidence and model estimates previously discussed (see section\xa03.6, section\xa03.7 and section\xa03.8). It concluded that, despite the uncertainty, amivantamab met both of NICE's criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## Because of the uncertainty, an acceptable ICER would be below £50,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. It recalled its conclusion from the first meeting that an acceptable ICER would be around £20,000 per QALY gained. But the committee also agreed that the end of life criteria applied to amivantamab. When the end of life weighting was applied, the committee said that the maximum acceptable ICER would be substantially less than £50,000 per QALY gained. The committee acknowledged that, since the first committee meeting, the company had attempted to reduce the uncertainty around the use and selection of real-world evidence. But it noted the high level of outstanding uncertainty in the company's model, specifically:\n\nthe lack of direct comparative evidence\n\nthe effect of evidence selection issues because of the lack of systematic identification of real-world evidence sources\n\nthe potential for residual confounding in the indirect treatment comparison\n\nthe potential effect of selection bias because of differences in the eligibility criteria for the real-world evidence sources\n\nthe lack of a fully incremental analysis because of using a blended comparator.The committee also took into account the lack of targeted treatment options available for this specific mutation and the emotional burden on people with EGFR exon\xa020 insertion mutation-positive NSCLC and their caregivers. It also heard that people with lung cancer may experience stigma, which could delay them seeking treatment. It noted the rarity of EGFR exon\xa020 insertion mutation-positive NSCLC and the difficulties this can create in generating evidence. The fact that amivantamab met the end of life criteria in this indication was also considered. Taking these factors into account and the uncertainty that remained, the committee concluded that an acceptable ICER would need to be below the maximum acceptable ICER for end of life treatments (£50,000 per QALY gained).\n\n## The most plausible ICER is above £50,000 per QALY gained\n\nThe company's updated base-case deterministic and probabilistic ICERs for amivantamab compared with the blended comparator arm were around £50,000 per QALY gained. This was when confidential commercial arrangements for amivantamab and all the comparators were included, so the exact ICERs cannot be reported here. The company's base case included the following assumptions, which were preferred by the committee:\n\nexcluding EGFR TKIs from the blended comparator arm (see section\xa03.2)\n\nusing the IPW method for the indirect treatment comparison (see section\xa03.7)\n\nusing utility values from NICE's technology appraisal guidance on nivolumab (see section\xa03.9)\n\nusing parametric modelling to represent survival in the blended comparator arm (see section\xa03.11)\n\nexcluding treatment waning (see section\xa03.14).But, for modelling time on treatment, the company's updated base case used the progression-free survival data from CHRYSALIS (see section\xa03.12). This differed from the committee's preferred approach, which was to use TTD data with the Gompertz curve applied (see section\xa03.13). The committee began by considering scenarios that included the additional costs for EGFR exon\xa020 insertion mutation testing (see section\xa03.15). It noted that these ICERs were all above £50,000 per QALY gained. So, both the company's and the ERG's preferred methods for modelling time on treatment gave ICERs that were above the maximum possible ICER once testing costs were included. But the committee's preferred approach increased the ICER substantially. The committee also noted the remaining uncertainty in the cost-effectiveness estimates and concluded that it could not recommend amivantamab for routine use.\n\n# Cancer Drugs Fund\n\n## Amivantamab does not meet the criteria to be included in the Cancer Drugs Fund\n\nHaving concluded that amivantamab could not be recommended for routine use, the committee then considered whether it could be recommended for treating exon\xa020 insertion mutation-positive NSCLC in the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company thought that the Cancer Drugs Fund would allow observational data collection on baseline characteristics, overall survival, TTD and subsequent therapies through the Systemic Anti-Cancer Therapy dataset. It also suggested that the Cancer Drugs Fund would allow data from NCRAS to be linked to other datasets, to increase the sample size of the real-world evidence available from NHS clinical practice. The company suggested that this may resolve the uncertainties with the US real-world evidence. The committee recalled that the main uncertainties in this appraisal related to the limitations of the company's approach to existing real-world evidence (including the real-world evidence selection issues to identifying real-world evidence sources; see section\xa03.5). The Cancer Drugs Fund lead said that, because CHRYSALIS was mature, making amivantamab available in the Cancer Drugs Fund would not generate data that would resolve the main uncertainties. They suggested that it may be difficult to get relevant additional data from the NCRAS that would increase the sample size of the retrospective real-world evidence available from NHS clinical practice. The committee recalled that the most plausible ICER was above £50,000 per QALY gained and noted the remaining uncertainty around this ICER. The committee concluded that it is unlikely that Cancer Drugs Fund data collection would reduce the uncertainties and improve the cost-effectiveness estimate for amivantamab. So, amivantamab could not be recommended for use in the Cancer Drugs Fund.\n\n# Other factors\n\n## Amivantamab is innovative but all benefits are captured in the analysis\n\nThe committee considered amivantamab to be innovative because it represents a step-change in the treatment of exon\xa020 insertion mutation-positive NSCLC. The company considered that there were additional benefits of amivantamab that were not captured within the model. It suggested that improvements in the aspects of daily life most valued by people with lung cancer and their caregivers were not intrinsically captured in the QALY framework. These aspects include being able to maintain independence, 'feeling normal' and having hope for the future. The company also noted that EGFR-positive NSCLC is associated with significant stigma because of being associated with smoking behaviours. This is despite this population having a larger proportion of people who are never-smokers, relative to other lung cancers. This stigma can result in a delay in diagnosis, which places a higher value on treatments for cancer at an advanced stage. The committee recognised that there is stigma associated with a lung cancer diagnosis and that the prognosis for people with EGFR-positive NSCLC is poor. It considered principle\xa09 of the principles that guide the development of NICE guidance and standards. This states that the committee should take into account that 'stigma may affect people's behaviour in a way that changes the effectiveness of an intervention and routine quality-of-life assessments may not capture the benefits of treatment'. No evidence of this was provided in this appraisal, nor of how treatment with amivantamab would relieve the stigma of a lung cancer diagnosis. It acknowledged the significant unmet need for these people because of a lack of targeted treatment options being available for this specific mutation. The committee also recognised the significant emotional burden that a diagnosis of EGFR-positive NSCLC has on both people with lung cancer and their caregivers. It thought that many of the benefits highlighted by the company, such as maintaining usual activities, would typically be captured with the EQ‑5D tool that underpins the QALY calculations. It noted that the poor prognosis and lack of treatment options were reflected by the end of life weighting being applied (see section\xa03.16). The committee accepted that amivantamab provides important benefits for people with exon\xa020 insertion mutation-positive NSCLC. It considered the unmet need and the burden of stigma in its deliberations. But the committee did not consider that there were any additional benefits that had not been captured in the QALY calculations.\n\n## There are no equality issues relevant to the recommendations\n\nThe company explained that exon\xa020 insertion mutation NSCLC is associated with people who have never smoked and has a higher prevalence in people from an East Asian family background. It also noted that lung cancer is often associated with stigma, which may result in a delay in seeking diagnosis and treatments. This may mean initial treatment options are not effective. The company considered that this stigma may be greater in people who have never smoked and people with an East Asian family background. The committee appreciated that differences in prevalence cannot usually be resolved in a technology appraisal, although it can consider whether a specific equality issue has a significant impact on access to treatment. The committee noted that there was no evidence suggesting an increase in stigma in people protected by equality legislation. Also, the recommendation for amivantamab is for the full population in the marketing authorisation. So, the committee agreed that its recommendation would not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no equality issues relevant to the recommendations.\n\n# Conclusion\n\n## Amivantamab is not recommended\n\nThe committee concluded that amivantamab is not recommended for treating EGFR exon\xa020 insertion mutation-positive NSCLC after platinum-based chemotherapy. The committee considered the uncertainty and the range in the cost-effectiveness estimates. It noted that the most plausible ICER was above the range considered to be a cost-effective use of NHS resources when the end of life modifier was applied."}	https://www.nice.org.uk/guidance/ta850	Evidence-based recommendations on amivantamab (Rybrevant) for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy in adults.
7e92dfb51742dca0f4e9c3fc4f74c7d6cdebdf60	nice	Pembrolizumab for neoadjuvant and adjuvant treatment of triple-negative early or locally advanced breast cancer	Pembrolizumab for neoadjuvant and adjuvant treatment of triple-negative early or locally advanced breast cancer Evidence-based recommendations on pembrolizumab (Keytruda) for neoadjuvant and adjuvant treatment of triple-negative early or locally advanced breast cancer in adults. # Recommendations Pembrolizumab is recommended, within its marketing authorisation, as an option with chemotherapy for neoadjuvant treatment and then continued alone as adjuvant treatment after surgery for adults with triple-negative: early breast cancer at high risk of recurrence or locally advanced breast cancer. It is recommended only if the company provides pembrolizumab according to the commercial arrangement. Why the committee made these recommendations Treatment for triple-negative early or locally advanced breast cancer is usually chemotherapy then surgery. Clinical trial evidence shows that adding pembrolizumab to chemotherapy before surgery (neoadjuvant), then continuing with pembrolizumab alone after surgery (adjuvant) increases the chance that the cancer will disappear. It also increases the time before any cancer recurs. It is not clear if pembrolizumab increases how long people live. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. So, pembrolizumab is recommended.# Information about pembrolizumab # Marketing authorisation indication Pembrolizumab (Keytruda, MSD) has a marketing authorisation 'in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, for the treatment of adults with locally advanced, or early-stage triple-negative breast cancer at high risk of recurrence'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for pembrolizumab. # Price The list price is £2,630 per 100 mg solution for infusion vial (excluding VAT; BNF online accessed September 2022). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # Clinical need ## Adding pembrolizumab to standard care would be a welcome option for people with triple-negative breast cancer The patient expert explained that there are limited effective treatment options available for triple-negative early and locally advanced breast cancer, despite its particularly poor prognosis. They explained that many people who have pembrolizumab with chemotherapy feel lucky to have this treatment, which is seen as an additional lifeline. The patient expert also explained that people know that pembrolizumab may cause some adverse events (see section 3.7). But they consider that the potential benefits of treatment far outweigh any risks. This is particularly because triple-negative breast cancer is associated with younger people, who may have young families. Also, the disease has an increased risk of recurrence compared with other forms of breast cancer. The committee concluded that recently, there have been limited advances in treatment options for triple-negative early and locally advanced breast cancer. It further concluded that there is an unmet need for treatments for this disease and adding pembrolizumab to standard care would be welcomed. # Treatment pathway ## Treatment for triple-negative early and locally advanced breast cancer varies, but adjuvant treatment is not standard care The clinical experts explained that standard care for triple-negative early or locally advanced breast cancer is chemotherapy as neoadjuvant treatment then surgery. They explained that the most common chemotherapy regimen is an anthracycline taxane combination plus a platinum therapy. The clinical experts also noted that it varies whether adjuvant treatment is offered or whether disease is only monitored after surgery. They explained that capecitabine may be offered after surgery if there is no pathological complete response after neoadjuvant treatment. However, they explained that there is mixed evidence on the efficacy of adjuvant capecitabine, and that standard care does not include any adjuvant treatment. The clinical experts explained that if pembrolizumab was available for this indication, they would expect that practice would change to include neoadjuvant and adjuvant treatment. The committee concluded that standard care for triple-negative early or locally advanced breast cancer is chemotherapy as neoadjuvant treatment, then surgery with no adjuvant treatment, although practice varies. # Clinical evidence ## Pathological complete response is an important outcome for people with triple-negative breast cancer The patient and clinical experts emphasised that although other clinical outcomes are important, pathological complete response is a particularly important outcome for people with triple-negative breast cancer. Pathological complete response means that all the detectable cancer has disappeared after neoadjuvant treatment. The clinical experts explained that pathological complete response is an important outcome, and suggests improved longer-term outcomes. The patient experts explained that a pathological complete response has a great psychological benefit because people are aware that it makes better long-term outcomes more likely. It also offers the opportunity to use less invasive, breast-conserving surgery. Reducing mastectomies is beneficial because they have a longer recovery time, and sometimes people need reconstructive surgery and later revisions. The clinical experts explained that people have an improved quality of life with less invasive surgery, and that there are potential cost savings to the NHS if the number of mastectomies was reduced. The committee concluded that pathological complete response is an important outcome for people with triple-negative breast cancer. ## KEYNOTE-522 is generalisable to people who would have pembrolizumab in the NHS KEYNOTE‑522 is a randomised, double-blind, placebo-controlled trial (n=1,174). It was done in 21 countries worldwide and included 40 people from the UK. The trial compared 2 treatment arms: chemotherapy plus pembrolizumab and chemotherapy plus placebo. The chemotherapy plus pembrolizumab arm included: neoadjuvant treatment with: carboplatin plus paclitaxel for cycles 1 to 4 doxorubicin or epirubicin plus cyclophosphamide for cycles 5 to 8 pembrolizumab for cycles 1 to 8 surgery adjuvant treatment with pembrolizumab for 9 cycles.The chemotherapy plus placebo arm included: neoadjuvant treatment with: carboplatin plus paclitaxel for cycles 1 to 4 doxorubicin or epirubicin plus cyclophosphamide for cycles 5 to 8 placebo for cycles 1 to 8 surgery adjuvant treatment with placebo for 9 cycles.The clinical experts explained that the chemotherapy regimens used in the trial were broadly similar to the treatments used most often in the NHS (see section 3.2). However, they noted that doxorubicin, which is used as part of the chemotherapy regimen in both arms in the trial, is not often used in the UK. They also explained that the population in the trial was reflective of the population in the marketing authorisation, which includes people with locally advanced or early-stage disease at high risk of recurrence. The clinical experts explained that although the study was done worldwide, most sites were in countries that have similar ethnicities to the UK, so the trial population was generalisable to UK clinical practice (see section 3.6). Overall, the clinical experts stated that based on the chemotherapy regimen and population included in the trial, they would expect the results from KEYNOTE‑522 to be generalisable to NHS clinical practice. The committee concluded that KEYNOTE‑522 is generalisable to people who would have pembrolizumab in the NHS. # Clinical effectiveness ## Pembrolizumab improves clinical outcomes compared with chemotherapy alone when considering the full trial population Median event-free survival and overall survival were not reached in either arm in KEYNOTE‑522. The median duration of follow up was 37.8 months. The clinical outcomes for the full trial population included: The proportion of people with pathological complete response was 63.0% (95% confidence interval 59.5 to 66.4%) in the chemotherapy plus pembrolizumab arm and 55.6% (95% CI 50.6 to 60.6%) in the chemotherapy plus placebo arm. The difference in pathological complete response rate was 7.5% (95% CI 1.6 to 13.4%) favouring the chemotherapy plus pembrolizumab arm. Event-free survival rate at 42‑month follow up was 83.5% (95% CI 80.5 to 86.0%) in the chemotherapy plus pembrolizumab arm and 74.9% (95% CI 69.8 to 79.2%) in the chemotherapy plus placebo arm. The difference in event-free survival rate at 42‑month follow up was 8.6% (hazard ratio 0.63, 95% CI 0.48 to 0.82) favouring the chemotherapy plus pembrolizumab arm. Overall survival rate at 42‑month follow up was 89.2% (95% CI 86.7 to 91.3%) in the chemotherapy plus pembrolizumab arm and 84.1% (95% CI 79.5 to 87.7%) in the chemotherapy plus placebo arm. The difference in overall survival rate at 42‑month follow up was 5.1% (hazard ratio 0.72, 95% CI 0.51 to 1.02) favouring the chemotherapy plus pembrolizumab arm.The committee noted that no statistically significant difference in overall survival was shown with adding pembrolizumab to standard care. But there was a statistically significant difference seen for event-free survival. The clinical experts noted that the benefits seen for complete pathological response and event-free survival suggested that, with longer follow up, benefits for overall survival would also be seen. The ERG agreed that the lack of statistically significant benefit seen for overall survival may be because of immature data. The clinical experts also highlighted that the trial data does show a significant improvement in pathological complete response, which is an important outcome (see section 3.3). The committee concluded that in the full trial population, adding pembrolizumab to standard care improves the rate of pathological complete response and event-free survival. ## There is no clear reason why there would be differences in effect due to ECOG score or geographical region Several subgroup analyses were pre-specified in the KEYNOTE‑522 study protocol. Most subgroups showed no difference in outcomes compared with the full trial population. However, for the subgroup of people with an Eastern Cooperative Oncology Group score of 1 (ECOG 1), the ERG noted that the hazard ratio point estimate for event-free survival was higher than for the full trial population (see section 3.5) and that the confidence intervals for this subgroup cross 1 (n=155; hazard ratio 0.81, 95% CI 0.41 to 1.62). The ERG also noted that there was a difference in the hazard ratio for the subgroup of people having treatment in Europe (referred to from now as the Europe subgroup) compared with the full trial population. This information is academic in confidence and cannot be reported here. The clinical experts explained that there is no clear reason why there would be less benefit in event-free survival for people with an ECOG score of 1. They suggested this result may be because of the small sample size in this subgroup. They suggested that a possible reason for the different hazard ratio for event-free survival rate in the Europe subgroup was because of differences in clinical practice in different countries and would be unlikely to be because of physiological differences. However, the company explained that the KEYNOTE‑522 protocol restricted the use of different treatment approaches. The clinical experts also explained that there is no evidence for differences in clinical outcomes for the different surgical approaches used worldwide. So the clinical experts could not identify a clear reason why event-free survival rate would be influenced by geographical region. The company highlighted that no explanation of the different results seen across regions could be identified by looking at the baseline characteristics of each population. It also explained that KEYNOTE‑522 was not powered to detect differences in subgroups by region so the results should be interpreted with caution. The Cancer Drugs Fund clinical lead highlighted that because the trial was not stratified by geographical region, it is possible that some imbalances between the treatment arms contributed to the different hazard ratios seen in different subgroups. They also highlighted that the hazard ratio for event-free survival for the subgroup including Europe, Israel, North America and Australia was close to the hazard ratio for the full trial population. The committee concluded that although the hazard ratios for event-free survival for the ECOG 1 and Europe subgroups were different to the hazard ratio for the full trial population, there was no underlying reason to explain why these differences were observed. ## There are additional adverse events associated with adding pembrolizumab to standard care KEYNOTE‑522 results showed that there were more serious adverse events in the chemotherapy plus pembrolizumab arm (43.6%) compared with the chemotherapy plus placebo arm (28.5%). The clinical experts explained that this result is expected with adding another treatment to standard care. They also noted that data on drug-related adverse events leading to death needs to be assessed as the data matures, but that there is not enough evidence at this stage to say that pembrolizumab increases the number of treatment-related deaths. The patient experts explained that the additional adverse events with adding pembrolizumab are manageable, and the potential benefits of treatment outweigh the potential adverse events. The clinical experts explained that the risk of adverse events would be considered by individuals. They would expect most people to accept these risks and tolerate the adverse events, given the potential benefits of adding pembrolizumab to chemotherapy. The committee concluded that additional adverse events are associated with adding pembrolizumab to standard care, and these should be taken into account by patients and clinicians when considering treatment options. # Economic model ## The company's economic model is acceptable for decision making The company presented a 4‑state Markov model to estimate the cost effectiveness of chemotherapy plus pembrolizumab compared with chemotherapy plus placebo. The 4 health states were event-free, locoregional recurrence, distant metastasis and death. The ERG highlighted that the distant metastasis state does not differentiate between pre-progressed and post-progressed disease. The company explained that evidence is limited for triple-negative breast cancer. So including distinct states for pre- and post-progression in the distant metastasis health state would need unnecessary assumptions and add complexity and uncertainty. The ERG also highlighted that for people who had first-line metastatic treatment in the distant metastasis state, the company's model included the costs for second and subsequent line metastatic treatments as a lump sum. Because these treatment costs make up around a third of all costs in the chemotherapy arm, the ERG raised concerns around the lack of precision using this approach. The committee understood that the model structure was limited by the evidence available for triple-negative breast cancer. It concluded that although there were limitations with the model, these could not be addressed without increasing the model's complexity and uncertainty. So it concluded that the company's model is acceptable for decision making. # Assumptions in the economic model ## It is appropriate to consider the full trial population in the economic model The ERG highlighted the different hazard ratios for event-free survival from KEYNOTE‑522 for people having treatment in Europe and in the full trial population (see section 3.6). The ERG suggested that the Europe subgroup is more likely to be generalisable to the UK than the full trial population. So it preferred to use the hazard ratio from the Europe subgroup to represent pembrolizumab's efficacy in the model. The company used pembrolizumab's efficacy from the full trial population in its model. The committee agreed that it is appropriate to consider evidence within the cost-effectiveness model that reflects the population in the NHS. However, it agreed it is also important to assess the reliability of the subgroup results and discussed that KEYNOTE‑522 was not powered to show a difference across regions. The committee considered the clinical experts' view that there is no clear reason why event-free survival would be influenced by geographical region and that the full trial population is generalisable to UK clinical practice (see section 3.4 and section 3.6). Given this, the committee agreed that it was not appropriate to use results from the Europe subgroup which is not powered to show a difference in effect, when results from the full trial population, which is appropriately powered, are available. Therefore, the committee concluded that it was appropriate to use the results from the full trial population in the economic model. ## The comparator treatment in KEYNOTE-522 is appropriate for use in the economic model The comparator included in the company's model was aligned with the comparator used in KEYNOTE‑522 (see section 3.4). The ERG stated that this might not reflect NHS clinical practice. It highlighted that more people had doxorubicin than epirubicin as neoadjuvant chemotherapy in KEYNOTE‑522 and this may not reflect how frequently these chemotherapy agents are used in practice. The ERG highlighted that a subgroup analysis in KEYNOTE‑522 showed better efficacy for doxorubicin than epirubicin. The clinical experts explained that doxorubicin is not often used in clinical practice (see section 3.4) but it is still a reasonable comparator. The ERG also questioned if placebo monotherapy as adjuvant treatment was appropriate because some people may have capecitabine. The clinical experts explained that standard care does not typically include adjuvant treatment so placebo after surgery is an appropriate comparator (see section 3.2). The committee concluded that the comparator in KEYNOTE‑522 was appropriate for use in the economic model. ## The ERG's approach to event-free survival extrapolation is methodologically appropriate, although it may be conservative Extrapolation of event-free survival Kaplan–Meier data from KEYNOTE‑522 was used to model transitions from the event-free health state to each of the other health states. The probability of the first event in each treatment arm being locoregional recurrence, distant metastasis or death was determined from KEYNOTE‑522. It was applied to the extrapolated event-free survival data to estimate the transition probabilities into each health state. The company used a log-normal curve for the chemotherapy plus placebo arm and a generalised gamma curve for the chemotherapy plus pembrolizumab arm. The ERG stated that, unless there are very strong arguments to not do so, survival extrapolation should use the same extrapolation curve in both treatment arms, as per NICE's Decision Support Unit technical support document 14. So it preferred to use a log-normal extrapolation of event-free survival in both arms because it did not consider that sufficient justification was provided for using different extrapolations for each treatment arm. The ERG was also concerned that in the company's model, the event-free survival rate accelerated within the extrapolated period, meaning the event-free survival gains are mostly from the unobserved extrapolated data. The company argued that it was appropriate to use different curves for each arm because chemotherapy and pembrolizumab have different mechanisms of action. It also stated that the log-normal curve for the chemotherapy plus pembrolizumab arm was inappropriate. This was because it did not show a plateau associated with a decrease in the number of progression events over time so would underestimate the pembrolizumab treatment effect. The clinical experts explained that most relapses of triple-negative breast cancer happen within the first 3 years of diagnosis. There is increased certainty of longer-term survival for people whose disease has not relapsed by this time. So it is reasonable that the extrapolated curves for event-free survival should plateau after 3 years. The committee concluded that the ERG's method of using the same extrapolation curve for each treatment arm was methodologically appropriate but this was likely to provide a conservative estimate of event-free survival. ## Both data sources for estimating overall survival in the distant metastasis state are uncertain In the model, the company used data on overall survival from KEYNOTE‑355 to estimate the transition probabilities from the distant metastasis state to death for people who had treatment for metastatic disease. KEYNOTE‑355 (n=882) is a randomised placebo-controlled trial in people with recurrent triple-negative inoperable or metastatic breast cancer. It compared chemotherapy plus pembrolizumab with chemotherapy plus placebo. The company used KEYNOTE‑355 data to estimate overall survival in the distant metastasis state because the data in KEYNOTE‑522 is immature. The ERG noted that there are differences in the observed survival between KEYNOTE‑522 and KEYNOTE‑355 so the populations in the studies may not be comparable. It preferred to use direct trial data from KEYNOTE‑522 to estimate transition probabilities in the distant metastasis state. The committee noted that KEYNOTE‑522 overall survival data for people whose disease has metastasised is immature, so is uncertain. However, it also noted the potential bias that could be introduced into the model by using data sourced from a different population. The committee concluded that there is uncertainty with both data sources for estimating overall survival in the distant metastasis state. ## The utility values used in the model have a limited impact on the incremental cost-effectiveness ratio The company's economic model used utility values sourced from EQ‑5D‑5L data from KEYNOTE‑522, mapped to EQ‑5D‑3L. The utility values were pooled across the chemotherapy plus pembrolizumab and the chemotherapy plus placebo arms for each health state. Event-free survival utilities were separated into values for being on and off treatment. The ERG highlighted that the utility values for the distant metastasis health state were relatively low compared with other studies, such as KEYNOTE‑355. However, it noted that this may be because of the small number of EQ‑5D‑5L questionnaires completed by people in KEYNOTE‑522 with disease that had metastasised. The ERG and the company did scenario analyses using utility data from other sources, which showed that the utility values had a very limited impact on the incremental cost-effectiveness ratio (ICER). The committee concluded that although there was some uncertainty around the validity of the utility values used in the model, it has a limited impact on the cost-effectiveness results. # Cost-effectiveness estimate ## Adding pembrolizumab to standard care for early and locally advanced triple-negative breast cancer is likely to be cost effective The company's model included the following assumptions: Estimating pembrolizumab efficacy from the full trial population (see section 3.9). Using chemotherapy regimens as used in KEYNOTE‑522 in the treatment and comparator arm (see section 3.10). Using a log-normal extrapolation of Kaplan-Meier data in the chemotherapy plus placebo arm (see section 3.11). Using a generalised gamma extrapolation of Kaplan-Meier data in the chemotherapy plus pembrolizumab arm (see section 3.11). Estimating overall survival in the distant metastasis state using data from KEYNOTE‑355 (see section 3.12). Estimating utility values from EQ‑5D‑5L data from KEYNOTE‑522 (see section 3.13).The ERG's base case included some of the same assumptions, but included different assumptions on: Estimating pembrolizumab efficacy, for which it preferred to use the hazard ratio from the Europe subgroup (see section 3.9). The choice of curve for extrapolation of Kaplan-Meier data in the chemotherapy plus pembrolizumab arm, for which it preferred to use a log-normal extrapolation (see section 3.11). The source of overall survival data in the distant metastasis state, for which it preferred to use KEYNOTE‑522 data (see section 3.12).The committee considered that the full trial population results for event-free survival should be used in the model because it was uncertain why there were differences in effect seen in the Europe subgroup (see section 3.9). However, it agreed that other assumptions included in the ERG's base case were reasonable. It noted that the ERG presented an alternative base case using the full trial population. The committee concluded that its preferred assumptions were those in the ERG's alternative base case, using the hazard ratio for event-free survival from the full trial population. The ICERs cannot be reported here because of confidential commercial arrangements for subsequent treatments in the pathway. However, the ERG's alternative base case is below the range normally considered a cost-effective use of NHS resources. The committee discussed the unmet need for treatment options for triple-negative early or locally advanced breast cancer (see section 3.1). It also discussed that there could be potential cost savings to the NHS, which had not been included in the model, if the number of invasive breast surgery procedures was reduced (see section 3.3). Considering all these factors, pembrolizumab with chemotherapy is likely to be a cost-effective use of NHS resources. # Conclusion ## Pembrolizumab is recommended The committee noted that based on its preferred assumptions, pembrolizumab with chemotherapy is likely to be cost effective compared with chemotherapy alone (see section 3.14). There was some uncertainty, particularly about the long-term outcome benefits of adding pembrolizumab to standard care. However, because the committee preferred conservative assumptions for event-free and overall survival, it considered that pembrolizumab is likely to be at the lower end of the range normally considered a cost-effective use of NHS resources. So pembrolizumab with chemotherapy as neoadjuvant treatment, and then continued alone as adjuvant treatment, is recommended for use in the NHS as an option for adults with triple-negative: early breast cancer at high risk of recurrence or locally advanced breast cancer.	{'Recommendations': 'Pembrolizumab is recommended, within its marketing authorisation, as an option with chemotherapy for neoadjuvant treatment and then continued alone as adjuvant treatment after surgery for adults with triple-negative:\n\nearly breast cancer at high risk of recurrence or\n\nlocally advanced breast cancer. It is recommended only if the company provides pembrolizumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nTreatment for triple-negative early or locally advanced breast cancer is usually chemotherapy then surgery.\n\nClinical trial evidence shows that adding pembrolizumab to chemotherapy before surgery (neoadjuvant), then continuing with pembrolizumab alone after surgery (adjuvant) increases the chance that the cancer will disappear. It also increases the time before any cancer recurs. It is not clear if pembrolizumab increases how long people live.\n\nThe cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. So, pembrolizumab is recommended.', 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, MSD) has a marketing authorisation 'in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, for the treatment of adults with locally advanced, or early-stage triple-negative breast cancer at high risk of recurrence'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nThe list price is £2,630 per 100\xa0mg solution for infusion vial (excluding VAT; BNF online accessed September 2022).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## Adding pembrolizumab to standard care would be a welcome option for people with triple-negative breast cancer\n\nThe patient expert explained that there are limited effective treatment options available for triple-negative early and locally advanced breast cancer, despite its particularly poor prognosis. They explained that many people who have pembrolizumab with chemotherapy feel lucky to have this treatment, which is seen as an additional lifeline. The patient expert also explained that people know that pembrolizumab may cause some adverse events (see section 3.7). But they consider that the potential benefits of treatment far outweigh any risks. This is particularly because triple-negative breast cancer is associated with younger people, who may have young families. Also, the disease has an increased risk of recurrence compared with other forms of breast cancer. The committee concluded that recently, there have been limited advances in treatment options for triple-negative early and locally advanced breast cancer. It further concluded that there is an unmet need for treatments for this disease and adding pembrolizumab to standard care would be welcomed.\n\n# Treatment pathway\n\n## Treatment for triple-negative early and locally advanced breast cancer varies, but adjuvant treatment is not standard care\n\nThe clinical experts explained that standard care for triple-negative early or locally advanced breast cancer is chemotherapy as neoadjuvant treatment then surgery. They explained that the most common chemotherapy regimen is an anthracycline taxane combination plus a platinum therapy. The clinical experts also noted that it varies whether adjuvant treatment is offered or whether disease is only monitored after surgery. They explained that capecitabine may be offered after surgery if there is no pathological complete response after neoadjuvant treatment. However, they explained that there is mixed evidence on the efficacy of adjuvant capecitabine, and that standard care does not include any adjuvant treatment. The clinical experts explained that if pembrolizumab was available for this indication, they would expect that practice would change to include neoadjuvant and adjuvant treatment. The committee concluded that standard care for triple-negative early or locally advanced breast cancer is chemotherapy as neoadjuvant treatment, then surgery with no adjuvant treatment, although practice varies.\n\n# Clinical evidence\n\n## Pathological complete response is an important outcome for people with triple-negative breast cancer\n\nThe patient and clinical experts emphasised that although other clinical outcomes are important, pathological complete response is a particularly important outcome for people with triple-negative breast cancer. Pathological complete response means that all the detectable cancer has disappeared after neoadjuvant treatment. The clinical experts explained that pathological complete response is an important outcome, and suggests improved longer-term outcomes. The patient experts explained that a pathological complete response has a great psychological benefit because people are aware that it makes better long-term outcomes more likely. It also offers the opportunity to use less invasive, breast-conserving surgery. Reducing mastectomies is beneficial because they have a longer recovery time, and sometimes people need reconstructive surgery and later revisions. The clinical experts explained that people have an improved quality of life with less invasive surgery, and that there are potential cost savings to the NHS if the number of mastectomies was reduced. The committee concluded that pathological complete response is an important outcome for people with triple-negative breast cancer.\n\n## KEYNOTE-522 is generalisable to people who would have pembrolizumab in the NHS\n\nKEYNOTE‑522 is a randomised, double-blind, placebo-controlled trial (n=1,174). It was done in 21\xa0countries worldwide and included 40\xa0people from the UK. The trial compared 2\xa0treatment arms: chemotherapy plus pembrolizumab and chemotherapy plus placebo. The chemotherapy plus pembrolizumab arm included:\n\nneoadjuvant treatment with:\n\n\n\ncarboplatin plus paclitaxel for cycles 1 to 4\n\ndoxorubicin or epirubicin plus cyclophosphamide for cycles 5 to 8\n\npembrolizumab for cycles 1 to 8\n\n\n\nsurgery\n\nadjuvant treatment with pembrolizumab for 9 cycles.The chemotherapy plus placebo arm included:\n\nneoadjuvant treatment with:\n\n\n\ncarboplatin plus paclitaxel for cycles 1 to 4\n\ndoxorubicin or epirubicin plus cyclophosphamide for cycles 5 to 8\n\nplacebo for cycles 1 to 8\n\n\n\nsurgery\n\nadjuvant treatment with placebo for 9 cycles.The clinical experts explained that the chemotherapy regimens used in the trial were broadly similar to the treatments used most often in the NHS (see section 3.2). However, they noted that doxorubicin, which is used as part of the chemotherapy regimen in both arms in the trial, is not often used in the UK. They also explained that the population in the trial was reflective of the population in the marketing authorisation, which includes people with locally advanced or early-stage disease at high risk of recurrence. The clinical experts explained that although the study was done worldwide, most sites were in countries that have similar ethnicities to the UK, so the trial population was generalisable to UK clinical practice (see section 3.6). Overall, the clinical experts stated that based on the chemotherapy regimen and population included in the trial, they would expect the results from KEYNOTE‑522 to be generalisable to NHS clinical practice. The committee concluded that KEYNOTE‑522 is generalisable to people who would have pembrolizumab in the NHS.\n\n# Clinical effectiveness\n\n## Pembrolizumab improves clinical outcomes compared with chemotherapy alone when considering the full trial population\n\nMedian event-free survival and overall survival were not reached in either arm in KEYNOTE‑522. The median duration of follow up was 37.8\xa0months. The clinical outcomes for the full trial population included:\n\nThe proportion of people with pathological complete response was 63.0% (95% confidence interval [CI] 59.5 to 66.4%) in the chemotherapy plus pembrolizumab arm and 55.6% (95% CI 50.6 to 60.6%) in the chemotherapy plus placebo arm.\n\nThe difference in pathological complete response rate was 7.5% (95% CI 1.6 to 13.4%) favouring the chemotherapy plus pembrolizumab arm.\n\nEvent-free survival rate at 42‑month follow up was 83.5% (95% CI 80.5 to 86.0%) in the chemotherapy plus pembrolizumab arm and 74.9% (95% CI 69.8 to 79.2%) in the chemotherapy plus placebo arm.\n\nThe difference in event-free survival rate at 42‑month follow up was 8.6% (hazard ratio 0.63, 95% CI 0.48 to 0.82) favouring the chemotherapy plus pembrolizumab arm.\n\nOverall survival rate at 42‑month follow up was 89.2% (95% CI 86.7 to 91.3%) in the chemotherapy plus pembrolizumab arm and 84.1% (95% CI 79.5 to 87.7%) in the chemotherapy plus placebo arm.\n\nThe difference in overall survival rate at 42‑month follow up was 5.1% (hazard ratio 0.72, 95% CI 0.51 to 1.02) favouring the chemotherapy plus pembrolizumab arm.The committee noted that no statistically significant difference in overall survival was shown with adding pembrolizumab to standard care. But there was a statistically significant difference seen for event-free survival. The clinical experts noted that the benefits seen for complete pathological response and event-free survival suggested that, with longer follow up, benefits for overall survival would also be seen. The ERG agreed that the lack of statistically significant benefit seen for overall survival may be because of immature data. The clinical experts also highlighted that the trial data does show a significant improvement in pathological complete response, which is an important outcome (see section 3.3). The committee concluded that in the full trial population, adding pembrolizumab to standard care improves the rate of pathological complete response and event-free survival.\n\n## There is no clear reason why there would be differences in effect due to ECOG score or geographical region\n\nSeveral subgroup analyses were pre-specified in the KEYNOTE‑522 study protocol. Most subgroups showed no difference in outcomes compared with the full trial population. However, for the subgroup of people with an Eastern Cooperative Oncology Group score of 1 (ECOG\xa01), the ERG noted that the hazard ratio point estimate for event-free survival was higher than for the full trial population (see section 3.5) and that the confidence intervals for this subgroup cross 1 (n=155; hazard ratio 0.81, 95% CI 0.41 to 1.62). The ERG also noted that there was a difference in the hazard ratio for the subgroup of people having treatment in Europe (referred to from now as the Europe subgroup) compared with the full trial population. This information is academic in confidence and cannot be reported here. The clinical experts explained that there is no clear reason why there would be less benefit in event-free survival for people with an ECOG score of 1. They suggested this result may be because of the small sample size in this subgroup. They suggested that a possible reason for the different hazard ratio for event-free survival rate in the Europe subgroup was because of differences in clinical practice in different countries and would be unlikely to be because of physiological differences. However, the company explained that the KEYNOTE‑522 protocol restricted the use of different treatment approaches. The clinical experts also explained that there is no evidence for differences in clinical outcomes for the different surgical approaches used worldwide. So the clinical experts could not identify a clear reason why event-free survival rate would be influenced by geographical region. The company highlighted that no explanation of the different results seen across regions could be identified by looking at the baseline characteristics of each population. It also explained that KEYNOTE‑522 was not powered to detect differences in subgroups by region so the results should be interpreted with caution. The Cancer Drugs Fund clinical lead highlighted that because the trial was not stratified by geographical region, it is possible that some imbalances between the treatment arms contributed to the different hazard ratios seen in different subgroups. They also highlighted that the hazard ratio for event-free survival for the subgroup including Europe, Israel, North America and Australia was close to the hazard ratio for the full trial population. The committee concluded that although the hazard ratios for event-free survival for the ECOG\xa01 and Europe subgroups were different to the hazard ratio for the full trial population, there was no underlying reason to explain why these differences were observed.\n\n## There are additional adverse events associated with adding pembrolizumab to standard care\n\nKEYNOTE‑522 results showed that there were more serious adverse events in the chemotherapy plus pembrolizumab arm (43.6%) compared with the chemotherapy plus placebo arm (28.5%). The clinical experts explained that this result is expected with adding another treatment to standard care. They also noted that data on drug-related adverse events leading to death needs to be assessed as the data matures, but that there is not enough evidence at this stage to say that pembrolizumab increases the number of treatment-related deaths. The patient experts explained that the additional adverse events with adding pembrolizumab are manageable, and the potential benefits of treatment outweigh the potential adverse events. The clinical experts explained that the risk of adverse events would be considered by individuals. They would expect most people to accept these risks and tolerate the adverse events, given the potential benefits of adding pembrolizumab to chemotherapy. The committee concluded that additional adverse events are associated with adding pembrolizumab to standard care, and these should be taken into account by patients and clinicians when considering treatment options.\n\n# Economic model\n\n## The company's economic model is acceptable for decision making\n\nThe company presented a 4‑state Markov model to estimate the cost effectiveness of chemotherapy plus pembrolizumab compared with chemotherapy plus placebo. The 4 health states were event-free, locoregional recurrence, distant metastasis and death. The ERG highlighted that the distant metastasis state does not differentiate between pre-progressed and post-progressed disease. The company explained that evidence is limited for triple-negative breast cancer. So including distinct states for pre- and post-progression in the distant metastasis health state would need unnecessary assumptions and add complexity and uncertainty. The ERG also highlighted that for people who had first-line metastatic treatment in the distant metastasis state, the company's model included the costs for second and subsequent line metastatic treatments as a lump sum. Because these treatment costs make up around a third of all costs in the chemotherapy arm, the ERG raised concerns around the lack of precision using this approach. The committee understood that the model structure was limited by the evidence available for triple-negative breast cancer. It concluded that although there were limitations with the model, these could not be addressed without increasing the model's complexity and uncertainty. So it concluded that the company's model is acceptable for decision making.\n\n# Assumptions in the economic model\n\n## It is appropriate to consider the full trial population in the economic model\n\nThe ERG highlighted the different hazard ratios for event-free survival from KEYNOTE‑522 for people having treatment in Europe and in the full trial population (see section 3.6). The ERG suggested that the Europe subgroup is more likely to be generalisable to the UK than the full trial population. So it preferred to use the hazard ratio from the Europe subgroup to represent pembrolizumab's efficacy in the model. The company used pembrolizumab's efficacy from the full trial population in its model. The committee agreed that it is appropriate to consider evidence within the cost-effectiveness model that reflects the population in the NHS. However, it agreed it is also important to assess the reliability of the subgroup results and discussed that KEYNOTE‑522 was not powered to show a difference across regions. The committee considered the clinical experts' view that there is no clear reason why event-free survival would be influenced by geographical region and that the full trial population is generalisable to UK clinical practice (see section 3.4 and section 3.6). Given this, the committee agreed that it was not appropriate to use results from the Europe subgroup which is not powered to show a difference in effect, when results from the full trial population, which is appropriately powered, are available. Therefore, the committee concluded that it was appropriate to use the results from the full trial population in the economic model.\n\n## The comparator treatment in KEYNOTE-522 is appropriate for use in the economic model\n\nThe comparator included in the company's model was aligned with the comparator used in KEYNOTE‑522 (see section 3.4). The ERG stated that this might not reflect NHS clinical practice. It highlighted that more people had doxorubicin than epirubicin as neoadjuvant chemotherapy in KEYNOTE‑522 and this may not reflect how frequently these chemotherapy agents are used in practice. The ERG highlighted that a subgroup analysis in KEYNOTE‑522 showed better efficacy for doxorubicin than epirubicin. The clinical experts explained that doxorubicin is not often used in clinical practice (see section 3.4) but it is still a reasonable comparator. The ERG also questioned if placebo monotherapy as adjuvant treatment was appropriate because some people may have capecitabine. The clinical experts explained that standard care does not typically include adjuvant treatment so placebo after surgery is an appropriate comparator (see section 3.2). The committee concluded that the comparator in KEYNOTE‑522 was appropriate for use in the economic model.\n\n## The ERG's approach to event-free survival extrapolation is methodologically appropriate, although it may be conservative\n\nExtrapolation of event-free survival Kaplan–Meier data from KEYNOTE‑522 was used to model transitions from the event-free health state to each of the other health states. The probability of the first event in each treatment arm being locoregional recurrence, distant metastasis or death was determined from KEYNOTE‑522. It was applied to the extrapolated event-free survival data to estimate the transition probabilities into each health state. The company used a log-normal curve for the chemotherapy plus placebo arm and a generalised gamma curve for the chemotherapy plus pembrolizumab arm. The ERG stated that, unless there are very strong arguments to not do so, survival extrapolation should use the same extrapolation curve in both treatment arms, as per NICE's Decision Support Unit technical support document 14. So it preferred to use a log-normal extrapolation of event-free survival in both arms because it did not consider that sufficient justification was provided for using different extrapolations for each treatment arm. The ERG was also concerned that in the company's model, the event-free survival rate accelerated within the extrapolated period, meaning the event-free survival gains are mostly from the unobserved extrapolated data. The company argued that it was appropriate to use different curves for each arm because chemotherapy and pembrolizumab have different mechanisms of action. It also stated that the log-normal curve for the chemotherapy plus pembrolizumab arm was inappropriate. This was because it did not show a plateau associated with a decrease in the number of progression events over time so would underestimate the pembrolizumab treatment effect. The clinical experts explained that most relapses of triple-negative breast cancer happen within the first 3\xa0years of diagnosis. There is increased certainty of longer-term survival for people whose disease has not relapsed by this time. So it is reasonable that the extrapolated curves for event-free survival should plateau after 3\xa0years. The committee concluded that the ERG's method of using the same extrapolation curve for each treatment arm was methodologically appropriate but this was likely to provide a conservative estimate of event-free survival.\n\n## Both data sources for estimating overall survival in the distant metastasis state are uncertain\n\nIn the model, the company used data on overall survival from KEYNOTE‑355 to estimate the transition probabilities from the distant metastasis state to death for people who had treatment for metastatic disease. KEYNOTE‑355 (n=882) is a randomised placebo-controlled trial in people with recurrent triple-negative inoperable or metastatic breast cancer. It compared chemotherapy plus pembrolizumab with chemotherapy plus placebo. The company used KEYNOTE‑355 data to estimate overall survival in the distant metastasis state because the data in KEYNOTE‑522 is immature. The ERG noted that there are differences in the observed survival between KEYNOTE‑522 and KEYNOTE‑355 so the populations in the studies may not be comparable. It preferred to use direct trial data from KEYNOTE‑522 to estimate transition probabilities in the distant metastasis state. The committee noted that KEYNOTE‑522 overall survival data for people whose disease has metastasised is immature, so is uncertain. However, it also noted the potential bias that could be introduced into the model by using data sourced from a different population. The committee concluded that there is uncertainty with both data sources for estimating overall survival in the distant metastasis state.\n\n## The utility values used in the model have a limited impact on the incremental cost-effectiveness ratio\n\nThe company's economic model used utility values sourced from EQ‑5D‑5L data from KEYNOTE‑522, mapped to EQ‑5D‑3L. The utility values were pooled across the chemotherapy plus pembrolizumab and the chemotherapy plus placebo arms for each health state. Event-free survival utilities were separated into values for being on and off treatment. The ERG highlighted that the utility values for the distant metastasis health state were relatively low compared with other studies, such as KEYNOTE‑355. However, it noted that this may be because of the small number of EQ‑5D‑5L questionnaires completed by people in KEYNOTE‑522 with disease that had metastasised. The ERG and the company did scenario analyses using utility data from other sources, which showed that the utility values had a very limited impact on the incremental cost-effectiveness ratio (ICER). The committee concluded that although there was some uncertainty around the validity of the utility values used in the model, it has a limited impact on the cost-effectiveness results.\n\n# Cost-effectiveness estimate\n\n## Adding pembrolizumab to standard care for early and locally advanced triple-negative breast cancer is likely to be cost effective\n\nThe company's model included the following assumptions:\n\nEstimating pembrolizumab efficacy from the full trial population (see section 3.9).\n\nUsing chemotherapy regimens as used in KEYNOTE‑522 in the treatment and comparator arm (see section 3.10).\n\nUsing a log-normal extrapolation of Kaplan-Meier data in the chemotherapy plus placebo arm (see section 3.11).\n\nUsing a generalised gamma extrapolation of Kaplan-Meier data in the chemotherapy plus pembrolizumab arm (see section 3.11).\n\nEstimating overall survival in the distant metastasis state using data from KEYNOTE‑355 (see section 3.12).\n\nEstimating utility values from EQ‑5D‑5L data from KEYNOTE‑522 (see section 3.13).The ERG's base case included some of the same assumptions, but included different assumptions on:\n\nEstimating pembrolizumab efficacy, for which it preferred to use the hazard ratio from the Europe subgroup (see section 3.9).\n\nThe choice of curve for extrapolation of Kaplan-Meier data in the chemotherapy plus pembrolizumab arm, for which it preferred to use a log-normal extrapolation (see section 3.11).\n\nThe source of overall survival data in the distant metastasis state, for which it preferred to use KEYNOTE‑522 data (see section 3.12).The committee considered that the full trial population results for event-free survival should be used in the model because it was uncertain why there were differences in effect seen in the Europe subgroup (see section 3.9). However, it agreed that other assumptions included in the ERG's base case were reasonable. It noted that the ERG presented an alternative base case using the full trial population. The committee concluded that its preferred assumptions were those in the ERG's alternative base case, using the hazard ratio for event-free survival from the full trial population. The ICERs cannot be reported here because of confidential commercial arrangements for subsequent treatments in the pathway. However, the ERG's alternative base case is below the range normally considered a cost-effective use of NHS resources. The committee discussed the unmet need for treatment options for triple-negative early or locally advanced breast cancer (see section 3.1). It also discussed that there could be potential cost savings to the NHS, which had not been included in the model, if the number of invasive breast surgery procedures was reduced (see section 3.3). Considering all these factors, pembrolizumab with chemotherapy is likely to be a cost-effective use of NHS resources.\n\n# Conclusion\n\n## Pembrolizumab is recommended\n\nThe committee noted that based on its preferred assumptions, pembrolizumab with chemotherapy is likely to be cost effective compared with chemotherapy alone (see section 3.14). There was some uncertainty, particularly about the long-term outcome benefits of adding pembrolizumab to standard care. However, because the committee preferred conservative assumptions for event-free and overall survival, it considered that pembrolizumab is likely to be at the lower end of the range normally considered a cost-effective use of NHS resources. So pembrolizumab with chemotherapy as neoadjuvant treatment, and then continued alone as adjuvant treatment, is recommended for use in the NHS as an option for adults with triple-negative:\n\nearly breast cancer at high risk of recurrence or\n\nlocally advanced breast cancer."}	https://www.nice.org.uk/guidance/ta851	Evidence-based recommendations on pembrolizumab (Keytruda) for neoadjuvant and adjuvant treatment of triple-negative early or locally advanced breast cancer in adults.
6374073d71f33e91d8ff1587bde8ff72c98c2bad	nice	Trifluridine–tipiracil for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma after 2 or more treatments	Trifluridine–tipiracil for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma after 2 or more treatments Evidence-based recommendations on trifluridine–tipiracil (Lonsurf) for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in adults after 2 or more treatments. # Recommendations Trifluridine–tipiracil is recommended, within its marketing authorisation, as an option for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in adults who have had 2 or more treatment regimens. It is only recommended if the company provides trifluridine–tipiracil according to the commercial arrangement. Why the committee made these recommendations This evaluation uses new cost-effectiveness estimates to update trifluridine–tipiracil for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma after 2 or more therapies (NICE technology appraisal guidance TA669). No new clinical evidence was reviewed. Standard treatment for metastatic gastric cancer and gastro-oesophageal junction adenocarcinoma, for most people who have had 2 or more treatments, is best supportive care. The clinical evidence suggests that people having trifluridine–tipiracil live longer compared with best supportive care. When taking into account the severity of the condition and its effect on quality and length of life, the most likely cost-effectiveness estimate is within the range that NICE normally considers an acceptable use of NHS resources. So, trifluridine–tipiracil is recommended.# Information about trifluridine–tipiracil # Marketing authorisation indication Trifluridine–tipiracil (Lonsurf, Servier) is indicated for 'monotherapy for the treatment of adult patients with metastatic gastric cancer including adenocarcinoma of the gastroesophageal junction, who have been previously treated with at least 2 prior systemic treatment regimens for advanced disease'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for trifluridine–tipiracil. # Price The list price of trifluridine–tipiracil is £500 per pack of 20 tablets containing 15 mg of trifluridine and 6.14 mg of tipiracil, and £666.67 per pack of 20 tablets containing 20 mg of trifluridine and 8.19 mg of tipiracil (excluding VAT; BNF online, accessed October 2022). The company has a commercial arrangement. This makes trifluridine–tipiracil available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The evaluation committee considered evidence submitted by Servier, a review of this submission by the external assessment group (EAG) and responses from stakeholders for the original appraisal. New cost-effectiveness estimates were submitted by Servier and considered for this update of NICE's technology appraisal guidance on trifluridine–tipiracil for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma after 2 or more therapies (TA669). See the committee papers for full details of the evidence. Unless otherwise indicated, gastric cancer refers to both gastric cancer and gastro-oesophageal junction adenocarcinoma. # Clinical management ## Treatment options The initial symptoms of gastric cancer are vague and similar to other stomach conditions, but for advanced disease they may include lack of appetite, weight loss, fluid in the abdomen and blood in the stool. The clinical experts estimated that life expectancy after 2 previous treatments is between 2 and 4 months in current practice. They explained that there is no standard treatment for previously treated metastatic gastric cancer but in clinical practice in the NHS in England, treatment is usually in line with the European Society for Medical Oncology (ESMO) guideline for gastric cancer. The clinical experts advised that paclitaxel is generally used after 1 treatment, and irinotecan may be used after 2 treatments but for most people it is not appropriate because of the risk of side effects. They estimated that third-line chemotherapy is used in about 10% of people, with most people having best supportive care alone. The committee was aware that the ESMO guideline had recently been updated to recommend trifluridine–tipiracil as a third-line treatment option for people with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. The committee noted that there was no patient expert submission for this appraisal, but the clinical experts explained that maintaining health-related quality of life is very important to people with metastatic gastric cancer. They advised that an oral treatment such as trifluridine–tipiracil would be preferred because it does not need many hospital visits, allowing people to spend more time at home. The committee concluded that there is an unmet need for third-line treatment options for gastric cancer. ## Comparators The company submitted cost-effectiveness analyses comparing trifluridine–tipiracil and best supportive care with placebo and best supportive care. It advised that there is a lack of evidence to support the use of third-line chemotherapy and that its expert advice suggested this is usually restricted to clinical trials. The committee recalled that third-line chemotherapy is appropriate but is used in only a small proportion of people in current practice, with most people having best supportive care alone (see section 3.1). The clinical experts explained that although there is no clear definition of best supportive care, it usually includes treatments to control symptoms such as pain. The committee concluded that the most appropriate comparator is best supportive care. # Clinical effectiveness ## Clinical trial evidence and generalisability The clinical evidence for trifluridine–tipiracil came from TAGS, a phase 3 randomised controlled trial. It compared trifluridine–tipiracil and best supportive care with placebo and best supportive care in 507 adults with metastatic gastric cancer (including 29% with gastro-oesophageal junction cancer) who had had at least 2 treatments for advanced disease, and who had an ECOG performance score of 0 or 1. The committee was aware of several issues that may impact the generalisability of the full intention-to-treat analysis from TAGS to the NHS in England: Of the full intention-to-treat population, 33% had had ramucirumab but this treatment is not available in the NHS in England (see NICE's technology appraisal guidance on ramucirumab for treating advanced gastric cancer or gastro-oesophageal junction adenocarcinoma previously treated with chemotherapy). The clinical experts explained that the subgroup of people who had not had ramucirumab is more likely to represent the population in the NHS in England. But they advised that having previous ramucirumab is not likely to affect the relative treatment effect of trifluridine–tipiracil. Of the full intention-to-treat population, 14% were from Japan. Census data in England and Wales suggest about 1.5% of people are categorised as 'other Asian', which is likely to include people from Japan. The EAG explained that in TAGS, patients from Japan had a longer median overall survival (6.3 months for trifluridine–tipiracil and 5.9 months for best supportive care) compared with people from other parts of the world (median overall survival 5.4 months for trifluridine–tipiracil and 3.3 months for best supportive care). It suggested that possible reasons for this are biological factors and differences in the treatment pathway.There were 63% of the full intention-to-treat population who had had 3 or more previous treatments. The clinical experts expected this to be less than 5% in clinical practice in England.In its original submission, the company used data from a subgroup of people from TAGS who had not had ramucirumab. The company highlighted that this subgroup included fewer people from Japan and fewer people who had 3 or more previous treatments than the full intention-to-treat population (the exact data are confidential and cannot be reported here). The committee noted that this subgroup still included a higher proportion of people from Japan than would be expected in England, which may make it less generalisable to NHS practice. In response to consultation, the company provided analyses using TAGS subgroup data from people who had had exactly 2 previous treatments (the third-line subgroup). The company stated that this subgroup represented most people who would have trifluridine–tipiracil in clinical practice. One analysis included data for people from all trial locations, while the other restricted the data to only include people who lived in Europe. The committee agreed that the data restricted to people who lived in Europe were likely to be generalisable to NHS practice. These data still provide a large enough sample size for robust analysis. It concluded that the third-line, European subgroup data from TAGS was acceptable for decision making. ## Propensity score analysis The EAG advised that the committee's preferred third-line, European subgroup (see section 3.3) had imbalances in patient characteristics between the 2 arms of the TAGS trial. Some of these could favour survival after treatment with trifluridine–tipiracil and some could favour survival after treatment with placebo (the exact numbers are confidential and cannot be reported here). The company accepted that any subgroup analysis may be at risk of imbalances in characteristics, but it felt there were no imbalances in verified prognostic factors in this analysis. After the second meeting, the committee requested additional analyses to adjust the third-line data for imbalances in: peritoneal metastases ECOG performance status intestinal or non-intestinal histology previous treatment with irinotecan, and region (not included in the Europe-only analysis).The EAG found the company's propensity score-based analyses reasonable, but noted that some uncertainty remained. This was because it was not clear whether all relevant characteristics had been included in the model. The committee understood that trifluridine–tipiracil improved overall survival compared with placebo and best supportive care in all unadjusted analyses. The company's adjusted analyses showed similar overall survival results (the exact data are confidential and cannot be reported here). The company explained that this was because of the small sample size and the 5 selected characteristics having opposing effects. The committee agreed that the company's rationale was acceptable, but there was still some uncertainty about whether all relevant factors were included in the analysis. However, the committee concluded that the adjusted analysis was acceptable, and took the uncertainty into account in its decision making. # Economic model ## Company's modelling approach The company included a partitioned survival cost-effectiveness model in its evidence submission. The model comprised 3 health states representing progression-free disease, progressed disease and death. Health-state occupancy over time was informed by survival functions from TAGS data. The EAG advised that the model was generally clear and appropriate. The committee concluded that the company's model was suitable for decision making. # Adverse events ## Neutropenia In TAGS, the most common side effects included nausea, anaemia, decreased appetite, vomiting, diarrhoea, fatigue, neutropenia, asthenia and thrombocytopenia. Anaemia was considerably more common in the trifluridine–tipiracil group than the placebo group (45% compared with 19%). Neutropenia was also more common (53% compared with 4%). The company included adverse events such as neutropenia in the model to capture their effect on health-related quality of life. The committee noted that in the summary of product characteristics for trifluridine–tipiracil, neutropenia was one of the most common side effects that led to treatment being stopped, delayed or interrupted. It concluded that neutropenia may affect health-related quality of life. ## Overall survival extrapolation The company extrapolated overall survival in both treatment arms using an accelerated failure time model, which included a dependent variable to capture the effect of treatment. This approach assumes that the relative treatment effect is constant over time. In its base-case analysis the company used a log-normal function that was applied for the entire duration of the model. The EAG explained that the Kaplan−Meier estimates from the intention-to-treat population, new analyses at consultation and analyses in the committee's preferred population (the third-line, European subgroup) all showed that trifluridine–tipiracil survival either crossed or almost converged with best supportive care survival. This indicates that the treatment effect was not constant over time. The committee heard that because of this, the EAG preferred separate functions that were fitted independently to each treatment arm. This had little difference in statistical fit compared with the dependent models. The company maintained its preference for the dependent model in its base-case analysis but accepted that other approaches may also be valid. The committee concluded that the model should use survival functions fitted independently to each trial arm to extrapolate overall survival. ## Full log-normal survival function The company used a log-normal function to extrapolate overall survival for the entire duration of the model in its base-case analysis. The clinical experts predicted that 20% to 25% of people survive to 6 months in current practice, which reduces to 10% to 15% at 1 year. The committee noted exploratory analyses that modelled overall survival using the relatively mature Kaplan−Meier estimates for the first 12 or 18 months of the model, then applied a parametric function to extrapolate beyond each timepoint. The EAG advised that using the Kaplan−Meier estimates was problematic because the timepoint when the observed data was replaced by the parametric function was arbitrary. Also, the available parametric functions had been estimated using the full duration of trial data rather than the end portion. The committee noted that the EAG's preferred method for extrapolating the overall survival was a parametric model used for the entire time horizon. It concluded that a full log-normal function was most plausible, and should be considered for decision making. # Trifluridine–tipiracil treatment duration ## Generalised gamma and Kaplan−Meier analysis The company's revised base-case analysis, using the committee's preferred approach (see section 3.4) used a generalised gamma function to model treatment duration, fitted to the adjusted TAGS third-line European subgroup. The committee noted that the Kaplan−Meier estimates showed that no patients were having trifluridine–tipiracil at 1 year. At the third meeting, the company confirmed that there were no other data on treatment duration for this population with metastatic gastric cancer. It also clarified that in the full TAGS population, the maximum time on trifluridine–tipiracil was around 1.2 years, indicating that very few people would be expected to remain on treatment for a long time. The EAG explained that it preferred to use an extrapolated function, rather than the Kaplan−Meier estimates, to better reflect uncertainty in the data. This is because in clinical practice there may be a small number of people who do stay on treatment for a long time, but this was not reflected in the Kaplan−Meier estimates. The EAG advised that the generalised gamma function was reasonable, but other parametric functions could not be ruled out based on their statistical fit to the data, including some that predicted more people having long-term treatment. The committee agreed that people are unlikely to remain on treatment with trifluridine–tipiracil for very long, and so functions with long tails were not appropriate. It agreed that the generalised gamma function was acceptable for decision making, but noted that using the Kaplan−Meier estimates may also be plausible. # Utility values ## Source of utility values The company's base-case utility values were 0.764 for the progression-free health state and 0.652 for progressed disease. These values came from TAGS data on EORTC QLQ‑C30. This is a disease-specific measure, mapped onto the generic EQ‑5D‑3L scale using an algorithm from a small Greek study that included people with non-metastatic gastric cancer. The committee was aware that at the clarification stage, the company did not provide cost-effectiveness results using alternative mapping studies from Versteegh et al. (2012) or Longworth et al. (2014), as requested by the EAG. The company clarified that this was because neither study was in gastric cancer and Versteegh et al. (2012) did not use the UK value set. The committee noted that the company's preferred utility values were higher than those used in NICE's technology appraisal guidance on ramucirumab, particularly for progressed disease (0.652 compared with 0.587). The utility values in that appraisal were based on EQ‑5D data from a trial (RAINBOW) and included people with metastatic disease after 1 previous treatment. The company did not consider those utility values appropriate because they did not account for correlation between utility scores for the same patient over time. The committee noted that the preferred utility values in the ramucirumab appraisal included data from multiple timepoints for the progression-free health state but not for progressed disease. The clinical experts advised that, in their opinion, the most appropriate data source would be the population from the TAGS trial who had at least 2 previous treatments, no previous treatment with ramucirumab and had good performance status. The committee concluded that the company's mapped utility values from TAGS were acceptable for decision making. ## Carer quality of life At consultation, the company highlighted a Turkish study of 72 patients with gastric cancer and 72 caregivers. This reported improvement in the carers' quality of life after a nursing care intervention. The company noted that the benefit for carers and families from delaying disease progression with trifluridine–tipiracil was not captured in its model. However, the committee concluded that there was no evidence that the quality-of-life gain would be significant and so carer quality-of-life improvement should not be considered in the model. # Severity modifier ## Highest QALY weighting For this update, the company provided evidence that metastatic gastric cancer after 2 or more treatments is a severe condition. The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company provided absolute and proportional quality-adjusted life year (QALY) shortfall estimates in line with NICE's health technology evaluations manual. Absolute QALY shortfall is the future health that is lost by people living with a condition, including quality and length of life, compared with the expected future health of people without the condition over their remaining lifetime. Proportional QALY shortfall represents the proportion of future health that is lost by people living with the condition, including quality and length of life. The company provided evidence for the committee's preferred population, the third-line European subgroup from the TAGS trial (see section 3.3). This population had a mean age of 62 and was 33.3% female. People with these characteristics without metastatic gastric cancer after 2 or more treatments would be expected to gain 11.69 QALYs. The company's model estimated that people with metastatic gastric cancer after 2 or more treatments who have best supportive care would be expected to gain 0.37 QALYs. The company used these estimates to calculate an absolute QALY shortfall of 11.3 and a proportional QALY shortfall of 0.97. The committee considered the advice about severity as a decision modifier, which allows it to apply a greater weight to the QALYs for technologies indicated for conditions with a high degree of severity. It noted that if either the absolute or the proportional QALY shortfall calculated falls on the cut-off between severity levels, the higher severity level will apply. The company stated that although the absolute QALY shortfall was less than 12, which would imply no QALY weight, the proportional QALY shortfall of 0.97 implies the highest QALY weight of 1.7. The EAG confirmed that the company's analyses had been implemented correctly and supported the use of the 1.7 QALY weight. The committee noted that uncertainty around inputs had not been fully explored. But it recognised that uncertainty had been explored in the original appraisal and that the new analyses were based on its preferred assumptions. So, the committee concluded that the highest severity weight of 1.7 applied to the QALYs was appropriate. # Cost-effectiveness estimates ## Company cost-effectiveness estimates The company's updated incremental cost-effectiveness ratio (ICER) for trifluridine–tipiracil compared with best supportive care for the third-line European subgroup was £29,347 per QALY gained, including the confidential commercial discount for trifluridine–tipiracil and a 1.7 QALY severity weight (see section 3.12). The committee noted that this analysis was based on its preferred assumptions, including the third-line European subgroup and the generalised gamma function for extrapolating trifluridine–tipiracil treatment duration. The committee concluded that the most plausible cost-effectiveness result was less than £30,000 per QALY gained. ## Recommended for routine use The committee considered that the acceptable decision-making threshold was £20,000 to £30,000 per QALY gained. The committee concluded that the most plausible ICER based on its preferred assumptions, was less than £30,000 per QALY gained. Therefore, trifluridine–tipiracil is recommended for routine use in the NHS. # Other factors ## Innovation The committee recalled the poor prognosis for people with metastatic gastric cancer and that there is an unmet need for treatment options after 2 or more treatments (see section 3.1). The company considered trifluridine–tipiracil to be innovative because it provides an alternative oral treatment option that increases overall survival. The committee recalled that trifluridine–tipiracil was clinically effective compared with best supportive care (see section 3.3), but it had not seen evidence of additional benefits that were not captured in the model. It concluded that all relevant benefits had been captured in the cost-effectiveness estimates. ## Equality issues The committee understood that no equalities issues were raised during scoping and technical engagement. It also noted that no potential equality issues were identified in the company submission. The committee concluded that no equalities issues were identified relevant to the recommendation.	{'Recommendations': 'Trifluridine–tipiracil is recommended, within its marketing authorisation, as an option for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in adults who have had 2\xa0or more treatment regimens. It is only recommended if the company provides trifluridine–tipiracil according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis evaluation uses new cost-effectiveness estimates to update trifluridine–tipiracil for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma after 2\xa0or more therapies (NICE technology appraisal guidance TA669). No new clinical evidence was reviewed.\n\nStandard treatment for metastatic gastric cancer and gastro-oesophageal junction adenocarcinoma, for most people who have had 2\xa0or more\xa0treatments, is best supportive care.\n\nThe clinical evidence suggests that people having trifluridine–tipiracil live longer compared with best supportive care. When taking into account the severity of the condition and its effect on quality and length of life, the most likely cost-effectiveness estimate is within the range that NICE normally considers an acceptable use of NHS resources. So, trifluridine–tipiracil is recommended.', 'Information about trifluridine–tipiracil': "# Marketing authorisation indication\n\nTrifluridine–tipiracil (Lonsurf, Servier) is indicated for 'monotherapy for the treatment of adult patients with metastatic gastric cancer including adenocarcinoma of the gastroesophageal junction, who have been previously treated with at least 2\xa0prior systemic treatment regimens for advanced disease'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for trifluridine–tipiracil.\n\n# Price\n\nThe list price of trifluridine–tipiracil is £500 per pack of 20\xa0tablets containing 15\xa0mg of trifluridine and 6.14\xa0mg of tipiracil, and £666.67 per pack of 20\xa0tablets containing 20\xa0mg of trifluridine and 8.19\xa0mg of tipiracil (excluding VAT; BNF online, accessed October\xa02022).\n\nThe company has a commercial arrangement. This makes trifluridine–tipiracil available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The evaluation committee considered evidence submitted by Servier, a review of this submission by the external assessment group (EAG) and responses from stakeholders for the original appraisal. New cost-effectiveness estimates were submitted by Servier and considered for this update of NICE's technology appraisal guidance on trifluridine–tipiracil for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma after 2\xa0or more therapies (TA669). See the committee papers for full details of the evidence.\n\nUnless otherwise indicated, gastric cancer refers to both gastric cancer and gastro-oesophageal junction adenocarcinoma.\n\n# Clinical management\n\n## Treatment options\n\nThe initial symptoms of gastric cancer are vague and similar to other stomach conditions, but for advanced disease they may include lack of appetite, weight loss, fluid in the abdomen and blood in the stool. The clinical experts estimated that life expectancy after 2\xa0previous treatments is between 2\xa0and 4\xa0months in current practice. They explained that there is no standard treatment for previously treated metastatic gastric cancer but in clinical practice in the NHS in England, treatment is usually in line with the European Society for Medical Oncology (ESMO) guideline for gastric cancer. The clinical experts advised that paclitaxel is generally used after 1\xa0treatment, and irinotecan may be used after 2\xa0treatments but for most people it is not appropriate because of the risk of side effects. They estimated that third-line chemotherapy is used in about 10% of people, with most people having best supportive care alone. The committee was aware that the ESMO guideline had recently been updated to recommend trifluridine–tipiracil as a third-line treatment option for people with an Eastern Cooperative Oncology Group (ECOG) performance score of 0\xa0or\xa01. The committee noted that there was no patient expert submission for this appraisal, but the clinical experts explained that maintaining health-related quality of life is very important to people with metastatic gastric cancer. They advised that an oral treatment such as trifluridine–tipiracil would be preferred because it does not need many hospital visits, allowing people to spend more time at home. The committee concluded that there is an unmet need for third-line treatment options for gastric cancer.\n\n## Comparators\n\nThe company submitted cost-effectiveness analyses comparing trifluridine–tipiracil and best supportive care with placebo and best supportive care. It advised that there is a lack of evidence to support the use of third-line chemotherapy and that its expert advice suggested this is usually restricted to clinical trials. The committee recalled that third-line chemotherapy is appropriate but is used in only a small proportion of people in current practice, with most people having best supportive care alone (see section\xa03.1). The clinical experts explained that although there is no clear definition of best supportive care, it usually includes treatments to control symptoms such as pain. The committee concluded that the most appropriate comparator is best supportive care.\n\n# Clinical effectiveness\n\n## Clinical trial evidence and generalisability\n\nThe clinical evidence for trifluridine–tipiracil came from TAGS, a phase\xa03 randomised controlled trial. It compared trifluridine–tipiracil and best supportive care with placebo and best supportive care in 507\xa0adults with metastatic gastric cancer (including 29% with gastro-oesophageal junction cancer) who had had at least 2\xa0treatments for advanced disease, and who had an ECOG performance score of 0\xa0or\xa01. The committee was aware of several issues that may impact the generalisability of the full intention-to-treat analysis from TAGS to the NHS in England:\n\nOf the full intention-to-treat population, 33% had had ramucirumab but this treatment is not available in the NHS in England (see NICE's technology appraisal guidance on ramucirumab for treating advanced gastric cancer or gastro-oesophageal junction adenocarcinoma previously treated with chemotherapy). The clinical experts explained that the subgroup of people who had not had ramucirumab is more likely to represent the population in the NHS in England. But they advised that having previous ramucirumab is not likely to affect the relative treatment effect of trifluridine–tipiracil.\n\nOf the full intention-to-treat population, 14% were from Japan. Census data in England and Wales suggest about 1.5% of people are categorised as 'other Asian', which is likely to include people from Japan. The EAG explained that in TAGS, patients from Japan had a longer median overall survival (6.3\xa0months for trifluridine–tipiracil and 5.9\xa0months for best supportive care) compared with people from other parts of the world (median overall survival 5.4\xa0months for trifluridine–tipiracil and 3.3\xa0months for best supportive care). It suggested that possible reasons for this are biological factors and differences in the treatment pathway.There were 63% of the full intention-to-treat population who had had 3\xa0or more previous treatments. The clinical experts expected this to be less than 5% in clinical practice in England.In its original submission, the company used data from a subgroup of people from TAGS who had not had ramucirumab. The company highlighted that this subgroup included fewer people from Japan and fewer people who had 3\xa0or more previous treatments than the full intention-to-treat population (the exact data are confidential and cannot be reported here). The committee noted that this subgroup still included a higher proportion of people from Japan than would be expected in England, which may make it less generalisable to NHS practice. In response to consultation, the company provided analyses using TAGS subgroup data from people who had had exactly 2\xa0previous treatments (the third-line subgroup). The company stated that this subgroup represented most people who would have trifluridine–tipiracil in clinical practice. One analysis included data for people from all trial locations, while the other restricted the data to only include people who lived in Europe. The committee agreed that the data restricted to people who lived in Europe were likely to be generalisable to NHS practice. These data still provide a large enough sample size for robust analysis. It concluded that the third-line, European subgroup data from TAGS was acceptable for decision making.\n\n## Propensity score analysis\n\nThe EAG advised that the committee's preferred third-line, European subgroup (see section\xa03.3) had imbalances in patient characteristics between the 2\xa0arms of the TAGS trial. Some of these could favour survival after treatment with trifluridine–tipiracil and some could favour survival after treatment with placebo (the exact numbers are confidential and cannot be reported here). The company accepted that any subgroup analysis may be at risk of imbalances in characteristics, but it felt there were no imbalances in verified prognostic factors in this analysis. After the second meeting, the committee requested additional analyses to adjust the third-line data for imbalances in:\n\nperitoneal metastases\n\nECOG performance status\n\nintestinal or non-intestinal histology\n\nprevious treatment with irinotecan, and\n\nregion (not included in the Europe-only analysis).The EAG found the company's propensity score-based analyses reasonable, but noted that some uncertainty remained. This was because it was not clear whether all relevant characteristics had been included in the model. The committee understood that trifluridine–tipiracil improved overall survival compared with placebo and best supportive care in all unadjusted analyses. The company's adjusted analyses showed similar overall survival results (the exact data are confidential and cannot be reported here). The company explained that this was because of the small sample size and the 5\xa0selected characteristics having opposing effects. The committee agreed that the company's rationale was acceptable, but there was still some uncertainty about whether all relevant factors were included in the analysis. However, the committee concluded that the adjusted analysis was acceptable, and took the uncertainty into account in its decision making.\n\n# Economic model\n\n## Company's modelling approach\n\nThe company included a partitioned survival cost-effectiveness model in its evidence submission. The model comprised 3\xa0health states representing progression-free disease, progressed disease and death. Health-state occupancy over time was informed by survival functions from TAGS data. The EAG advised that the model was generally clear and appropriate. The committee concluded that the company's model was suitable for decision making.\n\n# Adverse events\n\n## Neutropenia\n\nIn TAGS, the most common side effects included nausea, anaemia, decreased appetite, vomiting, diarrhoea, fatigue, neutropenia, asthenia and thrombocytopenia. Anaemia was considerably more common in the trifluridine–tipiracil group than the placebo group (45% compared with 19%). Neutropenia was also more common (53% compared with 4%). The company included adverse events such as neutropenia in the model to capture their effect on health-related quality of life. The committee noted that in the summary of product characteristics for trifluridine–tipiracil, neutropenia was one of the most common side effects that led to treatment being stopped, delayed or interrupted. It concluded that neutropenia may affect health-related quality of life.\n\n## Overall survival extrapolation\n\nThe company extrapolated overall survival in both treatment arms using an accelerated failure time model, which included a dependent variable to capture the effect of treatment. This approach assumes that the relative treatment effect is constant over time. In its base-case analysis the company used a log-normal function that was applied for the entire duration of the model. The EAG explained that the Kaplan−Meier estimates from the intention-to-treat population, new analyses at consultation and analyses in the committee's preferred population (the third-line, European subgroup) all showed that trifluridine–tipiracil survival either crossed or almost converged with best supportive care survival. This indicates that the treatment effect was not constant over time. The committee heard that because of this, the EAG preferred separate functions that were fitted independently to each treatment arm. This had little difference in statistical fit compared with the dependent models. The company maintained its preference for the dependent model in its base-case analysis but accepted that other approaches may also be valid. The committee concluded that the model should use survival functions fitted independently to each trial arm to extrapolate overall survival.\n\n## Full log-normal survival function\n\nThe company used a log-normal function to extrapolate overall survival for the entire duration of the model in its base-case analysis. The clinical experts predicted that 20% to 25% of people survive to 6\xa0months in current practice, which reduces to 10% to 15% at 1\xa0year. The committee noted exploratory analyses that modelled overall survival using the relatively mature Kaplan−Meier estimates for the first 12\xa0or 18\xa0months of the model, then applied a parametric function to extrapolate beyond each timepoint. The EAG advised that using the Kaplan−Meier estimates was problematic because the timepoint when the observed data was replaced by the parametric function was arbitrary. Also, the available parametric functions had been estimated using the full duration of trial data rather than the end portion. The committee noted that the EAG's preferred method for extrapolating the overall survival was a parametric model used for the entire time horizon. It concluded that a full log-normal function was most plausible, and should be considered for decision making.\n\n# Trifluridine–tipiracil treatment duration\n\n## Generalised gamma and Kaplan−Meier analysis\n\nThe company's revised base-case analysis, using the committee's preferred approach (see section\xa03.4) used a generalised gamma function to model treatment duration, fitted to the adjusted TAGS third-line European subgroup. The committee noted that the Kaplan−Meier estimates showed that no patients were having trifluridine–tipiracil at 1\xa0year. At the third meeting, the company confirmed that there were no other data on treatment duration for this population with metastatic gastric cancer. It also clarified that in the full TAGS population, the maximum time on trifluridine–tipiracil was around 1.2\xa0years, indicating that very few people would be expected to remain on treatment for a long time. The EAG explained that it preferred to use an extrapolated function, rather than the Kaplan−Meier estimates, to better reflect uncertainty in the data. This is because in clinical practice there may be a small number of people who do stay on treatment for a long time, but this was not reflected in the Kaplan−Meier estimates. The EAG advised that the generalised gamma function was reasonable, but other parametric functions could not be ruled out based on their statistical fit to the data, including some that predicted more people having long-term treatment. The committee agreed that people are unlikely to remain on treatment with trifluridine–tipiracil for very long, and so functions with long tails were not appropriate. It agreed that the generalised gamma function was acceptable for decision making, but noted that using the Kaplan−Meier estimates may also be plausible.\n\n# Utility values\n\n## Source of utility values\n\nThe company's base-case utility values were 0.764 for the progression-free health state and 0.652 for progressed disease. These values came from TAGS data on EORTC QLQ‑C30. This is a disease-specific measure, mapped onto the generic EQ‑5D‑3L scale using an algorithm from a small Greek study that included people with non-metastatic gastric cancer. The committee was aware that at the clarification stage, the company did not provide cost-effectiveness results using alternative mapping studies from Versteegh et al. (2012) or Longworth et al. (2014), as requested by the EAG. The company clarified that this was because neither study was in gastric cancer and Versteegh et al. (2012) did not use the UK value set. The committee noted that the company's preferred utility values were higher than those used in NICE's technology appraisal guidance on ramucirumab, particularly for progressed disease (0.652 compared with 0.587). The utility values in that appraisal were based on EQ‑5D data from a trial (RAINBOW) and included people with metastatic disease after 1\xa0previous treatment. The company did not consider those utility values appropriate because they did not account for correlation between utility scores for the same patient over time. The committee noted that the preferred utility values in the ramucirumab appraisal included data from multiple timepoints for the progression-free health state but not for progressed disease. The clinical experts advised that, in their opinion, the most appropriate data source would be the population from the TAGS trial who had at least 2\xa0previous treatments, no previous treatment with ramucirumab and had good performance status. The committee concluded that the company's mapped utility values from TAGS were acceptable for decision making.\n\n## Carer quality of life\n\nAt consultation, the company highlighted a Turkish study of 72\xa0patients with gastric cancer and 72\xa0caregivers. This reported improvement in the carers' quality of life after a nursing care intervention. The company noted that the benefit for carers and families from delaying disease progression with trifluridine–tipiracil was not captured in its model. However, the committee concluded that there was no evidence that the quality-of-life gain would be significant and so carer quality-of-life improvement should not be considered in the model.\n\n# Severity modifier\n\n## Highest QALY weighting\n\nFor this update, the company provided evidence that metastatic gastric cancer after 2\xa0or more treatments is a severe condition. The severity modifier allows the committee to give more weight to health benefits in the most severe conditions. The company provided absolute and proportional quality-adjusted life year (QALY) shortfall estimates in line with NICE's health technology evaluations manual. Absolute QALY shortfall is the future health that is lost by people living with a condition, including quality and length of life, compared with the expected future health of people without the condition over their remaining lifetime. Proportional QALY shortfall represents the proportion of future health that is lost by people living with the condition, including quality and length of life. The company provided evidence for the committee's preferred population, the third-line European subgroup from the TAGS trial (see section\xa03.3). This population had a mean age of 62 and was 33.3% female. People with these characteristics without metastatic gastric cancer after 2\xa0or more treatments would be expected to gain 11.69\xa0QALYs. The company's model estimated that people with metastatic gastric cancer after 2\xa0or more treatments who have best supportive care would be expected to gain 0.37\xa0QALYs. The company used these estimates to calculate an absolute QALY shortfall of 11.3 and a proportional QALY shortfall of 0.97. The committee considered the advice about severity as a decision modifier, which allows it to apply a greater weight to the QALYs for technologies indicated for conditions with a high degree of severity. It noted that if either the absolute or the proportional QALY shortfall calculated falls on the cut-off between severity levels, the higher severity level will apply. The company stated that although the absolute QALY shortfall was less than 12, which would imply no QALY weight, the proportional QALY shortfall of 0.97 implies the highest QALY weight of 1.7. The EAG confirmed that the company's analyses had been implemented correctly and supported the use of the 1.7\xa0QALY weight. The committee noted that uncertainty around inputs had not been fully explored. But it recognised that uncertainty had been explored in the original appraisal and that the new analyses were based on its preferred assumptions. So, the committee concluded that the highest severity weight of 1.7 applied to the QALYs was appropriate.\n\n# Cost-effectiveness estimates\n\n## Company cost-effectiveness estimates\n\nThe company's updated incremental cost-effectiveness ratio (ICER) for trifluridine–tipiracil compared with best supportive care for the third-line European subgroup was £29,347 per QALY gained, including the confidential commercial discount for trifluridine–tipiracil and a 1.7\xa0QALY severity weight (see section\xa03.12). The committee noted that this analysis was based on its preferred assumptions, including the third-line European subgroup and the generalised gamma function for extrapolating trifluridine–tipiracil treatment duration. The committee concluded that the most plausible cost-effectiveness result was less than £30,000 per QALY gained.\n\n## Recommended for routine use\n\nThe committee considered that the acceptable decision-making threshold was £20,000 to £30,000 per QALY gained. The committee concluded that the most plausible ICER based on its preferred assumptions, was less than £30,000 per QALY gained. Therefore, trifluridine–tipiracil is recommended for routine use in the NHS.\n\n# Other factors\n\n## Innovation\n\nThe committee recalled the poor prognosis for people with metastatic gastric cancer and that there is an unmet need for treatment options after 2\xa0or more treatments (see section\xa03.1). The company considered trifluridine–tipiracil to be innovative because it provides an alternative oral treatment option that increases overall survival. The committee recalled that trifluridine–tipiracil was clinically effective compared with best supportive care (see section\xa03.3), but it had not seen evidence of additional benefits that were not captured in the model. It concluded that all relevant benefits had been captured in the cost-effectiveness estimates.\n\n## Equality issues\n\nThe committee understood that no equalities issues were raised during scoping and technical engagement. It also noted that no potential equality issues were identified in the company submission. The committee concluded that no equalities issues were identified relevant to the recommendation."}	https://www.nice.org.uk/guidance/ta852	Evidence-based recommendations on trifluridine–tipiracil (Lonsurf) for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in adults after 2 or more treatments.
af9aba7e6eeaa91bcf4772012d5b7093ae71b7cd	nice	Esketamine nasal spray for treatment-resistant depression	Esketamine nasal spray for treatment-resistant depression Evidence-based recommendations on esketamine (Spravato) for treatment-resistant depression in adults. # Recommendations This guidance only includes recommendations for treatment-resistant depression. Esketamine nasal spray for treating major depressive disorder is being evaluated in NICE's technology appraisal guidance on esketamine for treating major depressive disorder in adults at imminent risk for suicide. Esketamine nasal spray with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is not recommended, within its marketing authorisation, for treatment-resistant depression that has not responded to at least 2 different antidepressants in the current moderate to severe depressive episode in adults. This recommendation is not intended to affect treatment with esketamine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations The company positioned esketamine nasal spray for people who have had at least 3 antidepressants before, with or without another treatment like lithium or an antipsychotic medicine. This is narrower than the marketing authorisation, and also how clinical experts advised esketamine would likely be used in NHS practice. The clinical evidence at this positioning is uncertain because it only considers a small number of people from the full clinical trial population. But it suggests that for people who have had at least 3 antidepressants with or without another treatment, esketamine with an SSRI or SNRI is likely more effective than placebo with an SSRI or SNRI. Because the trials were short the long-term benefits of esketamine are uncertain. Also, the trial evidence excluded people with characteristics of depression like psychosis or recent suicidal ideation with intent. This limits how well the evidence applies to the NHS, because people having treatment for depression in the NHS may have psychosis or recent suicidal ideation with intent. The clinical uncertainty means the economic modelling is also uncertain, including: how treatment-resistant depression was modelled how long people would take esketamine for the costs of using esketamine in the NHS. The limitations in the clinical evidence and economic model mean it is not possible to determine a reliable cost-effectiveness estimate. Esketamine is unlikely to be an acceptable use of NHS resources, so it is not recommended. Further research is recommended to address some of the uncertainties.# Information about esketamine # Marketing authorisation indication Esketamine nasal spray (Spravato, Janssen) with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated 'for adults with treatment-resistant major depressive disorder who have not responded to at least 2 different treatments with antidepressants in the current moderate to severe depressive episode'. The scope of this appraisal is only for this indication. # Dosage in the marketing authorisation The dosage schedule for esketamine is available in the summary of product characteristics for esketamine. # Price The device is single use and delivers 28 mg of esketamine in 2 sprays, one 14 mg spray per nostril. The list prices are as follows (excluding VAT; BNF online, accessed April 2022): £163 for a 28 mg dose (one 28 mg device) £326 for a 56 mg dose (two 28 mg devices) £489 for an 84 mg dose (three 28 mg devices).The company had a commercial arrangement, which would have applied if the technology had been recommended.# Committee discussion The appraisal committee considered evidence submitted by Janssen, reviews of these submissions by the evidence review group (ERG), NICE's technical report, and responses from stakeholders from 2 consultation documents. See the committee papers for full details of the evidence. # The condition and current treatment ## Treatment-resistant depression has a negative effect on people The patient experts explained that treatment-resistant depression has a substantial burden on all aspects of life, with a range of symptoms. The patient experts emphasised that people with treatment-resistant depression often have feelings of hopelessness, fear and despair. This can affect the person's family and carers. The clinical expert noted that the lives of children of people with treatment-resistant depression are also affected. The committee concluded that the condition has a negative effect on people, their families and carers. ## There is an unmet need for effective treatment options The patient experts explained that people with treatment-resistant depression often feel hopeless because treatments are ineffective. The clinical expert noted that people will try different courses of treatments to alleviate symptoms. The patient experts highlighted that, when multiple courses of treatment do not work, the feelings of hopelessness get worse. They added that this was an inherent aspect of the 'treatment-resistant' nature of the condition. A patient expert who had recovered from treatment-resistant depression emphasised the importance of independence and return of character upon remission. The clinical expert noted that a large proportion of people keep taking antidepressants that are not working, sometimes for a year or more. The committee concluded that the effectiveness of current treatments for treatment-resistant depression is limited and that there is an unmet need for new treatment options. # Treatment pathway and comparator ## Current clinical practice includes several different types of treatment The company submission defined treatment-resistant depression as 'people with major depressive disorder who fail to respond to 2 different oral antidepressants'. It included the recommended treatment pathway for this population from NICE's guideline on depression. Based on the guideline, NICE's esketamine appraisal scope and the company submission, the treatment options for people with treatment-resistant depression include: -ral treatments such as sertraline, citalopram, fluoxetine, venlafaxine, vortioxetine, mirtazapine, amitriptyline and monoamine oxidase inhibitors augmentation therapy (when an antidepressant is used with a non-antidepressant), for example, an antidepressant with lithium or an antidepressant with an antipsychotic treatment combination therapy (an antidepressant with another antidepressant) electroconvulsive therapy (ECT).NICE's guideline on depression also includes cognitive behavioural therapy (CBT) and other psychological therapies as options combined with the above treatments. However, the company noted that the treatment pathway in clinical practice is different to the guideline. The clinical expert explained that the treatment pathway for treatment-resistant depression can vary between services across the UK. They explained that, in general, most people with treatment-resistant depression have 3 to 4 standard oral antidepressant treatments from their GP. Only a small proportion (company estimate of 9.6%) are referred to a psychiatrist. Then, the first treatment choice is normally to optimise the dose of oral antidepressant or switch to a new oral treatment. Then 1 or 2 trials of augmentation therapy, with an antipsychotic drug or lithium combination therapy, would be considered before ECT. The committee acknowledged that the summary of product characteristics (SPC) states that esketamine nasal spray (from now, esketamine) must be prescribed by a psychiatrist. The clinical expert noted that people who have been referred to a psychiatrist are likely to be at risk of suicide or have symptoms that have not responded to any treatments for an extended period. The committee concluded that NICE's guideline on depression may not represent clinical practice and multiple further lines of treatment are considered for treatment-resistant depression. ## Esketamine is likely to be used later in the treatment pathway because it has a higher treatment burden than oral antidepressants The clinical expert explained that esketamine has a higher treatment burden than oral antidepressants. A person having esketamine would have to attend hospital or a suitable community health centre site twice a week and then weekly or every 2 weeks for some time, for approximately 2 hours or more each visit. Treatment-resistant depression is characterised by a lack of energy and motivation so this may not suit all people. Travel to and from the hospital may be difficult because it is not possible to drive after taking esketamine. So, carer support may be needed. For these reasons, the clinical expert considered that esketamine would be used later in the treatment pathway than it was in the clinical evidence, for depression that is more severe and more treatment resistant. This would be after 1 or 2 augmentation therapies. The committee noted that in clinical practice having 1 or 2 augmentation therapies would happen over several years. After the second consultation, consultees confirmed that the appropriate positioning for esketamine was after 1 to 2 augmentation therapies. The committee concluded that the treatment burden, combined with the administration and monitoring concerns (see section 3.18), would mean esketamine is used later in the treatment pathway. ## The 3 or more treatments and 3 or more treatments and augmentation subgroups are appropriate Treatment options for treatment-resistant depression depend on a person's treatment history, response to treatments and their preferences. Initially the company provided evidence for people whose depression had not responded to at least 2 treatments. But at the fourth committee meeting, the company provided evidence for 2 subgroups: depression that had not responded to at least 3 treatments in the current episode (from now, 3 or more treatments subgroup) depression that had not responded to 3 or more treatments and augmentation therapy in the current episode (from now, 3 or more treatments and augmentation subgroup).The company explained that the use of esketamine in these subgroups fulfils an unmet need for an option for people whose depression has not responded to several treatment options and where there is a high burden of illness. The committee recalled that the patient expert expressed feelings of hopelessness when depression does not respond to multiple courses of treatment. The committee considered that the burden of illness does increase at later lines of treatment so the 3 or more treatments and augmentation subgroup is the most appropriate positioning for esketamine. The committee concluded that it was appropriate to consider both subgroups based on the increased uncertainty of the evidence for later lines of therapy. ## Placebo with oral antidepressants may not be the most relevant comparator for the treatment subgroups The company submission included oral antidepressants as comparators, stating that these were the most common treatments for treatment-resistant depression and that they were the comparators used in the trials. The trials compared esketamine plus a newly started oral antidepressant with placebo plus a newly started oral antidepressant. The clinical experts highlighted that it does not reflect clinical practice to start a new oral antidepressant at the same time as esketamine. The committee noted that different treatments are used at different times and that esketamine may be used later in the treatment pathway (see section 3.3 and section 3.4). The clinical expert noted that esketamine may be used as a preferable alternative to ECT. Consultees commented that ECT would most often be offered to people who are more acutely unwell and whose depression may have psychotic characteristics. But esketamine would be used with caution in these situations as described in the SPC. The company provided a network meta-analysis of esketamine compared with all comparators for the acute phase of treatment (the time frame that measures initial response to a treatment). However, the company and ERG noted there was substantial heterogeneity in the study design, inclusion criteria and time of outcome measurement, because of a lack of available evidence, which made the results unreliable. The committee concluded that the results comparing esketamine with some of the relevant comparators listed in the scope, such as combination or augmentation therapy and ECT, were highly uncertain. So, it considered only the results from the trials. At the fourth committee meeting, the company did not update the comparators despite changing the proposed position of esketamine in the treatment pathway. The ERG noted that an augmentation therapy could be the appropriate comparator for the 3 or more treatments subgroup, because an augmentation therapy was included in the company's next line of treatment. The committee also noted that oral antidepressants would not be the only comparators in clinical practice. The committee concluded that the appropriate comparators for esketamine were highly uncertain but likely included augmentation therapy. It further concluded that it was unable to assess the relative effectiveness of esketamine compared with augmentation therapy based on the comparative evidence available. ## The effect of using psychological therapy with drug treatments is an unresolvable uncertainty with the evidence available The patient expert explained that psychological therapy can help with developing coping strategies and alleviate cognitive symptoms. An expert from NICE's guideline on depression noted that psychological therapies were not included as comparators or with combination treatments in the company's submission. The clinical expert explained that CBT is used with drug treatment to treat depression. But not all people with depression can effectively engage with CBT because of the severity of their physical and cognitive symptoms. A patient expert suggested that treatment with esketamine may improve symptoms for enough time for people to engage with CBT. But the clinical expert added that, because of the potential dissociative effects of esketamine treatment, someone would not be able to have psychological therapy immediately after having esketamine. The company clarified that people taking esketamine cannot have psychological therapy at the same time as having esketamine at their clinic visits, but could have therapy on a different day. At consultation, some consultees commented that there is limited evidence for the efficacy of psychological therapies in treating treatment-resistant depression and that including them was not considered for other pharmacological interventions. But in the fourth committee meeting, a patient expert added that they found intensive psychological therapies more useful than pharmacological treatments. However, the provision of intensive psychological therapies is inconsistent in the NHS. The patient expert noted that introducing more pharmacological treatments should not reduce other, already inconsistently provided, resources such as psychological therapies. The committee concluded that psychological therapies are an adjunctive therapy and a relevant part of the treatment pathway. But it noted that their effect would likely be variable depending on the treatment population and severity of depressive symptoms. It considered the estimation of clinical effectiveness of combining psychological therapies with esketamine treatment to be an unresolvable uncertainty with the evidence available. # Clinical effectiveness ## The results from the flexible dose of esketamine in TRANSFORM-2 are the main source of randomised evidence The company's key clinical effectiveness evidence came from 2 randomised phase 3 trials, TRANSFORM‑2 and SUSTAIN‑1. The company also provided supporting evidence from esketamine trials with different doses and populations (TRANSFORM‑1 and TRANSFORM‑3) and from 2 long-term safety studies (SUSTAIN‑2 and SUSTAIN‑3). The key trials were in adults aged 18 to 64 with treatment-resistant depression and compared: a flexible dose of esketamine plus oral antidepressant with placebo plus oral antidepressant.TRANSFORM‑2 provided randomised evidence for the acute phase of treatment for the 4‑week induction phase of the study, measuring symptom response and remission rates. SUSTAIN‑1 provided longer-term evidence about the continuation and maintenance of esketamine treatment. This was for people whose symptoms responded or people whose symptoms went into remission and were randomised to stop treatment. It measured symptom relapse rates. People could take part in SUSTAIN‑1 as new participants or they could transfer from TRANSFORM‑1 or TRANSFORM‑2 if their depression was in stable remission or stable response. Evidence for acute treatment of depression in people aged 65 and over came from TRANSFORM‑3, although this also included a lower starting dose of 28 mg, the same as in the SPC. The committee noted that the dose in TRANSFORM‑1 was a fixed regimen dose. The committee considered all of the clinical evidence, and noted that TRANSFORM‑1 and TRANSFORM‑3 did not show statistically significant improvements in outcomes for esketamine plus oral antidepressant compared with placebo plus oral antidepressant. ## MADRS is used to measure depression severity and treatment effect The Montgomery-Asberg Depression Rating Scale (MADRS) measures severity of depression. It is scored between 0 and 60, 0 meaning no depressive symptoms. Primary outcomes of response and remission in TRANSFORM‑2 and relapse rates in SUSTAIN‑1 were measured using MADRS. Moderate to severe depression was defined in TRANSFORM 2 as a MADRS score of 28 or more. The mean baseline MADRS score was around 37. Symptom response was defined as a reduction in score of 50% or more from baseline. The clinical expert explained that this is a standard criterion for response. Remission was defined as a MADRS score of 12 or less with minimal or no symptoms. The clinical expert considered that remission is normally measured by a MADRS score of 10 or less (as in NICE's technology appraisal guidance on vortioxetine) but that this would not substantially affect the results. Relapse was defined as a MADRS score of 22 or more for 2 consecutive assessments or other clinically relevant event such as hospitalisation for depression. Recovery was defined as symptoms remaining in remission for about 9 months and recurrence was defined as depression relapsing after recovery. Stable response and remission were also used to define entry criteria for SUSTAIN‑1. These were the same definitions as above, but remission criteria had to be met for 3 out of the 4 weeks before randomisation and response criteria had to be met for the last 2 weeks before randomisation. The clinical expert noted that MADRS is non-linear, meaning that a change in score at the lower end of the scale does not mean the same, in terms of clinical importance, as a change in score at the higher end of the scale. The committee noted that remission and relapse are fixed to MADRS, but response measurement depends on the score at baseline, which complicates interpretation. The committee also noted that the MADRS score used for relapse in SUSTAIN‑1 (22 or more) was not the same as the MADRS score for moderate to severe depression used in the selection criteria for TRANSFORM‑2 (28 or more). This affected the health state utility values and transitions in the economic model (see section 3.26 and section 3.21). The committee took this into account in its decision making. ## Trial data suggests that esketamine is likely more effective than the comparator in the 3 or more treatments subgroup but the evidence is uncertain The company initially positioned esketamine for people whose depression had not responded to at least 2 different antidepressants. For this population the adjusted mean reduction in MADRS score from baseline was 19.8 for esketamine and 15.8 for placebo plus oral antidepressant in TRANSFORM‑2. At the second committee meeting, the committee considered that it was difficult to distinguish the placebo response from the true treatment effect in the trial (see section 3.13). Also, the trial had a short 4‑week duration (see section 3.14). The committee concluded that it was unclear how effective esketamine was in the entire population. In response to the second consultation, the company provided this same trial data divided into 2 specific subgroups based on number of previous treatments. The company considered this analysis confidential and so it cannot be reported here. The company considered that the relative treatment effect of esketamine is greater in the 3 or more treatments subgroup than the full population. The ERG considered that the increased treatment effect for esketamine in the 3 or more treatments subgroup could be because of a lessened response in the placebo plus oral antidepressant arm. The committee noted that NICE's guide to the methods of technology appraisal 2013 (section 5.10.1) states a 'subgroup should be clearly defined and should preferably be identified on the basis of an expectation of differential clinical or cost effectiveness because of known, biologically plausible mechanisms'. The clinical expert considered that the difference in subgroups was plausible and would be expected, because a newly started oral antidepressant would likely be less effective in the 3 or more treatments subgroup than in the entire population. The committee considered that the evidence of benefit for esketamine in the full treatment population was driven by the change in MADRS score from baseline in the 3 or more treatments subgroup. However, it noted the following uncertainties with the subgroup analysis: The relatively small size of the 3 or more treatments subgroup and overall low patient numbers (the exact patient numbers are confidential and cannot be reported here). People in the 3 or more treatments subgroup in the trial might have different characteristics of depression than those expected to take esketamine in clinical practice (see section 3.16).In response to consultation, the company pooled and weighted clinical data from TRANSFORM‑2 and TRANSFORM‑3 (from now referred to as pooled TRANSFORM studies) for the 3 or more treatments subgroup. The NHS England clinical adviser noted that TRANSFORM‑3 was a smaller study than TRANSFORM‑2 with a 4‑week treatment phase. The committee considered there was still substantial uncertainty associated with the clinical evidence for esketamine but it is likely more effective than the comparator in the 3 or more treatments subgroup. ## The adjusted trial evidence for esketamine's benefit in the 3 or more treatments and augmentation subgroup is highly uncertain The company used the relative treatment effect between the 3 or more treatments subgroup and the 3 or more treatments and augmentation subgroup in SUSTAIN‑2, a long-term safety study. The proportional treatment effect was applied to the esketamine arm from the 3 or more treatments subgroup from the pooled TRANSFORM studies, generating an estimate of effectiveness for the esketamine arm in the 3 or more treatments and augmentation subgroup. The company maintained the efficacy from the pooled TRANSFORM studies for the oral antidepressant plus placebo arm. The ERG noted the effect of augmentation was unclear from the evidence provided and the difference in treatment effect between the esketamine arm and oral antidepressant plus placebo arm was uncertain. The ERG was also unclear why the company used the relative treatment effect from SUSTAIN‑2 instead of estimates from the TRANSFORM studies. The committee recalled the uncertainty about the comparators for both treatment subgroups. It noted that if the comparator for the 3 or more treatments and augmentation subgroup was not an oral antidepressant the effectiveness of the comparator could be underestimated. The committee concluded that the adjustment to the trial evidence to establish the benefit of esketamine in the 3 or more treatments and augmentation subgroup was highly uncertain. ## There is supportive evidence from 2 non-randomised studies in Europe In its response to consultation, the company provided data from 2 real-world studies to support the evidence for esketamine's treatment efficacy. One was a retrospective, observational study of 160 people (157 people were included in the analysis) taking esketamine who had treatment-resistant depression and who had an average of 2 suicide attempts during their life. The other study was a compassionate use study in Spain of 32 people whose depression had not responded to 2 or more antidepressants, 1 augmentation therapy and a non-pharmacological therapy. The company acknowledged there were a low number of people in both studies. The observational study showed a decrease in MADRS scores from baseline over 6 months. However, this was a single-arm observational study so there were no estimations of the effects of a comparator treatment. The ERG was unclear how the studies would overcome concerns regarding the generalisability of esketamine to the NHS. The committee acknowledged the effort of the company to identify additional supporting evidence but noted the low numbers of people in the studies and limitations of the observational evidence. # Limitations in the clinical evidence ## It is not appropriate to adjust the efficacy estimates of the comparator arm in the trials For the full population, the company considered that the efficacy estimates (response and remission) for the placebo plus oral antidepressant arm of the TRANSFORM‑2 trial were high compared with other studies considering depression. The company suggested a post-hoc adjustment of the TRANSFORM‑2 data to account for some of these differences. The committee considered the reasons for the high placebo response rate: In the trial, people visited the clinic more than in clinical practice. In the 4 weeks, people who had esketamine had 8 clinic visits. People who had the placebo nasal spray also had 8 clinic visits to preserve blinding. However, the company estimated that in clinical practice people taking oral antidepressants would only have 2 visits with healthcare professionals over a 4‑week period. The clinical expert highlighted that increased clinical contact could increase the effect of treatment. The committee considered that the additional clinical contact involved in administering esketamine included support from mental health nurses and establishing relationships. A patient expert noted this was an important part of treatment (see section 3.35). The committee noted that planned and structured clinical contact improves outcomes and that in NHS practice oral antidepressant treatment is ideally combined with other psychological therapies, which would also be structured. The expert from NICE's guideline on depression considered that the efficacy estimates in the placebo plus oral antidepressant arm seemed higher than expected. The ERG considered it inappropriate to apply adjustment to the placebo plus oral antidepressant arm because it is impossible to be confident about the placebo effect associated with esketamine in clinical practice. The committee concluded that the trial design may have increased clinical contact but there was no evidence this would cause the placebo response. It also concluded that any adjustment to account for clinical contact was not appropriate because of the risk of bias. In the trial, people may have had a high expectation of esketamine because it has a novel treatment mechanism. But the committee considered that blinding could be an issue in the trials. This is because for people having placebo plus oral antidepressant, the absence of psychoactive effects and other effects expected with esketamine could lead to consequent negative expectations and a lower response to treatment. So the true treatment effect is unclear if the blinding was not preserved, and adjustment of a placebo effect could lead to unknown biases. In the trial, people's symptoms also responded to the new oral antidepressant given alongside placebo. The committee noted that in clinical practice, oral antidepressants would not be newly started at the same time as esketamine, because it is not clinical practice to try 2 new therapies at the same time. So any response from trying the new oral antidepressant is difficult to separate from the treatment effect of esketamine. The committee noted that for the 3 or more treatments subgroup, a reduced response to the new oral antidepressant was likely to explain the lessened response of the comparator arm (see section 3.10). So any adjustment of placebo response could also account for this effect with unknown bias.The committee concluded that the randomised design of the trial helps to mitigate for the placebo response. So it was not appropriate to adjust the efficacy estimates of the placebo plus oral antidepressant arm in the trials. Any adjustment would not explore all potential sources of difference between treatment arms so could introduce bias. ## The response and remission evidence from the TRANSFORM studies should be considered with caution when used in the economic model For the full population with treatment-resistant depression, TRANSFORM‑2 measured a statistically significant difference in MADRS score after 28 days between esketamine plus newly started oral antidepressant compared with placebo plus newly started oral antidepressant. The committee noted a separation of treatment effect for the full trial population after 2 days (or 1 treatment), which remained for the duration of the 4 weeks. The NHS England clinical adviser added that the treatment benefit of esketamine in TRANSFORM‑3 was not statistically significant compared with placebo plus oral antidepressant. The NHS clinical adviser also stated that no rapid effect of esketamine was observed, with a separation of treatment effect compared with the placebo plus oral antidepressant arm after 22 days. The committee noted that NICE's guideline on depression recommended an initial assessment at 2 to 4 weeks to assess response to oral antidepressant, but further regular assessments and dose optimisation would be considered after this point. The committee considered that the evidence suggested there was likely to be changes in MADRS score as part of initial response to treatment. So, it considered that 4 weeks was not an appropriate endpoint on which to base longer-term extrapolations of response and remission. Also, a consultee commented that splitting data into 2 groups, response or remission compared with no response or remission, can lead to an overestimation of differences between arms. The committee acknowledged that this could have inflated the differences between arms which would increase the uncertainty of response and remission rates. For example, the committee noted that response to esketamine was higher for the 3 treatments or more subgroup, despite a lower change from baseline in MADRS score. The committee concluded that although the response and remission evidence from TRANSFORM‑2 showed a statistically significant difference between esketamine and placebo plus oral antidepressant, the data should be considered with caution when used to generate transition probabilities in the economic model because of the duration of the trial (see section 3.19). ## The withdrawal design of SUSTAIN-1 could introduce bias SUSTAIN‑1 measured withdrawal of esketamine for a randomised population of people whose depression was in stable response or stable remission. The ERG commented that there was potential for selection bias using these criteria. This is because if esketamine is tolerated, people who have the drug for 16 weeks and do not stop (induction and optimisation phases) stay in the trial by design. This means the people selected to stay in the trial are less likely to be affected by the treatment burden and do not have adverse events that make them stop treatment. So this does not represent the full population in the acute phase of treatment (from TRANSFORM trials) and may underestimate relapse rates for those taking esketamine. After the optimisation phase, some people were randomised to stop having esketamine and instead had placebo. Everyone continued taking the same oral antidepressant they had at the start of the trial. A consultee commented that there is potential for functional unblinding with this design because people randomised to placebo may notice the absence of psychoactive effects. The consequent negative expectations could affect the results. In response to the second consultation, the company provided analysis that showed censoring people who had dissociative symptoms and relapsed did not significantly affect the results. Because this analysis focused on dissociative effects only, the committee was not persuaded that this necessarily showed the blinding was effective. The committee concluded that the withdrawal design of SUSTAIN‑1 meant that if any unblinding had occurred, it would have biased the results in favour of esketamine. It noted that the withdrawal trial design was mandated by the regulator, but the faster onset of action may differ from oral antidepressants. ## The evidence from the trials is limited in its generalisability to the NHS The company assumed that data from TRANSFORM‑2 and SUSTAIN‑1 were generalisable to NHS clinical practice, but no people were recruited in the UK. Also, TRANSFORM‑2 and SUSTAIN‑1 excluded people: with moderate to severe substance or alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM‑5) criteria with some psychiatric comorbidities with depression that had not responded to at least 7 treatments with ECT in the current major depressive episode who had vagus nerve stimulation or deep brain stimulation who had suicidal ideation with intent in the previous 6 months or suicidal behaviour in the previous 12 months. The ERG noted that those excluded from TRANSFORM‑2 and SUSTAIN‑1 could represent a substantial proportion of people with treatment-resistant depression. It considered that excluding these people limited the generalisability of the trials to the NHS. The expert from NICE's guideline on depression agreed and noted that people with treatment-resistant depression are likely to have an increased risk of suicide. A clinical expert also noted that suicidal ideation is often an integral part of the disease. The committee noted that many people referred to a psychiatrist (a requirement of the SPC) in NHS clinical practice would be at higher risk of suicide. The clinical experts acknowledged the limitations of the other exclusion criteria but explained that these are standard for trials in this population. Comments received at consultation confirmed that uncertainty introduced by excluding these people is common in trials in this disease area. The committee was aware of the comments in the European public assessment report (EPAR) about the precautions that need to be taken if people with psychiatric comorbidities take esketamine. The committee also noted that the population in the TRANSFORM and SUSTAIN trials may not be in line with the population expected to have esketamine in clinical practice (see section 3.4) and that people with more severe symptoms may be more likely to be excluded using these criteria. The committee considered that the other exclusion criteria could inhibit the generalisability of the trial results. The committee concluded that excluding people with recent (defined in TRANSFORM‑2 and SUSTAIN‑1 as within 6 months to the start of the screening or prospective observational phase) suicidal ideation with intent or suicidal behaviour limited the generalisability of the trials to the NHS for people with treatment-resistant depression. It considered this was likely to be more of an issue when considering populations whose depression is more treatment resistant, which may correlate with increased potential for psychiatric comorbidities and suicidal ideation. ## Some of the clinical uncertainties are common in clinical trials in mental health The clinical expert considered that there was a mismatch between the evidence from the clinical trials and how esketamine would be used in clinical practice. They noted that it was difficult to collect randomised evidence in this disease area. The committee considered that some of these clinical uncertainties are common in clinical trials in mental health. The committee acknowledged that the treatment pathway is not clearly defined by line of therapy and instead is based on patient history and patient preference (see section 3.3). But it accepted the treatment line approach for the practical purposes of the economic modelling. The committee acknowledged it may be practically challenging to overcome this uncertainty so concluded this was currently an unresolvable uncertainty and did not consider it further. The committee also recalled the uncertainty of the benefit of esketamine in a later treatment line (see section 3.11). The committee noted that a trial done in the population that the treatment is being positioned in (3 or more treatments subgroup with or without augmentation) would help to overcome this uncertainty. It was aware of an ongoing phase 3 clinical trial (ESCAPE‑TRD), which it considered would be in a population more aligned with who would likely have esketamine in the NHS. So the committee concluded that this was a resolvable uncertainty. The committee accepted that clinical trials in depression have a mandated regulatory minimum length. It noted this when assessing esketamine's clinical-effectiveness evidence. But it noted that the trials are short and may not reflect clinical practice (see section 3.14 and section 3.4), which generated large uncertainty in the cost-effectiveness modelling. The committee considered that doing a longer trial than the mandated regulatory minimum length required could reduce this uncertainty. The committee highlighted that the lack of long-term evidence was a key uncertainty and noted an assumed long-term benefit was a key driver of the cost-effectiveness estimates. The committee concluded that the company could have done longer trials to meet the requirements of health technology assessment and so this was a resolvable uncertainty. The committee recalled that the study designs result in relatively larger placebo response than in other disease areas but preferred not to adjust the efficacy estimates of the comparator arm for the purposes of the economic modelling (see section 3.13). To overcome this uncertainty, the committee considered that a trial with a third arm without the placebo nasal spray may help with considering how people are affected by being in a trial (for example an improvement in MADRS score because of more frequent contact with trial investigators than would happen with clinicians in clinical practice). The committee noted that this would not necessarily overcome all the issues relating to the placebo response but would contribute to a better understanding of the relative effect of treatment observed in the trial. The committee concluded that this was a partially resolvable uncertainty. The committee stated that psychological therapy is likely an important part of treatment but provision and efficacy would vary substantially in a multinational clinical trial setting (see section 3.7). The committee noted that the uncertainty could have been overcome by doing an additional trial that included psychological therapy. But it acknowledged that this may be practically challenging because of the need for a longer follow-up and differences in the types of psychological therapies available. Also introducing another treatment into a clinical trial may make it difficult to measure the effect of esketamine. The committee noted that the uncertainty was partially resolvable and accepted the evidence without considering the effect of psychological therapies. The committee noted that excluding some people from the trial limits the generalisability of effectiveness results to later lines of therapy and NHS clinical practice (see section 3.16). It recalled that this may help with understanding relative effect so is common practice in clinical trials. But the committee recalled that the generalisability of the data led to substantial uncertainty in the cost-effectiveness estimates. The committee considered that the uncertainty could have been reduced if the trial was done in a population that was a closer match to the people most likely to have esketamine in NHS clinical practice but acknowledged the practical challenges of doing this. This is because it may lead to a more heterogenous population so it may be more difficult to measure the effect of esketamine. But the committee noted that some of the uncertainty could have been resolved if the company included people with recent suicidal ideation with intent. The committee considered this would likely not have increased the heterogeneity of the population with treatment-resistant depression. The committee concluded that this was a partially resolvable uncertainty.The committee recognised the difficulty of designing, recruiting and interpreting results from clinical trials in this disease area, and that the evidence requirements of health technology assessment may be different than the licensing requirements captured through regulatory endpoints (see section 4). The committee agreed that these clinical uncertainties were important to the economic modelling and took this into account when considering the degree of certainty of the cost-effectiveness results. The committee also acknowledged that there is ongoing research in this disease area could potentially address some of the uncertainties. # Safety ## Additional monitoring and supervision is required with esketamine in line with the SPC The European Medicines Agency identified some risks of esketamine use in the SPC. These included drug dependence, transient dissociative states and perception disorders, disturbances in consciousness, and increased blood pressure. A register for administering and monitoring esketamine to prevent dependence and misuse has been set up with the Medicines and Healthcare products Regulatory Agency (MHRA). The NHS commissioning expert explained that, because esketamine is a schedule 2 drug, it is subject to the full controlled drug requirements relating to prescriptions and storage. The committee acknowledged that the monitoring period would likely mitigate the other risks identified in the risk management plan and the committee did not need to consider these further. The committee considered comments received in consultation regarding suicides in people who stopped esketamine in a population who had no recent suicidal ideation or behaviour. The clinical expert explained that the increase in suicidal ideation could have happened despite people having esketamine, rather than because of it, given the nature of depression. The committee noted the SPC states that the effectiveness of esketamine in preventing suicide or in reducing suicidal ideation or behaviour has not been demonstrated. The SPC notes that general clinical experience shows that the risk of suicide may increase in the early stages of recovery. The committee considered that the MHRA are responsible for assessing safety concerns. It considered that the precautions regarding risk of suicide and supervision and monitoring in the SPC should be taken into account when prescribing esketamine, particularly during early treatment and after dose changes. The committee concluded that it was not a safety committee and could not make recommendations about safety. # Economic model ## The company's economic model uses uncertain clinical inputs so its results should be interpreted with caution The company economic model had 5 health states: major depressive episode (MDE), response, remission, recovery and death. The transitions between each health state were determined by the relapse, remission and response rates in the TRANSFORM studies and SUSTAIN‑2 (see section 3.10 and section 3.11) and values in the literature, for example, the STARD trial (a large-scale clinical trial for people with depression). All people start in the MDE state. In each of the arms and subgroups the first treatment is followed by 3 more potential subsequent treatments after non-response or relapse, and then a non-specified mixture of treatments (best supportive care). The committee considered that the key drivers of the economic model results in both treatment subgroups included the following: The pooled 4‑week initial response to treatment from the acute efficacy trials has the most influence on the modelled differences between treatment arms (see section 3.20) and is the only randomised comparative data that addresses the decision problem. The relapse rate for the esketamine treatment arm uses data from SUSTAIN‑1, which likely underestimates relapse rates because of selection bias from including only people with stable response and stable remission (see section 3.15 and section 3.21). The relapse rate for the placebo plus oral antidepressant arm uses data from the STARD trial which has generalisability issues and bias from using a different trial design and population (see section 3.21). The effect of the 3 lines of subsequent treatments does not reflect how subsequent treatments are used in clinical practice (see section 3.22). The efficacy of the non-specified mixture of treatments after the subsequent treatments has a substantial effect on the modelled long-term outcomes, resulting in a large amount of time spent in the MDE health state, which is a key driver of the costs (see section 3.22 and section 3.32).The committee concluded that the clinical inputs informing the model are highly uncertain and that any modelled results should be interpreted with caution. ## The modelled difference between treatment arms is driven by response and remission in the acute phase of treatment The first 4-week cycle of the economic model represents the transition from the MDE health state to response or remission, informed mostly by TRANSFORM‑2 with some information from TRANSFORM‑3. The committee noted that the initial response rate was uncertain because of the short time frame and because it included a placebo response that may not be seen in clinical practice. The committee noted the importance of this initial response or remission rate because later transitions to different health states are more gradual, determined by relapse rates and subsequent treatments. So, the committee noted a key driver of the difference between arms was the initial response. So, accurate response and remission rates in the acute phase of treatment are needed to give robust results. ## The relapse rate data comes from different sources, which leads to uncertainty and potential generalisability issues For the relapse rates in the economic model, the esketamine arm used transitions between health states from the SUSTAIN‑1 trial. The comparator arm used relapse data from the STARD trial. The relapse and loss of response rates for SUSTAIN‑1 are based on a MADRS score of 22 or more for 2 consecutive assessments. The committee noted that this was not equivalent to the inclusion criteria in the trials, which was a MADRS score of 28 or more. The committee considered it unclear if some transitions categorised as relapses are rather fluctuations in severity of depression, consistent with a chronic disease model (see section 3.23) and whether the transition would mean a change of treatment in clinical practice. The STARD trial used a Quick Inventory of Depressive Symptomatology–Self-Report score of 11 or more to measure relapse. The committee considered that the different definitions of relapse criteria contribute uncertainty to the comparison. The committee also had concerns about the generalisability of the trial design and population of STARD to NHS practice. The committee concluded that using different sources of data for relapse leads to potential generalisability issues and bias in the economic model. ## The effect of subsequent treatments does not match what would be seen in clinical practice The ERG noted that the response and remission rates of subsequent treatments used in the company's original base case could not be validated and were likely to be underestimated. The ERG proposed a scenario that applied a proportional reduction in each line of therapy based on data from the STARD trial. In response to consultation, the company provided this scenario in its revised base case. The response and remission rates were calculated on a 4‑weekly basis to be implemented per cycle in the model. This meant people moved between treatments quickly if their symptoms did not respond within 4 weeks. The committee considered that moving through treatments would not happen that quickly in clinical practice. It also recalled the uncertainty with using the STAR*D trial data and its generalisability to UK practice in the expected population (see section 3.21). Also, the proportional reduction was applied to the loss of response and relapse rates, which resulted in a relapse rate of 99% every 4 weeks for the non-specified treatment mix that represents best supportive care. The ERG considered this to be implausible so provided a scenario with a cap on relapse and loss of response as described in the original submission. After the third meeting, the company base case included further changes to this modelling assumption. The committee considered that despite the increased efficacy of subsequent treatments, the best supportive care transitions still had the greatest effect on long-term outcomes, which were highly uncertain. This mostly affected the costs because it meant a large amount of time was spent in the MDE health state. The committee considered there was minimal evidence for all transitions in the best supportive care state, and there was considerable uncertainty about how the course of the disease was modelled. It concluded that neither the company's revised base case nor the ERG's treatment cap would accurately model what happens to patients in clinical practice. Instead, the company and the ERG estimated the proportion of people in the MDE health state at later stages of the model, for which there was no available evidence. ## The disease course of treatment-resistant depression is uncertain and further research is needed In the second appraisal consultation document, the committee considered that the economic model likely overestimated the number of people in the MDE health state in both treatment arms and did not reflect the course of the disease or its episodic nature. In response to consultation, the company provided a targeted literature review that it considered supported the modelled output. The model output suggested that, for a person with treatment-resistant depression, 66% of a person's life is spent in the MDE health state. The targeted review showed generally low longer-term remission rates. However, the committee noted heterogeneity in the definition of remission and response, trial design and inclusion criteria of the trials included in the review. In particular, it considered that the trials in the review may have included people with depression that was much more treatment resistant and severe than the modelled population. The company also provided evidence from a UK cohort, which showed the mean duration of an episode of treatment-resistant depression was 6.1 years. The ERG provided another data source which was a large retrospective cohort study of insurance databases in the US. This study attempted to characterise the treatment journey for someone with treatment-resistant depression at an episodic level based on length of treatment on oral antidepressants. The results showed the mean length of a first episode of treatment-resistant depression was 1.56 years, and the mean length of remission for those who had a second episode was 0.90 years. The clinical expert considered this data would be of limited use because it used time on treatment data and it would not necessarily fit to an episodic model. The ERG considered that a treatment-resistant episode was inconsistently defined and would likely be measuring different outcomes. It noted that the outcomes of interest for modelling the MDE health state were the severity of depression for the full time horizon (see section 3.24) and the costs accrued while in the state (see section 3.31). The committee also considered consultee comments that stated that improvements in depression are generally maintained at the end of acute treatment, and on average symptoms improve further. It also heard from consultees who commented that depression can be highly episodic, and that treatment can be successful when people adhere to it. The clinical expert estimated that currently 20% to 30% of people with treatment-resistant depression have chronic longer-term disease that has not responded to any treatment. For these people, severity would likely fluctuate, and this would not fit the episodic disease model well. After the company repositioned esketamine as a treatment used at a later line, the committee considered a chronic longer-term disease model may be more appropriate to capture the profile of this group. The committee noted substantial uncertainty with all the longer-term data for treatment-resistant depression and agreed with the ERG that the available evidence is likely measuring heterogeneous outcomes in heterogeneous populations. The committee understood the difficulties of modelling a heterogeneous population with differing disease models. But it concluded that the analysis did not appropriately capture either the chronic or episodic nature of the condition. It also concluded that the literature for longer-term outcomes for treatment-resistant depression is poor, so the outcomes are highly uncertain. The committee recommended further research to understand the course of the disease (see section 4). ## The long-term evidence of esketamine is too uncertain to justify a substantial modelled benefit over a 20-year time horizon The company originally modelled a 5‑year time horizon to reflect that treatment-resistant depression is an episodic condition. The ERG noted that differences in the modelled costs and quality-adjusted life years (QALYs) between treatments continued for 20 years, so it preferred a 20‑year time horizon. The clinical experts considered a longer time horizon was appropriate because depression is a chronic condition for some people. The expert from NICE's guideline on depression agreed that a longer time horizon was needed to account for the duration of the condition and the need for any subsequent treatments. After the company repositioned esketamine as a treatment used at a later line, the committee considered the 20‑year time horizon was likely appropriate. But it noted that there was insufficient data to populate this model for the full time horizon because of the uncertainty about the inputs into the model and esketamine's long-term outcomes (see section 3.23). It noted that the model was sensitive to assumptions about the length of the time horizon because esketamine costs were modelled in the short term but benefits accrued over the full time horizon. The committee also recalled that the disease course of treatment-resistant depression is uncertain and capturing the fluctuating nature of the condition and treatment is difficult. The committee explored this uncertainty through sensitivity analysis. It concluded that the long-term evidence for esketamine is too uncertain to justify substantial modelled benefit over the full time horizon. ## It is not appropriate to include an effect of esketamine on mortality in the model In its economic model, the company assumed there were 2 risks for dying: all-cause mortality risk (specific to age and gender) and an excess annual mortality for treatment-resistant depression associated with suicide. The company initially modelled a reduction in treatment-resistant depression (which is associated with excess mortality). This indirectly decreased the risk of excess mortality with esketamine. The committee considered it plausible that esketamine could affect mortality. However, with the other structural uncertainties and no evidence of longer-term benefit of esketamine, the committee considered this was speculative. It also noted that the SPC states: 'The long-term efficacy of Spravato to prevent suicide has not been established'. Because of issues with generalisability, excluding people with recent suicidal ideation with intent and the lack of data, the committee concluded it could not accept a reduced suicide, or mortality, risk. # Utility values ## The difference in utility values between health states is likely overestimated The company measured utility in the TRANSFORM‑2 and SUSTAIN‑1 trials as EQ‑5D‑5L measurements and mapped these to EQ‑5D‑3L utility values as in the NICE reference case. These utility values were applied to the modelled health states. The committee noted that the utility value for MDE of 0.417 was measured from the baseline utility scores in TRANSFORM‑2 at a mean MADRS score of 37. However, the transition from relapse or remission to the MDE state needed a MADRS score of 22 or more for 2 consecutive assessments. The committee recalled that response criteria were not fixed to absolute MADRS values. This made interpreting the utility values difficult because they could have come from people with MADRS scores of between 13 and a maximum value above the threshold for relapse of 22 or more. In response to consultation, the company provided a scenario that provided MDE state utility values that represented people with moderate depression to include a lower relapse rate. The ERG noted this did not address the problem of the estimate of relapse based on the threshold with a lower MADRS score. The committee noted that symptom severity could fluctuate, and that this would not be consistent with a fixed state with large utility transitions. The clinical expert noted that a MADRS score of 37 represents very severe depression as would be expected during an acute period of depressive symptoms. The committee considered that in clinical practice, people will likely have less severe MADRS scores on average for prolonged periods of time. It recalled the difficulty of defining and characterising a treatment episode. The clinical expert added that people tend to have symptoms at least half of the time, but these symptoms are not always severe enough to reach diagnostic criteria. The committee was also concerned that the utility values within each health state could be highly heterogeneous. It concluded that the MDE health state utility would likely represent the baseline utility values of patients with a MADRS score of 37, but would likely underestimate quality of life over the full time horizon. ## It is appropriate to consider applying a carer disutility in the model and to consider the effect without it The company submission included a disutility value applied to the model for the effect of treatment-resistant depression on carers and families. This was done by applying a disutility to the MDE health state. This was the difference in utility between carers of people with symptomatic treatment-resistant depression and carers of people with treatment-resistant depression that was in remission. The ERG noted that this implied that carers of all people in the MDE health state would have a utility value associated with being in remission. The ERG argued that a methodologically better way to estimate disutility for a specific state is to subtract the utility of that state from the utility for full health. The ERG applied a lower value to the disutility by using this method to calculate the utility values. The committee acknowledged that treatment-resistant depression affects carers and families and considered the ERG scenario to be the most appropriate. But it considered that there was uncertainty about how appropriate including a carer disutility was. This was because of the lack of data on the direct effect treatment-resistant depression had on carers. The committee noted the lack of evidence on any direct benefit to carers after treatment with esketamine. It also noted the potential for an increased treatment burden for carers as well as people with depression. The committee considered that carer utility is only applied in the MDE health state, which is likely to be overpopulated in the economic model. It noted that carer disutility was not considered in NICE's technology appraisal guidance on vortioxetine. The committee concluded that it was appropriate to consider scenarios with both the ERG carer disutility scenario and no carer disutility because the effect was uncertain. ## The disutility of adverse events should have been considered in the modelling The committee recalled that esketamine is associated with some potentially serious adverse events. SUSTAIN‑2 reported 6.9% of people had serious adverse events including depression, suicidal ideation, suicide attempt, anxiety and gastroenteritis. The most common treatment-emergent adverse events (any event not present before the start of treatment) included dizziness and dissociation. The company did not consider the disutility or cost of these adverse events in the model because most adverse events were resolved on the day (75% of adverse events were resolved on the day in SUSTAIN‑2) and so it considered these were transient. The patient expert described unwanted effects they experienced while having esketamine. The committee considered that a large proportion of patients may experience these effects, and it was likely a major consideration for the treatment experience. It considered these events could be experienced up to once a week which, combined with fear of these adverse events, could cumulatively contribute to a substantial disutility associated with the treatment that was not captured in the model. The committee concluded that adverse events of treatment had not been fully explored, but would contribute additional uncertainty to the modelled treatment benefit. # Stopping treatment ## There is limited evidence on the effect of stopping esketamine for reasons other than lack of efficacy The company assumed that some people would stop taking esketamine for reasons other than lack of efficacy, in line with the criteria in the SPC and additional guidance on stopping treatment. In response to consultation, the company provided scenarios for stopping treatment and scenarios that explored a utility decrement after stopping treatment. The stopping rates were based on research questionnaires from clinicians. Stopping treatment was assumed to stop costs for esketamine incurring but have no effect on QALYs. The company modelled that 60% of people whose depression was in stable remission would immediately stop treatment after 2 years. The ERG also provided a scenario that assumed no immediate treatment stopping and instead modelled a continued exponential reduction based on extrapolation of the trial data. This was because no evidence was submitted that showed the effect of stopping on long-term symptoms or quality of life. The ERG and clinical experts also highlighted that there was no data to accurately determine stopping rates in clinical practice. The ERG noted that no data was collected for people who stopped treatment for reasons other than lack of efficacy after recovery, and the reasons why they stopped were not explored. The committee noted that the SUSTAIN‑1 trial is designed to answer the clinical question of whether stopping treatment affects relapse rates. It showed that there is a significant effect of stopping treatment. However, the committee noted this was measured at 16 weeks of treatment rather than after recovery. The committee considered it likely that people would stop esketamine for various reasons over a 2‑year period. This could include recovery, adverse events or because of the high treatment burden associated with its use. However, it considered that the research data informing the company revised base case may not be generalisable to NHS practice. This was because it classified people into risk levels and applied these to the full population in SUSTAIN‑1. With the company's revised positioning, this could include people whose depression would be resistant to more lines of therapy than in SUSTAIN‑1, likely have more comorbidities and may include more people who would have prolonged or repeated use of esketamine. The committee also noted that the data for the utility decrement came from the SUSTAIN‑2 study and had limited use in the model because of the high proportion in the MDE state, so did not explore this scenario further. The committee concluded that more data for stopping treatment for reasons other than lack of efficacy was needed to justify modelling the additional stopping guidance provided by the company. ## Stopping treatment in clinical practice would be based on people's individual circumstances and may include prolonged or repeated treatment The clinical expert explained that stopping treatment is variable in clinical practice. They would expect that the decision to stop treatment would be made after a discussion of the person's individual circumstances. They also considered that this could involve treatment pauses to assess how a person feels without esketamine. The clinical expert noted that the best indicator for what treatment would work would be what the person's depression had responded to previously. Also, people who consider esketamine to be effective may want to carry on taking it. A patient expert suggested that if treatment with esketamine worked for someone then they would consider having the treatment again when symptoms returned. They also noted that people would be concerned and worried about relapse if they stopped treatment. Another patient expert explained that their esketamine treatment was in the process of being tapered off slowly with careful monitoring of response. The committee recognised that people would be fully involved in the decisions about continuing treatment, and that decisions about how long treatment lasts and reasons for stopping it vary based on individual circumstances. The committee also considered that it is possible more people's symptoms would respond to treatment, but not all of them would be considered to be in remission if their depression were more treatment resistant or severe at baseline. These people would not stop treatment immediately at 2 years using the company's stopping criteria. The committee also noted the uncertain course of the disease. It considered that a fluctuation in symptom severity might not mean that esketamine was stopped, as it was in the trials. It concluded that in clinical practice stopping treatment may not be guided by the company criteria and could include ongoing repeated or prolonged treatment based on symptom severity. This would particularly be the case for the expected population in NHS clinical practice and the 3 or more treatments subgroup. # Resource use ## The cost of a course of esketamine treatment may be underestimated The company confirmed that the dose of esketamine used in the model was an average from the trial evidence. The committee was concerned that it had not been presented with a dose response curve or a clear analysis of how the flexible dosing strategy was implemented. It also considered that it was unclear if people develop a tolerance to esketamine and need increased doses (up to the maximum dose) to achieve the same therapeutic effect. This would be particularly important for people who have treatment for a long time. The committee noted that frequency of dose during maintenance was dependent on meeting remission criteria (for a weekly dose, MADRS score of more than 12, and for a 2‑weekly dose, a MADRS score of 12 or less). The committee considered that a change in what is considered remission, for example a MADRS score of 10 or less (as in NICE's technology appraisal guidance on vortioxetine), could affect the costs of treatment. Also, in line with a chronic disease model, some people who met the relapse criteria may have been considered to have had a fluctuation in symptom severity, rather than a relapse. So, they may have had prolonged or repeated treatment. Also, issues with generalisability of the trial evidence and esketamine's changed positioning in the treatment pathway could increase the number of people whose depression was considered to have only responded, compared with people with depression considered to be in remission. The committee noted that the new observational data presented after the third committee meeting likely used higher or more frequent dosing for most people than was modelled. Although the committee considered that this was not used in the economic model, it might represent the expected use in clinical practice. The committee concluded that the model may underestimate the cost of a course of esketamine treatment for the intended treatment population. It also noted that a course of treatment may not easily be defined in the context of a chronic condition with repeated or prolonged treatment. ## Healthcare resource use costs are highly uncertain and contribute to the economic model's uncertainty The company modelled healthcare resource use by health state as defined in the economic model. The committee noted the importance of the MDE health state because of the amount of time people spent in it. The company measured resource use for each health state using a retrospective chart review of patients in UK clinical practice. This asked 30 psychiatrists and 9 GPs to provide resource use for the last 10 people with treatment-resistant depression they had seen. These were converted into costs by health state in the company study. These costs included primary care visits, secondary care visits, psychological-based interventions, occupational therapy, hospitalisations and crisis resolution home teams. The clinical expert considered that, in clinical practice, the distribution of costs in treatment-resistant depression were heavily skewed. This means most healthcare resource is used by a proportionally small number of people. The committee understood this was mostly through a small number of people needing hospitalisation. The committee noted that there was potential for selection bias because people that are seen more frequently are more likely to be included in the study. The committee was concerned that some of the costs seemed implausibly high. For example, crisis resolution and home treatment teams contributed 33% of all costs in the MDE health state, which was nearly equivalent to the total costs of hospitalisation. The ERG provided an alternative healthcare resource use scenario using a large database of general practice records used in Byford et al. (2011). This was used in NICE's technology appraisal guidance on vortioxetine and NICE's guideline on depression to provide cost information. The ERG considered that only the population with severe depression should be used to represent people in the MDE health state. However, it noted that the definitions used in the Byford study for severity included many types of depression, including depression with psychosis. Only people who had at least 2 treatments and whose symptoms had not remitted within a year were included in the Byford study costs for the MDE health state. This did not match the company's definition of treatment-resistant depression. Also, the Byford study linked primary care records with secondary care referrals and hospitalisations. The company considered that the study did not fully capture hospitalisation costs or community interventions, which have increased since the study was done. The committee agreed that some of the costs of secondary care or hospitalisation could have been missed in the Byford dataset because of the study design. However, the committee noted the substantial difference between the 2 studies, with the costs associated with the MDE health state in Byford being around 8% of what was reported in the company's retrospective chart review. After the third committee meeting, the company proposed 2 new treatment subgroups. It modelled a split of 75% of costs from its own costing study and 25% from the Byford study for the 3 or more treatments subgroup, and 100% of costs from its own costing study for the 3 or more treatments and augmentation subgroup. It also presented supporting evidence from a secondary care mental health setting using Clinical Record Interactive Search data from the South London and Maudsley NHS Foundation Trust. The company considered it showed increasing healthcare resource use with each line of therapy. The ERG noted that, similar to the company cost study, the costs were largely driven by hospitalisations (in cost of bed days). There was also evidence of strongly skewed data, with high costs on average, but with most people not requiring any hospitalisation. The ERG also noted that the relationship between increasing healthcare resource use and line of therapy was not clearly defined and the difference between 3 prior oral antidepressants and 4 prior oral antidepressants was minimal. The committee noted that all of the evidence considered about resource use was characterised by strongly skewed data, which introduced substantial uncertainty to estimates of non-pharmacological healthcare resource costs within the model. These accounted for almost all of the total costs over the full time horizon in the company base case and were a key driver of the cost-effectiveness results. The committee considered that the generalisability of the treatment costing study to NHS clinical practice was crucial to understanding whether esketamine would reduce hospitalisations and other healthcare resource use. It questioned whether the same people who are hospitalised would have esketamine, because there are precautions for its use for people with certain psychiatric comorbidities. The committee noted that cost savings are a key driver of the cost-effectiveness estimates. The committee also noted that cost savings are driven by reducing costs in a small group of people (those who would be hospitalised). But it considered there was no evidence that esketamine would be beneficial in the group of people for whom hospital costs are largest. While the evidence showed there was an improvement in MADRS scores in the subgroups it was not possible to predict the benefits for subgroups within these subgroups. The committee also heard from clinical experts that for some people who are hospitalised, other options such as ECT are more likely to be considered than esketamine. The committee concluded that the modelled benefit of esketamine was not robust given the uncertainty in the evidence. It recommended further research to fully understand the costs associated with treatment-resistant depression and hospitalisations (see section 4). ## Significant investment would be needed to use esketamine in the NHS The company assumed people in the 3 or more treatments and augmentation subgroup would have treatment in secondary care. It also assumed that the implementation of esketamine would be done using existing infrastructure. So, the company did not include costs for implementation in this subgroup. The ERG noted it was unclear how a change in infrastructure would not be needed for the 3 or more treatments and augmentation subgroup. For the 3 or more treatments subgroup the company proposal to convert ECT suites to esketamine treatment clinics was used to inform costs in the economic analysis. The company included administration costs for esketamine in the economic model, but did not consider any other costs, considering these to be minimal with the conversion of ECT suites. It also said it would provide staff training to administer and monitor esketamine, needed to manage adverse effects, at no additional cost. The NHS commissioning experts noted several costs for adopting esketamine that were not included in the analysis: costs of conversion of ECT suites or sourcing other appropriate treatment settings costs of medical equipment to monitor and manage any post-dose medical complications staff training to manage post-dose complications, including potential costs of recruitment if there are not enough staff currently available in practice costs associated with the controlled nature of the drug, including storage, transportation, disposal and adequate staffing and governance training costs associated with transporting people to have esketamine in hospital.The NHS commissioning expert also noted that resources would be needed for each new person having treatment with esketamine. The committee noted that the costs of implementation would depend on the expected population in clinical use and the expected treatment setting. The committee noted that NICE's guide to the methods of technology appraisal 2013 (section 5.5.8) states that if introduction of the technology needs changes in infrastructure, costs or savings should be included in the analysis. The committee noted that NICE's guide to the methods of technology appraisal 2013 (section 6.2.14) states that the 'committee will want to be increasingly certain of the cost effectiveness of a technology as the impact of the adoption of the technology on NHS resources increases'. The committee concluded that there would need to be significant investment to use esketamine in the NHS using the company's implementation proposal, which was not fully captured in the analysis. It considered the costs using the company's proposal would underestimate the true cost of implementing esketamine clinics in clinical practice. ## The company's implementation proposal using converted ECT suites as treatment clinics may not be feasible The company proposed a plan to convert ECT suites to esketamine treatment clinics as part of esketamine's implementation proposal. The NHS commissioning expert explained the current 5‑year plan for mental healthcare implementation in England. The plan focuses on integrated primary care and community care for people with serious mental illnesses such as treatment-resistant depression. The committee considered it was unclear what treatment setting esketamine would be used in, because: a psychiatric referral is needed it is proposed to be delivered in hospitals in converted ECT suites integrating secondary mental health care with primary and community care is currently challenging, for example, there are long waiting lists.The company considered that esketamine would not take long to become part of NHS practice, quoting market research that showed 82% of mental health trusts have some plans for how they would use esketamine. However, the NHS commissioning experts considered the plan to be impractical because negotiating use of ECT suites may be complex for some trusts and not possible for others. They considered that esketamine's use could not be limited to trusts that have an ECT suite that can be easily converted. The committee was aware of a potential equality issue (see section 3.40), and considered that esketamine's use in a community mental health specialist clinic would enable easier access to treatment. The clinical expert noted that some trusts have large geographical areas and access would not be available for everyone. The NHS commissioning experts also advised that the structure and delivery of services would need to be changed to accommodate esketamine. So, a longer timeframe than NICE mandates for NHS England to comply with the recommendations would be needed to establish esketamine in clinical practice. They explained that significant investment would be needed for esketamine to become part of NHS clinical practice, beyond the costs proposed as part of the company's implementation plan. They noted that esketamine would have to displace other mental health treatments because of its cost. However, this was dependent on the proposal to convert ECT suites. The committee considered the balance between new treatment options and maintaining the ability to offer ECT for people who need it. The committee concluded that, based on NHS England's commissioning experts' feedback, the company's proposal to implement esketamine clinics in ECT suites may not be feasible. ## It is not possible to accurately estimate nursing and monitoring costs without certainty about esketamine's treatment setting The committee recalled the precautions regarding risk of suicide and close supervision and monitoring in the SPC (see section 3.18). The company proposed administration and nursing costs for esketamine based on its proposal to run esketamine clinics in converted ECT suites. This assumed a ratio of 2 nurses to 6 patients when esketamine is administered, and 1 nurse to 6 patients during monitoring after treatment. The ERG preferred to model a 1 to 1 ratio throughout administration and monitoring because it considered this to be the most plausible in clinical practice. The clinical expert suggested that a ratio of 1 to 1 or 1 to 2 may be necessary when a service first starts administering esketamine, but that the ratio may increase to 1 nurse to a group of patients once the service becomes experienced and established. However, there could be logistical challenges in scheduling administration and monitoring with many people at one time. The patient expert said that building a relationship with a healthcare professional was an important part of treatment and recovery. At the second appraisal committee meeting, the committee concluded that a 1 to 2 ratio of nurses to patients could be appropriate. In response to the second consultation the company estimated a 1 to 2 ratio of nurses to patients in the 3 or more treatments subgroup and a 1 to 1 ratio of nurses to patients in the 3 or more treatments and augmentation subgroup. But the committee noted that its previous conclusion would only apply if using the company's proposed implementation plan to run esketamine clinics in ECT suites. If implemented differently, the administration and monitoring costs would change and it would not be possible to estimate ratios of nurses to patients. So the committee could not conclude on what would be the most plausible costs of nursing and monitoring. # Cost-effectiveness estimates ## The cost-effectiveness estimates for esketamine in both treatment subgroups are highly uncertain The company's cost-effectiveness estimate included a patient access scheme discount, the results of which cannot be presented because of confidentiality. The company's revised base case after the fourth committee meeting gave an incremental cost-effectiveness ratio (ICER) range below £20,000 per QALY gained for esketamine plus oral antidepressant compared with oral antidepressant alone in both treatment subgroups. The ERG's ICER range was generally higher than the company's estimates. The committee considered that the company and ERG's estimates were subject to substantial uncertainties, including: being based on clinical evidence that does not represent the expected use of esketamine in NHS clinical practice (see section 3.4) how appropriate the comparators are (see section 3.6) the clinical inputs informing the economic model (see sections 3.13 to 3.17) the limited generalisability of the trial evidence (see section 3.16) a cap on relapse and loss of response (see section 3.22) the uncertainty of long-term outcomes for depression (see section 3.24) a preference for no excess effect of esketamine on mortality (see section 3.25) a preference for a range considering no carer disutility and sensitivity analysis with the ERG's method of applying carer disutility (see section 3.27) uncertainty about when people would stop esketamine (see section 3.29 to 3.30) the costs of esketamine and potential for repeat or prolonged treatment (see section 3.31) the healthcare resource use in treatment-resistant depression (see section 3.32) the substantial costs of adopting esketamine in clinical practice that have not been included in the model, which would bias the results in favour of esketamine (see section 3.33 and section 3.34).NICE's guide to the methods of technology appraisal 2013 notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICERs. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the substantial resolvable uncertainty in all components of the economic modelling and ICER calculation, the committee considered that the benefits and costs of treatment with esketamine were highly uncertain. # Other factors ## It is not methodologically appropriate to consider the societal burden of depression in this appraisal The company considered that treatment-resistant depression has a substantial societal burden, mostly because of time off work. The committee noted that NICE's guide to the methods of technology appraisal 2013 (section 5.1.7) states 'the perspective on outcomes should be all direct health effects, whether for patients or other people'. And section 5.1.9 states 'the reference-case perspective on costs is that of the NHS and personal social services'. The committee recalled that considering benefits incurred outside of the NHS and personal social services was not detailed in the remit from the Department of Health and Social Care and the final scope. The committee also noted that productivity costs are not included in the reference case. If a non-reference case has been agreed with the Department of Health and Social Care, productivity costs are not included in this either. The committee concluded it was not appropriate to consider the societal burden of treatment-resistant depression. ## Mental health services need further investment The company considered that there has historically been significant underinvestment in mental health services. It noted that this context could be considered in the decision for esketamine, because more treatment options and investment in the area could contribute to the parity of esteem between physical and mental health (as required by the Health and Social Care Act 2012). The clinical and commissioning experts agreed that mental health services are stretched, contributing to a shortage in secondary care, meaning many people with treatment-resistant depression are not able to access services. The committee understood the NHS has a responsibility to deliver parity of esteem for physical and mental health, and considered the uncertainties around current mental health service provision in its decision. It acknowledged the funding issues in mental health and the limited new treatment options. The committee also noted that improved access to psychological therapies could benefit people with depression, particularly as patient experts noted regional disparities with access to treatment. However, it recalled that NICE's remit from the Department of Health and Social Care for this technology appraisal was to appraise the clinical and cost effectiveness of esketamine within its licensed indication. The committee concluded that equity of access could not be addressed as part of this appraisal. ## Esketamine is innovative because it has a novel biological mechanism The company considers esketamine to be innovative because it represents a step change in the treatment of treatment-resistant depression. The company noted esketamine has a novel biological mechanism of action in a disease area that has not had a new mechanism for 30 years. Also, esketamine is sprayed in the nose which means it works rapidly and is non-invasive compared with ECT. The committee considered that the biological mechanism of esketamine could be innovative, but it was uncertain if it would be a step change in treatment because of the uncertainty of the clinical evidence. The committee concluded that it had not been presented with robust evidence of additional benefits not captured in the QALY calculations. ## Equalities The company, patient organisation and the ERG highlighted that, because esketamine nasal spray needs to be administered and monitored at a clinic, geographical access may be an equalities consideration. The committee considered that symptoms of depression include lack of energy and motivation, so it may be difficult for people to travel a long way to attend esketamine clinics. It considered that administering esketamine in a community setting would be necessary to ensure equity of access to treatment and that conversion of ECT suites would be insufficient to address these equity concerns. Also, the patient expert raised that people with physical health conditions may need additional support when accessing treatment, and the patient organisation noted that some people may have difficulties self-administering treatment or attending a clinic. But because the committee's recommendation does not restrict access to treatment for some people over others, the committee agreed these were not potential equalities issues. The NHS commissioning expert raised concerns about equity of access for people in the criminal justice system. The committee considered that the recommendations do not prevent access to esketamine in the criminal justice system over any other setting. It understood that there were likely to be existing processes in place for managing controlled substances in the criminal justice system, which would not prevent access to esketamine were it recommended. The patient organisation raised that there may be cultural or religious objections to treatment with esketamine. The committee was aware that these objections may also apply for other existing treatments for depression. However, it agreed that this equality issue could not be addressed in a recommendation. The clinical expert noted people who are underserved are more likely, in the clinical expert's experience, to have severe depression. The committee recognised that depression can have a substantial and long-term adverse effect on a person's ability to do normal day-to-day activities. So people with depression may be covered under the disability provision of the Equality Act (2010). The committee was mindful that its role is to appraise treatments and recommend those that are a clinically and cost-effective use of NHS resources. The committee carefully considered the uncertainties common in clinical trials in mental health and recognised the difficulties of collecting clinical data in the population of people with treatment-resistant depression (see section 3.17). It noted that no specific adjustments to the considerations of evidence had been proposed. So it considered all the available evidence including a wide range of views from patient and clinical experts alongside clinical trial data. The committee concluded that it was still unable to recommend esketamine for routine use (see section 3.41). # Conclusion ## Esketamine is not recommended The committee considered the burden that treatment-resistant depression has on people, the unmet need for effective treatment options and the innovative nature of how esketamine is administered. The committee acknowledged that obtaining reliable clinical evidence for technologies for depression can be challenging. It noted specifically the challenges of defining the treatment pathway and including psychological therapies, understanding and accounting for placebo effects, and the generalisability of clinical trials in treatments for depression to routine clinical practice. It also noted that large inequities remain in treatments for mental health conditions compared with other disease areas and considered this in its decision making. However, the costs and benefits of esketamine were very uncertain. The committee noted NICE's guide to the methods of technology appraisal 2013 (section 6.3.3) states that 'the committee will be more cautious about recommending a technology when they are less certain about the ICERs presented' and took this into account in its decision making. The committee recalled the clinical uncertainties, summarised in section 3.17, and noted these increased the uncertainty in the clinical inputs in the economic model and that some of these were partially or fully resolvable with further evidence. The committee highlighted that the company could have done more to reduce the uncertainties, including doing longer trials in a population who are more likely to have esketamine in clinical practice. The committee noted that the ICER range was likely to be an underestimate because of the uncertainty in the long-term benefits, stopping treatment, healthcare resource use and implementation costs. On balance, after taking these factors into account, the committee considered that esketamine was not a cost-effective use of NHS resources for the full marketing authorisation. The committee also noted that the ICER range in both subgroups considered could be below or within the range NICE normally considers a cost-effective use of NHS resources. However, not all the issues outlined above were included in these ICER calculations either. These ICERs are highly uncertain and the range would likely underestimate the true cost effectiveness of esketamine. So esketamine could not be considered a cost-effective use of NHS resources for the 3 or more treatments subgroup and 3 or more treatments and augmentation subgroup. So, esketamine is not recommended for use in the NHS for treating treatment-resistant depression.# Recommendations for research Further research is recommended to help address remaining clinical and cost-effectiveness uncertainties for esketamine, summarised in section 3.36. Further research is recommended in the wider clinical area of depression on: how clinical data from regulatory trials in depression could appropriately be used in health technology assessment and decision modelling the natural history and long-term course of treatment-resistant depression and health-related quality of life in the long-term characterising the healthcare resource use of people with depression, including exploring which people use services like hospitals and crisis resolution home teams.	{'Recommendations': "This guidance only includes recommendations for treatment-resistant depression.\n\nEsketamine nasal spray for treating major depressive disorder is being evaluated in NICE's technology appraisal guidance on esketamine for treating major depressive disorder in adults at imminent risk for suicide.\n\nEsketamine nasal spray with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is not recommended, within its marketing authorisation, for treatment-resistant depression that has not responded to at least 2 different antidepressants in the current moderate to severe depressive episode in adults.\n\nThis recommendation is not intended to affect treatment with esketamine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThe company positioned esketamine nasal spray for people who have had at least 3 antidepressants before, with or without another treatment like lithium or an antipsychotic medicine. This is narrower than the marketing authorisation, and also how clinical experts advised esketamine would likely be used in NHS practice.\n\nThe clinical evidence at this positioning is uncertain because it only considers a small number of people from the full clinical trial population. But it suggests that for people who have had at least 3 antidepressants with or without another treatment, esketamine with an SSRI or SNRI is likely more effective than placebo with an SSRI or SNRI. Because the trials were short the long-term benefits of esketamine are uncertain.\n\nAlso, the trial evidence excluded people with characteristics of depression like psychosis or recent suicidal ideation with intent. This limits how well the evidence applies to the NHS, because people having treatment for depression in the NHS may have psychosis or recent suicidal ideation with intent.\n\nThe clinical uncertainty means the economic modelling is also uncertain, including:\n\nhow treatment-resistant depression was modelled\n\nhow long people would take esketamine for\n\nthe costs of using esketamine in the NHS.\n\nThe limitations in the clinical evidence and economic model mean it is not possible to determine a reliable cost-effectiveness estimate. Esketamine is unlikely to be an acceptable use of NHS resources, so it is not recommended. Further research is recommended to address some of the uncertainties.", 'Information about esketamine': "# Marketing authorisation indication\n\nEsketamine nasal spray (Spravato, Janssen) with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated 'for adults with treatment-resistant major depressive disorder who have not responded to at least 2 different treatments with antidepressants in the current moderate to severe depressive episode'. The scope of this appraisal is only for this indication.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule for esketamine is available in the summary of product characteristics for esketamine.\n\n# Price\n\nThe device is single use and delivers 28\xa0mg of esketamine in 2 sprays, one 14\xa0mg spray per nostril. The list prices are as follows (excluding VAT; BNF online, accessed April 2022):\n\n£163 for a 28\xa0mg dose (one 28\xa0mg device)\n\n£326 for a 56\xa0mg dose (two 28\xa0mg devices)\n\n£489 for an 84\xa0mg dose (three 28\xa0mg devices).The company had a commercial arrangement, which would have applied if the technology had been recommended.", 'Committee discussion': "The appraisal committee considered evidence submitted by Janssen, reviews of these submissions by the evidence review group (ERG), NICE's technical report, and responses from stakeholders from 2 consultation documents. See the committee papers for full details of the evidence.\n\n# The condition and current treatment\n\n## Treatment-resistant depression has a negative effect on people\n\nThe patient experts explained that treatment-resistant depression has a substantial burden on all aspects of life, with a range of symptoms. The patient experts emphasised that people with treatment-resistant depression often have feelings of hopelessness, fear and despair. This can affect the person's family and carers. The clinical expert noted that the lives of children of people with treatment-resistant depression are also affected. The committee concluded that the condition has a negative effect on people, their families and carers.\n\n## There is an unmet need for effective treatment options\n\nThe patient experts explained that people with treatment-resistant depression often feel hopeless because treatments are ineffective. The clinical expert noted that people will try different courses of treatments to alleviate symptoms. The patient experts highlighted that, when multiple courses of treatment do not work, the feelings of hopelessness get worse. They added that this was an inherent aspect of the 'treatment-resistant' nature of the condition. A patient expert who had recovered from treatment-resistant depression emphasised the importance of independence and return of character upon remission. The clinical expert noted that a large proportion of people keep taking antidepressants that are not working, sometimes for a year or more. The committee concluded that the effectiveness of current treatments for treatment-resistant depression is limited and that there is an unmet need for new treatment options.\n\n# Treatment pathway and comparator\n\n## Current clinical practice includes several different types of treatment\n\nThe company submission defined treatment-resistant depression as 'people with major depressive disorder who fail to respond to 2 different oral antidepressants'. It included the recommended treatment pathway for this population from NICE's guideline on depression. Based on the guideline, NICE's esketamine appraisal scope and the company submission, the treatment options for people with treatment-resistant depression include:\n\noral treatments such as sertraline, citalopram, fluoxetine, venlafaxine, vortioxetine, mirtazapine, amitriptyline and monoamine oxidase inhibitors\n\naugmentation therapy (when an antidepressant is used with a non-antidepressant), for example, an antidepressant with lithium or an antidepressant with an antipsychotic treatment\n\ncombination therapy (an antidepressant with another antidepressant)\n\nelectroconvulsive therapy (ECT).NICE's guideline on depression also includes cognitive behavioural therapy (CBT) and other psychological therapies as options combined with the above treatments. However, the company noted that the treatment pathway in clinical practice is different to the guideline. The clinical expert explained that the treatment pathway for treatment-resistant depression can vary between services across the UK. They explained that, in general, most people with treatment-resistant depression have 3 to 4 standard oral antidepressant treatments from their GP. Only a small proportion (company estimate of 9.6%) are referred to a psychiatrist. Then, the first treatment choice is normally to optimise the dose of oral antidepressant or switch to a new oral treatment. Then 1 or 2 trials of augmentation therapy, with an antipsychotic drug or lithium combination therapy, would be considered before ECT. The committee acknowledged that the summary of product characteristics (SPC) states that esketamine nasal spray (from now, esketamine) must be prescribed by a psychiatrist. The clinical expert noted that people who have been referred to a psychiatrist are likely to be at risk of suicide or have symptoms that have not responded to any treatments for an extended period. The committee concluded that NICE's guideline on depression may not represent clinical practice and multiple further lines of treatment are considered for treatment-resistant depression.\n\n## Esketamine is likely to be used later in the treatment pathway because it has a higher treatment burden than oral antidepressants\n\nThe clinical expert explained that esketamine has a higher treatment burden than oral antidepressants. A person having esketamine would have to attend hospital or a suitable community health centre site twice a week and then weekly or every 2\xa0weeks for some time, for approximately 2\xa0hours or more each visit. Treatment-resistant depression is characterised by a lack of energy and motivation so this may not suit all people. Travel to and from the hospital may be difficult because it is not possible to drive after taking esketamine. So, carer support may be needed. For these reasons, the clinical expert considered that esketamine would be used later in the treatment pathway than it was in the clinical evidence, for depression that is more severe and more treatment resistant. This would be after 1 or 2 augmentation therapies. The committee noted that in clinical practice having 1 or 2 augmentation therapies would happen over several years. After the second consultation, consultees confirmed that the appropriate positioning for esketamine was after 1 to 2 augmentation therapies. The committee concluded that the treatment burden, combined with the administration and monitoring concerns (see section 3.18), would mean esketamine is used later in the treatment pathway.\n\n## The 3 or more treatments and 3 or more treatments and augmentation subgroups are appropriate\n\nTreatment options for treatment-resistant depression depend on a person's treatment history, response to treatments and their preferences. Initially the company provided evidence for people whose depression had not responded to at least 2 treatments. But at the fourth committee meeting, the company provided evidence for 2 subgroups:\n\ndepression that had not responded to at least 3 treatments in the current episode (from now, 3 or more treatments subgroup)\n\ndepression that had not responded to 3 or more treatments and augmentation therapy in the current episode (from now, 3 or more treatments and augmentation subgroup).The company explained that the use of esketamine in these subgroups fulfils an unmet need for an option for people whose depression has not responded to several treatment options and where there is a high burden of illness. The committee recalled that the patient expert expressed feelings of hopelessness when depression does not respond to multiple courses of treatment. The committee considered that the burden of illness does increase at later lines of treatment so the 3 or more treatments and augmentation subgroup is the most appropriate positioning for esketamine. The committee concluded that it was appropriate to consider both subgroups based on the increased uncertainty of the evidence for later lines of therapy.\n\n## Placebo with oral antidepressants may not be the most relevant comparator for the treatment subgroups\n\nThe company submission included oral antidepressants as comparators, stating that these were the most common treatments for treatment-resistant depression and that they were the comparators used in the trials. The trials compared esketamine plus a newly started oral antidepressant with placebo plus a newly started oral antidepressant. The clinical experts highlighted that it does not reflect clinical practice to start a new oral antidepressant at the same time as esketamine. The committee noted that different treatments are used at different times and that esketamine may be used later in the treatment pathway (see section 3.3 and section 3.4). The clinical expert noted that esketamine may be used as a preferable alternative to ECT. Consultees commented that ECT would most often be offered to people who are more acutely unwell and whose depression may have psychotic characteristics. But esketamine would be used with caution in these situations as described in the SPC. The company provided a network meta-analysis of esketamine compared with all comparators for the acute phase of treatment (the time frame that measures initial response to a treatment). However, the company and ERG noted there was substantial heterogeneity in the study design, inclusion criteria and time of outcome measurement, because of a lack of available evidence, which made the results unreliable. The committee concluded that the results comparing esketamine with some of the relevant comparators listed in the scope, such as combination or augmentation therapy and ECT, were highly uncertain. So, it considered only the results from the trials. At the fourth committee meeting, the company did not update the comparators despite changing the proposed position of esketamine in the treatment pathway. The ERG noted that an augmentation therapy could be the appropriate comparator for the 3 or more treatments subgroup, because an augmentation therapy was included in the company's next line of treatment. The committee also noted that oral antidepressants would not be the only comparators in clinical practice. The committee concluded that the appropriate comparators for esketamine were highly uncertain but likely included augmentation therapy. It further concluded that it was unable to assess the relative effectiveness of esketamine compared with augmentation therapy based on the comparative evidence available.\n\n## The effect of using psychological therapy with drug treatments is an unresolvable uncertainty with the evidence available\n\nThe patient expert explained that psychological therapy can help with developing coping strategies and alleviate cognitive symptoms. An expert from NICE's guideline on depression noted that psychological therapies were not included as comparators or with combination treatments in the company's submission. The clinical expert explained that CBT is used with drug treatment to treat depression. But not all people with depression can effectively engage with CBT because of the severity of their physical and cognitive symptoms. A patient expert suggested that treatment with esketamine may improve symptoms for enough time for people to engage with CBT. But the clinical expert added that, because of the potential dissociative effects of esketamine treatment, someone would not be able to have psychological therapy immediately after having esketamine. The company clarified that people taking esketamine cannot have psychological therapy at the same time as having esketamine at their clinic visits, but could have therapy on a different day. At consultation, some consultees commented that there is limited evidence for the efficacy of psychological therapies in treating treatment-resistant depression and that including them was not considered for other pharmacological interventions. But in the fourth committee meeting, a patient expert added that they found intensive psychological therapies more useful than pharmacological treatments. However, the provision of intensive psychological therapies is inconsistent in the NHS. The patient expert noted that introducing more pharmacological treatments should not reduce other, already inconsistently provided, resources such as psychological therapies. The committee concluded that psychological therapies are an adjunctive therapy and a relevant part of the treatment pathway. But it noted that their effect would likely be variable depending on the treatment population and severity of depressive symptoms. It considered the estimation of clinical effectiveness of combining psychological therapies with esketamine treatment to be an unresolvable uncertainty with the evidence available.\n\n# Clinical effectiveness\n\n## The results from the flexible dose of esketamine in TRANSFORM-2 are the main source of randomised evidence\n\nThe company's key clinical effectiveness evidence came from 2 randomised phase 3 trials, TRANSFORM‑2 and SUSTAIN‑1. The company also provided supporting evidence from esketamine trials with different doses and populations (TRANSFORM‑1 and TRANSFORM‑3) and from 2 long-term safety studies (SUSTAIN‑2 and SUSTAIN‑3). The key trials were in adults aged\xa018 to 64 with treatment-resistant depression and compared:\n\na flexible dose of esketamine plus oral antidepressant with\n\nplacebo plus oral antidepressant.TRANSFORM‑2 provided randomised evidence for the acute phase of treatment for the 4‑week induction phase of the study, measuring symptom response and remission rates. SUSTAIN‑1 provided longer-term evidence about the continuation and maintenance of esketamine treatment. This was for people whose symptoms responded or people whose symptoms went into remission and were randomised to stop treatment. It measured symptom relapse rates. People could take part in SUSTAIN‑1 as new participants or they could transfer from TRANSFORM‑1 or TRANSFORM‑2 if their depression was in stable remission or stable response. Evidence for acute treatment of depression in people aged\xa065 and over came from TRANSFORM‑3, although this also included a lower starting dose of 28\xa0mg, the same as in the SPC. The committee noted that the dose in TRANSFORM‑1 was a fixed regimen dose. The committee considered all of the clinical evidence, and noted that TRANSFORM‑1 and TRANSFORM‑3 did not show statistically significant improvements in outcomes for esketamine plus oral antidepressant compared with placebo plus oral antidepressant.\n\n## MADRS is used to measure depression severity and treatment effect\n\nThe Montgomery-Asberg Depression Rating Scale (MADRS) measures severity of depression. It is scored between 0 and 60, 0 meaning no depressive symptoms. Primary outcomes of response and remission in TRANSFORM‑2 and relapse rates in SUSTAIN‑1 were measured using MADRS. Moderate to severe depression was defined in TRANSFORM\xa02 as a MADRS score of 28 or more. The mean baseline MADRS score was around 37. Symptom response was defined as a reduction in score of 50% or more from baseline. The clinical expert explained that this is a standard criterion for response. Remission was defined as a MADRS score of 12 or less with minimal or no symptoms. The clinical expert considered that remission is normally measured by a MADRS score of 10 or less (as in NICE's technology appraisal guidance on vortioxetine) but that this would not substantially affect the results. Relapse was defined as a MADRS score of 22 or more for 2 consecutive assessments or other clinically relevant event such as hospitalisation for depression. Recovery was defined as symptoms remaining in remission for about 9\xa0months and recurrence was defined as depression relapsing after recovery. Stable response and remission were also used to define entry criteria for SUSTAIN‑1. These were the same definitions as above, but remission criteria had to be met for 3 out of the 4\xa0weeks before randomisation and response criteria had to be met for the last 2\xa0weeks before randomisation. The clinical expert noted that MADRS is non-linear, meaning that a change in score at the lower end of the scale does not mean the same, in terms of clinical importance, as a change in score at the higher end of the scale. The committee noted that remission and relapse are fixed to MADRS, but response measurement depends on the score at baseline, which complicates interpretation. The committee also noted that the MADRS score used for relapse in SUSTAIN‑1 (22 or more) was not the same as the MADRS score for moderate to severe depression used in the selection criteria for TRANSFORM‑2 (28 or more). This affected the health state utility values and transitions in the economic model (see section 3.26 and section 3.21). The committee took this into account in its decision making.\n\n## Trial data suggests that esketamine is likely more effective than the comparator in the 3 or more treatments subgroup but the evidence is uncertain\n\nThe company initially positioned esketamine for people whose depression had not responded to at least 2 different antidepressants. For this population the adjusted mean reduction in MADRS score from baseline was 19.8 for esketamine and 15.8 for placebo plus oral antidepressant in TRANSFORM‑2. At the second committee meeting, the committee considered that it was difficult to distinguish the placebo response from the true treatment effect in the trial (see section 3.13). Also, the trial had a short 4‑week duration (see section\xa03.14). The committee concluded that it was unclear how effective esketamine was in the entire population. In response to the second consultation, the company provided this same trial data divided into 2 specific subgroups based on number of previous treatments. The company considered this analysis confidential and so it cannot be reported here. The company considered that the relative treatment effect of esketamine is greater in the 3 or more treatments subgroup than the full population. The ERG considered that the increased treatment effect for esketamine in the 3 or more treatments subgroup could be because of a lessened response in the placebo plus oral antidepressant arm. The committee noted that NICE's guide to the methods of technology appraisal 2013 (section 5.10.1) states a 'subgroup should be clearly defined and should preferably be identified on the basis of an expectation of differential clinical or cost effectiveness because of known, biologically plausible mechanisms'. The clinical expert considered that the difference in subgroups was plausible and would be expected, because a newly started oral antidepressant would likely be less effective in the 3 or more treatments subgroup than in the entire population. The committee considered that the evidence of benefit for esketamine in the full treatment population was driven by the change in MADRS score from baseline in the 3 or more treatments subgroup. However, it noted the following uncertainties with the subgroup analysis:\n\nThe relatively small size of the 3 or more treatments subgroup and overall low patient numbers (the exact patient numbers are confidential and cannot be reported here).\n\nPeople in the 3 or more treatments subgroup in the trial might have different characteristics of depression than those expected to take esketamine in clinical practice (see section 3.16).In response to consultation, the company pooled and weighted clinical data from TRANSFORM‑2 and TRANSFORM‑3 (from now referred to as pooled TRANSFORM studies) for the 3 or more treatments subgroup. The NHS England clinical adviser noted that TRANSFORM‑3 was a smaller study than TRANSFORM‑2 with a 4‑week treatment phase. The committee considered there was still substantial uncertainty associated with the clinical evidence for esketamine but it is likely more effective than the comparator in the 3 or more treatments subgroup.\n\n## The adjusted trial evidence for esketamine's benefit in the 3 or more treatments and augmentation subgroup is highly uncertain\n\nThe company used the relative treatment effect between the 3 or more treatments subgroup and the 3 or more treatments and augmentation subgroup in SUSTAIN‑2, a long-term safety study. The proportional treatment effect was applied to the esketamine arm from the 3 or more treatments subgroup from the pooled TRANSFORM studies, generating an estimate of effectiveness for the esketamine arm in the 3 or more treatments and augmentation subgroup. The company maintained the efficacy from the pooled TRANSFORM studies for the oral antidepressant plus placebo arm. The ERG noted the effect of augmentation was unclear from the evidence provided and the difference in treatment effect between the esketamine arm and oral antidepressant plus placebo arm was uncertain. The ERG was also unclear why the company used the relative treatment effect from SUSTAIN‑2 instead of estimates from the TRANSFORM studies. The committee recalled the uncertainty about the comparators for both treatment subgroups. It noted that if the comparator for the 3 or more treatments and augmentation subgroup was not an oral antidepressant the effectiveness of the comparator could be underestimated. The committee concluded that the adjustment to the trial evidence to establish the benefit of esketamine in the 3 or more treatments and augmentation subgroup was highly uncertain.\n\n## There is supportive evidence from 2 non-randomised studies in Europe\n\nIn its response to consultation, the company provided data from 2 real-world studies to support the evidence for esketamine's treatment efficacy. One was a retrospective, observational study of 160\xa0people (157\xa0people were included in the analysis) taking esketamine who had treatment-resistant depression and who had an average of 2 suicide attempts during their life. The other study was a compassionate use study in Spain of 32\xa0people whose depression had not responded to 2 or more antidepressants, 1 augmentation therapy and a non-pharmacological therapy. The company acknowledged there were a low number of people in both studies. The observational study showed a decrease in MADRS scores from baseline over 6\xa0months. However, this was a single-arm observational study so there were no estimations of the effects of a comparator treatment. The ERG was unclear how the studies would overcome concerns regarding the generalisability of esketamine to the NHS. The committee acknowledged the effort of the company to identify additional supporting evidence but noted the low numbers of people in the studies and limitations of the observational evidence.\n\n# Limitations in the clinical evidence\n\n## It is not appropriate to adjust the efficacy estimates of the comparator arm in the trials\n\nFor the full population, the company considered that the efficacy estimates (response and remission) for the placebo plus oral antidepressant arm of the TRANSFORM‑2 trial were high compared with other studies considering depression. The company suggested a post-hoc adjustment of the TRANSFORM‑2 data to account for some of these differences. The committee considered the reasons for the high placebo response rate:\n\nIn the trial, people visited the clinic more than in clinical practice. In the 4\xa0weeks, people who had esketamine had 8 clinic visits. People who had the placebo nasal spray also had 8 clinic visits to preserve blinding. However, the company estimated that in clinical practice people taking oral antidepressants would only have 2 visits with healthcare professionals over a 4‑week period. The clinical expert highlighted that increased clinical contact could increase the effect of treatment. The committee considered that the additional clinical contact involved in administering esketamine included support from mental health nurses and establishing relationships. A patient expert noted this was an important part of treatment (see section 3.35). The committee noted that planned and structured clinical contact improves outcomes and that in NHS practice oral antidepressant treatment is ideally combined with other psychological therapies, which would also be structured. The expert from NICE's guideline on depression considered that the efficacy estimates in the placebo plus oral antidepressant arm seemed higher than expected. The ERG considered it inappropriate to apply adjustment to the placebo plus oral antidepressant arm because it is impossible to be confident about the placebo effect associated with esketamine in clinical practice. The committee concluded that the trial design may have increased clinical contact but there was no evidence this would cause the placebo response. It also concluded that any adjustment to account for clinical contact was not appropriate because of the risk of bias.\n\nIn the trial, people may have had a high expectation of esketamine because it has a novel treatment mechanism. But the committee considered that blinding could be an issue in the trials. This is because for people having placebo plus oral antidepressant, the absence of psychoactive effects and other effects expected with esketamine could lead to consequent negative expectations and a lower response to treatment. So the true treatment effect is unclear if the blinding was not preserved, and adjustment of a placebo effect could lead to unknown biases.\n\nIn the trial, people's symptoms also responded to the new oral antidepressant given alongside placebo. The committee noted that in clinical practice, oral antidepressants would not be newly started at the same time as esketamine, because it is not clinical practice to try 2 new therapies at the same time. So any response from trying the new oral antidepressant is difficult to separate from the treatment effect of esketamine. The committee noted that for the 3 or more treatments subgroup, a reduced response to the new oral antidepressant was likely to explain the lessened response of the comparator arm (see section 3.10). So any adjustment of placebo response could also account for this effect with unknown bias.The committee concluded that the randomised design of the trial helps to mitigate for the placebo response. So it was not appropriate to adjust the efficacy estimates of the placebo plus oral antidepressant arm in the trials. Any adjustment would not explore all potential sources of difference between treatment arms so could introduce bias.\n\n## The response and remission evidence from the TRANSFORM studies should be considered with caution when used in the economic model\n\nFor the full population with treatment-resistant depression, TRANSFORM‑2 measured a statistically significant difference in MADRS score after 28\xa0days between esketamine plus newly started oral antidepressant compared with placebo plus newly started oral antidepressant. The committee noted a separation of treatment effect for the full trial population after 2\xa0days (or 1\xa0treatment), which remained for the duration of the 4\xa0weeks. The NHS England clinical adviser added that the treatment benefit of esketamine in TRANSFORM‑3 was not statistically significant compared with placebo plus oral antidepressant. The NHS clinical adviser also stated that no rapid effect of esketamine was observed, with a separation of treatment effect compared with the placebo plus oral antidepressant arm after 22\xa0days. The committee noted that NICE's guideline on depression recommended an initial assessment at 2 to 4\xa0weeks to assess response to oral antidepressant, but further regular assessments and dose optimisation would be considered after this point. The committee considered that the evidence suggested there was likely to be changes in MADRS score as part of initial response to treatment. So, it considered that 4\xa0weeks was not an appropriate endpoint on which to base longer-term extrapolations of response and remission. Also, a consultee commented that splitting data into 2 groups, response or remission compared with no response or remission, can lead to an overestimation of differences between arms. The committee acknowledged that this could have inflated the differences between arms which would increase the uncertainty of response and remission rates. For example, the committee noted that response to esketamine was higher for the 3 treatments or more subgroup, despite a lower change from baseline in MADRS score. The committee concluded that although the response and remission evidence from TRANSFORM‑2 showed a statistically significant difference between esketamine and placebo plus oral antidepressant, the data should be considered with caution when used to generate transition probabilities in the economic model because of the duration of the trial (see section\xa03.19).\n\n## The withdrawal design of SUSTAIN-1 could introduce bias\n\nSUSTAIN‑1 measured withdrawal of esketamine for a randomised population of people whose depression was in stable response or stable remission. The ERG commented that there was potential for selection bias using these criteria. This is because if esketamine is tolerated, people who have the drug for 16\xa0weeks and do not stop (induction and optimisation phases) stay in the trial by design. This means the people selected to stay in the trial are less likely to be affected by the treatment burden and do not have adverse events that make them stop treatment. So this does not represent the full population in the acute phase of treatment (from TRANSFORM trials) and may underestimate relapse rates for those taking esketamine. After the optimisation phase, some people were randomised to stop having esketamine and instead had placebo. Everyone continued taking the same oral antidepressant they had at the start of the trial. A consultee commented that there is potential for functional unblinding with this design because people randomised to placebo may notice the absence of psychoactive effects. The consequent negative expectations could affect the results. In response to the second consultation, the company provided analysis that showed censoring people who had dissociative symptoms and relapsed did not significantly affect the results. Because this analysis focused on dissociative effects only, the committee was not persuaded that this necessarily showed the blinding was effective. The committee concluded that the withdrawal design of SUSTAIN‑1 meant that if any unblinding had occurred, it would have biased the results in favour of esketamine. It noted that the withdrawal trial design was mandated by the regulator, but the faster onset of action may differ from oral antidepressants.\n\n## The evidence from the trials is limited in its generalisability to the NHS\n\nThe company assumed that data from TRANSFORM‑2 and SUSTAIN‑1 were generalisable to NHS clinical practice, but no people were recruited in the UK. Also, TRANSFORM‑2 and SUSTAIN‑1 excluded people:\n\nwith moderate to severe substance or alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM‑5) criteria\n\nwith some psychiatric comorbidities\n\nwith depression that had not responded to at least 7 treatments with ECT in the current major depressive episode\n\nwho had vagus nerve stimulation or deep brain stimulation\n\nwho had suicidal ideation with intent in the previous 6\xa0months or suicidal behaviour in the previous 12\xa0months. The ERG noted that those excluded from TRANSFORM‑2 and SUSTAIN‑1 could represent a substantial proportion of people with treatment-resistant depression. It considered that excluding these people limited the generalisability of the trials to the NHS. The expert from NICE's guideline on depression agreed and noted that people with treatment-resistant depression are likely to have an increased risk of suicide. A clinical expert also noted that suicidal ideation is often an integral part of the disease. The committee noted that many people referred to a psychiatrist (a requirement of the SPC) in NHS clinical practice would be at higher risk of suicide. The clinical experts acknowledged the limitations of the other exclusion criteria but explained that these are standard for trials in this population. Comments received at consultation confirmed that uncertainty introduced by excluding these people is common in trials in this disease area. The committee was aware of the comments in the European public assessment report (EPAR) about the precautions that need to be taken if people with psychiatric comorbidities take esketamine. The committee also noted that the population in the TRANSFORM and SUSTAIN trials may not be in line with the population expected to have esketamine in clinical practice (see section 3.4) and that people with more severe symptoms may be more likely to be excluded using these criteria. The committee considered that the other exclusion criteria could inhibit the generalisability of the trial results. The committee concluded that excluding people with recent (defined in TRANSFORM‑2 and SUSTAIN‑1 as within 6\xa0months to the start of the screening or prospective observational phase) suicidal ideation with intent or suicidal behaviour limited the generalisability of the trials to the NHS for people with treatment-resistant depression. It considered this was likely to be more of an issue when considering populations whose depression is more treatment resistant, which may correlate with increased potential for psychiatric comorbidities and suicidal ideation.\n\n## Some of the clinical uncertainties are common in clinical trials in mental health\n\nThe clinical expert considered that there was a mismatch between the evidence from the clinical trials and how esketamine would be used in clinical practice. They noted that it was difficult to collect randomised evidence in this disease area. The committee considered that some of these clinical uncertainties are common in clinical trials in mental health.\n\nThe committee acknowledged that the treatment pathway is not clearly defined by line of therapy and instead is based on patient history and patient preference (see section 3.3). But it accepted the treatment line approach for the practical purposes of the economic modelling. The committee acknowledged it may be practically challenging to overcome this uncertainty so concluded this was currently an unresolvable uncertainty and did not consider it further.\n\nThe committee also recalled the uncertainty of the benefit of esketamine in a later treatment line (see section 3.11). The committee noted that a trial done in the population that the treatment is being positioned in (3 or more treatments subgroup with or without augmentation) would help to overcome this uncertainty. It was aware of an ongoing phase 3 clinical trial (ESCAPE‑TRD), which it considered would be in a population more aligned with who would likely have esketamine in the NHS. So the committee concluded that this was a resolvable uncertainty.\n\nThe committee accepted that clinical trials in depression have a mandated regulatory minimum length. It noted this when assessing esketamine's clinical-effectiveness evidence. But it noted that the trials are short and may not reflect clinical practice (see section 3.14 and section 3.4), which generated large uncertainty in the cost-effectiveness modelling. The committee considered that doing a longer trial than the mandated regulatory minimum length required could reduce this uncertainty. The committee highlighted that the lack of long-term evidence was a key uncertainty and noted an assumed long-term benefit was a key driver of the cost-effectiveness estimates. The committee concluded that the company could have done longer trials to meet the requirements of health technology assessment and so this was a resolvable uncertainty.\n\nThe committee recalled that the study designs result in relatively larger placebo response than in other disease areas but preferred not to adjust the efficacy estimates of the comparator arm for the purposes of the economic modelling (see section 3.13). To overcome this uncertainty, the committee considered that a trial with a third arm without the placebo nasal spray may help with considering how people are affected by being in a trial (for example an improvement in MADRS score because of more frequent contact with trial investigators than would happen with clinicians in clinical practice). The committee noted that this would not necessarily overcome all the issues relating to the placebo response but would contribute to a better understanding of the relative effect of treatment observed in the trial. The committee concluded that this was a partially resolvable uncertainty.\n\nThe committee stated that psychological therapy is likely an important part of treatment but provision and efficacy would vary substantially in a multinational clinical trial setting (see section 3.7). The committee noted that the uncertainty could have been overcome by doing an additional trial that included psychological therapy. But it acknowledged that this may be practically challenging because of the need for a longer follow-up and differences in the types of psychological therapies available. Also introducing another treatment into a clinical trial may make it difficult to measure the effect of esketamine. The committee noted that the uncertainty was partially resolvable and accepted the evidence without considering the effect of psychological therapies.\n\nThe committee noted that excluding some people from the trial limits the generalisability of effectiveness results to later lines of therapy and NHS clinical practice (see section 3.16). It recalled that this may help with understanding relative effect so is common practice in clinical trials. But the committee recalled that the generalisability of the data led to substantial uncertainty in the cost-effectiveness estimates. The committee considered that the uncertainty could have been reduced if the trial was done in a population that was a closer match to the people most likely to have esketamine in NHS clinical practice but acknowledged the practical challenges of doing this. This is because it may lead to a more heterogenous population so it may be more difficult to measure the effect of esketamine. But the committee noted that some of the uncertainty could have been resolved if the company included people with recent suicidal ideation with intent. The committee considered this would likely not have increased the heterogeneity of the population with treatment-resistant depression. The committee concluded that this was a partially resolvable uncertainty.The committee recognised the difficulty of designing, recruiting and interpreting results from clinical trials in this disease area, and that the evidence requirements of health technology assessment may be different than the licensing requirements captured through regulatory endpoints (see section\xa04). The committee agreed that these clinical uncertainties were important to the economic modelling and took this into account when considering the degree of certainty of the cost-effectiveness results. The committee also acknowledged that there is ongoing research in this disease area could potentially address some of the uncertainties.\n\n# Safety\n\n## Additional monitoring and supervision is required with esketamine in line with the SPC\n\nThe European Medicines Agency identified some risks of esketamine use in the SPC. These included drug dependence, transient dissociative states and perception disorders, disturbances in consciousness, and increased blood pressure. A register for administering and monitoring esketamine to prevent dependence and misuse has been set up with the Medicines and Healthcare products Regulatory Agency (MHRA). The NHS commissioning expert explained that, because esketamine is a schedule 2 drug, it is subject to the full controlled drug requirements relating to prescriptions and storage. The committee acknowledged that the monitoring period would likely mitigate the other risks identified in the risk management plan and the committee did not need to consider these further. The committee considered comments received in consultation regarding suicides in people who stopped esketamine in a population who had no recent suicidal ideation or behaviour. The clinical expert explained that the increase in suicidal ideation could have happened despite people having esketamine, rather than because of it, given the nature of depression. The committee noted the SPC states that the effectiveness of esketamine in preventing suicide or in reducing suicidal ideation or behaviour has not been demonstrated. The SPC notes that general clinical experience shows that the risk of suicide may increase in the early stages of recovery. The committee considered that the MHRA are responsible for assessing safety concerns. It considered that the precautions regarding risk of suicide and supervision and monitoring in the SPC should be taken into account when prescribing esketamine, particularly during early treatment and after dose changes. The committee concluded that it was not a safety committee and could not make recommendations about safety.\n\n# Economic model\n\n## The company's economic model uses uncertain clinical inputs so its results should be interpreted with caution\n\nThe company economic model had 5 health states: major depressive episode (MDE), response, remission, recovery and death. The transitions between each health state were determined by the relapse, remission and response rates in the TRANSFORM studies and SUSTAIN‑2 (see section 3.10 and section 3.11) and values in the literature, for example, the STARD trial (a large-scale clinical trial for people with depression). All people start in the MDE state. In each of the arms and subgroups the first treatment is followed by 3 more potential subsequent treatments after non-response or relapse, and then a non-specified mixture of treatments (best supportive care). The committee considered that the key drivers of the economic model results in both treatment subgroups included the following:\n\nThe pooled 4‑week initial response to treatment from the acute efficacy trials has the most influence on the modelled differences between treatment arms (see section 3.20) and is the only randomised comparative data that addresses the decision problem.\n\nThe relapse rate for the esketamine treatment arm uses data from SUSTAIN‑1, which likely underestimates relapse rates because of selection bias from including only people with stable response and stable remission (see section 3.15 and section 3.21).\n\nThe relapse rate for the placebo plus oral antidepressant arm uses data from the STARD trial which has generalisability issues and bias from using a different trial design and population (see section 3.21).\n\nThe effect of the 3 lines of subsequent treatments does not reflect how subsequent treatments are used in clinical practice (see section 3.22).\n\nThe efficacy of the non-specified mixture of treatments after the subsequent treatments has a substantial effect on the modelled long-term outcomes, resulting in a large amount of time spent in the MDE health state, which is a key driver of the costs (see section 3.22 and section 3.32).The committee concluded that the clinical inputs informing the model are highly uncertain and that any modelled results should be interpreted with caution.\n\n## The modelled difference between treatment arms is driven by response and remission in the acute phase of treatment\n\nThe first 4-week cycle of the economic model represents the transition from the MDE health state to response or remission, informed mostly by TRANSFORM‑2 with some information from TRANSFORM‑3. The committee noted that the initial response rate was uncertain because of the short time frame and because it included a placebo response that may not be seen in clinical practice. The committee noted the importance of this initial response or remission rate because later transitions to different health states are more gradual, determined by relapse rates and subsequent treatments. So, the committee noted a key driver of the difference between arms was the initial response. So, accurate response and remission rates in the acute phase of treatment are needed to give robust results.\n\n## The relapse rate data comes from different sources, which leads to uncertainty and potential generalisability issues\n\nFor the relapse rates in the economic model, the esketamine arm used transitions between health states from the SUSTAIN‑1 trial. The comparator arm used relapse data from the STARD trial. The relapse and loss of response rates for SUSTAIN‑1 are based on a MADRS score of 22 or more for 2 consecutive assessments. The committee noted that this was not equivalent to the inclusion criteria in the trials, which was a MADRS score of 28 or more. The committee considered it unclear if some transitions categorised as relapses are rather fluctuations in severity of depression, consistent with a chronic disease model (see section\xa03.23) and whether the transition would mean a change of treatment in clinical practice. The STARD trial used a Quick Inventory of Depressive Symptomatology–Self-Report score of 11 or more to measure relapse. The committee considered that the different definitions of relapse criteria contribute uncertainty to the comparison. The committee also had concerns about the generalisability of the trial design and population of STARD to NHS practice. The committee concluded that using different sources of data for relapse leads to potential generalisability issues and bias in the economic model.\n\n## The effect of subsequent treatments does not match what would be seen in clinical practice\n\nThe ERG noted that the response and remission rates of subsequent treatments used in the company's original base case could not be validated and were likely to be underestimated. The ERG proposed a scenario that applied a proportional reduction in each line of therapy based on data from the STARD trial. In response to consultation, the company provided this scenario in its revised base case. The response and remission rates were calculated on a 4‑weekly basis to be implemented per cycle in the model. This meant people moved between treatments quickly if their symptoms did not respond within 4\xa0weeks. The committee considered that moving through treatments would not happen that quickly in clinical practice. It also recalled the uncertainty with using the STAR*D trial data and its generalisability to UK practice in the expected population (see section 3.21). Also, the proportional reduction was applied to the loss of response and relapse rates, which resulted in a relapse rate of 99% every 4\xa0weeks for the non-specified treatment mix that represents best supportive care. The ERG considered this to be implausible so provided a scenario with a cap on relapse and loss of response as described in the original submission. After the third meeting, the company base case included further changes to this modelling assumption. The committee considered that despite the increased efficacy of subsequent treatments, the best supportive care transitions still had the greatest effect on long-term outcomes, which were highly uncertain. This mostly affected the costs because it meant a large amount of time was spent in the MDE health state. The committee considered there was minimal evidence for all transitions in the best supportive care state, and there was considerable uncertainty about how the course of the disease was modelled. It concluded that neither the company's revised base case nor the ERG's treatment cap would accurately model what happens to patients in clinical practice. Instead, the company and the ERG estimated the proportion of people in the MDE health state at later stages of the model, for which there was no available evidence.\n\n## The disease course of treatment-resistant depression is uncertain and further research is needed\n\nIn the second appraisal consultation document, the committee considered that the economic model likely overestimated the number of people in the MDE health state in both treatment arms and did not reflect the course of the disease or its episodic nature. In response to consultation, the company provided a targeted literature review that it considered supported the modelled output. The model output suggested that, for a person with treatment-resistant depression, 66% of a person's life is spent in the MDE health state. The targeted review showed generally low longer-term remission rates. However, the committee noted heterogeneity in the definition of remission and response, trial design and inclusion criteria of the trials included in the review. In particular, it considered that the trials in the review may have included people with depression that was much more treatment resistant and severe than the modelled population. The company also provided evidence from a UK cohort, which showed the mean duration of an episode of treatment-resistant depression was 6.1\xa0years. The ERG provided another data source which was a large retrospective cohort study of insurance databases in the US. This study attempted to characterise the treatment journey for someone with treatment-resistant depression at an episodic level based on length of treatment on oral antidepressants. The results showed the mean length of a first episode of treatment-resistant depression was 1.56\xa0years, and the mean length of remission for those who had a second episode was 0.90\xa0years. The clinical expert considered this data would be of limited use because it used time on treatment data and it would not necessarily fit to an episodic model. The ERG considered that a treatment-resistant episode was inconsistently defined and would likely be measuring different outcomes. It noted that the outcomes of interest for modelling the MDE health state were the severity of depression for the full time horizon (see section\xa03.24) and the costs accrued while in the state (see section 3.31). The committee also considered consultee comments that stated that improvements in depression are generally maintained at the end of acute treatment, and on average symptoms improve further. It also heard from consultees who commented that depression can be highly episodic, and that treatment can be successful when people adhere to it. The clinical expert estimated that currently 20% to 30% of people with treatment-resistant depression have chronic longer-term disease that has not responded to any treatment. For these people, severity would likely fluctuate, and this would not fit the episodic disease model well. After the company repositioned esketamine as a treatment used at a later line, the committee considered a chronic longer-term disease model may be more appropriate to capture the profile of this group. The committee noted substantial uncertainty with all the longer-term data for treatment-resistant depression and agreed with the ERG that the available evidence is likely measuring heterogeneous outcomes in heterogeneous populations. The committee understood the difficulties of modelling a heterogeneous population with differing disease models. But it concluded that the analysis did not appropriately capture either the chronic or episodic nature of the condition. It also concluded that the literature for longer-term outcomes for treatment-resistant depression is poor, so the outcomes are highly uncertain. The committee recommended further research to understand the course of the disease (see section 4).\n\n## The long-term evidence of esketamine is too uncertain to justify a substantial modelled benefit over a 20-year time horizon\n\nThe company originally modelled a 5‑year time horizon to reflect that treatment-resistant depression is an episodic condition. The ERG noted that differences in the modelled costs and quality-adjusted life years (QALYs) between treatments continued for 20\xa0years, so it preferred a 20‑year time horizon. The clinical experts considered a longer time horizon was appropriate because depression is a chronic condition for some people. The expert from NICE's guideline on depression agreed that a longer time horizon was needed to account for the duration of the condition and the need for any subsequent treatments. After the company repositioned esketamine as a treatment used at a later line, the committee considered the 20‑year time horizon was likely appropriate. But it noted that there was insufficient data to populate this model for the full time horizon because of the uncertainty about the inputs into the model and esketamine's long-term outcomes (see section 3.23). It noted that the model was sensitive to assumptions about the length of the time horizon because esketamine costs were modelled in the short term but benefits accrued over the full time horizon. The committee also recalled that the disease course of treatment-resistant depression is uncertain and capturing the fluctuating nature of the condition and treatment is difficult. The committee explored this uncertainty through sensitivity analysis. It concluded that the long-term evidence for esketamine is too uncertain to justify substantial modelled benefit over the full time horizon.\n\n## It is not appropriate to include an effect of esketamine on mortality in the model\n\nIn its economic model, the company assumed there were 2 risks for dying: all-cause mortality risk (specific to age and gender) and an excess annual mortality for treatment-resistant depression associated with suicide. The company initially modelled a reduction in treatment-resistant depression (which is associated with excess mortality). This indirectly decreased the risk of excess mortality with esketamine. The committee considered it plausible that esketamine could affect mortality. However, with the other structural uncertainties and no evidence of longer-term benefit of esketamine, the committee considered this was speculative. It also noted that the SPC states: 'The long-term efficacy of Spravato to prevent suicide has not been established'. Because of issues with generalisability, excluding people with recent suicidal ideation with intent and the lack of data, the committee concluded it could not accept a reduced suicide, or mortality, risk.\n\n# Utility values\n\n## The difference in utility values between health states is likely overestimated\n\nThe company measured utility in the TRANSFORM‑2 and SUSTAIN‑1 trials as EQ‑5D‑5L measurements and mapped these to EQ‑5D‑3L utility values as in the NICE reference case. These utility values were applied to the modelled health states. The committee noted that the utility value for MDE of 0.417 was measured from the baseline utility scores in TRANSFORM‑2 at a mean MADRS score of 37. However, the transition from relapse or remission to the MDE state needed a MADRS score of 22 or more for 2 consecutive assessments. The committee recalled that response criteria were not fixed to absolute MADRS values. This made interpreting the utility values difficult because they could have come from people with MADRS scores of between 13 and a maximum value above the threshold for relapse of 22 or more. In response to consultation, the company provided a scenario that provided MDE state utility values that represented people with moderate depression to include a lower relapse rate. The ERG noted this did not address the problem of the estimate of relapse based on the threshold with a lower MADRS score. The committee noted that symptom severity could fluctuate, and that this would not be consistent with a fixed state with large utility transitions. The clinical expert noted that a MADRS score of 37 represents very severe depression as would be expected during an acute period of depressive symptoms. The committee considered that in clinical practice, people will likely have less severe MADRS scores on average for prolonged periods of time. It recalled the difficulty of defining and characterising a treatment episode. The clinical expert added that people tend to have symptoms at least half of the time, but these symptoms are not always severe enough to reach diagnostic criteria. The committee was also concerned that the utility values within each health state could be highly heterogeneous. It concluded that the MDE health state utility would likely represent the baseline utility values of patients with a MADRS score of 37, but would likely underestimate quality of life over the full time horizon.\n\n## It is appropriate to consider applying a carer disutility in the model and to consider the effect without it\n\nThe company submission included a disutility value applied to the model for the effect of treatment-resistant depression on carers and families. This was done by applying a disutility to the MDE health state. This was the difference in utility between carers of people with symptomatic treatment-resistant depression and carers of people with treatment-resistant depression that was in remission. The ERG noted that this implied that carers of all people in the MDE health state would have a utility value associated with being in remission. The ERG argued that a methodologically better way to estimate disutility for a specific state is to subtract the utility of that state from the utility for full health. The ERG applied a lower value to the disutility by using this method to calculate the utility values. The committee acknowledged that treatment-resistant depression affects carers and families and considered the ERG scenario to be the most appropriate. But it considered that there was uncertainty about how appropriate including a carer disutility was. This was because of the lack of data on the direct effect treatment-resistant depression had on carers. The committee noted the lack of evidence on any direct benefit to carers after treatment with esketamine. It also noted the potential for an increased treatment burden for carers as well as people with depression. The committee considered that carer utility is only applied in the MDE health state, which is likely to be overpopulated in the economic model. It noted that carer disutility was not considered in NICE's technology appraisal guidance on vortioxetine. The committee concluded that it was appropriate to consider scenarios with both the ERG carer disutility scenario and no carer disutility because the effect was uncertain.\n\n## The disutility of adverse events should have been considered in the modelling\n\nThe committee recalled that esketamine is associated with some potentially serious adverse events. SUSTAIN‑2 reported 6.9% of people had serious adverse events including depression, suicidal ideation, suicide attempt, anxiety and gastroenteritis. The most common treatment-emergent adverse events (any event not present before the start of treatment) included dizziness and dissociation. The company did not consider the disutility or cost of these adverse events in the model because most adverse events were resolved on the day (75% of adverse events were resolved on the day in SUSTAIN‑2) and so it considered these were transient. The patient expert described unwanted effects they experienced while having esketamine. The committee considered that a large proportion of patients may experience these effects, and it was likely a major consideration for the treatment experience. It considered these events could be experienced up to once a week which, combined with fear of these adverse events, could cumulatively contribute to a substantial disutility associated with the treatment that was not captured in the model. The committee concluded that adverse events of treatment had not been fully explored, but would contribute additional uncertainty to the modelled treatment benefit.\n\n# Stopping treatment\n\n## There is limited evidence on the effect of stopping esketamine for reasons other than lack of efficacy\n\nThe company assumed that some people would stop taking esketamine for reasons other than lack of efficacy, in line with the criteria in the SPC and additional guidance on stopping treatment. In response to consultation, the company provided scenarios for stopping treatment and scenarios that explored a utility decrement after stopping treatment. The stopping rates were based on research questionnaires from clinicians. Stopping treatment was assumed to stop costs for esketamine incurring but have no effect on QALYs. The company modelled that 60% of people whose depression was in stable remission would immediately stop treatment after 2\xa0years. The ERG also provided a scenario that assumed no immediate treatment stopping and instead modelled a continued exponential reduction based on extrapolation of the trial data. This was because no evidence was submitted that showed the effect of stopping on long-term symptoms or quality of life. The ERG and clinical experts also highlighted that there was no data to accurately determine stopping rates in clinical practice. The ERG noted that no data was collected for people who stopped treatment for reasons other than lack of efficacy after recovery, and the reasons why they stopped were not explored. The committee noted that the SUSTAIN‑1 trial is designed to answer the clinical question of whether stopping treatment affects relapse rates. It showed that there is a significant effect of stopping treatment. However, the committee noted this was measured at 16\xa0weeks of treatment rather than after recovery. The committee considered it likely that people would stop esketamine for various reasons over a 2‑year period. This could include recovery, adverse events or because of the high treatment burden associated with its use. However, it considered that the research data informing the company revised base case may not be generalisable to NHS practice. This was because it classified people into risk levels and applied these to the full population in SUSTAIN‑1. With the company's revised positioning, this could include people whose depression would be resistant to more lines of therapy than in SUSTAIN‑1, likely have more comorbidities and may include more people who would have prolonged or repeated use of esketamine. The committee also noted that the data for the utility decrement came from the SUSTAIN‑2 study and had limited use in the model because of the high proportion in the MDE state, so did not explore this scenario further. The committee concluded that more data for stopping treatment for reasons other than lack of efficacy was needed to justify modelling the additional stopping guidance provided by the company.\n\n## Stopping treatment in clinical practice would be based on people's individual circumstances and may include prolonged or repeated treatment\n\nThe clinical expert explained that stopping treatment is variable in clinical practice. They would expect that the decision to stop treatment would be made after a discussion of the person's individual circumstances. They also considered that this could involve treatment pauses to assess how a person feels without esketamine. The clinical expert noted that the best indicator for what treatment would work would be what the person's depression had responded to previously. Also, people who consider esketamine to be effective may want to carry on taking it. A patient expert suggested that if treatment with esketamine worked for someone then they would consider having the treatment again when symptoms returned. They also noted that people would be concerned and worried about relapse if they stopped treatment. Another patient expert explained that their esketamine treatment was in the process of being tapered off slowly with careful monitoring of response. The committee recognised that people would be fully involved in the decisions about continuing treatment, and that decisions about how long treatment lasts and reasons for stopping it vary based on individual circumstances. The committee also considered that it is possible more people's symptoms would respond to treatment, but not all of them would be considered to be in remission if their depression were more treatment resistant or severe at baseline. These people would not stop treatment immediately at 2\xa0years using the company's stopping criteria. The committee also noted the uncertain course of the disease. It considered that a fluctuation in symptom severity might not mean that esketamine was stopped, as it was in the trials. It concluded that in clinical practice stopping treatment may not be guided by the company criteria and could include ongoing repeated or prolonged treatment based on symptom severity. This would particularly be the case for the expected population in NHS clinical practice and the 3 or more treatments subgroup.\n\n# Resource use\n\n## The cost of a course of esketamine treatment may be underestimated\n\nThe company confirmed that the dose of esketamine used in the model was an average from the trial evidence. The committee was concerned that it had not been presented with a dose response curve or a clear analysis of how the flexible dosing strategy was implemented. It also considered that it was unclear if people develop a tolerance to esketamine and need increased doses (up to the maximum dose) to achieve the same therapeutic effect. This would be particularly important for people who have treatment for a long time. The committee noted that frequency of dose during maintenance was dependent on meeting remission criteria (for a weekly dose, MADRS score of more than 12, and for a 2‑weekly dose, a MADRS score of 12 or less). The committee considered that a change in what is considered remission, for example a MADRS score of 10 or less (as in NICE's technology appraisal guidance on vortioxetine), could affect the costs of treatment. Also, in line with a chronic disease model, some people who met the relapse criteria may have been considered to have had a fluctuation in symptom severity, rather than a relapse. So, they may have had prolonged or repeated treatment. Also, issues with generalisability of the trial evidence and esketamine's changed positioning in the treatment pathway could increase the number of people whose depression was considered to have only responded, compared with people with depression considered to be in remission. The committee noted that the new observational data presented after the third committee meeting likely used higher or more frequent dosing for most people than was modelled. Although the committee considered that this was not used in the economic model, it might represent the expected use in clinical practice. The committee concluded that the model may underestimate the cost of a course of esketamine treatment for the intended treatment population. It also noted that a course of treatment may not easily be defined in the context of a chronic condition with repeated or prolonged treatment.\n\n## Healthcare resource use costs are highly uncertain and contribute to the economic model's uncertainty\n\nThe company modelled healthcare resource use by health state as defined in the economic model. The committee noted the importance of the MDE health state because of the amount of time people spent in it. The company measured resource use for each health state using a retrospective chart review of patients in UK clinical practice. This asked 30\xa0psychiatrists and 9\xa0GPs to provide resource use for the last 10\xa0people with treatment-resistant depression they had seen. These were converted into costs by health state in the company study. These costs included primary care visits, secondary care visits, psychological-based interventions, occupational therapy, hospitalisations and crisis resolution home teams. The clinical expert considered that, in clinical practice, the distribution of costs in treatment-resistant depression were heavily skewed. This means most healthcare resource is used by a proportionally small number of people. The committee understood this was mostly through a small number of people needing hospitalisation. The committee noted that there was potential for selection bias because people that are seen more frequently are more likely to be included in the study. The committee was concerned that some of the costs seemed implausibly high. For example, crisis resolution and home treatment teams contributed 33% of all costs in the MDE health state, which was nearly equivalent to the total costs of hospitalisation. The ERG provided an alternative healthcare resource use scenario using a large database of general practice records used in Byford et al. (2011). This was used in NICE's technology appraisal guidance on vortioxetine and NICE's guideline on depression to provide cost information. The ERG considered that only the population with severe depression should be used to represent people in the MDE health state. However, it noted that the definitions used in the Byford study for severity included many types of depression, including depression with psychosis. Only people who had at least 2 treatments and whose symptoms had not remitted within a year were included in the Byford study costs for the MDE health state. This did not match the company's definition of treatment-resistant depression. Also, the Byford study linked primary care records with secondary care referrals and hospitalisations. The company considered that the study did not fully capture hospitalisation costs or community interventions, which have increased since the study was done. The committee agreed that some of the costs of secondary care or hospitalisation could have been missed in the Byford dataset because of the study design. However, the committee noted the substantial difference between the 2 studies, with the costs associated with the MDE health state in Byford being around 8% of what was reported in the company's retrospective chart review. After the third committee meeting, the company proposed 2 new treatment subgroups. It modelled a split of 75% of costs from its own costing study and 25% from the Byford study for the 3 or more treatments subgroup, and 100% of costs from its own costing study for the 3 or more treatments and augmentation subgroup. It also presented supporting evidence from a secondary care mental health setting using Clinical Record Interactive Search data from the South London and Maudsley NHS Foundation Trust. The company considered it showed increasing healthcare resource use with each line of therapy. The ERG noted that, similar to the company cost study, the costs were largely driven by hospitalisations (in cost of bed days). There was also evidence of strongly skewed data, with high costs on average, but with most people not requiring any hospitalisation. The ERG also noted that the relationship between increasing healthcare resource use and line of therapy was not clearly defined and the difference between 3 prior oral antidepressants and 4 prior oral antidepressants was minimal. The committee noted that all of the evidence considered about resource use was characterised by strongly skewed data, which introduced substantial uncertainty to estimates of non-pharmacological healthcare resource costs within the model. These accounted for almost all of the total costs over the full time horizon in the company base case and were a key driver of the cost-effectiveness results. The committee considered that the generalisability of the treatment costing study to NHS clinical practice was crucial to understanding whether esketamine would reduce hospitalisations and other healthcare resource use. It questioned whether the same people who are hospitalised would have esketamine, because there are precautions for its use for people with certain psychiatric comorbidities. The committee noted that cost savings are a key driver of the cost-effectiveness estimates. The committee also noted that cost savings are driven by reducing costs in a small group of people (those who would be hospitalised). But it considered there was no evidence that esketamine would be beneficial in the group of people for whom hospital costs are largest. While the evidence showed there was an improvement in MADRS scores in the subgroups it was not possible to predict the benefits for subgroups within these subgroups. The committee also heard from clinical experts that for some people who are hospitalised, other options such as ECT are more likely to be considered than esketamine. The committee concluded that the modelled benefit of esketamine was not robust given the uncertainty in the evidence. It recommended further research to fully understand the costs associated with treatment-resistant depression and hospitalisations (see section 4).\n\n## Significant investment would be needed to use esketamine in the NHS\n\nThe company assumed people in the 3 or more treatments and augmentation subgroup would have treatment in secondary care. It also assumed that the implementation of esketamine would be done using existing infrastructure. So, the company did not include costs for implementation in this subgroup. The ERG noted it was unclear how a change in infrastructure would not be needed for the 3 or more treatments and augmentation subgroup. For the 3 or more treatments subgroup the company proposal to convert ECT suites to esketamine treatment clinics was used to inform costs in the economic analysis. The company included administration costs for esketamine in the economic model, but did not consider any other costs, considering these to be minimal with the conversion of ECT suites. It also said it would provide staff training to administer and monitor esketamine, needed to manage adverse effects, at no additional cost. The NHS commissioning experts noted several costs for adopting esketamine that were not included in the analysis:\n\ncosts of conversion of ECT suites or sourcing other appropriate treatment settings\n\ncosts of medical equipment to monitor and manage any post-dose medical complications\n\nstaff training to manage post-dose complications, including potential costs of recruitment if there are not enough staff currently available in practice\n\ncosts associated with the controlled nature of the drug, including storage, transportation, disposal and adequate staffing and governance training\n\ncosts associated with transporting people to have esketamine in hospital.The NHS commissioning expert also noted that resources would be needed for each new person having treatment with esketamine. The committee noted that the costs of implementation would depend on the expected population in clinical use and the expected treatment setting. The committee noted that NICE's guide to the methods of technology appraisal 2013 (section 5.5.8) states that if introduction of the technology needs changes in infrastructure, costs or savings should be included in the analysis. The committee noted that NICE's guide to the methods of technology appraisal 2013 (section 6.2.14) states that the 'committee will want to be increasingly certain of the cost effectiveness of a technology as the impact of the adoption of the technology on NHS resources increases'. The committee concluded that there would need to be significant investment to use esketamine in the NHS using the company's implementation proposal, which was not fully captured in the analysis. It considered the costs using the company's proposal would underestimate the true cost of implementing esketamine clinics in clinical practice.\n\n## The company's implementation proposal using converted ECT suites as treatment clinics may not be feasible\n\nThe company proposed a plan to convert ECT suites to esketamine treatment clinics as part of esketamine's implementation proposal. The NHS commissioning expert explained the current 5‑year plan for mental healthcare implementation in England. The plan focuses on integrated primary care and community care for people with serious mental illnesses such as treatment-resistant depression. The committee considered it was unclear what treatment setting esketamine would be used in, because:\n\na psychiatric referral is needed\n\nit is proposed to be delivered in hospitals in converted ECT suites\n\nintegrating secondary mental health care with primary and community care is currently challenging, for example, there are long waiting lists.The company considered that esketamine would not take long to become part of NHS practice, quoting market research that showed 82% of mental health trusts have some plans for how they would use esketamine. However, the NHS commissioning experts considered the plan to be impractical because negotiating use of ECT suites may be complex for some trusts and not possible for others. They considered that esketamine's use could not be limited to trusts that have an ECT suite that can be easily converted. The committee was aware of a potential equality issue (see section 3.40), and considered that esketamine's use in a community mental health specialist clinic would enable easier access to treatment. The clinical expert noted that some trusts have large geographical areas and access would not be available for everyone. The NHS commissioning experts also advised that the structure and delivery of services would need to be changed to accommodate esketamine. So, a longer timeframe than NICE mandates for NHS England to comply with the recommendations would be needed to establish esketamine in clinical practice. They explained that significant investment would be needed for esketamine to become part of NHS clinical practice, beyond the costs proposed as part of the company's implementation plan. They noted that esketamine would have to displace other mental health treatments because of its cost. However, this was dependent on the proposal to convert ECT suites. The committee considered the balance between new treatment options and maintaining the ability to offer ECT for people who need it. The committee concluded that, based on NHS England's commissioning experts' feedback, the company's proposal to implement esketamine clinics in ECT suites may not be feasible.\n\n## It is not possible to accurately estimate nursing and monitoring costs without certainty about esketamine's treatment setting\n\nThe committee recalled the precautions regarding risk of suicide and close supervision and monitoring in the SPC (see section 3.18). The company proposed administration and nursing costs for esketamine based on its proposal to run esketamine clinics in converted ECT suites. This assumed a ratio of 2 nurses to 6 patients when esketamine is administered, and 1 nurse to 6 patients during monitoring after treatment. The ERG preferred to model a 1 to 1 ratio throughout administration and monitoring because it considered this to be the most plausible in clinical practice. The clinical expert suggested that a ratio of 1 to 1 or 1 to 2 may be necessary when a service first starts administering esketamine, but that the ratio may increase to 1 nurse to a group of patients once the service becomes experienced and established. However, there could be logistical challenges in scheduling administration and monitoring with many people at one time. The patient expert said that building a relationship with a healthcare professional was an important part of treatment and recovery. At the second appraisal committee meeting, the committee concluded that a 1 to 2 ratio of nurses to patients could be appropriate. In response to the second consultation the company estimated a 1 to 2 ratio of nurses to patients in the 3 or more treatments subgroup and a 1 to 1 ratio of nurses to patients in the 3 or more treatments and augmentation subgroup. But the committee noted that its previous conclusion would only apply if using the company's proposed implementation plan to run esketamine clinics in ECT suites. If implemented differently, the administration and monitoring costs would change and it would not be possible to estimate ratios of nurses to patients. So the committee could not conclude on what would be the most plausible costs of nursing and monitoring.\n\n# Cost-effectiveness estimates\n\n## The cost-effectiveness estimates for esketamine in both treatment subgroups are highly uncertain\n\nThe company's cost-effectiveness estimate included a patient access scheme discount, the results of which cannot be presented because of confidentiality. The company's revised base case after the fourth committee meeting gave an incremental cost-effectiveness ratio (ICER) range below £20,000 per QALY gained for esketamine plus oral antidepressant compared with oral antidepressant alone in both treatment subgroups. The ERG's ICER range was generally higher than the company's estimates. The committee considered that the company and ERG's estimates were subject to substantial uncertainties, including:\n\nbeing based on clinical evidence that does not represent the expected use of esketamine in NHS clinical practice (see section 3.4)\n\nhow appropriate the comparators are (see section 3.6)\n\nthe clinical inputs informing the economic model (see sections 3.13 to 3.17)\n\nthe limited generalisability of the trial evidence (see section 3.16)\n\na cap on relapse and loss of response (see section 3.22)\n\nthe uncertainty of long-term outcomes for depression (see section 3.24)\n\na preference for no excess effect of esketamine on mortality (see section 3.25)\n\na preference for a range considering no carer disutility and sensitivity analysis with the ERG's method of applying carer disutility (see section 3.27)\n\nuncertainty about when people would stop esketamine (see section 3.29 to 3.30)\n\nthe costs of esketamine and potential for repeat or prolonged treatment (see section 3.31)\n\nthe healthcare resource use in treatment-resistant depression (see section 3.32)\n\nthe substantial costs of adopting esketamine in clinical practice that have not been included in the model, which would bias the results in favour of esketamine (see section 3.33 and section 3.34).NICE's guide to the methods of technology appraisal 2013 notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICERs. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the substantial resolvable uncertainty in all components of the economic modelling and ICER calculation, the committee considered that the benefits and costs of treatment with esketamine were highly uncertain.\n\n# Other factors\n\n## It is not methodologically appropriate to consider the societal burden of depression in this appraisal\n\nThe company considered that treatment-resistant depression has a substantial societal burden, mostly because of time off work. The committee noted that NICE's guide to the methods of technology appraisal 2013 (section 5.1.7) states 'the perspective on outcomes should be all direct health effects, whether for patients or other people'. And section 5.1.9 states 'the reference-case perspective on costs is that of the NHS and personal social services'. The committee recalled that considering benefits incurred outside of the NHS and personal social services was not detailed in the remit from the Department of Health and Social Care and the final scope. The committee also noted that productivity costs are not included in the reference case. If a non-reference case has been agreed with the Department of Health and Social Care, productivity costs are not included in this either. The committee concluded it was not appropriate to consider the societal burden of treatment-resistant depression.\n\n## Mental health services need further investment\n\nThe company considered that there has historically been significant underinvestment in mental health services. It noted that this context could be considered in the decision for esketamine, because more treatment options and investment in the area could contribute to the parity of esteem between physical and mental health (as required by the Health and Social Care Act 2012). The clinical and commissioning experts agreed that mental health services are stretched, contributing to a shortage in secondary care, meaning many people with treatment-resistant depression are not able to access services. The committee understood the NHS has a responsibility to deliver parity of esteem for physical and mental health, and considered the uncertainties around current mental health service provision in its decision. It acknowledged the funding issues in mental health and the limited new treatment options. The committee also noted that improved access to psychological therapies could benefit people with depression, particularly as patient experts noted regional disparities with access to treatment. However, it recalled that NICE's remit from the Department of Health and Social Care for this technology appraisal was to appraise the clinical and cost effectiveness of esketamine within its licensed indication. The committee concluded that equity of access could not be addressed as part of this appraisal.\n\n## Esketamine is innovative because it has a novel biological mechanism\n\nThe company considers esketamine to be innovative because it represents a step change in the treatment of treatment-resistant depression. The company noted esketamine has a novel biological mechanism of action in a disease area that has not had a new mechanism for 30\xa0years. Also, esketamine is sprayed in the nose which means it works rapidly and is non-invasive compared with ECT. The committee considered that the biological mechanism of esketamine could be innovative, but it was uncertain if it would be a step change in treatment because of the uncertainty of the clinical evidence. The committee concluded that it had not been presented with robust evidence of additional benefits not captured in the QALY calculations.\n\n## Equalities\n\nThe company, patient organisation and the ERG highlighted that, because esketamine nasal spray needs to be administered and monitored at a clinic, geographical access may be an equalities consideration. The committee considered that symptoms of depression include lack of energy and motivation, so it may be difficult for people to travel a long way to attend esketamine clinics. It considered that administering esketamine in a community setting would be necessary to ensure equity of access to treatment and that conversion of ECT suites would be insufficient to address these equity concerns. Also, the patient expert raised that people with physical health conditions may need additional support when accessing treatment, and the patient organisation noted that some people may have difficulties self-administering treatment or attending a clinic. But because the committee's recommendation does not restrict access to treatment for some people over others, the committee agreed these were not potential equalities issues. The NHS commissioning expert raised concerns about equity of access for people in the criminal justice system. The committee considered that the recommendations do not prevent access to esketamine in the criminal justice system over any other setting. It understood that there were likely to be existing processes in place for managing controlled substances in the criminal justice system, which would not prevent access to esketamine were it recommended. The patient organisation raised that there may be cultural or religious objections to treatment with esketamine. The committee was aware that these objections may also apply for other existing treatments for depression. However, it agreed that this equality issue could not be addressed in a recommendation. The clinical expert noted people who are underserved are more likely, in the clinical expert's experience, to have severe depression. The committee recognised that depression can have a substantial and long-term adverse effect on a person's ability to do normal day-to-day activities. So people with depression may be covered under the disability provision of the Equality Act (2010). The committee was mindful that its role is to appraise treatments and recommend those that are a clinically and cost-effective use of NHS resources. The committee carefully considered the uncertainties common in clinical trials in mental health and recognised the difficulties of collecting clinical data in the population of people with treatment-resistant depression (see section\xa03.17). It noted that no specific adjustments to the considerations of evidence had been proposed. So it considered all the available evidence including a wide range of views from patient and clinical experts alongside clinical trial data. The committee concluded that it was still unable to recommend esketamine for routine use (see section\xa03.41).\n\n# Conclusion\n\n## Esketamine is not recommended\n\nThe committee considered the burden that treatment-resistant depression has on people, the unmet need for effective treatment options and the innovative nature of how esketamine is administered. The committee acknowledged that obtaining reliable clinical evidence for technologies for depression can be challenging. It noted specifically the challenges of defining the treatment pathway and including psychological therapies, understanding and accounting for placebo effects, and the generalisability of clinical trials in treatments for depression to routine clinical practice. It also noted that large inequities remain in treatments for mental health conditions compared with other disease areas and considered this in its decision making. However, the costs and benefits of esketamine were very uncertain. The committee noted NICE's guide to the methods of technology appraisal 2013 (section 6.3.3) states that 'the committee will be more cautious about recommending a technology when they are less certain about the ICERs presented' and took this into account in its decision making. The committee recalled the clinical uncertainties, summarised in section 3.17, and noted these increased the uncertainty in the clinical inputs in the economic model and that some of these were partially or fully resolvable with further evidence. The committee highlighted that the company could have done more to reduce the uncertainties, including doing longer trials in a population who are more likely to have esketamine in clinical practice. The committee noted that the ICER range was likely to be an underestimate because of the uncertainty in the long-term benefits, stopping treatment, healthcare resource use and implementation costs. On balance, after taking these factors into account, the committee considered that esketamine was not a cost-effective use of NHS resources for the full marketing authorisation. The committee also noted that the ICER range in both subgroups considered could be below or within the range NICE normally considers a cost-effective use of NHS resources. However, not all the issues outlined above were included in these ICER calculations either. These ICERs are highly uncertain and the range would likely underestimate the true cost effectiveness of esketamine. So esketamine could not be considered a cost-effective use of NHS resources for the 3 or more treatments subgroup and 3 or more treatments and augmentation subgroup. So, esketamine is not recommended for use in the NHS for treating treatment-resistant depression.", 'Recommendations for research': 'Further research is recommended to help address remaining clinical and cost-effectiveness uncertainties for esketamine, summarised in section 3.36.\n\nFurther research is recommended in the wider clinical area of depression on:\n\nhow clinical data from regulatory trials in depression could appropriately be used in health technology assessment and decision modelling\n\nthe natural history and long-term course of treatment-resistant depression and health-related quality of life in the long-term\n\ncharacterising the healthcare resource use of people with depression, including exploring which people use services like hospitals and crisis resolution home teams.'}	https://www.nice.org.uk/guidance/ta854	Evidence-based recommendations on esketamine (Spravato) for treatment-resistant depression in adults.
4143d23cad078ded4ceff392e174606a0c851ca8	nice	Intrapartum care for healthy women and babies	Intrapartum care for healthy women and babies This guideline covers the care of healthy women and their babies, during labour and immediately after the birth. It focuses on women who give birth between 37 and 42 weeks of pregnancy (‘term’). The guideline helps women to make an informed choice about where to have their baby. It also aims to reduce variation in aspects of care. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Place of birth ## Choosing planned place of birth Explain to both multiparous and nulliparous women who are at low risk of complications that giving birth is generally very safe for both the woman and her baby. Explain to both multiparous and nulliparous women that they may choose any birth setting (home, freestanding midwifery unit, alongside midwifery unit or obstetric unit), and support them in their choice of setting wherever they choose to give birth: Advise low‑risk multiparous women that planning to give birth at home or in a midwifery‑led unit (freestanding or alongside) is particularly suitable for them because the rate of interventions is lower and the outcome for the baby is no different compared with an obstetric unit. Advise low‑risk nulliparous women that planning to give birth in a midwifery‑led unit (freestanding or alongside) is particularly suitable for them because the rate of interventions is lower and the outcome for the baby is no different compared with an obstetric unit. Explain that if they plan birth at home there is a small increase in the risk of an adverse outcome for the baby. Using table 1 and table 2, explain to low‑risk multiparous women that: planning birth at home or in a freestanding midwifery unit is associated with a higher rate of spontaneous vaginal birth than planning birth in an alongside midwifery unit, and these 3 settings are associated with higher rates of spontaneous vaginal birth than planning birth in an obstetric unit planning birth in an obstetric unit is associated with a higher rate of interventions, such as instrumental vaginal birth, caesarean section and episiotomy, compared with planning birth in other settings there are no differences in outcomes for the baby associated with planning birth in any setting. Home (number of incidences per 1,000 multiparous women giving birth) Freestanding midwifery unit (number of incidences per 1,000 multiparous women giving birth) Alongside midwifery unit (number of incidences per 1,000 multiparous women giving birth) Obstetric unit (number of 1,000 incidences per multiparous women giving birth) Spontaneous vaginal birth Transfer to an obstetric unit Regional analgesia (epidural and/or spinal)* Episiotomy Caesarean birth Instrumental birth (forceps or ventouse) Blood transfusion - Figures from Birthplace 2011 and Blix et al. 2012 (all other figures from Birthplace 2011). Estimated transfer rate from an obstetric unit to a different obstetric unit owing to lack of capacity or expertise. * Blix reported epidural analgesia and Birthplace reported spinal or epidural analgesia. Outcomes Home (number of babies per 1,000 births) Freestanding midwifery unit (number of babies per 1,000 births) Alongside midwifery unit (number of babies per 1,000 births) Obstetric unit (number of babies per 1,000 births) Babies without serious medical problems Babies with serious medical problems* - Serious medical problems were combined in the study: neonatal encephalopathy and meconium aspiration syndrome were the most common adverse events, together accounting for 75% of the total. Stillbirths after the start of care in labour and death of the baby in the first week of life accounted for 13% of the events. Fractured humerus and clavicle were uncommon outcomes (less than 4% of adverse events). For the frequency of these events (how often any of them actually occurred), see appendix A. Using table 3 and table 4, explain to low‑risk nulliparous women that: planning birth at home or in a freestanding midwifery unit is associated with a higher rate of spontaneous vaginal birth than planning birth in an alongside midwifery unit, and these 3 settings are associated with higher rates of spontaneous vaginal birth than planning birth in an obstetric unit planning birth in an obstetric unit is associated with a higher rate of interventions, such as instrumental vaginal birth, caesarean section and episiotomy, compared with planning birth in other settings there are no differences in outcomes for the baby associated with planning birth in an alongside midwifery unit, a freestanding midwifery unit or an obstetric unit planning birth at home is associated with an overall small increase (about 4 more per 1,000 births) in the risk of a baby having a serious medical problem compared with planning birth in other settings. Home (number of incidences per 1,000 nulliparous women giving birth) Freestanding midwifery unit (number of incidences per 1,000 nulliparous women giving birth) Alongside midwifery unit (number of incidences per 1,000 nulliparous women giving birth) Obstetric unit (number of incidences per 1,000 nulliparous women giving birth) Spontaneous vaginal birth Transfer to an obstetric unit Regional analgesia (epidural and/or spinal)* Episiotomy Caesarean birth Instrumental birth (forceps or ventouse) Blood transfusion - Figures from Birthplace 2011 and Blix et al. 2012 (all other figures from Birthplace 2011). Estimated transfer rate from an obstetric unit to a different obstetric unit owing to lack of capacity or expertise. * Blix reported epidural analgesia and Birthplace reported spinal or epidural analgesia. Outcomes Home (number of babies per 1,000 births) Freestanding midwifery unit (number of babies per 1,000 births) Alongside midwifery unit (number of babies per 1,000 births) Obstetric unit (number of babies per 1,000 births) Babies without serious medical problems Babies with serious medical problems* - Serious medical problems were combined in the study: neonatal encephalopathy and meconium aspiration syndrome were the most common adverse events, together accounting for 75% of the total. Stillbirths after the start of care in labour and death of the baby in the first week of life accounted for 13% of the events. Fractured humerus and clavicle were uncommon outcomes – less than 4% of adverse events. For the frequency of these events (how often any of them actually occurred), see appendix A. Ensure that all healthcare professionals involved in the care of pregnant women are familiar with the types and frequencies of serious medical problems that can affect babies (see appendix A), in order to be able to provide this information to women if they request it. Commissioners and providers (this can also include networks of providers) should ensure that all 4 birth settings are available to all women (in the local area or in a neighbouring area). Give the woman the following information, including local statistics, about all local birth settings: Access to midwives, including: the likelihood of being cared for in labour by a familiar midwife the likelihood of receiving one‑to‑one care throughout labour (not necessarily being cared for by the same midwife for the whole of labour). Access to medical staff (obstetric, anaesthetic and neonatal). Access to pain relief, including birthing pools, Entonox, other drugs and regional analgesia. The likelihood of being transferred to an obstetric unit (if this is not the woman's chosen place of birth), the reasons why this might happen and the time it may take. Refer to table 5 if no local data are available. Primary reason for transfer to an obstetric unit* Number of women transferred from home (n=3,529) Number of women transferred from a freestanding midwifery unit (n=2,457) Number of women transferred from an alongside midwifery unit (n=4,401) Delay during first or second stage of labour Abnormal fetal heart rate Request for regional analgesia Meconium staining Retained placenta Repair of perineal trauma Neonatal concerns (postpartum) Other - Main reason for transfer to an obstetric unit for each woman (there may be more than 1 reason). If further discussion is wanted by either the midwife or the woman about the choice of planned place of birth, arrange this with a consultant midwife or supervisor of midwives, and/or a consultant obstetrician if there are obstetric issues. When discussing the woman's choice of place of birth with her, do not disclose personal views or judgements about her choices. Use tables 6, 7, 8 and 9 as part of an assessment for a woman choosing her planned place of birth: Table 6 and table 7 show medical conditions or situations in which there is increased risk for the woman or baby during or shortly after labour, where care in an obstetric unit would be expected to reduce this risk. The factors listed in table 8 and table 9 are not reasons in themselves for advising birth within an obstetric unit, but indicate that further consideration of birth setting may be required. Discuss these risks and the additional care that can be provided in the obstetric unit with the woman so that she can make an informed choice about planned place of birth. Disease area Medical condition Cardiovascular Confirmed cardiac disease Hypertensive disorders Respiratory Asthma requiring an increase in treatment or hospital treatment Cystic fibrosis Haematological Haemoglobinopathies – sickle‑cell disease, beta‑thalassaemia major History of thromboembolic disorders Immune thrombocytopenia purpura or other platelet disorder or platelet count below 100×109/litre Von Willebrand's disease Bleeding disorder in the woman or unborn baby Atypical antibodies which carry a risk of haemolytic disease of the newborn Endocrine Hyperthyroidism Diabetes Infective Risk factors associated with group B streptococcus whereby antibiotics in labour would be recommended Hepatitis B/C with abnormal liver function tests Carrier of/infected with HIV Toxoplasmosis – women receiving treatment Current active infection of chicken pox/rubella/genital herpes in the woman or baby Tuberculosis under treatment Immune Systemic lupus erythematosus Scleroderma Renal Abnormal renal function Renal disease requiring supervision by a renal specialist Neurological Epilepsy Myasthenia gravis Previous cerebrovascular accident Gastrointestinal Liver disease associated with current abnormal liver function tests Psychiatric Psychiatric disorder requiring current inpatient care Factor Additional information Previous complications Unexplained stillbirth/neonatal death or previous death related to intrapartum difficulty Previous baby with neonatal encephalopathy Pre‑eclampsia requiring preterm birth Placental abruption with adverse outcome Eclampsia Uterine rupture Primary postpartum haemorrhage requiring additional treatment or blood transfusion Retained placenta requiring manual removal in theatre Caesarean section Shoulder dystocia Current pregnancy Multiple birth Placenta praevia Pre‑eclampsia or pregnancy‑induced hypertension Preterm labour or preterm prelabour rupture of membranes Placental abruption Anaemia – haemoglobin less than 85 g/litre at onset of labour Confirmed intrauterine death Induction of labour Substance misuse Alcohol dependency requiring assessment or treatment Onset of gestational diabetes Malpresentation – breech or transverse lie BMI at booking of greater than 35 kg/m2 Recurrent antepartum haemorrhage Small for gestational age in this pregnancy (less than fifth centile or reduced growth velocity on ultrasound) Abnormal fetal heart rate/doppler studies Ultrasound diagnosis of oligo‑/polyhydramnios Previous gynaecological history Myomectomy Hysterotomy Disease area Medical condition Cardiovascular Cardiac disease without intrapartum implications Haematological Atypical antibodies not putting the baby at risk of haemolytic disease Sickle‑cell trait Thalassaemia trait Anaemia – haemoglobin 85 to 105 g/litre at onset of labour Infective Hepatitis B/C with normal liver function tests Immune Non‑specific connective tissue disorders Endocrine Unstable hypothyroidism such that a change in treatment is required Skeletal/neurological Spinal abnormalities Previous fractured pelvis Neurological deficits Gastrointestinal Liver disease without current abnormal liver function Crohn's disease Ulcerative colitis Factor Additional information Previous complications Stillbirth/neonatal death with a known non‑recurrent cause Pre‑eclampsia developing at term Placental abruption with good outcome History of previous baby more than 4.5 kg Extensive vaginal, cervical, or third‑ or fourth‑degree perineal trauma Previous term baby with jaundice requiring exchange transfusion Current pregnancy Antepartum bleeding of unknown origin (single episode after 24 weeks of gestation) BMI at booking of 30 to 35 kg/m2 Blood pressure of 140 mmHg systolic or 90 mmHg diastolic or more on 2 occasions Clinical or ultrasound suspicion of macrosomia Para 4 or more Recreational drug use Under current outpatient psychiatric care Age over 35 at booking Fetal indications Fetal abnormality Previous gynaecological history Major gynaecological surgery Cone biopsy or large loop excision of the transformation zone Fibroids ## Women's experience in all birth settings For all women giving birth in all birth settings, follow the principles in the NICE guideline on patient experience in adult NHS services. Providers, senior staff and all healthcare professionals should ensure that in all birth settings there is a culture of respect for each woman as an individual undergoing a significant and emotionally intense life experience, so that the woman is in control, is listened to and is cared for with compassion, and that appropriate informed consent is sought. Senior staff should demonstrate, through their own words and behaviour, appropriate ways of relating to and talking about women and their birth companion(s), and of talking about birth and the choices to be made when giving birth. ## One‑to‑one care in all birth settings Maternity services should: provide a model of care that supports one‑to‑one care in labour for all women and benchmark services and identify overstaffing or understaffing by using workforce planning models and/or woman‑to‑midwife ratios. ## Service organisation and clinical governance Ensure that all women giving birth have timely access to an obstetric unit if they need transfer of care for medical reasons or because they request regional analgesia. Commissioners and providers (this can also include networks of providers) should ensure that there are: robust protocols in place for transfer of care between settings (see also the section on general principles for transfer of care) clear local pathways for the continued care of women who are transferred from one setting to another, including: when crossing provider boundaries if the nearest obstetric or neonatal unit is closed to admissions or the local midwifery‑led unit is full. Commissioners and providers (this can also include networks of providers) should ensure that there are multidisciplinary clinical governance structures in place to enable the oversight of all birth settings. These structures should include, as a minimum, midwifery (including a supervisor of midwives), obstetric, anaesthetic and neonatal expertise, and adequately supported user representation. # Care throughout labour ## Communication Treat all women in labour with respect. Ensure that the woman is in control of and involved in what is happening to her, and recognise that the way in which care is given is key to this. To facilitate this, establish a rapport with the woman, ask her about her wants and expectations for labour, and be aware of the importance of tone and demeanour, and of the actual words used. Use this information to support and guide her through her labour. To establish communication with the woman: Greet the woman with a smile and a personal welcome, establish her language needs, introduce yourself and explain your role in her care. Maintain a calm and confident approach so that your demeanour reassures the woman that all is going well. Knock and wait before entering the woman's room, respecting it as her personal space, and ask others to do the same. Ask how the woman is feeling and whether there is anything in particular she is worried about. If the woman has a written birth plan, read and discuss it with her. Assess the woman's knowledge of strategies for coping with pain and provide balanced information to find out which available approaches are acceptable to her. Encourage the woman to adapt the environment to meet her individual needs. Ask her permission before all procedures and observations, focusing on the woman rather than the technology or the documentation. Show the woman and her birth companion(s) how to summon help and reassure her that she may do so whenever and as often as she needs to. When leaving the room, let her know when you will return. Involve the woman in any handover of care to another professional, either when additional expertise has been brought in or at the end of a shift. ## Mobilisation Encourage and help the woman to move and adopt whatever positions she finds most comfortable throughout labour. ## Support Encourage the woman to have support from birth companion(s) of her choice. ## Hygiene measures Tap water may be used if cleansing is required before vaginal examination. Routine hygiene measures taken by staff caring for women in labour, including standard hand hygiene and single‑use non‑sterile gloves, are appropriate to reduce cross‑contamination between women, babies and healthcare professionals. Selection of protective equipment must be based on an assessment of the risk of transmission of microorganisms to the woman, and the risk of contamination of the healthcare worker's clothing and skin by women's blood, body fluids, secretions or excretions. This is in accordance with the following health and safety legislation (current at the time NICE's guideline on healthcare-associated infections was published ): Health and Safety at Work Act 1974, Management of Health and Safety at Work Regulations 1999, Health and Safety Regulations 2002, Control of Substances Hazardous to Health Regulations 2002, Personal Protective Equipment Regulations 2002 and Health and Social Care Act 2008). This recommendation is adapted from NICE's guideline on healthcare-associated infections. # Latent first stage of labour ## Definitions of the latent and established first stages of labour For the purposes of this guideline, use the following definitions of labour: Latent first stage of labour – a period of time, not necessarily continuous, when: there are painful contractions and there is some cervical change, including cervical effacement and dilatation up to 4 cm. Established first stage of labour – when: there are regular painful contractions and there is progressive cervical dilatation from 4 cm. ## Education and early assessment Give all nulliparous women information antenatally about: what to expect in the latent first stage of labour how to work with any pain they experience how to contact their midwifery care team and what to do in an emergency. Offer all nulliparous women antenatal education about the signs of labour, consisting of: how to differentiate between Braxton Hicks contractions and active labour contractions the expected frequency of contractions and how long they last recognition of amniotic fluid ('waters breaking') description of normal vaginal loss. Consider an early assessment of labour by telephone triage provided by a dedicated triage midwife for all women. Consider a face‑to‑face early assessment of labour for all low‑risk nulliparous women, either: at home (regardless of planned place of birth) or in an assessment facility in her planned place of birth (midwifery‑led unit or obstetric unit), comprising one‑to‑one midwifery care for at least 1 hour. Include the following in any early or triage assessment of labour: ask the woman how she is, and about her wishes, expectations and any concerns she has ask the woman about the baby's movements, including any changes give information about what the woman can expect in the latent first stage of labour and how to work with any pain she experiences give information about what to expect when she accesses care agree a plan of care with the woman, including guidance about who she should contact next and when provide guidance and support to the woman's birth companion(s). The triage midwife should document the guidance that she gives to the woman. If a woman seeks advice or attends a midwifery‑led unit or obstetric unit with painful contractions, but is not in established labour: recognise that a woman may experience painful contractions without cervical change, and although she is described as not being in labour, she may well think of herself as being 'in labour' by her own definition -ffer her individualised support, and analgesia if needed encourage her to remain at or return home, unless doing so leads to a significant risk that she could give birth without a midwife present or become distressed. ## Pain relief Advise the woman and her birth companion(s) that breathing exercises, immersion in water and massage may reduce pain during the latent first stage of labour. (See also the recommendation on timing of regional analgesia.) Do not offer or advise aromatherapy, yoga or acupressure for pain relief during the latent first stage of labour. If a woman wants to use any of these techniques, respect her wishes. # Initial assessment When performing an initial assessment of a woman in labour, listen to her story and take into account her preferences and her emotional and psychological needs. Carry out an initial assessment to determine if midwifery‑led care in any setting is suitable for the woman, irrespective of any previous plan. The assessment should comprise the following: Observations of the woman: Review the antenatal notes (including all antenatal screening results) and discuss these with the woman. Ask her about the length, strength and frequency of her contractions. Ask her about any pain she is experiencing and discuss her options for pain relief. Record her pulse, blood pressure and temperature, and carry out urinalysis. Record if she has had any vaginal loss. Observations of the unborn baby: Ask the woman about the baby's movements in the last 24 hours. Palpate the woman's abdomen to determine the fundal height, the baby's lie, presentation, position, engagement of the presenting part, and frequency and duration of contractions. Auscultate the fetal heart rate for a minimum of 1 minute immediately after a contraction. Palpate the woman's pulse to differentiate between the heartbeats of the woman and the baby.In addition (see also recommendation 1.4.5): If there is uncertainty about whether the woman is in established labour, a vaginal examination may be helpful after a period of assessment, but is not always necessary. If the woman appears to be in established labour, offer a vaginal examination. Transfer the woman to obstetric‑led care, following the section on the general principles for transfer of care, if any of the following are observed on initial assessment: Observations of the woman: pulse over 120 beats/minute on 2 occasions 30 minutes apart a single reading of either raised diastolic blood pressure of 110 mmHg or more or raised systolic blood pressure of 160 mmHg or more either raised diastolic blood pressure of 90 mmHg or more or raised systolic blood pressure of 140 mmHg or more on 2 consecutive readings taken 30 minutes apart a reading of 2+ of protein on urinalysis and a single reading of either raised diastolic blood pressure (90 mmHg or more) or raised systolic blood pressure (140 mmHg or more) temperature of 38°C or above on a single reading, or 37.5°C or above on 2 consecutive readings 1 hour apart any vaginal blood loss other than a show rupture of membranes more than 24 hours before the onset of established labour (see the section on babies born to women with prelabour rupture of the membranes at term) the presence of significant meconium (see the section on presence of meconium) pain reported by the woman that differs from the pain normally associated with contractions any risk factors recorded in the woman's notes that indicate the need for obstetric led care. Observations of the unborn baby: any abnormal presentation, including cord presentation transverse or oblique lie high (4/5 to 5/5 palpable) or free‑floating head in a nulliparous woman suspected fetal growth restriction or macrosomia suspected anhydramnios or polyhydramnios fetal heart rate below 110 or above 160 beats/minute a deceleration in fetal heart rate heard on intermittent auscultation reduced fetal movements in the last 24 hours reported by the woman.If none of these are observed, continue with midwifery-led care unless the woman requests transfer (see also the section on measuring fetal heart rate as part of initial assessment). If any of the factors in recommendation 1.4.3 are observed but birth is imminent, assess whether birth in the current location is preferable to transferring the woman to an obstetric unit and discuss this with the coordinating midwife. When conducting a vaginal examination: be sure that the examination is necessary and will add important information to the decision‑making process recognise that a vaginal examination can be very distressing for a woman, especially if she is already in pain, highly anxious and in an unfamiliar environment explain the reason for the examination and what will be involved ensure the woman's informed consent, privacy, dignity and comfort explain sensitively the findings of the examination and any impact on the birth plan to the woman and her birth companion(s). ## Measuring fetal heart rate as part of initial assessment Offer auscultation of the fetal heart rate at first contact with a woman in suspected or established labour, and at each further assessment: Use either a Pinard stethoscope or doppler ultrasound. Carry out auscultation immediately after a contraction for at least 1 minute and record it as a single rate. Record accelerations and decelerations if heard. Palpate the maternal pulse to differentiate between the maternal and fetal heartbeats. Be aware that for women at low risk of complications there is insufficient evidence about whether cardiotocography as part of the initial assessment either improves outcomes or results in harm for women and their babies, compared with intermittent auscultation alone. If a woman at low risk of complications requests cardiotocography as part of the initial assessment: discuss the risks, benefits and limitations of cardiotocography with her, and support her in her choice explain that, if she is in a setting where cardiotocography is not available, she will need to be transferred to obstetric-led care. Offer continuous cardiotocography if any of the risk factors listed in recommendation 1.4.3 in the section on initial assessment are identified on initial assessment, and explain to the woman why this is being offered. (See also the NICE guideline on fetal monitoring in labour for further guidance on fetal monitoring.) Offer cardiotocography if intermittent auscultation indicates possible fetal heart rate abnormalities, and explain to the woman why this is being offered. If the trace is normal (see the section on the use of cardiotocography for monitoring during labour in the NICE guideline on fetal monitoring in labour) after 20 minutes, return to intermittent auscultation unless the woman asks to stay on continuous cardiotocography. If fetal death is suspected despite the presence of an apparently recorded fetal heart rate, offer real-time ultrasound assessment to check fetal viability. # Ongoing assessment Transfer the woman to obstetric‑led care (following the general principles for transfer of care) if any of the following are observed at any point, unless the risks of transfer outweigh the benefits: Observations of the woman: pulse over 120 beats/minute on 2 occasions 30 minutes apart a single reading of either raised diastolic blood pressure of 110 mmHg or more or raised systolic blood pressure of 160 mmHg or more either raised diastolic blood pressure of 90 mmHg or more or raised systolic blood pressure of 140 mmHg or more on 2 consecutive readings taken 30 minutes apart a reading of 2+ of protein on urinalysis and a single reading of either raised diastolic blood pressure (90 mmHg or more) or raised systolic blood pressure (140 mmHg or more) temperature of 38°C or above on a single reading, or 37.5°C or above on 2 consecutive occasions 1 hour apart any vaginal blood loss other than a show the presence of significant meconium (see the section on presence of meconium) pain reported by the woman that differs from the pain normally associated with contractions confirmed delay in the first or second stage of labour request by the woman for additional pain relief using regional analgesia -bstetric emergency – including antepartum haemorrhage, cord prolapse, postpartum haemorrhage, maternal seizure or collapse, or a need for advanced neonatal resuscitation retained placenta third‑degree or fourth‑degree tear or other complicated perineal trauma that needs suturing. Observations of the unborn baby: any abnormal presentation, including cord presentation transverse or oblique lie high (4/5 to 5/5 palpable) or free‑floating head in a nulliparous woman suspected fetal growth restriction or macrosomia suspected anhydramnios or polyhydramnios fetal heart rate below 110 or above 160 beats/minute a deceleration in fetal heart rate heard on intermittent auscultation.If none of these are observed, continue with midwifery-led care unless the woman requests transfer (see also recommendation 1.4.6 in the section on measuring fetal heart rate as part of initial assessment). ## Presence of meconium As part of ongoing assessment, document the presence or absence of significant meconium. This is defined as dark green or black amniotic fluid that is thick or tenacious, or any meconium‑stained amniotic fluid containing lumps of meconium. If significant meconium is present, ensure that: healthcare professionals trained in fetal blood sampling are available during labour and healthcare professionals trained in advanced neonatal life support are readily available for the birth. If significant meconium is present, transfer the woman to obstetric‑led care provided that it is safe to do so and the birth is unlikely to occur before transfer is completed. Follow the general principles for transfer of care described in section 1.6. # General principles for transfer of care Transfer of care refers to the transfer between midwifery‑led care and obstetric‑led care. This may or may not involve transport from one location to another. Women who are receiving midwifery‑led care in an obstetric unit can have their care transferred to obstetric‑led care without being moved. Base any decisions about transfer of care on clinical findings, and discuss the options with the woman and her birth companion(s). If contemplating transfer of care: talk with the woman and her birth companion(s) about the reasons for this and what they can expect, including the time needed for transfer address any concerns she has and try to allay her anxiety ensure that her wishes are respected and her informed consent is obtained. When arranging transfer of care, the midwife attending the labour should contact the ambulance service (if appropriate) and the coordinating midwife in the obstetric unit. The coordinating midwife should then alert the relevant healthcare professionals (obstetric, anaesthetic and neonatal). When arranging transfer from one location to another, ensure the following: Before transfer, the woman is dressed, wrapped in a blanket or otherwise covered in a way that she feels is comfortable and appropriate. The woman is made to feel as comfortable as possible before and during transfer. Any ambulance staff or other personnel involved are aware that some positions may make the woman uncomfortable or afraid and could affect her labour, so she should be encouraged to choose how to move and what position to adopt if possible, in accordance with ambulance service protocols. Communication and companionship are maintained. Explain the arrangements for transfer to the woman and her birth companion(s). A midwife who has been involved in her care up to that point should travel with her and carry out a handover of care that involves the woman. Arrangements are in place to enable the woman's birth companion(s) to travel with her in the ambulance if that is what she wants. If this is not possible or not wanted, check that the birth companion(s) have or can arrange their own transport. If a woman is transferred to an obstetric unit after the birth (see the section on care of the woman after birth), ensure that her baby goes with her. # Care in established labour ## Support in labour Provide a woman in established labour with supportive one‑to‑one care. Do not leave a woman in established labour on her own except for short periods or at the woman's request. For guidance on ensuring continuity of care, see recommendation 1.4.1 in the NICE guideline on patient experience in adult NHS services. ## Controlling gastric acidity Do not offer either H2‑receptor antagonists or antacids routinely to low‑risk women. Either H2‑receptor antagonists or antacids should be considered for women who receive opioids or who have or develop risk factors that make a general anaesthetic more likely. Inform the woman that she may drink during established labour and that isotonic drinks may be more beneficial than water. Inform the woman that she may eat a light diet in established labour unless she has received opioids or she develops risk factors that make a general anaesthetic more likely. # Pain relief in labour: non‑regional ## Attitudes to pain and pain relief in childbirth Healthcare professionals should think about how their own values and beliefs inform their attitude to coping with pain in labour and ensure their care supports the woman's choice. ## Pain‑relieving strategies If a woman chooses to use breathing and relaxation techniques in labour, support her in this choice. If a woman chooses to use massage techniques in labour that have been taught to birth companions, support her in this choice. Offer the woman the opportunity to labour in water for pain relief. For women labouring in water, monitor the temperature of the woman and the water hourly to ensure that the woman is comfortable and not becoming pyrexial. The temperature of the water should not be above 37.5°C. Keep baths and birthing pools clean using a protocol agreed with the microbiology department and, in the case of birthing pools, in accordance with the manufacturer's guidelines. Do not use injected water papules. Do not offer acupuncture, acupressure or hypnosis, but do not prevent women who wish to use these techniques from doing so. Support the playing of music of the woman's choice in labour. ## Non‑pharmacological analgesia Do not offer transcutaneous electrical nerve stimulation (TENS) to women in established labour. ## Inhalational analgesia Ensure that Entonox (a 50:50 mixture of oxygen and nitrous oxide) is available in all birth settings as it may reduce pain in labour, but inform the woman that it may make her feel nauseous and light‑headed. ## Intravenous and intramuscular opioids Ensure that pethidine, diamorphine or other opioids are available in all birth settings. Inform the woman that these will provide limited pain relief during labour and may have significant side effects for both her (drowsiness, nausea and vomiting) and her baby (short‑term respiratory depression and drowsiness which may last several days). Inform the woman that pethidine, diamorphine or other opioids may interfere with breastfeeding. If an intravenous or intramuscular opioid is used, also administer an antiemetic. Women should not enter water (a birthing pool or bath) within 2 hours of opioid administration or if they feel drowsy. # Pain relief in labour: regional analgesia ## Information about regional analgesia If a woman is contemplating regional analgesia, talk with her about the risks and benefits and the implications for her labour, including the arrangements and time involved for transfer of care to an obstetric unit if she is at home or in a midwifery unit (follow the general principles for transfer of care). Provide information about epidural analgesia, including the following: It is available only in obstetric units. It provides more effective pain relief than opioids. It is not associated with long‑term backache. It is not associated with a longer first stage of labour or an increased chance of a caesarean birth. It is associated with a longer second stage of labour and an increased chance of vaginal instrumental birth. It will be accompanied by a more intensive level of monitoring and intravenous access, and so mobility may be reduced. ## Timing of regional analgesia If a woman in labour asks for regional analgesia, comply with her request. This includes women in severe pain in the latent first stage of labour. ## Care and observations for women with regional analgesia Always secure intravenous access before starting regional analgesia. Preloading and maintenance fluid infusion need not be administered routinely before establishing low‑dose epidural analgesia and combined spinal–epidural analgesia. Undertake the following additional observations for women with regional analgesia: During establishment of regional analgesia or after further boluses (10 ml or more of low‑dose solutions), measure blood pressure every 5 minutes for 15 minutes. If the woman is not pain‑free 30 minutes after each administration of local anaesthetic/opioid solution, recall the anaesthetist. Assess the level of the sensory block hourly. Encourage women with regional analgesia to move and adopt whatever upright positions they find comfortable throughout labour. Once established, continue regional analgesia until after completion of the third stage of labour and any necessary perineal repair. Upon confirmation of full cervical dilatation in a woman with regional analgesia, unless the woman has an urge to push or the baby's head is visible, pushing should be delayed for at least 1 hour and longer if the woman wishes, after which actively encourage her to push during contractions. After diagnosis of full dilatation in a woman with regional analgesia, agree a plan with the woman in order to ensure that birth will have occurred within 4 hours regardless of parity. Do not routinely use oxytocin in the second stage of labour for women with regional analgesia. Perform continuous cardiotocography for at least 30 minutes during establishment of regional analgesia and after administration of each further bolus of 10 ml or more. ## Establishing and maintaining regional analgesia Use either epidural or combined spinal–epidural analgesia for establishing regional analgesia in labour. If rapid analgesia is required, use combined spinal–epidural analgesia. Establish combined spinal–epidural analgesia with bupivacaine and fentanyl. Establish epidural analgesia with a low‑concentration local anaesthetic and opioid solution with, for example, 10 to 15 ml of 0.0625 to 0.1% bupivacaine with 1 to 2 micrograms per ml fentanyl. The initial dose of local anaesthetic plus opioid is essentially a test dose, so administer cautiously to ensure that inadvertent intrathecal injection has not occurred. Use low‑concentration local anaesthetic and opioid solutions (0.0625 to 0.1% bupivacaine or equivalent combined with 2.0 micrograms per ml fentanyl) for maintaining epidural analgesia in labour. Do not use high concentrations of local anaesthetic solutions (0.25% or above of bupivacaine or equivalent) routinely for either establishing or maintaining epidural analgesia. Either patient‑controlled epidural analgesia or intermittent bolus given by healthcare professionals are the preferred modes of administration for maintenance of epidural analgesia. # Monitoring during labour The recommendations in this section have been withdrawn. For advice on monitoring during labour, see the NICE guideline on fetal monitoring in labour. # Prelabour rupture of membranes at term Do not carry out a speculum examination if it is certain that the membranes have ruptured. If it is uncertain whether prelabour rupture of the membranes has occurred, offer the woman a speculum examination to determine whether the membranes have ruptured. Avoid digital vaginal examination in the absence of contractions. Advise women presenting with prelabour rupture of the membranes at term that: the risk of serious neonatal infection is 1%, rather than 0.5% for women with intact membranes % of women with prelabour rupture of the membranes will go into labour within 24 hours induction of labour (see NICE's guideline on inducing labour) is appropriate approximately 24 hours after rupture of the membranes. Until the induction is started or if expectant management beyond 24 hours is chosen by the woman: do not offer lower vaginal swabs and measurement of maternal C‑reactive protein to detect any infection that may be developing, advise the woman to record her temperature every 4 hours during waking hours and to report immediately any change in the colour or smell of her vaginal loss inform the woman that bathing or showering is not associated with an increase in infection, but that having sexual intercourse may be. Assess fetal movement and heart rate at initial contact and then every 24 hours after rupture of the membranes while the woman is not in labour, and advise the woman to report immediately any decrease in fetal movements. If labour has not started 24 hours after rupture of the membranes, advise the woman to give birth where there is access to neonatal services and to stay in hospital for at least 12 hours after the birth. # First stage of labour See the recommendation on definitions of the latent and established first stages of labour. Do not offer or advise clinical intervention if labour is progressing normally and the woman and baby are well. In all stages of labour, women who have left the normal care pathway because of the development of complications can return to it if/when the complication is resolved. ## Duration of the first stage Inform women that, while the length of established first stage of labour varies between women: first labours last on average 8 hours and are unlikely to last over 18 hours second and subsequent labours last on average 5 hours and are unlikely to last over 12 hours. ## Observations during the established first stage Do not routinely use verbal assessment using a numerical pain score. Use a pictorial record of labour (partogram) once labour is established. Where the partogram includes an action line, use the World Health Organization (WHO) recommendation of a 4‑hour action line (the WHO partograph in management of labour, published in 1994 as part of the Maternal Health and Safe Motherhood Programme. Lancet 343: 1399 to 404). See also the WHO Multicountry Survey on Maternal and Newborn Health. Record the following observations during the first stage of labour: half‑hourly documentation of frequency of contractions hourly pulse ‑hourly temperature and blood pressure frequency of passing urine -ffer a vaginal examination (see recommendation 1.4.5 in the section on initial assessment) 4‑hourly or if there is concern about progress or in response to the woman's wishes (after abdominal palpation and assessment of vaginal loss). If any of the indications for transfer are met (see the recommendation on ongoing assessment), transfer the woman to obstetric‑led care. Follow the general principles for transfer of care. Give ongoing consideration to the woman's emotional and psychological needs, including her desire for pain relief. Encourage the woman to communicate her need for analgesia at any point during labour. ## Possible routine interventions in the first stage Do not routinely offer the package known as active management of labour (one‑to‑one continuous support; strict definition of established labour; early routine amniotomy; routine 2‑hourly vaginal examination; oxytocin if labour becomes slow). In normally progressing labour, do not perform amniotomy routinely. Do not use combined early amniotomy with use of oxytocin routinely. ## Delay in the first stage If delay in the established first stage is suspected, take the following into account: parity cervical dilatation and rate of change uterine contractions station and position of presenting part the woman's emotional state referral to the appropriate healthcare professional.Offer the woman support, hydration, and appropriate and effective pain relief. If delay in the established first stage is suspected, assess all aspects of progress in labour when diagnosing delay, including: cervical dilatation of less than 2 cm in 4 hours for first labours cervical dilatation of less than 2 cm in 4 hours or a slowing in the progress of labour for second or subsequent labours descent and rotation of the baby's head changes in the strength, duration and frequency of uterine contractions. If delay is diagnosed, transfer the woman to obstetric‑led care. Follow the general principles for transfer of care. If delay in the established first stage of labour is suspected, amniotomy should be considered for all women with intact membranes, after explanation of the procedure and advice that it will shorten her labour by about an hour and may increase the strength and pain of her contractions. Whether or not a woman has agreed to an amniotomy, advise all women with suspected delay in the established first stage of labour to have a vaginal examination 2 hours later, and diagnose delay if progress is less than 1 cm. For women with intact membranes in whom delay in the established first stage of labour is confirmed, advise the woman to have an amniotomy, and to have a repeat vaginal examination 2 hours later whether her membranes are ruptured or intact. For all women with confirmed delay in the established first stage of labour: transfer the woman to obstetric‑led care for an obstetric review and a decision about management options, including the use of oxytocin (follow the general principles for transfer of care) explain to her that using oxytocin after spontaneous or artificial rupture of the membranes will bring forward the time of birth but will not influence the mode of birth or other outcomes. For a multiparous woman with confirmed delay in the established first stage of labour, an obstetrician should perform a full assessment, including abdominal palpation and vaginal examination, before a decision is made about using oxytocin. Offer all women with delay in the established first stage of labour support and effective pain relief. Inform the woman that oxytocin will increase the frequency and strength of her contractions and that its use will mean that her baby should be monitored continuously. Offer the woman an epidural before oxytocin is started. If oxytocin is used, ensure that the time between increments of the dose is no more frequent than every 30 minutes. Increase oxytocin until there are 4 to 5 contractions in 10 minutes. (See also recommendation 1.12.14 and recommendation 1.3.8 in the NICE guideline on fetal monitoring in labour.) Advise the woman to have a vaginal examination 4 hours after starting oxytocin in established labour: If cervical dilatation has increased by less than 2 cm after 4 hours of oxytocin, further obstetric review is required to assess the need for caesarean section. If cervical dilatation has increased by 2 cm or more, advise 4‑hourly vaginal examinations. # Second stage of labour ## Definition of the second stage For the purposes of this guideline, use the following definitions of labour: Passive second stage of labour: the finding of full dilatation of the cervix before or in the absence of involuntary expulsive contractions. Onset of the active second stage of labour: the baby is visible expulsive contractions with a finding of full dilatation of the cervix or other signs of full dilatation of the cervix active maternal effort following confirmation of full dilatation of the cervix in the absence of expulsive contractions. ## Observations during the second stage Carry out the following observations in the second stage of labour, record all observations on the partogram and assess whether transfer of care may be needed (see the recommendation on ongoing assessment). : half‑hourly documentation of the frequency of contractions hourly blood pressure continued 4‑hourly temperature frequency of passing urine -ffer a vaginal examination (see recommendation 1.4.5 in the section on initial assessment) hourly in the active second stage, or in response to the woman's wishes (after abdominal palpation and assessment of vaginal loss). In addition: Continue to take the woman's emotional and psychological needs into account. Assess progress, which should include the woman's behaviour, the effectiveness of pushing and the baby's wellbeing, taking into account the baby's position and station at the onset of the second stage. These factors will assist in deciding the timing of further vaginal examination and any need for transfer to obstetric led care. Perform intermittent auscultation of the fetal heart rate immediately after a contraction for at least 1 minute, at least every 5 minutes. Palpate the woman's pulse every 15 minutes to differentiate between the two heartbeats. Ongoing consideration should be given to the woman's position, hydration, coping strategies and pain relief throughout the second stage. ## Duration of the second stage and definition of delay For a nulliparous woman: birth would be expected to take place within 3 hours of the start of the active second stage in most women diagnose delay in the active second stage when it has lasted 2 hours and refer the woman to a healthcare professional trained to undertake an operative vaginal birth if birth is not imminent. For a multiparous woman: birth would be expected to take place within 2 hours of the start of the active second stage in most women diagnose delay in the active second stage when it has lasted 1 hour and refer the woman to a healthcare professional trained to undertake an operative vaginal birth if birth is not imminent. For a nulliparous woman, suspect delay if progress (in terms of rotation and/or descent of the presenting part) is inadequate after 1 hour of active second stage. Offer vaginal examination and then offer amniotomy if the membranes are intact. For a multiparous woman, suspect delay if progress (in terms of rotation and/or descent of the presenting part) is inadequate after 30 minutes of active second stage. Offer vaginal examination and then offer amniotomy if the membranes are intact. If full dilatation of the cervix has been confirmed in a woman without regional analgesia, but she does not get an urge to push, carry out further assessment after 1 hour. ## Oxytocin in the second stage Consideration should be given to the use of oxytocin, with the offer of regional analgesia, for nulliparous women if contractions are inadequate at the onset of the second stage. ## The woman's position and pushing in the second stage Discourage the woman from lying supine or semi‑supine in the second stage of labour and encourage her to adopt any other position that she finds most comfortable. Inform the woman that in the second stage she should be guided by her own urge to push. If pushing is ineffective or if requested by the woman, offer strategies to assist birth, such as support, change of position, emptying of the bladder and encouragement. ## Intrapartum interventions to reduce perineal trauma Do not perform perineal massage in the second stage of labour. Either the 'hands on' (guarding the perineum and flexing the baby's head) or the 'hands poised' (with hands off the perineum and baby's head but in readiness) technique can be used to facilitate spontaneous birth. Do not offer lidocaine spray to reduce pain in the second stage of labour. Do not carry out a routine episiotomy during spontaneous vaginal birth. Inform any woman with a history of severe perineal trauma that her risk of repeat severe perineal trauma is not increased in a subsequent birth, compared with women having their first baby. Do not offer episiotomy routinely at vaginal birth after previous third‑ or fourth‑degree trauma. In order for a woman who has had previous third- or fourth‑degree trauma to make an informed choice, talk with her about the future mode of birth, encompassing: current urgency or incontinence symptoms the degree of previous trauma risk of recurrence the success of the repair undertaken the psychological effect of the previous trauma management of her labour. Inform any woman with infibulated genital mutilation of the risks of difficulty with vaginal examination, catheterisation and application of fetal scalp electrodes. Inform her of the risks of delay in the second stage and spontaneous laceration together with the need for an anterior episiotomy and the possible need for defibulation in labour. If an episiotomy is performed, the recommended technique is a mediolateral episiotomy originating at the vaginal fourchette and usually directed to the right side. The angle to the vertical axis should be between 45 and 60 degrees at the time of the episiotomy. Perform an episiotomy if there is a clinical need, such as instrumental birth or suspected fetal compromise. Provide tested effective analgesia before carrying out an episiotomy, except in an emergency because of acute fetal compromise. ## Water birth Inform women that there is insufficient high‑quality evidence to either support or discourage giving birth in water. ## Delay in the second stage If there is delay in the second stage of labour, or if the woman is excessively distressed, support and sensitive encouragement and the woman's need for analgesia/anaesthesia are particularly important. An obstetrician should assess a woman with confirmed delay in the second stage (after transfer to obstetric‑led care, following the general principles for transfer of care) before contemplating the use of oxytocin. After initial obstetric assessment of a woman with delay in the second stage, maintain ongoing obstetric review every 15 to 30 minutes. ## Instrumental birth and delayed second stage Think about offering instrumental birth if there is concern about the baby's wellbeing or there is a prolonged second stage. Recognise that, on rare occasions, the woman's need for help in the second stage may be an indication to assist by offering instrumental birth when supportive care has not helped. The choice of instrument depends on a balance of clinical circumstance and practitioner experience. Because instrumental birth is an operative procedure, advise the woman to have tested effective anaesthesia. If a woman declines anaesthesia, offer a pudendal block combined with local anaesthetic to the perineum during instrumental birth. If there is concern about fetal compromise, offer either tested effective anaesthesia or, if time does not allow this, a pudendal block combined with local anaesthetic to the perineum during instrumental birth. Advise the woman to have a caesarean section if vaginal birth is not possible (see the NICE guideline on caesarean birth). . ## Expediting birth If the birth needs to be expedited for maternal or fetal reasons, assess both the risk to the baby and the safety of the woman. Assessments should include: the degree of urgency clinical findings on abdominal and vaginal examination choice of mode of birth (and whether to use forceps or ventouse if an instrumental birth is indicated) anticipated degree of difficulty, including the likelihood of success if instrumental birth is attempted location any time that may be needed for transfer to obstetric‑led care the need for additional analgesia or anaesthesia the woman's preferences. Talk with the woman and her birth companion(s) about why the birth needs to be expedited and what the options are. Inform the team about the degree of urgency. Record the time at which the decision to expedite the birth is made. # Third stage of labour Recognise that the time immediately after the birth is when the woman and her birth companion(s) are meeting and getting to know the baby. Ensure that any care or interventions are sensitive to this and minimise separation or disruption of the mother and baby. ## Definition of the third stage For the purposes of this guideline, use the following definitions: The third stage of labour is the time from the birth of the baby to the expulsion of the placenta and membranes. Active management of the third stage involves a package of care comprising the following components: routine use of uterotonic drugs deferred clamping and cutting of the cord controlled cord traction after signs of separation of the placenta. Physiological management of the third stage involves a package of care that includes the following components: no routine use of uterotonic drugs no clamping of the cord until pulsation has stopped delivery of the placenta by maternal effort. ## Prolonged third stage Diagnose a prolonged third stage of labour if it is not completed within 30 minutes of the birth with active management or within 60 minutes of the birth with physiological management. Follow the recommendations on managing retained placenta. ## Observations in the third stage Record the following observations for a woman in the third stage of labour: her general physical condition, as shown by her colour, respiration and her own report of how she feels vaginal blood loss. If there is postpartum haemorrhage, a retained placenta or maternal collapse, or any other concerns about the woman's wellbeing: transfer her to obstetric‑led care (following the general principles for transfer of care) carry out frequent observations to assess whether resuscitation is needed. ## Active and physiological management of the third stage Explain to the woman antenatally about what to expect with each package of care for managing the third stage of labour and the benefits and risks associated with each. Explain to the woman that active management: shortens the third stage compared with physiological management is associated with nausea and vomiting in about 100 in 1,000 women is associated with an approximate risk of 13 in 1,000 of a haemorrhage of more than 1 litre is associated with an approximate risk of 14 in 1,000 of a blood transfusion. Explain to the woman that physiological management: is associated with nausea and vomiting in about 50 in 1,000 women is associated with an approximate risk of 29 in 1,000 of a haemorrhage of more than 1 litre is associated with an approximate risk of 40 in 1,000 of a blood transfusion. Discuss again with the woman at the initial assessment in labour (see the section on initial assessment) about the different options for managing the third stage and ways of supporting her during delivery of the placenta, and ask if she has any preferences. Advise the woman to have active management of the third stage, because it is associated with a lower risk of a postpartum haemorrhage and/or blood transfusion. If a woman at low risk of postpartum haemorrhage requests physiological management of the third stage, support her in her choice. Document in the records the decision that is agreed with the woman about management of the third stage. For active management, administer 10 IU of oxytocin by intramuscular injection with the birth of the anterior shoulder or immediately after the birth of the baby and before the cord is clamped and cut. Use oxytocin as it is associated with fewer side effects than oxytocin plus ergometrine. After administering oxytocin, clamp and cut the cord. Do not clamp the cord earlier than 1 minute from the birth of the baby unless there is concern about the integrity of the cord or the baby has a heart rate below 60 beats/minute that is not getting faster. Clamp the cord before 5 minutes in order to perform controlled cord traction as part of active management. If the woman requests that the cord is clamped and cut later than 5 minutes, support her in her choice. After cutting the cord, use controlled cord traction. Perform controlled cord traction as part of active management only after administration of oxytocin and signs of separation of the placenta. Record the timing of cord clamping in both active and physiological management. Advise a change from physiological management to active management if either of the following occur: haemorrhage the placenta is not delivered within 1 hour of the birth of the baby. Offer a change from physiological management to active management if the woman wants to shorten the third stage. Do not use either umbilical oxytocin infusion or prostaglandin routinely in the third stage of labour. ## Retained placenta Secure intravenous access if the placenta is retained, and explain to the woman why this is needed. Do not use umbilical vein agents if the placenta is retained. Do not use intravenous oxytocic agents routinely to deliver a retained placenta. Give intravenous oxytocic agents if the placenta is retained and the woman is bleeding excessively. If the placenta is retained and there is concern about the woman's condition: -ffer a vaginal examination to assess the need to undertake manual removal of the placenta explain that this assessment can be painful and advise her to have analgesia. If the woman reports inadequate analgesia during the assessment, stop the examination and address this immediately. If uterine exploration is necessary and the woman is not already in an obstetric unit, arrange urgent transfer (following the general principles for transfer of care). Do not carry out uterine exploration or manual removal of the placenta without an anaesthetic. ## Postpartum haemorrhage Advise women with risk factors for postpartum haemorrhage to give birth in an obstetric unit, where more emergency treatment options are available. Antenatal risk factors: previous retained placenta or postpartum haemorrhage maternal haemoglobin level below 85 g/litre at onset of labour BMI greater than 35 kg/m2 grand multiparity (parity 4 or more) antepartum haemorrhage -verdistention of the uterus (for example, multiple pregnancy, polyhydramnios or macrosomia) existing uterine abnormalities low‑lying placenta maternal age of 35 years or older. Risk factors in labour: induction prolonged first, second or third stage of labour -xytocin use precipitate labour -perative birth or caesarean section. If a woman has risk factors for postpartum haemorrhage, highlight these in her notes, and make and discuss with her a care plan covering the third stage of labour. If a woman has a postpartum haemorrhage: call for help give immediate clinical treatment: emptying of the bladder and uterine massage and uterotonic drugs and intravenous fluids and controlled cord traction if the placenta has not yet been delivered continuously assess blood loss and the woman's condition, and identify the source of the bleeding give supplementary oxygen arrange for transfer of the woman to obstetric‑led care (following the general principles for transfer of care). Administer a bolus of one of the following as first‑line treatment for postpartum haemorrhage: -xytocin (10 IU intravenous) or ergometrine (0.5 mg intramuscular) or combined oxytocin and ergometrine (5 IU/0.5 mg intramuscular). Offer second‑line treatment for postpartum haemorrhage if needed. No particular uterotonic drug can be recommended over any other; options include: repeat bolus of: -xytocin (intravenous) ergometrine (intramuscular, or cautiously intravenously) combined oxytocin and ergometrine (intramuscular) misoprostol -xytocin infusion carboprost (intramuscular). Assess the need for adjuvant options for managing significant continuing postpartum haemorrhage, including: tranexamic acid (intravenous) rarely, in the presence of otherwise normal clotting factors, rFactor VIIa, in consultation with a haematologist. Allocate a member of the healthcare team to stay with the woman and her birth companion(s), explain what is happening, answer any questions and offer support throughout the emergency situation. If the haemorrhage continues: perform examination under anaesthetic ensure that the uterus is empty and repair any trauma consider balloon tamponade before surgical options. Be aware that no particular surgical procedure can be recommended over any other for treating postpartum haemorrhage. The maternity service and ambulance service should have strategies in place in order to respond quickly and appropriately if a woman has a postpartum haemorrhage in any setting. # Care of the newborn baby ## Initial assessment of the newborn baby and mother–baby bonding Recommendations 1.15.6, 1.15.8 and 1.15.9 have been adapted from NICE's guideline on postnatal care; refer to this guideline for more information on immediate postnatal care (within 2 hours of birth). Record the Apgar score routinely at 1 and 5 minutes for all births. Record the time from birth to the onset of regular respirations. If the baby is born in poor condition (on the basis of abnormal breathing, heart rate or tone): follow the recommendations in the section on neonatal resuscitation and take paired cord‑blood samples for blood gas analysis, after clamping the cord using 2 clamps.Continue to evaluate and record the baby's condition until it is improved and stable. Do not take paired cord blood samples (for blood gas analysis) routinely. Ensure that a second clamp to allow double‑clamping of the cord is available in all birth settings. Encourage women to have skin‑to‑skin contact with their babies as soon as possible after the birth. In order to keep the baby warm, dry and cover him or her with a warm, dry blanket or towel while maintaining skin‑to‑skin contact with the woman. Avoid separation of a woman and her baby within the first hour of the birth for routine postnatal procedures, for example, weighing, measuring and bathing, unless these measures are requested by the woman, or are necessary for the immediate care of the baby. Encourage initiation of breastfeeding as soon as possible after the birth, ideally within 1 hour. Record head circumference, body temperature and birth weight soon after the first hour following birth. Undertake an initial examination to detect any major physical abnormality and to identify any problems that require referral. Ensure that any examination or treatment of the baby is undertaken with the consent of the parents and either in their presence or, if this is not possible, with their knowledge. ## Neonatal resuscitation In the first minutes after birth, evaluate the condition of the baby – specifically respiration, heart rate and tone – in order to determine whether resuscitation is needed according to nationally accredited guidelines on neonatal resuscitation. All relevant healthcare professionals caring for women during birth should attend annually a course in neonatal resuscitation that is consistent with nationally accredited guidelines on neonatal resuscitation. In all birth settings: bear in mind that it will be necessary to call for help if the baby needs resuscitation, and plan accordingly ensure that there are facilities for resuscitation, and for transferring the baby to another location if necessary develop emergency referral pathways for both the woman and the baby, and implement these if necessary. If a newborn baby needs basic resuscitation, start with air. Minimise separation of the baby and mother, taking into account the clinical circumstances. Throughout an emergency situation in which the baby needs resuscitation, allocate a member of the healthcare team to talk with, and offer support to, the woman and any birth companion(s). ## Care of babies in the presence of meconium In the presence of any degree of meconium: do not suction the baby's upper airways (nasopharynx and oropharynx) before birth of the shoulders and trunk do not suction the baby's upper airways (nasopharynx and oropharynx) if the baby has normal respiration, heart rate and tone do not intubate if the baby has normal respiration, heart rate and tone. If there has been significant meconium (see recommendation 1.5.2 in the section on presence of meconium) and the baby does not have normal respiration, heart rate and tone, follow nationally accredited guidelines on neonatal resuscitation, including early laryngoscopy and suction under direct vision. If there has been significant meconium and the baby is healthy, closely observe the baby within a unit with immediate access to a neonatologist. Perform these observations at 1 and 2 hours of age and then 2‑hourly until 12 hours of age. If there has been non‑significant meconium, observe the baby at 1 and 2 hours of age in all birth settings. If any of the following are observed after any degree of meconium, ask a neonatologist to assess the baby (transfer both the woman and baby if they are at home or in a freestanding midwifery unit, following the general principles for transfer of care): respiratory rate above 60 per minute the presence of grunting heart rate below 100 or above 160 beats/minute capillary refill time above 3 seconds body temperature of 38°C or above, or 37.5°C on 2 occasions 30 minutes apart -xygen saturation below 95% (measuring oxygen saturation is optional after non‑significant meconium) presence of central cyanosis, confirmed by pulse oximetry if available. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. Explain the findings to the woman, and inform her about what to look out for and who to talk to if she has any concerns. ## Babies born to women with prelabour rupture of the membranes at term Closely observe any baby born to a woman with prelabour rupture of the membranes (more than 24 hours before the onset of established labour) at term for the first 12 hours of life (at 1 hour, 2 hours, 6 hours and 12 hours) in all settings. Include assessment of: temperature heart rate respiratory rate presence of respiratory grunting significant subcostal recession presence of nasal flare presence of central cyanosis, confirmed by pulse oximetry if available skin perfusion assessed by capillary refill floppiness, general wellbeing and feeding.If any of these are observed, ask a neonatologist to assess the baby (transfer both the woman and baby if they are at home or in a freestanding midwifery unit, following the general principles for transfer of care). Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. If there are no signs of infection in the woman, do not give antibiotics to either the woman or the baby, even if the membranes have been ruptured for over 24 hours. If there is evidence of infection in the woman, prescribe a full course of broad‑spectrum intravenous antibiotics. Advise women with prelabour rupture of the membranes to inform their healthcare professionals immediately of any concerns they have about their baby's wellbeing in the first 5 days after birth, particularly in the first 12 hours when the risk of infection is greatest. Do not perform blood, cerebrospinal fluid and/or surface culture tests in an asymptomatic baby. Refer a baby with any symptom of possible sepsis, or born to a woman who has evidence of chorioamnionitis, to a neonatal care specialist immediately. # Care of the woman after birth ## Initial assessment Carry out the following observations of the woman after birth: Record her temperature, pulse and blood pressure. Transfer the woman (with her baby) to obstetric‑led care if any of the relevant indications listed in the recommendation on ongoing assessment are met. Uterine contraction and lochia. Examine the placenta and membranes: assess their condition, structure, cord vessels and completeness. Transfer the woman (with her baby) to obstetric‑led care if the placenta is incomplete. Early assessment of the woman's emotional and psychological condition in response to labour and birth. Successful voiding of the bladder. Assess whether to transfer the woman (with her baby) to obstetric‑led care after 6 hours if her bladder is palpable and she is unable to pass urine.If transferring the woman to obstetric‑led care, follow the general principles for transfer of care. ## Perineal care Define perineal or genital trauma caused by either tearing or episiotomy as follows: first degree – injury to skin only second degree – injury to the perineal muscles but not the anal sphincter third degree – injury to the perineum involving the anal sphincter complex: a – less than 50% of external anal sphincter thickness torn b – more than 50% of external anal sphincter thickness torn c – internal anal sphincter torn. fourth degree – injury to the perineum involving the anal sphincter complex (external and internal anal sphincter) and anal epithelium. Before assessing for genital trauma: explain to the woman what is planned and why -ffer inhalational analgesia ensure good lighting position the woman so that she is comfortable and so that the genital structures can be seen clearly. Perform the initial examination gently and with sensitivity. It may be done in the immediate period after birth. If genital trauma is identified after birth, offer further systematic assessment, including a rectal examination. Include the following in a systematic assessment of genital trauma: further explanation of what is planned and why confirmation by the woman that tested effective local or regional analgesia is in place visual assessment of the extent of perineal trauma to include the structures involved, the apex of the injury and assessment of bleeding a rectal examination to assess whether there has been any damage to the external or internal anal sphincter if there is any suspicion that the perineal muscles are damaged. Ensure that the timing of this systematic assessment does not interfere with mother–baby bonding unless the woman has bleeding that requires urgent attention. Assist the woman to adopt a position that allows adequate visual assessment of the degree of trauma and for repair. Only maintain this position for as long as necessary for systematic assessment and repair. If it is not possible to adequately assess the trauma, transfer the woman (with her baby) to obstetric‑led care, following the general principles for transfer of care. Seek advice from a more experienced midwife or obstetrician if there is uncertainty about the nature or extent of the trauma. Transfer the woman (with her baby) to obstetric‑led care (following the general principles for transfer of care) if the repair needs further surgical or anaesthetic expertise. Document the systematic assessment and its results fully, possibly pictorially. All relevant healthcare professionals should attend training in perineal/genital assessment and repair, and ensure that they maintain these skills. Undertake repair of the perineum as soon as possible to minimise the risk of infection and blood loss. When carrying out perineal repair: ensure that tested effective analgesia is in place, using infiltration with up to 20 ml of 1% lidocaine or equivalent top up the epidural or insert a spinal anaesthetic if necessary. If the woman reports inadequate pain relief at any point, address this immediately. Advise the woman that in the case of first‑degree trauma, the wound should be sutured in order to improve healing, unless the skin edges are well opposed. Advise the woman that in the case of second‑degree trauma, the muscle should be sutured in order to improve healing. If the skin is opposed after suturing of the muscle in second‑degree trauma, there is no need to suture it. If the skin does require suturing, use a continuous subcuticular technique. Undertake perineal repair using a continuous non‑locked suturing technique for the vaginal wall and muscle layer. Use an absorbable synthetic suture material to suture the perineum. Offer rectal non‑steroidal anti‑inflammatory drugs routinely after perineal repair of first‑ and second‑degree trauma provided these drugs are not contraindicated. Observe the following basic principles when performing perineal repairs: Repair perineal trauma using aseptic techniques. Check equipment and count swabs and needles before and after the procedure. Good lighting is essential to see and identify the structures involved. Ensure that difficult trauma is repaired by an experienced practitioner in theatre under regional or general anaesthesia. Insert an indwelling catheter for 24 hours to prevent urinary retention. Ensure that good anatomical alignment of the wound is achieved and that consideration is given to the cosmetic results. Carry out rectal examination after completing the repair to ensure that suture material has not been accidentally inserted through the rectal mucosa. After completion of the repair, document an accurate detailed account covering the extent of the trauma, the method of repair and the materials used. Give the woman information about the extent of the trauma, pain relief, diet, hygiene and the importance of pelvic‑floor exercises (see the NICE guideline on pelvic floor dysfunction). # Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context Giving birth is a life‑changing event. The care that a woman receives during labour has the potential to affect her – both physically and emotionally, in the short and longer term – and the health of her baby. Good communication, support and compassion from staff, and having her wishes respected, can help her feel in control of what is happening and contribute to making birth a positive experience for the woman and her birth companion(s). This guideline covers the care of healthy women who go into labour at term (37+0 to 41+6 weeks). About 700,000 women give birth in England and Wales each year, of whom about 40% are having their first baby. Most of these women are healthy and have a straightforward pregnancy. Almost 90% of women will give birth to a single baby after 37 weeks of pregnancy, with the baby presenting head first. About two‑thirds of women go into labour spontaneously. Therefore, most women giving birth in England and Wales are covered by this guideline. Since the original guideline was published in 2007, the number of women giving birth in England and Wales each year has risen, the rate of intervention (instrumental births and caesarean section) has increased slightly, and there has been some reconfiguration of services. The decision to update the guideline in 2014 was made based on developments in the NHS and new evidence becoming available that could affect the recommendations from 2007. It is important that the woman is given information and advice about all available settings when she is deciding where to have her baby, so that she is able to make a fully informed decision. This includes information about outcomes for the different settings. It is also vital to recognise when transfer of care from midwifery‑led care to obstetric‑led care is indicated because of increased risk to the woman and/or her baby resulting from complications that have developed during labour. Uncertainty and inconsistency of care has been identified in a number of areas, such as choosing place of birth, care during the latent first stage of labour, fetal assessment and monitoring during labour (particularly cardiotocography compared with intermittent auscultation) and management of the third stage of labour. These and other related topics are addressed in the guideline. The guideline is intended to cover the care of healthy women with uncomplicated pregnancies entering labour at low risk of developing intrapartum complications. In addition, recommendations are included that address the care of women who start labour as 'low risk' but who go on to develop complications. These include the care of women with prelabour rupture of membranes at term, care of the woman and baby when meconium is present, indications for continuous cardiotocography, interpretation of cardiotocograph traces, and management of retained placenta and postpartum haemorrhage. Aspects of intrapartum care for women at risk of developing intrapartum complications are covered by a range of NICE guidelines on specific conditions and a further guideline is planned on the intrapartum care of women at high risk of complications during pregnancy and the intrapartum period.# Recommendations for research The guideline committee has made the following recommendations for research. # Models of midwifery-led care In December 2021, we stood down this recommendation for research as continuity of care in maternity services is now a national policy in the UK following on from the National Maternity Review on Better Births and the subsequent Maternity Transformation Programme. # Effect of information giving on place of birth How does the provision of accurate, evidence‑based information affect women's decision‑making processes and choice of place of birth? ## Why this is important A report by Coxon et al. (2013) identifies in detail why women make choices about where to give birth and how these choices can be influenced. Influences may include written and verbal information (both online and from midwives and doctors), previous experience, and word‑of‑mouth advice from friends and family. The Birthplace study concluded that giving birth outside an obstetric unit is the optimal choice for low‑risk women. This finding should be used to restructure the way in which information is provided, so that it is presented in a more accurate, less risk‑based way in order to support women's choices. This change should be evaluated in a quantitative observational study and/or qualitative study that records any changes in women's choice‑making about place of birth. Outcomes include understanding why and how women make choices about where to give birth and how this can influence the provision of appropriate and accessible information, a measure of informed decision‑making, and fearfulness and absence of fearfulness when choosing place of birth. # Long‑term consequences of planning birth in different settings What are the long‑term consequences for women and babies of planning birth in different settings? ## Why this is important The long‑term consequences of birth experiences and birth outcomes are poorly understood, particularly in relation to place of birth. A large population‑based observational study would compare women's experiences and outcomes in different birth settings (with subgroup analysis by mode of birth) in relation to the wellbeing of the women and their children over different periods of time (for example, 2, 5, 10, 15, 20 and 30 years). A secondary analysis could compare different providers where birth philosophies are different. Outcomes would be compared by accessing medical records and through qualitative interviews. Primary outcomes are long‑term physical morbidity, pain after birth, readmission to hospital, infection, psychological morbidity (for example, postnatal depression, bonding, relationship breakdown with partner, fear of giving birth in future) and breastfeeding rates. Secondary outcomes are impact on attachment between mother and child, obesity in children, autoimmune disease, chronic illness, educational achievement and family functioning. # Education about the latent first stage of labour Does enhanced education specifically about the latent first stage of labour increase the number of nulliparous women who wait until they are in established labour before attending the obstetric or midwifery unit (or calling the midwife to a home birth), compared with women who do not receive this education? ## Why this is important Studies show that antenatal education about labour and birth in general makes a difference to some birth outcomes, but there is limited evidence focusing on education about the latent first stage of labour specifically. The aim of this study (randomised controlled trial or prospective observational study) would be to compare 2 groups of women experiencing their first labour and birth: a group who receive an education session in late pregnancy covering what to expect in the latent first stage of labour and how to recognise the onset of established labour, and a group who have not received this focused education. Primary outcomes would be mode of birth, satisfaction with the birth experience and the woman's physical and emotional wellbeing after birth. Secondary outcomes would be use of pharmacological pain relief, use of oxytocin to augment labour, and time from first contact in confirmed established labour to birth. # Postpartum haemorrhage What is the most effective treatment for primary postpartum haemorrhage? ## Why this is important There is uncertainty about the most effective drug treatments and dosage regimes, and about which other treatments should be used, for women who develop a postpartum haemorrhage. The most effective sequencing of interventions is also uncertain. The psychological impact of postpartum haemorrhage for women can be significant, and identifying the approach that minimises this impact is important. Randomised controlled trials comparing different dosage regimes for oxytocin and misoprostol, as well as comparisons with ergometrine and carboprost, are needed. Trials of mechanical measures such as intrauterine balloons or interventional radiology as early second‑line treatment (rather than an alternative drug treatment) are also needed. Alternatively, a trial comparing the effectiveness of a complex intervention (for example, an educational component, sequence of interventions, immediate feedback and quality improvements) compared with standard care could be undertaken. Important outcomes include blood and blood product transfusion, need for further intervention, need for hysterectomy and psychological outcomes for the woman.# Appendix A: Adverse outcomes Adverse outcome: in order to be able to count enough adverse events to be able to say that the results recorded are not just a result of chance, the Birthplace UK (2011) study used a composite definition of 'adverse outcome'. The definition includes the following outcomes: stillbirth during labour, death of the baby in the first week after birth, neonatal encephalopathy (disordered brain function caused by oxygen deprivation before or during birth), meconium aspiration syndrome, and physical birth injuries (brachial plexus injury and bone fractures). The term 'serious medical problems' has been used to describe this composite outcome in the guideline recommendations. Outcome Actual number of babies affected out of (63,955 to 64,535*; number per 1,000) Percentage of all adverse outcomes measured Stillbirth after start of care in labour -ut of 64,535 (0.22 per 1,000) Death of the baby in the first week after birth -ut of 64,292 (0.28 per 1,000) Neonatal encephalopathy (disordered brain function caused by oxygen deprivation before or during birth) (clinical diagnosis) -ut of 63,955 (1.6 per 1,000) Meconium aspiration syndrome (the baby breathes meconium into their lungs) -ut of 63,955 (1.3 per 1,000) Brachial plexus injury -ut of 63,955 (0.38 per 1,000) Bone fractures -ut of 63,955 (0.17 per 1,000) Total (of all outcomes included in the 'adverse outcome' composite measure) -ut of 63,955 to 64,535) (approximately 4 per 1,000) Note: Each of the categories above are mutually exclusive and outcomes listed higher in the table take precedence over outcomes listed lower down. For example, if a baby with neonatal encephalopathy died within 7 days the outcome is classified as an early neonatal death. - Denominator varies because of missing values. Does not equal 100% because of rounding.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Place of birth\n\n## Choosing planned place of birth\n\nExplain to both multiparous and nulliparous women who are at low risk of complications that giving birth is generally very safe for both the woman and her baby. \n\nExplain to both multiparous and nulliparous women that they may choose any birth setting (home, freestanding midwifery unit, alongside midwifery unit or obstetric unit), and support them in their choice of setting wherever they choose to give birth:\n\nAdvise low‑risk multiparous women that planning to give birth at home or in a midwifery‑led unit (freestanding or alongside) is particularly suitable for them because the rate of interventions is lower and the outcome for the baby is no different compared with an obstetric unit.\n\nAdvise low‑risk nulliparous women that planning to give birth in a midwifery‑led unit (freestanding or alongside) is particularly suitable for them because the rate of interventions is lower and the outcome for the baby is no different compared with an obstetric unit. Explain that if they plan birth at home there is a small increase in the risk of an adverse outcome for the baby. \n\nUsing table 1 and table 2, explain to low‑risk multiparous women that:\n\nplanning birth at home or in a freestanding midwifery unit is associated with a higher rate of spontaneous vaginal birth than planning birth in an alongside midwifery unit, and these 3\xa0settings are associated with higher rates of spontaneous vaginal birth than planning birth in an obstetric unit\n\nplanning birth in an obstetric unit is associated with a higher rate of interventions, such as instrumental vaginal birth, caesarean section and episiotomy, compared with planning birth in other settings\n\nthere are no differences in outcomes for the baby associated with planning birth in any setting. \n\n-\n\nHome (number of incidences per 1,000 multiparous women giving birth)\n\nFreestanding midwifery unit\n\n(number of incidences per 1,000 multiparous women giving birth)\n\nAlongside midwifery unit (number of incidences per 1,000 multiparous women giving birth)\n\nObstetric unit (number of 1,000 incidences per multiparous women giving birth)\n\nSpontaneous vaginal birth\n\n\n\n\n\n\n\n\n\nTransfer to an obstetric unit\n\n\n\n\n\n\n\n\n\nRegional analgesia (epidural and/or spinal)*\n\n\n\n\n\n\n\n\n\nEpisiotomy\n\n\n\n\n\n\n\n\n\nCaesarean birth\n\n\n\n\n\n\n\n\n\nInstrumental birth (forceps or ventouse)\n\n\n\n\n\n\n\n\n\nBlood transfusion\n\n\n\n\n\n\n\n\n\n Figures from Birthplace 2011 and Blix et al. 2012 (all other figures from Birthplace 2011).\n\n Estimated transfer rate from an obstetric unit to a different obstetric unit owing to lack of capacity or expertise.\n\n* Blix reported epidural analgesia and Birthplace reported spinal or epidural analgesia.\n\nOutcomes\n\nHome (number of babies per 1,000 births)\n\nFreestanding midwifery unit (number of babies per 1,000 births)\n\nAlongside midwifery unit (number of babies per 1,000 births)\n\nObstetric unit (number of babies per 1,000 births)\n\nBabies without serious medical problems\n\n\n\n\n\n\n\n\n\nBabies with serious medical problems\n\n\n\n\n\n\n\n\n\n Serious medical problems were combined in the study: neonatal encephalopathy and meconium aspiration syndrome were the most common adverse events, together accounting for 75% of the total. Stillbirths after the start of care in labour and death of the baby in the first week of life accounted for 13% of the events. Fractured humerus and clavicle were uncommon outcomes (less than 4% of adverse events). For the frequency of these events (how often any of them actually occurred), see appendix A.\n\nUsing table 3 and table 4, explain to low‑risk nulliparous women that:\n\nplanning birth at home or in a freestanding midwifery unit is associated with a higher rate of spontaneous vaginal birth than planning birth in an alongside midwifery unit, and these 3\xa0settings are associated with higher rates of spontaneous vaginal birth than planning birth in an obstetric unit\n\nplanning birth in an obstetric unit is associated with a higher rate of interventions, such as instrumental vaginal birth, caesarean section and episiotomy, compared with planning birth in other settings\n\nthere are no differences in outcomes for the baby associated with planning birth in an alongside midwifery unit, a freestanding midwifery unit or an obstetric unit\n\nplanning birth at home is associated with an overall small increase (about 4\xa0more per 1,000\xa0births) in the risk of a baby having a serious medical problem compared with planning birth in other settings. \n\n–\n\nHome (number of incidences per 1,000 nulliparous women giving birth)\n\nFreestanding midwifery unit (number of incidences per 1,000 nulliparous women giving birth)\n\nAlongside midwifery unit (number of incidences per 1,000 nulliparous women giving birth)\n\nObstetric unit (number of incidences per 1,000 nulliparous women giving birth)\n\n\n\nSpontaneous vaginal birth\n\n\n\n\n\n\n\n\n\nTransfer to an obstetric unit\n\n\n\n\n\n\n\n\n\nRegional analgesia (epidural and/or spinal)*\n\n\n\n\n\n\n\n\n\nEpisiotomy\n\n\n\n\n\n\n\n\n\nCaesarean birth\n\n\n\n\n\n\n\n\n\nInstrumental birth (forceps or ventouse)\n\n\n\n\n\n\n\n\n\nBlood transfusion\n\n\n\n\n\n\n\n\n\n Figures from Birthplace 2011 and Blix et al. 2012 (all other figures from Birthplace 2011).\n\n Estimated transfer rate from an obstetric unit to a different obstetric unit owing to lack of capacity or expertise.\n\n* Blix reported epidural analgesia and Birthplace reported spinal or epidural analgesia.\n\nOutcomes\n\nHome (number of babies per 1,000 births)\n\nFreestanding midwifery unit (number of babies per 1,000 births)\n\nAlongside midwifery unit (number of babies per 1,000 births)\n\nObstetric unit (number of babies per 1,000 births)\n\nBabies without serious medical problems\n\n\n\n\n\n\n\n\n\nBabies with serious medical problems\n\n\n\n\n\n\n\n\n\n Serious medical problems were combined in the study: neonatal encephalopathy and meconium aspiration syndrome were the most common adverse events, together accounting for 75% of the total. Stillbirths after the start of care in labour and death of the baby in the first week of life accounted for 13% of the events. Fractured humerus and clavicle were uncommon outcomes – less than 4% of adverse events. For the frequency of these events (how often any of them actually occurred), see appendix A.\n\nEnsure that all healthcare professionals involved in the care of pregnant women are familiar with the types and frequencies of serious medical problems that can affect babies (see appendix A), in order to be able to provide this information to women if they request it. \n\nCommissioners and providers (this can also include networks of providers) should ensure that all 4\xa0birth settings are available to all women (in the local area or in a neighbouring area). \n\nGive the woman the following information, including local statistics, about all local birth settings:\n\nAccess to midwives, including:\n\n\n\nthe likelihood of being cared for in labour by a familiar midwife\n\nthe likelihood of receiving one‑to‑one care throughout labour (not necessarily being cared for by the same midwife for the whole of labour).\n\n\n\nAccess to medical staff (obstetric, anaesthetic and neonatal).\n\nAccess to pain relief, including birthing pools, Entonox, other drugs and regional analgesia.\n\nThe likelihood of being transferred to an obstetric unit (if this is not the woman's chosen place of birth), the reasons why this might happen and the time it may take. Refer to table 5 if no local data are available. \n\nPrimary reason for transfer to an obstetric unit\n\nNumber of women transferred from home (n=3,529)\n\nNumber of women transferred from a freestanding midwifery unit (n=2,457)\n\nNumber of women transferred from an alongside midwifery unit (n=4,401)\n\nDelay during first or second stage of labour\n\n,144 (32.4%)\n\n(37.1%)\n\n,548 (35.2%)\n\nAbnormal fetal heart rate\n\n(7.0%)\n\n(10.5%)\n\n(10.8%)\n\nRequest for regional analgesia\n\n(5.1%)\n\n(6.6%)\n\n(13.3%)\n\nMeconium staining\n\n(12.2%)\n\n(12.2%)\n\n(12.2%)\n\nRetained placenta\n\n(7.0%)\n\n(7.3%)\n\n(4.6%)\n\nRepair of perineal trauma\n\n(10.9%)\n\n(7.5%)\n\n(8.4%)\n\nNeonatal concerns (postpartum)\n\n(5.1%)\n\n(2.6%)\n\n(0.0%)\n\nOther\n\n(20.1%)\n\n(16.2%)\n\n(16.3%)\n\n Main reason for transfer to an obstetric unit for each woman (there may be more than 1 reason).\n\nIf further discussion is wanted by either the midwife or the woman about the choice of planned place of birth, arrange this with a consultant midwife or supervisor of midwives, and/or a consultant obstetrician if there are obstetric issues. \n\nWhen discussing the woman's choice of place of birth with her, do not disclose personal views or judgements about her choices. \n\nUse tables 6, 7, 8 and 9 as part of an assessment for a woman choosing her planned place of birth:\n\nTable 6 and table 7 show medical conditions or situations in which there is increased risk for the woman or baby during or shortly after labour, where care in an obstetric unit would be expected to reduce this risk.\n\nThe factors listed in table 8 and table 9 are not reasons in themselves for advising birth within an obstetric unit, but indicate that further consideration of birth setting may be required.\n\nDiscuss these risks and the additional care that can be provided in the obstetric unit with the woman so that she can make an informed choice about planned place of birth. [2007, amended 2014]\n\nDisease area\n\nMedical condition\n\nCardiovascular\n\nConfirmed cardiac disease\n\nHypertensive disorders\n\nRespiratory\n\nAsthma requiring an increase in treatment or hospital treatment\n\nCystic fibrosis\n\nHaematological\n\nHaemoglobinopathies – sickle‑cell disease, beta‑thalassaemia major\n\nHistory of thromboembolic disorders\n\nImmune thrombocytopenia purpura or other platelet disorder or platelet count below 100×109/litre\n\nVon Willebrand's disease\n\nBleeding disorder in the woman or unborn baby\n\nAtypical antibodies which carry a risk of haemolytic disease of the newborn\n\nEndocrine\n\nHyperthyroidism\n\nDiabetes\n\nInfective\n\nRisk factors associated with group\xa0B streptococcus whereby antibiotics in labour would be recommended\n\nHepatitis\xa0B/C with abnormal liver function tests\n\nCarrier of/infected with HIV\n\nToxoplasmosis – women receiving treatment\n\nCurrent active infection of chicken pox/rubella/genital herpes in the woman or baby\n\nTuberculosis under treatment\n\nImmune\n\nSystemic lupus erythematosus\n\nScleroderma\n\nRenal\n\nAbnormal renal function\n\nRenal disease requiring supervision by a renal specialist\n\nNeurological\n\nEpilepsy\n\nMyasthenia gravis\n\nPrevious cerebrovascular accident\n\nGastrointestinal\n\nLiver disease associated with current abnormal liver function tests\n\nPsychiatric\n\nPsychiatric disorder requiring current inpatient care\n\nFactor\n\nAdditional information\n\nPrevious complications\n\nUnexplained stillbirth/neonatal death or previous death related to intrapartum difficulty\n\nPrevious baby with neonatal encephalopathy\n\nPre‑eclampsia requiring preterm birth\n\nPlacental abruption with adverse outcome\n\nEclampsia\n\nUterine rupture\n\nPrimary postpartum haemorrhage requiring additional treatment or blood transfusion\n\nRetained placenta requiring manual removal in theatre\n\nCaesarean section\n\nShoulder dystocia\n\nCurrent pregnancy\n\n\n\nMultiple birth\n\nPlacenta praevia\n\nPre‑eclampsia or pregnancy‑induced hypertension\n\nPreterm labour or preterm prelabour rupture of membranes\n\nPlacental abruption\n\nAnaemia – haemoglobin less than 85\xa0g/litre at onset of labour\n\nConfirmed intrauterine death\n\nInduction of labour\n\nSubstance misuse\n\nAlcohol dependency requiring assessment or treatment\n\nOnset of gestational diabetes\n\nMalpresentation – breech or transverse lie\n\nBMI at booking of greater than 35\xa0kg/m2\n\nRecurrent antepartum haemorrhage\n\nSmall for gestational age in this pregnancy (less than fifth centile or reduced growth velocity on ultrasound)\n\nAbnormal fetal heart rate/doppler studies\n\nUltrasound diagnosis of oligo‑/polyhydramnios\n\nPrevious gynaecological history\n\nMyomectomy\n\nHysterotomy\n\nDisease area\n\nMedical condition\n\nCardiovascular\n\nCardiac disease without intrapartum implications\n\nHaematological\n\nAtypical antibodies not putting the baby at risk of haemolytic disease\n\nSickle‑cell trait\n\nThalassaemia trait\n\nAnaemia – haemoglobin 85\xa0to\xa0105\xa0g/litre at onset of labour\n\nInfective\n\nHepatitis\xa0B/C with normal liver function tests\n\nImmune\n\nNon‑specific connective tissue disorders\n\nEndocrine\n\nUnstable hypothyroidism such that a change in treatment is required\n\nSkeletal/neurological\n\nSpinal abnormalities\n\nPrevious fractured pelvis\n\nNeurological deficits\n\nGastrointestinal\n\nLiver disease without current abnormal liver function\n\nCrohn's disease\n\nUlcerative colitis\n\nFactor\n\nAdditional information\n\nPrevious complications\n\nStillbirth/neonatal death with a known non‑recurrent cause\n\nPre‑eclampsia developing at term\n\nPlacental abruption with good outcome\n\nHistory of previous baby more than 4.5\xa0kg\n\nExtensive vaginal, cervical, or third‑ or fourth‑degree perineal trauma\n\nPrevious term baby with jaundice requiring exchange transfusion\n\nCurrent pregnancy\n\nAntepartum bleeding of unknown origin (single episode after 24\xa0weeks of gestation)\n\nBMI at booking of 30\xa0to\xa035\xa0kg/m2\n\nBlood pressure of 140\xa0mmHg systolic or 90\xa0mmHg diastolic or more on 2\xa0occasions\n\nClinical or ultrasound suspicion of macrosomia\n\nPara\xa04 or more\n\nRecreational drug use\n\nUnder current outpatient psychiatric care\n\nAge over\xa035 at booking\n\nFetal indications\n\nFetal abnormality\n\nPrevious gynaecological history\n\nMajor gynaecological surgery\n\nCone biopsy or large loop excision of the transformation zone\n\nFibroids\n\n## Women's experience in all birth settings\n\nFor all women giving birth in all birth settings, follow the principles in the NICE guideline on patient experience in adult NHS services. \n\nProviders, senior staff and all healthcare professionals should ensure that in all birth settings there is a culture of respect for each woman as an individual undergoing a significant and emotionally intense life experience, so that the woman is in control, is listened to and is cared for with compassion, and that appropriate informed consent is sought. \n\nSenior staff should demonstrate, through their own words and behaviour, appropriate ways of relating to and talking about women and their birth companion(s), and of talking about birth and the choices to be made when giving birth. \n\n## One‑to‑one care in all birth settings\n\nMaternity services should:\n\nprovide a model of care that supports one‑to‑one care in labour for all women and\n\nbenchmark services and identify overstaffing or understaffing by using workforce planning models and/or woman‑to‑midwife ratios. \n\n## Service organisation and clinical governance\n\nEnsure that all women giving birth have timely access to an obstetric unit if they need transfer of care for medical reasons or because they request regional analgesia. \n\nCommissioners and providers (this can also include networks of providers) should ensure that there are:\n\nrobust protocols in place for transfer of care between settings (see also the section on general principles for transfer of care)\n\nclear local pathways for the continued care of women who are transferred from one setting to another, including:\n\n\n\nwhen crossing provider boundaries\n\nif the nearest obstetric or neonatal unit is closed to admissions or the local midwifery‑led unit is full. \n\n\n\nCommissioners and providers (this can also include networks of providers) should ensure that there are multidisciplinary clinical governance structures in place to enable the oversight of all birth settings. These structures should include, as a minimum, midwifery (including a supervisor of midwives), obstetric, anaesthetic and neonatal expertise, and adequately supported user representation. \n\n# Care throughout labour\n\n## Communication\n\nTreat all women in labour with respect. Ensure that the woman is in control of and involved in what is happening to her, and recognise that the way in which care is given is key to this. To facilitate this, establish a rapport with the woman, ask her about her wants and expectations for labour, and be aware of the importance of tone and demeanour, and of the actual words used. Use this information to support and guide her through her labour. \n\nTo establish communication with the woman:\n\nGreet the woman with a smile and a personal welcome, establish her language needs, introduce yourself and explain your role in her care.\n\nMaintain a calm and confident approach so that your demeanour reassures the woman that all is going well.\n\nKnock and wait before entering the woman's room, respecting it as her personal space, and ask others to do the same.\n\nAsk how the woman is feeling and whether there is anything in particular she is worried about.\n\nIf the woman has a written birth plan, read and discuss it with her.\n\nAssess the woman's knowledge of strategies for coping with pain and provide balanced information to find out which available approaches are acceptable to her.\n\nEncourage the woman to adapt the environment to meet her individual needs.\n\nAsk her permission before all procedures and observations, focusing on the woman rather than the technology or the documentation.\n\nShow the woman and her birth companion(s) how to summon help and reassure her that she may do so whenever and as often as she needs to. When leaving the room, let her know when you will return.\n\nInvolve the woman in any handover of care to another professional, either when additional expertise has been brought in or at the end of a shift. \n\n## Mobilisation\n\nEncourage and help the woman to move and adopt whatever positions she finds most comfortable throughout labour. \n\n## Support\n\nEncourage the woman to have support from birth companion(s) of her choice. \n\n## Hygiene measures\n\nTap water may be used if cleansing is required before vaginal examination. \n\nRoutine hygiene measures taken by staff caring for women in labour, including standard hand hygiene and single‑use non‑sterile gloves, are appropriate to reduce cross‑contamination between women, babies and healthcare professionals. \n\nSelection of protective equipment must be based on an assessment of the risk of transmission of microorganisms to the woman, and the risk of contamination of the healthcare worker's clothing and skin by women's blood, body fluids, secretions or excretions. This is in accordance with the following health and safety legislation (current at the time NICE's guideline on healthcare-associated infections was published [March 2012]): Health and Safety at Work Act 1974, Management of Health and Safety at Work Regulations 1999, Health and Safety Regulations 2002, Control of Substances Hazardous to Health Regulations 2002, Personal Protective Equipment Regulations 2002 and Health and Social Care Act 2008). [2007, amended 2014]This recommendation is adapted from NICE's guideline on healthcare-associated infections.\n\n# Latent first stage of labour\n\n## Definitions of the latent and established first stages of labour\n\nFor the purposes of this guideline, use the following definitions of labour:\n\nLatent first stage of labour – a period of time, not necessarily continuous, when:\n\n\n\nthere are painful contractions and\n\nthere is some cervical change, including cervical effacement and dilatation up to 4\xa0cm.\n\n\n\nEstablished first stage of labour – when:\n\n\n\nthere are regular painful contractions and\n\nthere is progressive cervical dilatation from 4\xa0cm. \n\n\n\n## Education and early assessment\n\nGive all nulliparous women information antenatally about:\n\nwhat to expect in the latent first stage of labour\n\nhow to work with any pain they experience\n\nhow to contact their midwifery care team and what to do in an emergency. \n\nOffer all nulliparous women antenatal education about the signs of labour, consisting of:\n\nhow to differentiate between Braxton Hicks contractions and active labour contractions\n\nthe expected frequency of contractions and how long they last\n\nrecognition of amniotic fluid ('waters breaking')\n\ndescription of normal vaginal loss. \n\nConsider an early assessment of labour by telephone triage provided by a dedicated triage midwife for all women. \n\nConsider a face‑to‑face early assessment of labour for all low‑risk nulliparous women, either:\n\nat home (regardless of planned place of birth) or\n\nin an assessment facility in her planned place of birth (midwifery‑led unit or obstetric unit), comprising one‑to‑one midwifery care for at least 1\xa0hour. \n\nInclude the following in any early or triage assessment of labour:\n\nask the woman how she is, and about her wishes, expectations and any concerns she has\n\nask the woman about the baby's movements, including any changes\n\ngive information about what the woman can expect in the latent first stage of labour and how to work with any pain she experiences\n\ngive information about what to expect when she accesses care\n\nagree a plan of care with the woman, including guidance about who she should contact next and when\n\nprovide guidance and support to the woman's birth companion(s). \n\nThe triage midwife should document the guidance that she gives to the woman. \n\nIf a woman seeks advice or attends a midwifery‑led unit or obstetric unit with painful contractions, but is not in established labour:\n\nrecognise that a woman may experience painful contractions without cervical change, and although she is described as not being in labour, she may well think of herself as being 'in labour' by her own definition\n\noffer her individualised support, and analgesia if needed\n\nencourage her to remain at or return home, unless doing so leads to a significant risk that she could give birth without a midwife present or become distressed. \n\n## Pain relief\n\nAdvise the woman and her birth companion(s) that breathing exercises, immersion in water and massage may reduce pain during the latent first stage of labour. (See also the recommendation on timing of regional analgesia.) \n\nDo not offer or advise aromatherapy, yoga or acupressure for pain relief during the latent first stage of labour. If a woman wants to use any of these techniques, respect her wishes. \n\n# Initial assessment\n\nWhen performing an initial assessment of a woman in labour, listen to her story and take into account her preferences and her emotional and psychological needs. \n\nCarry out an initial assessment to determine if midwifery‑led care in any setting is suitable for the woman, irrespective of any previous plan. The assessment should comprise the following:\n\nObservations of the woman:\n\n\n\nReview the antenatal notes (including all antenatal screening results) and discuss these with the woman.\n\nAsk her about the length, strength and frequency of her contractions.\n\nAsk her about any pain she is experiencing and discuss her options for pain relief.\n\nRecord her pulse, blood pressure and temperature, and carry out urinalysis.\n\nRecord if she has had any vaginal loss.\n\n\n\nObservations of the unborn baby:\n\n\n\nAsk the woman about the baby's movements in the last 24\xa0hours.\n\nPalpate the woman's abdomen to determine the fundal height, the baby's lie, presentation, position, engagement of the presenting part, and frequency and duration of contractions.\n\n\n\nAuscultate the fetal heart rate for a minimum of 1\xa0minute immediately after a contraction. Palpate the woman's pulse to differentiate between the heartbeats of the woman and the baby.In addition (see also recommendation 1.4.5):\n\nIf there is uncertainty about whether the woman is in established labour, a vaginal examination may be helpful after a period of assessment, but is not always necessary.\n\nIf the woman appears to be in established labour, offer a vaginal examination. \n\nTransfer the woman to obstetric‑led care, following the section on the general principles for transfer of care, if any of the following are observed on initial assessment:\n\nObservations of the woman:\n\n\n\npulse over 120\xa0beats/minute on 2\xa0occasions 30\xa0minutes apart\n\na single reading of either raised diastolic blood pressure of 110\xa0mmHg or more or raised systolic blood pressure of 160\xa0mmHg or more\n\neither raised diastolic blood pressure of 90\xa0mmHg or more or raised systolic blood pressure of 140\xa0mmHg or more on 2\xa0consecutive readings taken 30\xa0minutes apart\n\na reading of 2+\xa0of protein on urinalysis and a single reading of either raised diastolic blood pressure (90\xa0mmHg or more) or raised systolic blood pressure (140\xa0mmHg or more)\n\ntemperature of 38°C or above on a single reading, or 37.5°C or above on 2\xa0consecutive readings 1\xa0hour apart\n\nany vaginal blood loss other than a show\n\nrupture of membranes more than 24\xa0hours before the onset of established labour (see the section on babies born to women with prelabour rupture of the membranes at term)\n\nthe presence of significant meconium (see the section on presence of meconium)\n\npain reported by the woman that differs from the pain normally associated with contractions\n\nany risk factors recorded in the woman's notes that indicate the need for obstetric led care.\n\n\n\nObservations of the unborn baby:\n\n\n\nany abnormal presentation, including cord presentation\n\ntransverse or oblique lie\n\nhigh (4/5\xa0to\xa05/5\xa0palpable) or free‑floating head in a nulliparous woman\n\nsuspected fetal growth restriction or macrosomia\n\nsuspected anhydramnios or polyhydramnios\n\nfetal heart rate below 110\xa0or above 160\xa0beats/minute\n\na deceleration in fetal heart rate heard on intermittent auscultation\n\nreduced fetal movements in the last 24\xa0hours reported by the woman.If none of these are observed, continue with midwifery-led care unless the woman requests transfer (see also the section on measuring fetal heart rate as part of initial assessment). \n\n\n\nIf any of the factors in recommendation\xa01.4.3 are observed but birth is imminent, assess whether birth in the current location is preferable to transferring the woman to an obstetric unit and discuss this with the coordinating midwife. \n\nWhen conducting a vaginal examination:\n\nbe sure that the examination is necessary and will add important information to the decision‑making process\n\nrecognise that a vaginal examination can be very distressing for a woman, especially if she is already in pain, highly anxious and in an unfamiliar environment\n\nexplain the reason for the examination and what will be involved\n\nensure the woman's informed consent, privacy, dignity and comfort\n\nexplain sensitively the findings of the examination and any impact on the birth plan to the woman and her birth companion(s). \n\n## Measuring fetal heart rate as part of initial assessment\n\nOffer auscultation of the fetal heart rate at first contact with a woman in suspected or established labour, and at each further assessment:\n\nUse either a Pinard stethoscope or doppler ultrasound.\n\nCarry out auscultation immediately after a contraction for at least 1\xa0minute and record it as a single rate.\n\nRecord accelerations and decelerations if heard.\n\nPalpate the maternal pulse to differentiate between the maternal and fetal heartbeats. \n\nBe aware that for women at low risk of complications there is insufficient evidence about whether cardiotocography as part of the initial assessment either improves outcomes or results in harm for women and their babies, compared with intermittent auscultation alone. \n\nIf a woman at low risk of complications requests cardiotocography as part of the initial assessment:\n\ndiscuss the risks, benefits and limitations of cardiotocography with her, and support her in her choice\n\nexplain that, if she is in a setting where cardiotocography is not available, she will need to be transferred to obstetric-led care. \n\nOffer continuous cardiotocography if any of the risk factors listed in recommendation 1.4.3 in the section on initial assessment are identified on initial assessment, and explain to the woman why this is being offered. (See also the NICE guideline on fetal monitoring in labour for further guidance on fetal monitoring.) \n\nOffer cardiotocography if intermittent auscultation indicates possible fetal heart rate abnormalities, and explain to the woman why this is being offered. If the trace is normal (see the section on the use of cardiotocography for monitoring during labour in the NICE guideline on fetal monitoring in labour) after 20\xa0minutes, return to intermittent auscultation unless the woman asks to stay on continuous cardiotocography. \n\nIf fetal death is suspected despite the presence of an apparently recorded fetal heart rate, offer real-time ultrasound assessment to check fetal viability. \n\n# Ongoing assessment\n\nTransfer the woman to obstetric‑led care (following the general principles for transfer of care) if any of the following are observed at any point, unless the risks of transfer outweigh the benefits:\n\nObservations of the woman:\n\n\n\npulse over 120\xa0beats/minute on 2\xa0occasions 30\xa0minutes apart\n\na single reading of either raised diastolic blood pressure of 110\xa0mmHg or more or raised systolic blood pressure of 160\xa0mmHg or more\n\neither raised diastolic blood pressure of 90\xa0mmHg or more or raised systolic blood pressure of 140\xa0mmHg or more on 2\xa0consecutive readings taken 30\xa0minutes apart\n\na reading of 2+\xa0of protein on urinalysis and a single reading of either raised diastolic blood pressure (90\xa0mmHg or more) or raised systolic blood pressure (140\xa0mmHg or more)\n\ntemperature of 38°C or above on a single reading, or 37.5°C or above on 2\xa0consecutive occasions 1\xa0hour apart\n\nany vaginal blood loss other than a show\n\nthe presence of significant meconium (see the section on presence of meconium)\n\npain reported by the woman that differs from the pain normally associated with contractions\n\nconfirmed delay in the first or second stage of labour\n\nrequest by the woman for additional pain relief using regional analgesia\n\nobstetric emergency – including antepartum haemorrhage, cord prolapse, postpartum haemorrhage, maternal seizure or collapse, or a need for advanced neonatal resuscitation\n\nretained placenta\n\nthird‑degree or fourth‑degree tear or other complicated perineal trauma that needs suturing.\n\n\n\nObservations of the unborn baby:\n\n\n\nany abnormal presentation, including cord presentation\n\ntransverse or oblique lie\n\nhigh (4/5\xa0to\xa05/5\xa0palpable) or free‑floating head in a nulliparous woman\n\nsuspected fetal growth restriction or macrosomia\n\nsuspected anhydramnios or polyhydramnios\n\nfetal heart rate below 110\xa0or above 160\xa0beats/minute\n\na deceleration in fetal heart rate heard on intermittent auscultation.If none of these are observed, continue with midwifery-led care unless the woman requests transfer (see also recommendation 1.4.6 in the section on measuring fetal heart rate as part of initial assessment). \n\n\n\n## Presence of meconium\n\nAs part of ongoing assessment, document the presence or absence of significant meconium. This is defined as dark green or black amniotic fluid that is thick or tenacious, or any meconium‑stained amniotic fluid containing lumps of meconium. \n\nIf significant meconium is present, ensure that:\n\nhealthcare professionals trained in fetal blood sampling are available during labour and\n\nhealthcare professionals trained in advanced neonatal life support are readily available for the birth. \n\nIf significant meconium is present, transfer the woman to obstetric‑led care provided that it is safe to do so and the birth is unlikely to occur before transfer is completed. Follow the general principles for transfer of care described in section\xa01.6. \n\n# General principles for transfer of care\n\nTransfer of care refers to the transfer between midwifery‑led care and obstetric‑led care. This may or may not involve transport from one location to another. Women who are receiving midwifery‑led care in an obstetric unit can have their care transferred to obstetric‑led care without being moved.\n\nBase any decisions about transfer of care on clinical findings, and discuss the options with the woman and her birth companion(s). \n\nIf contemplating transfer of care:\n\ntalk with the woman and her birth companion(s) about the reasons for this and what they can expect, including the time needed for transfer\n\naddress any concerns she has and try to allay her anxiety\n\nensure that her wishes are respected and her informed consent is obtained. \n\nWhen arranging transfer of care, the midwife attending the labour should contact the ambulance service (if appropriate) and the coordinating midwife in the obstetric unit. The coordinating midwife should then alert the relevant healthcare professionals (obstetric, anaesthetic and neonatal). \n\nWhen arranging transfer from one location to another, ensure the following:\n\nBefore transfer, the woman is dressed, wrapped in a blanket or otherwise covered in a way that she feels is comfortable and appropriate.\n\nThe woman is made to feel as comfortable as possible before and during transfer.\n\nAny ambulance staff or other personnel involved are aware that some positions may make the woman uncomfortable or afraid and could affect her labour, so she should be encouraged to choose how to move and what position to adopt if possible, in accordance with ambulance service protocols.\n\nCommunication and companionship are maintained. Explain the arrangements for transfer to the woman and her birth companion(s). A midwife who has been involved in her care up to that point should travel with her and carry out a handover of care that involves the woman.\n\nArrangements are in place to enable the woman's birth companion(s) to travel with her in the ambulance if that is what she wants. If this is not possible or not wanted, check that the birth companion(s) have or can arrange their own transport. \n\nIf a woman is transferred to an obstetric unit after the birth (see the section on care of the woman after birth), ensure that her baby goes with her. \n\n# Care in established labour\n\n## Support in labour\n\nProvide a woman in established labour with supportive one‑to‑one care. \n\nDo not leave a woman in established labour on her own except for short periods or at the woman's request. \n\nFor guidance on ensuring continuity of care, see recommendation 1.4.1 in the NICE guideline on patient experience in adult NHS services. \n\n## Controlling gastric acidity\n\nDo not offer either H2‑receptor antagonists or antacids routinely to low‑risk women. \n\nEither H2‑receptor antagonists or antacids should be considered for women who receive opioids or who have or develop risk factors that make a general anaesthetic more likely. \n\nInform the woman that she may drink during established labour and that isotonic drinks may be more beneficial than water. \n\nInform the woman that she may eat a light diet in established labour unless she has received opioids or she develops risk factors that make a general anaesthetic more likely. \n\n# Pain relief in labour: non‑regional\n\n## Attitudes to pain and pain relief in childbirth\n\nHealthcare professionals should think about how their own values and beliefs inform their attitude to coping with pain in labour and ensure their care supports the woman's choice. \n\n## Pain‑relieving strategies\n\nIf a woman chooses to use breathing and relaxation techniques in labour, support her in this choice. \n\nIf a woman chooses to use massage techniques in labour that have been taught to birth companions, support her in this choice. \n\nOffer the woman the opportunity to labour in water for pain relief. \n\nFor women labouring in water, monitor the temperature of the woman and the water hourly to ensure that the woman is comfortable and not becoming pyrexial. The temperature of the water should not be above 37.5°C. \n\nKeep baths and birthing pools clean using a protocol agreed with the microbiology department and, in the case of birthing pools, in accordance with the manufacturer's guidelines. \n\nDo not use injected water papules. \n\nDo not offer acupuncture, acupressure or hypnosis, but do not prevent women who wish to use these techniques from doing so. \n\nSupport the playing of music of the woman's choice in labour. \n\n## Non‑pharmacological analgesia\n\nDo not offer transcutaneous electrical nerve stimulation (TENS) to women in established labour. \n\n## Inhalational analgesia\n\nEnsure that Entonox (a 50:50 mixture of oxygen and nitrous oxide) is available in all birth settings as it may reduce pain in labour, but inform the woman that it may make her feel nauseous and light‑headed. \n\n## Intravenous and intramuscular opioids\n\nEnsure that pethidine, diamorphine or other opioids are available in all birth settings. Inform the woman that these will provide limited pain relief during labour and may have significant side effects for both her (drowsiness, nausea and vomiting) and her baby (short‑term respiratory depression and drowsiness which may last several days). \n\nInform the woman that pethidine, diamorphine or other opioids may interfere with breastfeeding. \n\nIf an intravenous or intramuscular opioid is used, also administer an antiemetic. \n\nWomen should not enter water (a birthing pool or bath) within 2\xa0hours of opioid administration or if they feel drowsy. \n\n# Pain relief in labour: regional analgesia\n\n## Information about regional analgesia\n\nIf a woman is contemplating regional analgesia, talk with her about the risks and benefits and the implications for her labour, including the arrangements and time involved for transfer of care to an obstetric unit if she is at home or in a midwifery unit (follow the general principles for transfer of care). [2007, amended 2014]\n\nProvide information about epidural analgesia, including the following:\n\nIt is available only in obstetric units.\n\nIt provides more effective pain relief than opioids.\n\nIt is not associated with long‑term backache.\n\nIt is not associated with a longer first stage of labour or an increased chance of a caesarean birth.\n\nIt is associated with a longer second stage of labour and an increased chance of vaginal instrumental birth.\n\nIt will be accompanied by a more intensive level of monitoring and intravenous access, and so mobility may be reduced. [2007, amended 2014]\n\n## Timing of regional analgesia\n\nIf a woman in labour asks for regional analgesia, comply with her request. This includes women in severe pain in the latent first stage of labour. \n\n## Care and observations for women with regional analgesia\n\nAlways secure intravenous access before starting regional analgesia. \n\nPreloading and maintenance fluid infusion need not be administered routinely before establishing low‑dose epidural analgesia and combined spinal–epidural analgesia. \n\nUndertake the following additional observations for women with regional analgesia:\n\nDuring establishment of regional analgesia or after further boluses (10\xa0ml or more of low‑dose solutions), measure blood pressure every 5\xa0minutes for 15\xa0minutes.\n\nIf the woman is not pain‑free 30\xa0minutes after each administration of local anaesthetic/opioid solution, recall the anaesthetist.\n\nAssess the level of the sensory block hourly. \n\nEncourage women with regional analgesia to move and adopt whatever upright positions they find comfortable throughout labour. \n\nOnce established, continue regional analgesia until after completion of the third stage of labour and any necessary perineal repair. \n\nUpon confirmation of full cervical dilatation in a woman with regional analgesia, unless the woman has an urge to push or the baby's head is visible, pushing should be delayed for at least 1\xa0hour and longer if the woman wishes, after which actively encourage her to push during contractions. \n\nAfter diagnosis of full dilatation in a woman with regional analgesia, agree a plan with the woman in order to ensure that birth will have occurred within 4\xa0hours regardless of parity. \n\nDo not routinely use oxytocin in the second stage of labour for women with regional analgesia. \n\nPerform continuous cardiotocography for at least 30\xa0minutes during establishment of regional analgesia and after administration of each further bolus of 10\xa0ml or more. [2007, amended 2014]\n\n## Establishing and maintaining regional analgesia\n\nUse either epidural or combined spinal–epidural analgesia for establishing regional analgesia in labour. \n\nIf rapid analgesia is required, use combined spinal–epidural analgesia. \n\nEstablish combined spinal–epidural analgesia with bupivacaine and fentanyl. \n\nEstablish epidural analgesia with a low‑concentration local anaesthetic and opioid solution with, for example, 10\xa0to\xa015\xa0ml of 0.0625\xa0to\xa00.1% bupivacaine with 1\xa0to\xa02\xa0micrograms per\xa0ml fentanyl. The initial dose of local anaesthetic plus opioid is essentially a test dose, so administer cautiously to ensure that inadvertent intrathecal injection has not occurred. \n\nUse low‑concentration local anaesthetic and opioid solutions (0.0625\xa0to\xa00.1% bupivacaine or equivalent combined with 2.0\xa0micrograms per ml fentanyl) for maintaining epidural analgesia in labour. \n\nDo not use high concentrations of local anaesthetic solutions (0.25% or above of bupivacaine or equivalent) routinely for either establishing or maintaining epidural analgesia. \n\nEither patient‑controlled epidural analgesia or intermittent bolus given by healthcare professionals are the preferred modes of administration for maintenance of epidural analgesia. \n\n# Monitoring during labour\n\nThe recommendations in this section have been withdrawn. For advice on monitoring during labour, see the NICE guideline on fetal monitoring in labour.\n\n# Prelabour rupture of membranes at term\n\nDo not carry out a speculum examination if it is certain that the membranes have ruptured. \n\nIf it is uncertain whether prelabour rupture of the membranes has occurred, offer the woman a speculum examination to determine whether the membranes have ruptured. Avoid digital vaginal examination in the absence of contractions. \n\nAdvise women presenting with prelabour rupture of the membranes at term that:\n\nthe risk of serious neonatal infection is 1%, rather than 0.5% for women with intact membranes\n\n% of women with prelabour rupture of the membranes will go into labour within 24\xa0hours\n\ninduction of labour (see NICE's guideline on inducing labour) is appropriate approximately 24\xa0hours after rupture of the membranes. \n\nUntil the induction is started or if expectant management beyond 24\xa0hours is chosen by the woman:\n\ndo not offer lower vaginal swabs and measurement of maternal C‑reactive protein\n\nto detect any infection that may be developing, advise the woman to record her temperature every 4\xa0hours during waking hours and to report immediately any change in the colour or smell of her vaginal loss\n\ninform the woman that bathing or showering is not associated with an increase in infection, but that having sexual intercourse may be. \n\nAssess fetal movement and heart rate at initial contact and then every 24\xa0hours after rupture of the membranes while the woman is not in labour, and advise the woman to report immediately any decrease in fetal movements. \n\nIf labour has not started 24\xa0hours after rupture of the membranes, advise the woman to give birth where there is access to neonatal services and to stay in hospital for at least 12\xa0hours after the birth. \n\n# First stage of labour\n\nSee the recommendation on definitions of the latent and established first stages of labour.\n\nDo not offer or advise clinical intervention if labour is progressing normally and the woman and baby are well. \n\nIn all stages of labour, women who have left the normal care pathway because of the development of complications can return to it if/when the complication is resolved. \n\n## Duration of the first stage\n\nInform women that, while the length of established first stage of labour varies between women:\n\nfirst labours last on average 8\xa0hours and are unlikely to last over 18\xa0hours\n\nsecond and subsequent labours last on average 5\xa0hours and are unlikely to last over 12\xa0hours. \n\n## Observations during the established first stage\n\nDo not routinely use verbal assessment using a numerical pain score. \n\nUse a pictorial record of labour (partogram) once labour is established. \n\nWhere the partogram includes an action line, use the World Health Organization (WHO) recommendation of a 4‑hour action line (the WHO partograph in management of labour, published in 1994 as part of the Maternal Health and Safe Motherhood Programme. Lancet 343: 1399\xa0to\xa0404). See also the\xa0WHO Multicountry Survey on Maternal and Newborn Health.\n\nRecord the following observations during the first stage of labour:\n\nhalf‑hourly documentation of frequency of contractions\n\nhourly pulse\n\n‑hourly temperature and blood pressure\n\nfrequency of passing urine\n\noffer a vaginal examination (see recommendation 1.4.5 in the section on initial assessment) 4‑hourly or if there is concern about progress or in response to the woman's wishes (after abdominal palpation and assessment of vaginal loss). If any of the indications for transfer are met (see the recommendation on ongoing assessment), transfer the woman to obstetric‑led care. Follow the general principles for transfer of care. \n\nGive ongoing consideration to the woman's emotional and psychological needs, including her desire for pain relief. \n\nEncourage the woman to communicate her need for analgesia at any point during labour. \n\n## Possible routine interventions in the first stage\n\nDo not routinely offer the package known as active management of labour (one‑to‑one continuous support; strict definition of established labour; early routine amniotomy; routine 2‑hourly vaginal examination; oxytocin if labour becomes slow). \n\nIn normally progressing labour, do not perform amniotomy routinely. \n\nDo not use combined early amniotomy with use of oxytocin routinely. \n\n## Delay in the first stage\n\nIf delay in the established first stage is suspected, take the following into account:\n\nparity\n\ncervical dilatation and rate of change\n\nuterine contractions\n\nstation and position of presenting part\n\nthe woman's emotional state\n\nreferral to the appropriate healthcare professional.Offer the woman support, hydration, and appropriate and effective pain relief. \n\nIf delay in the established first stage is suspected, assess all aspects of progress in labour when diagnosing delay, including:\n\ncervical dilatation of less than 2\xa0cm in 4\xa0hours for first labours\n\ncervical dilatation of less than 2\xa0cm in 4\xa0hours or a slowing in the progress of labour for second or subsequent labours\n\ndescent and rotation of the baby's head\n\nchanges in the strength, duration and frequency of uterine contractions. If delay is diagnosed, transfer the woman to obstetric‑led care. Follow the general principles for transfer of care. \n\nIf delay in the established first stage of labour is suspected, amniotomy should be considered for all women with intact membranes, after explanation of the procedure and advice that it will shorten her labour by about an hour and may increase the strength and pain of her contractions. \n\nWhether or not a woman has agreed to an amniotomy, advise all women with suspected delay in the established first stage of labour to have a vaginal examination 2\xa0hours later, and diagnose delay if progress is less than 1\xa0cm. \n\nFor women with intact membranes in whom delay in the established first stage of labour is confirmed, advise the woman to have an amniotomy, and to have a repeat vaginal examination 2\xa0hours later whether her membranes are ruptured or intact. \n\nFor all women with confirmed delay in the established first stage of labour:\n\ntransfer the woman to obstetric‑led care for an obstetric review and a decision about management options, including the use of oxytocin (follow the general principles for transfer of care) \n\nexplain to her that using oxytocin after spontaneous or artificial rupture of the membranes will bring forward the time of birth but will not influence the mode of birth or other outcomes. \n\nFor a multiparous woman with confirmed delay in the established first stage of labour, an obstetrician should perform a full assessment, including abdominal palpation and vaginal examination, before a decision is made about using oxytocin. \n\nOffer all women with delay in the established first stage of labour support and effective pain relief. \n\nInform the woman that oxytocin will increase the frequency and strength of her contractions and that its use will mean that her baby should be monitored continuously. Offer the woman an epidural before oxytocin is started. \n\nIf oxytocin is used, ensure that the time between increments of the dose is no more frequent than every 30\xa0minutes. Increase oxytocin until there are 4\xa0to\xa05\xa0contractions in 10\xa0minutes. (See also recommendation 1.12.14 and recommendation 1.3.8 in the NICE guideline on fetal monitoring in labour.) \n\nAdvise the woman to have a vaginal examination 4\xa0hours after starting oxytocin in established labour:\n\nIf cervical dilatation has increased by less than 2\xa0cm after 4\xa0hours of oxytocin, further obstetric review is required to assess the need for caesarean section.\n\nIf cervical dilatation has increased by 2\xa0cm or more, advise 4‑hourly vaginal examinations. \n\n# Second stage of labour\n\n## Definition of the second stage\n\nFor the purposes of this guideline, use the following definitions of labour:\n\nPassive second stage of labour:\n\n\n\nthe finding of full dilatation of the cervix before or in the absence of involuntary expulsive contractions.\n\n\n\nOnset of the active second stage of labour:\n\n\n\nthe baby is visible\n\nexpulsive contractions with a finding of full dilatation of the cervix or other signs of full dilatation of the cervix\n\nactive maternal effort following confirmation of full dilatation of the cervix in the absence of expulsive contractions. \n\n\n\n## Observations during the second stage\n\nCarry out the following observations in the second stage of labour, record all observations on the partogram and assess whether transfer of care may be needed (see the recommendation on ongoing assessment). [2007, amended 2014]:\n\nhalf‑hourly documentation of the frequency of contractions \n\nhourly blood pressure \n\ncontinued 4‑hourly temperature \n\nfrequency of passing urine \n\noffer a vaginal examination (see recommendation 1.4.5 in the section on initial assessment) hourly in the active second stage, or in response to the woman's wishes (after abdominal palpation and assessment of vaginal loss). In addition:\n\nContinue to take the woman's emotional and psychological needs into account. \n\nAssess progress, which should include the woman's behaviour, the effectiveness of pushing and the baby's wellbeing, taking into account the baby's position and station at the onset of the second stage. These factors will assist in deciding the timing of further vaginal examination and any need for transfer to obstetric led care. [2007, amended 2014]\n\nPerform intermittent auscultation of the fetal heart rate immediately after a contraction for at least 1\xa0minute, at least every 5\xa0minutes. Palpate the woman's pulse every 15\xa0minutes to differentiate between the two heartbeats. [2007, amended 2014]\n\nOngoing consideration should be given to the woman's position, hydration, coping strategies and pain relief throughout the second stage. \n\n## Duration of the second stage and definition of delay\n\nFor a nulliparous woman:\n\nbirth would be expected to take place within 3\xa0hours of the start of the active second stage in most women\n\ndiagnose delay in the active second stage when it has lasted 2\xa0hours and refer the woman to a healthcare professional trained to undertake an operative vaginal birth if birth is not imminent. \n\nFor a multiparous woman:\n\nbirth would be expected to take place within 2\xa0hours of the start of the active second stage in most women\n\ndiagnose delay in the active second stage when it has lasted 1\xa0hour and refer the woman to a healthcare professional trained to undertake an operative vaginal birth if birth is not imminent. \n\nFor a nulliparous woman, suspect delay if progress (in terms of rotation and/or descent of the presenting part) is inadequate after 1\xa0hour of active second stage. Offer vaginal examination and then offer amniotomy if the membranes are intact. [2007, amended 2014]\n\nFor a multiparous woman, suspect delay if progress (in terms of rotation and/or descent of the presenting part) is inadequate after 30\xa0minutes of active second stage. Offer vaginal examination and then offer amniotomy if the membranes are intact. \n\nIf full dilatation of the cervix has been confirmed in a woman without regional analgesia, but she does not get an urge to push, carry out further assessment after 1\xa0hour. \n\n## Oxytocin in the second stage\n\nConsideration should be given to the use of oxytocin, with the offer of regional analgesia, for nulliparous women if contractions are inadequate at the onset of the second stage. \n\n## The woman's position and pushing in the second stage\n\nDiscourage the woman from lying supine or semi‑supine in the second stage of labour and encourage her to adopt any other position that she finds most comfortable. \n\nInform the woman that in the second stage she should be guided by her own urge to push. \n\nIf pushing is ineffective or if requested by the woman, offer strategies to assist birth, such as support, change of position, emptying of the bladder and encouragement. \n\n## Intrapartum interventions to reduce perineal trauma\n\nDo not perform perineal massage in the second stage of labour. \n\nEither the 'hands on' (guarding the perineum and flexing the baby's head) or the 'hands poised' (with hands off the perineum and baby's head but in readiness) technique can be used to facilitate spontaneous birth. \n\nDo not offer lidocaine spray to reduce pain in the second stage of labour. \n\nDo not carry out a routine episiotomy during spontaneous vaginal birth. \n\nInform any woman with a history of severe perineal trauma that her risk of repeat severe perineal trauma is not increased in a subsequent birth, compared with women having their first baby. \n\nDo not offer episiotomy routinely at vaginal birth after previous third‑ or fourth‑degree trauma. \n\nIn order for a woman who has had previous third- or fourth‑degree trauma to make an informed choice, talk with her about the future mode of birth, encompassing:\n\ncurrent urgency or incontinence symptoms\n\nthe degree of previous trauma\n\nrisk of recurrence\n\nthe success of the repair undertaken\n\nthe psychological effect of the previous trauma\n\nmanagement of her labour. \n\nInform any woman with infibulated genital mutilation of the risks of difficulty with vaginal examination, catheterisation and application of fetal scalp electrodes. Inform her of the risks of delay in the second stage and spontaneous laceration together with the need for an anterior episiotomy and the possible need for defibulation in labour. \n\nIf an episiotomy is performed, the recommended technique is a mediolateral episiotomy originating at the vaginal fourchette and usually directed to the right side. The angle to the vertical axis should be between 45\xa0and 60\xa0degrees at the time of the episiotomy. \n\nPerform an episiotomy if there is a clinical need, such as instrumental birth or suspected fetal compromise. \n\nProvide tested effective analgesia before carrying out an episiotomy, except in an emergency because of acute fetal compromise. \n\n## Water birth\n\nInform women that there is insufficient high‑quality evidence to either support or discourage giving birth in water. \n\n## Delay in the second stage\n\nIf there is delay in the second stage of labour, or if the woman is excessively distressed, support and sensitive encouragement and the woman's need for analgesia/anaesthesia are particularly important. \n\nAn obstetrician should assess a woman with confirmed delay in the second stage (after transfer to obstetric‑led care, following the general principles for transfer of care) before contemplating the use of oxytocin. \n\nAfter initial obstetric assessment of a woman with delay in the second stage, maintain ongoing obstetric review every 15\xa0to\xa030\xa0minutes. \n\n## Instrumental birth and delayed second stage\n\nThink about offering instrumental birth if there is concern about the baby's wellbeing or there is a prolonged second stage. \n\nRecognise that, on rare occasions, the woman's need for help in the second stage may be an indication to assist by offering instrumental birth when supportive care has not helped. \n\nThe choice of instrument depends on a balance of clinical circumstance and practitioner experience. \n\nBecause instrumental birth is an operative procedure, advise the woman to have tested effective anaesthesia. \n\nIf a woman declines anaesthesia, offer a pudendal block combined with local anaesthetic to the perineum during instrumental birth. \n\nIf there is concern about fetal compromise, offer either tested effective anaesthesia or, if time does not allow this, a pudendal block combined with local anaesthetic to the perineum during instrumental birth. \n\nAdvise the woman to have a caesarean section if vaginal birth is not possible (see the NICE guideline on caesarean birth). .\n\n## Expediting birth\n\nIf the birth needs to be expedited for maternal or fetal reasons, assess both the risk to the baby and the safety of the woman. Assessments should include:\n\nthe degree of urgency\n\nclinical findings on abdominal and vaginal examination\n\nchoice of mode of birth (and whether to use forceps or ventouse if an instrumental birth is indicated)\n\nanticipated degree of difficulty, including the likelihood of success if instrumental birth is attempted\n\nlocation\n\nany time that may be needed for transfer to obstetric‑led care\n\nthe need for additional analgesia or anaesthesia\n\nthe woman's preferences. \n\nTalk with the woman and her birth companion(s) about why the birth needs to be expedited and what the options are. \n\nInform the team about the degree of urgency. \n\nRecord the time at which the decision to expedite the birth is made. \n\n# Third stage of labour\n\nRecognise that the time immediately after the birth is when the woman and her birth companion(s) are meeting and getting to know the baby. Ensure that any care or interventions are sensitive to this and minimise separation or disruption of the mother and baby. \n\n## Definition of the third stage\n\nFor the purposes of this guideline, use the following definitions:\n\nThe third stage of labour is the time from the birth of the baby to the expulsion of the placenta and membranes.\n\nActive management of the third stage involves a package of care comprising the following components:\n\n\n\nroutine use of uterotonic drugs\n\ndeferred clamping and cutting of the cord\n\ncontrolled cord traction after signs of separation of the placenta.\n\n\n\nPhysiological management of the third stage involves a package of care that includes the following components:\n\n\n\nno routine use of uterotonic drugs\n\nno clamping of the cord until pulsation has stopped\n\ndelivery of the placenta by maternal effort. \n\n\n\n## Prolonged third stage\n\nDiagnose a prolonged third stage of labour if it is not completed within 30\xa0minutes of the birth with active management or within 60\xa0minutes of the birth with physiological management. Follow the recommendations on managing retained placenta. \n\n## Observations in the third stage\n\nRecord the following observations for a woman in the third stage of labour:\n\nher general physical condition, as shown by her colour, respiration and her own report of how she feels\n\nvaginal blood loss. \n\nIf there is postpartum haemorrhage, a retained placenta or maternal collapse, or any other concerns about the woman's wellbeing:\n\ntransfer her to obstetric‑led care (following the general principles for transfer of care)\n\ncarry out frequent observations to assess whether resuscitation is needed. \n\n## Active and physiological management of the third stage\n\nExplain to the woman antenatally about what to expect with each package of care for managing the third stage of labour and the benefits and risks associated with each. \n\nExplain to the woman that active management:\n\nshortens the third stage compared with physiological management\n\nis associated with nausea and vomiting in about\xa0100 in 1,000\xa0women\n\nis associated with an approximate risk of 13\xa0in 1,000\xa0of a haemorrhage of more than 1\xa0litre\n\nis associated with an approximate risk of\xa014\xa0in 1,000\xa0of a blood transfusion. \n\nExplain to the woman that physiological management:\n\nis associated with nausea and vomiting in about 50\xa0in 1,000\xa0women\n\nis associated with an approximate risk of 29\xa0in 1,000\xa0of a haemorrhage of more than 1\xa0litre\n\nis associated with an approximate risk of 40\xa0in 1,000\xa0of a blood transfusion. \n\nDiscuss again with the woman at the initial assessment in labour (see the section on initial assessment) about the different options for managing the third stage and ways of supporting her during delivery of the placenta, and ask if she has any preferences. \n\nAdvise the woman to have active management of the third stage, because it is associated with a lower risk of a postpartum haemorrhage and/or blood transfusion. \n\nIf a woman at low risk of postpartum haemorrhage requests physiological management of the third stage, support her in her choice. \n\nDocument in the records the decision that is agreed with the woman about management of the third stage. \n\nFor active management, administer 10\xa0IU of oxytocin by intramuscular injection with the birth of the anterior shoulder or immediately after the birth of the baby and before the cord is clamped and cut. Use oxytocin as it is associated with fewer side effects than oxytocin plus ergometrine. \n\nAfter administering oxytocin, clamp and cut the cord.\n\nDo not clamp the cord earlier than 1\xa0minute from the birth of the baby unless there is concern about the integrity of the cord or the baby has a heart rate below 60\xa0beats/minute that is not getting faster.\n\nClamp the cord before 5\xa0minutes in order to perform controlled cord traction as part of active management.\n\nIf the woman requests that the cord is clamped and cut later than 5\xa0minutes, support her in her choice. \n\nAfter cutting the cord, use controlled cord traction. \n\nPerform controlled cord traction as part of active management only after administration of oxytocin and signs of separation of the placenta. \n\nRecord the timing of cord clamping in both active and physiological management. \n\nAdvise a change from physiological management to active management if either of the following occur:\n\nhaemorrhage\n\nthe placenta is not delivered within 1\xa0hour of the birth of the baby. \n\nOffer a change from physiological management to active management if the woman wants to shorten the third stage. \n\nDo not use either umbilical oxytocin infusion or prostaglandin routinely in the third stage of labour. \n\n## Retained placenta\n\nSecure intravenous access if the placenta is retained, and explain to the woman why this is needed. \n\nDo not use umbilical vein agents if the placenta is retained. \n\nDo not use intravenous oxytocic agents routinely to deliver a retained placenta. \n\nGive intravenous oxytocic agents if the placenta is retained and the woman is bleeding excessively. \n\nIf the placenta is retained and there is concern about the woman's condition:\n\noffer a vaginal examination to assess the need to undertake manual removal of the placenta\n\nexplain that this assessment can be painful and advise her to have analgesia. \n\nIf the woman reports inadequate analgesia during the assessment, stop the examination and address this immediately. \n\nIf uterine exploration is necessary and the woman is not already in an obstetric unit, arrange urgent transfer (following the general principles for transfer of care). \n\nDo not carry out uterine exploration or manual removal of the placenta without an anaesthetic. \n\n## Postpartum haemorrhage\n\nAdvise women with risk factors for postpartum haemorrhage to give birth in an obstetric unit, where more emergency treatment options are available.\n\nAntenatal risk factors:\n\n\n\nprevious retained placenta or postpartum haemorrhage\n\nmaternal haemoglobin level below 85\xa0g/litre at onset of labour\n\nBMI greater than 35\xa0kg/m2\n\ngrand multiparity (parity\xa04 or more)\n\nantepartum haemorrhage\n\noverdistention of the uterus (for example, multiple pregnancy, polyhydramnios or macrosomia)\n\nexisting uterine abnormalities\n\nlow‑lying placenta\n\nmaternal age of 35\xa0years or older.\n\n\n\nRisk factors in labour:\n\n\n\ninduction\n\nprolonged first, second or third stage of labour\n\noxytocin use\n\nprecipitate labour\n\noperative birth or caesarean section. \n\n\n\nIf a woman has risk factors for postpartum haemorrhage, highlight these in her notes, and make and discuss with her a care plan covering the third stage of labour. \n\nIf a woman has a postpartum haemorrhage:\n\ncall for help\n\ngive immediate clinical treatment:\n\n\n\nemptying of the bladder and\n\nuterine massage and\n\nuterotonic drugs and\n\nintravenous fluids and\n\ncontrolled cord traction if the placenta has not yet been delivered\n\n\n\ncontinuously assess blood loss and the woman's condition, and identify the source of the bleeding\n\ngive supplementary oxygen\n\narrange for transfer of the woman to obstetric‑led care (following the general principles for transfer of care). \n\nAdminister a bolus of one of the following as first‑line treatment for postpartum haemorrhage:\n\noxytocin (10\xa0IU intravenous) or\n\nergometrine (0.5\xa0mg intramuscular) or\n\ncombined oxytocin and ergometrine (5\xa0IU/0.5\xa0mg intramuscular). \n\nOffer second‑line treatment for postpartum haemorrhage if needed. No particular uterotonic drug can be recommended over any other; options include:\n\nrepeat bolus of:\n\n\n\noxytocin (intravenous)\n\nergometrine (intramuscular, or cautiously intravenously)\n\ncombined oxytocin and ergometrine (intramuscular)\n\n\n\nmisoprostol\n\noxytocin infusion\n\ncarboprost (intramuscular). \n\nAssess the need for adjuvant options for managing significant continuing postpartum haemorrhage, including:\n\ntranexamic acid (intravenous)\n\nrarely, in the presence of otherwise normal clotting factors, rFactor VIIa, in consultation with a haematologist. \n\nAllocate a member of the healthcare team to stay with the woman and her birth companion(s), explain what is happening, answer any questions and offer support throughout the emergency situation. \n\nIf the haemorrhage continues:\n\nperform examination under anaesthetic\n\nensure that the uterus is empty and repair any trauma\n\nconsider balloon tamponade before surgical options. \n\nBe aware that no particular surgical procedure can be recommended over any other for treating postpartum haemorrhage. \n\nThe maternity service and ambulance service should have strategies in place in order to respond quickly and appropriately if a woman has a postpartum haemorrhage in any setting. \n\n# Care of the newborn baby\n\n## Initial assessment of the newborn baby and mother–baby bonding\n\nRecommendations 1.15.6, 1.15.8 and 1.15.9 have been adapted from NICE's guideline on postnatal care; refer to this guideline for more information on immediate postnatal care (within 2\xa0hours of birth).\n\nRecord the Apgar score routinely at 1\xa0and 5\xa0minutes for all births. \n\nRecord the time from birth to the onset of regular respirations. \n\nIf the baby is born in poor condition (on the basis of abnormal breathing, heart rate or tone):\n\nfollow the recommendations in the section on neonatal resuscitation\xa0and\n\ntake paired cord‑blood samples for blood gas analysis, after clamping the cord using 2\xa0clamps.Continue to evaluate and record the baby's condition until it is improved and stable. \n\nDo not take paired cord blood samples (for blood gas analysis) routinely. \n\nEnsure that a second clamp to allow double‑clamping of the cord is available in all birth settings. \n\nEncourage women to have skin‑to‑skin contact with their babies as soon as possible after the birth. \n\nIn order to keep the baby warm, dry and cover him or her with a warm, dry blanket or towel while maintaining skin‑to‑skin contact with the woman. \n\nAvoid separation of a woman and her baby within the first hour of the birth for routine postnatal procedures, for example, weighing, measuring and bathing, unless these measures are requested by the woman, or are necessary for the immediate care of the baby. \n\nEncourage initiation of breastfeeding as soon as possible after the birth, ideally within 1\xa0hour. \n\nRecord head circumference, body temperature and birth weight soon after the first hour following birth. \n\nUndertake an initial examination to detect any major physical abnormality and to identify any problems that require referral. \n\nEnsure that any examination or treatment of the baby is undertaken with the consent of the parents and either in their presence or, if this is not possible, with their knowledge. \n\n## Neonatal resuscitation\n\nIn the first minutes after birth, evaluate the condition of the baby – specifically respiration, heart rate and tone – in order to determine whether resuscitation is needed according to nationally accredited guidelines on neonatal resuscitation. \n\nAll relevant healthcare professionals caring for women during birth should attend annually a course in neonatal resuscitation that is consistent with nationally accredited guidelines on neonatal resuscitation. \n\nIn all birth settings:\n\nbear in mind that it will be necessary to call for help if the baby needs resuscitation, and plan accordingly\n\nensure that there are facilities for resuscitation, and for transferring the baby to another location if necessary\n\ndevelop emergency referral pathways for both the woman and the baby, and implement these if necessary. \n\nIf a newborn baby needs basic resuscitation, start with air. \n\nMinimise separation of the baby and mother, taking into account the clinical circumstances. \n\nThroughout an emergency situation in which the baby needs resuscitation, allocate a member of the healthcare team to talk with, and offer support to, the woman and any birth companion(s). \n\n## Care of babies in the presence of meconium\n\nIn the presence of any degree of meconium:\n\ndo not suction the baby's upper airways (nasopharynx and oropharynx) before birth of the shoulders and trunk\n\ndo not suction the baby's upper airways (nasopharynx and oropharynx) if the baby has normal respiration, heart rate and tone\n\ndo not intubate if the baby has normal respiration, heart rate and tone. \n\nIf there has been significant meconium (see recommendation 1.5.2 in the section on presence of meconium) and the baby does not have normal respiration, heart rate and tone, follow nationally accredited guidelines on neonatal resuscitation, including early laryngoscopy and suction under direct vision. \n\nIf there has been significant meconium and the baby is healthy, closely observe the baby within a unit with immediate access to a neonatologist. Perform these observations at 1\xa0and 2\xa0hours of age and then 2‑hourly until 12\xa0hours of age. \n\nIf there has been non‑significant meconium, observe the baby at 1\xa0and 2\xa0hours of age in all birth settings. \n\nIf any of the following are observed after any degree of meconium, ask a neonatologist to assess the baby (transfer both the woman and baby if they are at home or in a freestanding midwifery unit, following the general principles for transfer of care):\n\nrespiratory rate above 60\xa0per minute\n\nthe presence of grunting\n\nheart rate below 100\xa0or above 160\xa0beats/minute\n\ncapillary refill time above 3\xa0seconds\n\nbody temperature of 38°C or above, or 37.5°C on 2\xa0occasions 30\xa0minutes apart\n\noxygen saturation below 95% (measuring oxygen saturation is optional after non‑significant meconium)\n\npresence of central cyanosis, confirmed by pulse oximetry if available. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nExplain the findings to the woman, and inform her about what to look out for and who to talk to if she has any concerns. \n\n## Babies born to women with prelabour rupture of the membranes at term\n\nClosely observe any baby born to a woman with prelabour rupture of the membranes (more than 24\xa0hours before the onset of established labour) at term for the first 12\xa0hours of life (at 1\xa0hour, 2\xa0hours, 6\xa0hours and 12\xa0hours) in all settings. Include assessment of:\n\ntemperature\n\nheart rate\n\nrespiratory rate\n\npresence of respiratory grunting\n\nsignificant subcostal recession\n\npresence of nasal flare\n\npresence of central cyanosis, confirmed by pulse oximetry if available\n\nskin perfusion assessed by capillary refill\n\nfloppiness, general wellbeing and feeding.If any of these are observed, ask a neonatologist to assess the baby (transfer both the woman and baby if they are at home or in a freestanding midwifery unit, following the general principles for transfer of care). Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nIf there are no signs of infection in the woman, do not give antibiotics to either the woman or the baby, even if the membranes have been ruptured for over 24\xa0hours. \n\nIf there is evidence of infection in the woman, prescribe a full course of broad‑spectrum intravenous antibiotics. \n\nAdvise women with prelabour rupture of the membranes to inform their healthcare professionals immediately of any concerns they have about their baby's wellbeing in the first 5\xa0days after birth, particularly in the first 12\xa0hours when the risk of infection is greatest. \n\nDo not perform blood, cerebrospinal fluid and/or surface culture tests in an asymptomatic baby. \n\nRefer a baby with any symptom of possible sepsis, or born to a woman who has evidence of chorioamnionitis, to a neonatal care specialist immediately. \n\n# Care of the woman after birth\n\n## Initial assessment\n\nCarry out the following observations of the woman after birth:\n\nRecord her temperature, pulse and blood pressure. Transfer the woman (with her baby) to obstetric‑led care if any of the relevant indications listed in the recommendation on ongoing assessment are met.\n\nUterine contraction and lochia.\n\nExamine the placenta and membranes: assess their condition, structure, cord vessels and completeness. Transfer the woman (with her baby) to obstetric‑led care if the placenta is incomplete.\n\nEarly assessment of the woman's emotional and psychological condition in response to labour and birth.\n\nSuccessful voiding of the bladder. Assess whether to transfer the woman (with her baby) to obstetric‑led care after 6\xa0hours if her bladder is palpable and she is unable to pass urine.If transferring the woman to obstetric‑led care, follow the general principles for transfer of care. \n\n## Perineal care\n\nDefine perineal or genital trauma caused by either tearing or episiotomy as follows:\n\nfirst degree – injury to skin only\n\nsecond degree – injury to the perineal muscles but not the anal sphincter\n\nthird degree – injury to the perineum involving the anal sphincter complex:\n\n\n\na – less than 50% of external anal sphincter thickness torn\n\nb – more than 50% of external anal sphincter thickness torn\n\nc – internal anal sphincter torn.\n\n\n\nfourth degree – injury to the perineum involving the anal sphincter complex (external and internal anal sphincter) and anal epithelium. \n\nBefore assessing for genital trauma:\n\nexplain to the woman what is planned and why\n\noffer inhalational analgesia\n\nensure good lighting\n\nposition the woman so that she is comfortable and so that the genital structures can be seen clearly. \n\nPerform the initial examination gently and with sensitivity. It may be done in the immediate period after birth. \n\nIf genital trauma is identified after birth, offer further systematic assessment, including a rectal examination. \n\nInclude the following in a systematic assessment of genital trauma:\n\nfurther explanation of what is planned and why\n\nconfirmation by the woman that tested effective local or regional analgesia is in place\n\nvisual assessment of the extent of perineal trauma to include the structures involved, the apex of the injury and assessment of bleeding\n\na rectal examination to assess whether there has been any damage to the external or internal anal sphincter if there is any suspicion that the perineal muscles are damaged. \n\nEnsure that the timing of this systematic assessment does not interfere with mother–baby bonding unless the woman has bleeding that requires urgent attention. \n\nAssist the woman to adopt a position that allows adequate visual assessment of the degree of trauma and for repair. Only maintain this position for as long as necessary for systematic assessment and repair. If it is not possible to adequately assess the trauma, transfer the woman (with her baby) to obstetric‑led care, following the general principles for transfer of care. [2007, amended 2014]\n\nSeek advice from a more experienced midwife or obstetrician if there is uncertainty about the nature or extent of the trauma. Transfer the woman (with her baby) to obstetric‑led care (following the general principles for transfer of care) if the repair needs further surgical or anaesthetic expertise. [2007, amended 2014]\n\nDocument the systematic assessment and its results fully, possibly pictorially. \n\nAll relevant healthcare professionals should attend training in perineal/genital assessment and repair, and ensure that they maintain these skills. \n\nUndertake repair of the perineum as soon as possible to minimise the risk of infection and blood loss. \n\nWhen carrying out perineal repair:\n\nensure that tested effective analgesia is in place, using infiltration with up to 20\xa0ml of 1%\xa0lidocaine or equivalent\n\ntop up the epidural or insert a spinal anaesthetic if necessary. \n\nIf the woman reports inadequate pain relief at any point, address this immediately. \n\nAdvise the woman that in the case of first‑degree trauma, the wound should be sutured in order to improve healing, unless the skin edges are well opposed. \n\nAdvise the woman that in the case of second‑degree trauma, the muscle should be sutured in order to improve healing. \n\nIf the skin is opposed after suturing of the muscle in second‑degree trauma, there is no need to suture it. \n\nIf the skin does require suturing, use a continuous subcuticular technique. \n\nUndertake perineal repair using a continuous non‑locked suturing technique for the vaginal wall and muscle layer. \n\nUse an absorbable synthetic suture material to suture the perineum. \n\nOffer rectal non‑steroidal anti‑inflammatory drugs routinely after perineal repair of first‑ and second‑degree trauma provided these drugs are not contraindicated. \n\nObserve the following basic principles when performing perineal repairs:\n\nRepair perineal trauma using aseptic techniques.\n\nCheck equipment and count swabs and needles before and after the procedure.\n\nGood lighting is essential to see and identify the structures involved.\n\nEnsure that difficult trauma is repaired by an experienced practitioner in theatre under regional or general anaesthesia.\n\nInsert an indwelling catheter for 24\xa0hours to prevent urinary retention.\n\nEnsure that good anatomical alignment of the wound is achieved and that consideration is given to the cosmetic results.\n\nCarry out rectal examination after completing the repair to ensure that suture material has not been accidentally inserted through the rectal mucosa.\n\nAfter completion of the repair, document an accurate detailed account covering the extent of the trauma, the method of repair and the materials used.\n\nGive the woman information about the extent of the trauma, pain relief, diet, hygiene and the importance of pelvic‑floor exercises (see the NICE guideline on pelvic floor dysfunction). ", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "Giving birth is a life‑changing event. The care that a woman receives during labour has the potential to affect her – both physically and emotionally, in the short and longer term – and the health of her baby. Good communication, support and compassion from staff, and having her wishes respected, can help her feel in control of what is happening and contribute to making birth a positive experience for the woman and her birth companion(s).\n\nThis guideline covers the care of healthy women who go into labour at term (37+0\xa0to\xa041+6\xa0weeks). About 700,000\xa0women give birth in England and Wales each year, of whom about 40% are having their first baby. Most of these women are healthy and have a straightforward pregnancy. Almost 90% of women will give birth to a single baby after 37\xa0weeks of pregnancy, with the baby presenting head first. About two‑thirds of women go into labour spontaneously. Therefore, most women giving birth in England and Wales are covered by this guideline.\n\nSince the original guideline was published in 2007, the number of women giving birth in England and Wales each year has risen, the rate of intervention (instrumental births and caesarean section) has increased slightly, and there has been some reconfiguration of services. The decision to update the guideline in 2014 was made based on developments in the NHS and new evidence becoming available that could affect the recommendations from 2007.\n\nIt is important that the woman is given information and advice about all available settings when she is deciding where to have her baby, so that she is able to make a fully informed decision. This includes information about outcomes for the different settings. It is also vital to recognise when transfer of care from midwifery‑led care to obstetric‑led care is indicated because of increased risk to the woman and/or her baby resulting from complications that have developed during labour.\n\nUncertainty and inconsistency of care has been identified in a number of areas, such as choosing place of birth, care during the latent first stage of labour, fetal assessment and monitoring during labour (particularly cardiotocography compared with intermittent auscultation) and management of the third stage of labour. These and other related topics are addressed in the guideline.\n\nThe guideline is intended to cover the care of healthy women with uncomplicated pregnancies entering labour at low risk of developing intrapartum complications. In addition, recommendations are included that address the care of women who start labour as 'low risk' but who go on to develop complications. These include the care of women with prelabour rupture of membranes at term, care of the woman and baby when meconium is present, indications for continuous cardiotocography, interpretation of cardiotocograph traces, and management of retained placenta and postpartum haemorrhage. Aspects of intrapartum care for women at risk of developing intrapartum complications are covered by a range of NICE guidelines on specific conditions and a further guideline is planned on the intrapartum care of women at high risk of complications during pregnancy and the intrapartum period.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Models of midwifery-led care\n\nIn December 2021, we stood down this recommendation for research as continuity of care in maternity services is now a national policy in the UK following on from the National Maternity Review on Better Births and the subsequent Maternity Transformation Programme.\n\n# Effect of information giving on place of birth\n\nHow does the provision of accurate, evidence‑based information affect women's decision‑making processes and choice of place of birth?\n\n## Why this is important\n\nA report by Coxon et al. (2013) identifies in detail why women make choices about where to give birth and how these choices can be influenced. Influences may include written and verbal information (both online and from midwives and doctors), previous experience, and word‑of‑mouth advice from friends and family. The Birthplace study concluded that giving birth outside an obstetric unit is the optimal choice for low‑risk women. This finding should be used to restructure the way in which information is provided, so that it is presented in a more accurate, less risk‑based way in order to support women's choices. This change should be evaluated in a quantitative observational study and/or qualitative study that records any changes in women's choice‑making about place of birth. Outcomes include understanding why and how women make choices about where to give birth and how this can influence the provision of appropriate and accessible information, a measure of informed decision‑making, and fearfulness and absence of fearfulness when choosing place of birth.\n\n# Long‑term consequences of planning birth in different settings\n\nWhat are the long‑term consequences for women and babies of planning birth in different settings?\n\n## Why this is important\n\nThe long‑term consequences of birth experiences and birth outcomes are poorly understood, particularly in relation to place of birth. A large population‑based observational study would compare women's experiences and outcomes in different birth settings (with subgroup analysis by mode of birth) in relation to the wellbeing of the women and their children over different periods of time (for example, 2, 5, 10, 15, 20\xa0and 30\xa0years). A secondary analysis could compare different providers where birth philosophies are different. Outcomes would be compared by accessing medical records and through qualitative interviews. Primary outcomes are long‑term physical morbidity, pain after birth, readmission to hospital, infection, psychological morbidity (for example, postnatal depression, bonding, relationship breakdown with partner, fear of giving birth in future) and breastfeeding rates. Secondary outcomes are impact on attachment between mother and child, obesity in children, autoimmune disease, chronic illness, educational achievement and family functioning.\n\n# Education about the latent first stage of labour\n\nDoes enhanced education specifically about the latent first stage of labour increase the number of nulliparous women who wait until they are in established labour before attending the obstetric or midwifery unit (or calling the midwife to a home birth), compared with women who do not receive this education?\n\n## Why this is important\n\nStudies show that antenatal education about labour and birth in general makes a difference to some birth outcomes, but there is limited evidence focusing on education about the latent first stage of labour specifically. The aim of this study (randomised controlled trial or prospective observational study) would be to compare 2\xa0groups of women experiencing their first labour and birth: a group who receive an education session in late pregnancy covering what to expect in the latent first stage of labour and how to recognise the onset of established labour, and a group who have not received this focused education. Primary outcomes would be mode of birth, satisfaction with the birth experience and the woman's physical and emotional wellbeing after birth. Secondary outcomes would be use of pharmacological pain relief, use of oxytocin to augment labour, and time from first contact in confirmed established labour to birth.\n\n# Postpartum haemorrhage\n\nWhat is the most effective treatment for primary postpartum haemorrhage?\n\n## Why this is important\n\nThere is uncertainty about the most effective drug treatments and dosage regimes, and about which other treatments should be used, for women who develop a postpartum haemorrhage. The most effective sequencing of interventions is also uncertain. The psychological impact of postpartum haemorrhage for women can be significant, and identifying the approach that minimises this impact is important. Randomised controlled trials comparing different dosage regimes for oxytocin and misoprostol, as well as comparisons with ergometrine and carboprost, are needed. Trials of mechanical measures such as intrauterine balloons or interventional radiology as early second‑line treatment (rather than an alternative drug treatment) are also needed. Alternatively, a trial comparing the effectiveness of a complex intervention (for example, an educational component, sequence of interventions, immediate feedback and quality improvements) compared with standard care could be undertaken. Important outcomes include blood and blood product transfusion, need for further intervention, need for hysterectomy and psychological outcomes for the woman.", 'Appendix A: Adverse outcomes': "Adverse outcome: in order to be able to count enough adverse events to be able to say that the results recorded are not just a result of chance, the Birthplace UK (2011) study used a composite definition of 'adverse outcome'. The definition includes the following outcomes: stillbirth during labour, death of the baby in the first week after birth, neonatal encephalopathy (disordered brain function caused by oxygen deprivation before or during birth), meconium aspiration syndrome, and physical birth injuries (brachial plexus injury and bone fractures). The term 'serious medical problems' has been used to describe this composite outcome in the guideline recommendations.\n\nOutcome\n\nActual number of babies affected out of (63,955 to 64,535;\n\nnumber per 1,000)\n\nPercentage of all adverse outcomes measured\n\nStillbirth after start of care in labour\n\nout of 64,535\n\n(0.22 per 1,000)\n\n%\n\nDeath of the baby in the first week after birth\n\nout of 64,292\n\n(0.28 per 1,000)\n\n%\n\nNeonatal encephalopathy (disordered brain function caused by oxygen deprivation before or during birth) (clinical diagnosis)\n\nout of 63,955\n\n(1.6 per 1,000)\n\n%\n\nMeconium aspiration syndrome (the baby breathes meconium into their lungs)\n\nout of 63,955\n\n(1.3 per 1,000)\n\n%\n\nBrachial plexus injury\n\nout of 63,955\n\n(0.38 per 1,000)\n\n%\n\nBone fractures\n\nout of 63,955\n\n(0.17 per 1,000)\n\n%\n\nTotal (of all outcomes included in the 'adverse outcome' composite measure)\n\nout of 63,955 to 64,535)\n\n(approximately 4 per 1,000)\n\n%\n\nNote: Each of the categories above are mutually exclusive and outcomes listed higher in the table take precedence over outcomes listed lower down. For example, if a baby with neonatal encephalopathy died within 7\xa0days the outcome is classified as an early neonatal death.\n\n Denominator varies because of missing values.\n\n** Does not equal 100% because of rounding."}	https://www.nice.org.uk/guidance/cg190	This guideline covers the care of healthy women and their babies, during labour and immediately after the birth. It focuses on women who give birth between 37 and 42 weeks of pregnancy (‘term’). The guideline helps women to make an informed choice about where to have their baby. It also aims to reduce variation in aspects of care.
e7e90a28a25d06c9b5fdd9d8c4c4783dbc97d3d2	nice	Fetal monitoring in labour	Fetal monitoring in labour This guideline covers methods for monitoring the wellbeing of the baby during labour. It includes risk assessment to determine the appropriate level of fetal monitoring, using clinical assessment in addition to fetal monitoring, and interpreting and acting on monitoring findings. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Information and supported decision-making For more guidance on providing information, including providing accessible information, see the NICE guidelines on patient experience in adult NHS services and shared decision-making. Discuss fetal monitoring options with a woman as part of her antenatal care and document the discussions and decisions in her personalised care plan. Throughout labour, provide women with information on the fetal monitoring method being advised and the reasons for this advice. Support the woman's decision about fetal monitoring during labour. Include birthing companion(s) in these discussions if appropriate, and if that is what the woman wants. Document these discussions and decisions in the woman's notes. Keep women and their birthing companion(s) informed about what is happening if additional advice or review is being sought by the care team, for example from a senior midwife or obstetrician. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and supported decision-making . Loading. Please wait. # Assessment during labour and methods for fetal monitoring ## General principles Perform and document a systematic assessment of the condition of the woman and unborn baby every hour, or more frequently if there are concerns. See the NICE guideline on intrapartum care for more information on the monitoring recommendations for different stages of labour. Discuss the results of each hourly assessment with the woman and base recommendations about care in labour on her preferences and: her reports of the frequency, length and strength of her contractions any antenatal and intrapartum risk factors for fetal compromise the current wellbeing of the woman and unborn baby how labour is progressing.Include birthing companion(s) in these discussions if appropriate, and if that is what the woman wants. Remember that: fetal heart rate monitoring is a tool to provide guidance on fetal condition, and not a standalone diagnostic tool the findings from monitoring need to be looked at together with the developing clinical picture for both woman and baby. Ensure one-to-one support is maintained by having a midwife remain with the woman throughout labour. If the midwife needs to leave the room or there needs to be a change in staff, ensure the woman knows this is happening. ## Initial assessment Perform an initial assessment of antenatal risk factors for fetal compromise at the onset of labour to determine whether intermittent auscultation or cardiotocography (CTG) is offered as the initial method of fetal heart rate monitoring. Take into account the recommendations for fetal monitoring for women who are considered to be at higher risk of complications during labour because of existing medical conditions or obstetric complications (see the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies) or for women with multiple pregnancies (see the section on fetal monitoring during labour in twin pregnancy in the NICE guideline on twin and triplet pregnancy). Confirm with the woman which method of fetal monitoring has already been advised as part of their personalised care plan. Explain to the woman that risk assessment is a continual process, and the advised method of fetal heart rate monitoring may change throughout the course of labour. Explain to women that if there are no identified risk factors for fetal compromise: there is a risk of increased interventions with continuous CTG monitoring compared with intermittent auscultation, which may outweigh the benefits and advice she is given by her midwife or obstetrician on the method of fetal heart rate monitoring will take into account the whole clinical picture. ## Intermittent auscultation Offer women with a low risk of complications, fetal heart rate monitoring with intermittent auscultation when in established first stage of labour. Do this as follows: use either a Pinard stethoscope or doppler ultrasound carry out intermittent auscultation immediately after a palpated contraction for at least 1 minute, repeated at least once every 15 minutes, and record it as a single rate on a partogram and in the woman's notes record accelerations and decelerations, if heard palpate (and record on the partogram) the maternal pulse hourly, or more often if there are any concerns, to ensure differentiation between the maternal and fetal heartbeats if no fetal heartbeat is detected, offer urgent real-time ultrasound assessment to check fetal viability. Once the woman has signs of, or is in confirmed second stage of labour: perform intermittent auscultation immediately after a palpated contraction for at least 1 minute, repeated at least once every 5 minutes and record it as a single rate on a partogram and in the woman's notes palpate the woman's pulse simultaneously to differentiate between the maternal and fetal heart rates if there are concerns about differentiating between the 2 heart rates, seek help and consider changing the method of fetal heart rate monitoring (see recommendation 1.4.6). If, on intermittent auscultation, there is an increase in the fetal heart rate (as plotted on the partogram) of 20 beats a minute or more from the start of labour, or a deceleration is heard: carry out intermittent auscultation more frequently (for example, after 3 consecutive contractions) carry out a full review, taking into account the whole clinical picture including antenatal and existing or new intrapartum risk factors, maternal observations, contraction frequency (including hypertonus) and the progress of labour. If fetal heart rate concerns are confirmed: summon help advise continuous CTG monitoring, and explain to the woman and her birth companion(s) why it is recommended, and the implications for her choices of type and place of care transfer the woman from midwifery-led to obstetric-led care, providing that it is safe and appropriate to do so (follow the general principles for transfer of care in the NICE guideline on intrapartum care for healthy women and babies). Return to intermittent auscultation if continuous CTG monitoring has been started because of concerns arising from intermittent auscultation but the CTG trace is normal after 20 minutes, unless the woman decides to remain on continuous CTG monitoring. Advise continuous CTG monitoring if: fetal heart rate concerns arise with intermittent auscultation and are ongoing, or intrapartum maternal or fetal risk factors develop (see the section on indications for continuous cardiotocography monitoring in labour). ## Continuous cardiotocography Do not use the advice in this guideline to categorise antenatal CTG traces. Use the advice in this guideline to interpret and categorise intrapartum CTG traces, but when interpreting how the baby is coping with labour take into account maternal, fetal and labour factors as well as CTG changes. Consider a lower threshold for escalation when there are any antenatal or intrapartum risk factors that could lead to fetal compromise. Encourage and help women to be as mobile as possible, to find positions that are comfortable for them, and to change position as often as they wish. Offer continuous CTG monitoring as part of fetal assessment if any antenatal or intrapartum risk factors for fetal compromise are present. See the section on indications for continuous cardiotocography monitoring in labour. Discuss with the woman and her birth companion(s) the reasons for offering continuous CTG monitoring, and explain that: a combination of antenatal risk factors, intrapartum risk factors and continuous CTG monitoring are used to evaluate the baby's condition in labour continuous CTG monitoring is used to monitor the baby's heart rate and the labour contractions it may restrict her mobility and the option to labour in water a normal CTG trace indicates that the baby is coping well with labour changes to the baby's heart rate pattern during labour are common and do not necessarily cause concern, however they may represent developing fetal compromise so maintaining continuous CTG monitoring is advised if these occur if the CTG trace changes or is not normal there will be less certainty about the condition of the baby and so maintaining continuous CTG monitoring is advised, in conjunction with a full assessment including checks for developing intrapartum risk factors such as the presence of meconium, sepsis and slow progress in labour advice about her care during labour and birth will be based on an assessment of several factors, including her preferences, her condition and the condition of her baby, as well as the findings from the CTG. ## Telemetry Ensure wireless transducers are kept charged and maintained so that they are ready to use. Switch from wireless to wired transducers as soon as possible if there is signal loss which is not resolved by reducing the distance between the base unit and the woman, in order to confirm whether or not there is a clinical problem. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment during labour and methods for fetal monitoring . Loading. Please wait. # Indications for continuous cardiotocography monitoring in labour ## Antenatal risk factors Offer continuous cardiotocography (CTG) monitoring to women in labour if it is in their personalised care plan. Offer continuous CTG monitoring for women in labour who have any of the following antenatal maternal risk factors: previous caesarean birth or other full thickness uterine scar any hypertensive disorder needing medication prolonged ruptured membranes (but women who are already in established labour at 24 hours after their membranes ruptured do not need CTG unless there are other concerns) any vaginal blood loss other than a show suspected chorioamnionitis or maternal sepsis pre-existing diabetes (type 1 or type 2) and gestational diabetes requiring medication. Offer continuous CTG monitoring for women in labour who have any of the following antenatal fetal risk factors: non-cephalic presentation (including breech, transverse, oblique and cord), including while a decision is made about mode of birth fetal growth restriction (estimated fetal weight below 3rd centile) small for gestational age (estimated fetal weight below 10th centile) with other high-risk features such as abnormal doppler scan results, reduced liquor volume or reduced growth velocity advanced gestational age (more than 42+0 weeks at the onset of established labour) anhydramnios or polyhydramnios reduced fetal movements in the 24 hours before the onset of regular contractions. Consider continuous CTG monitoring if, based on clinical assessment and multidisciplinary review, there are concerns about other antenatal factors not listed above that may lead to fetal compromise. ## Ongoing risk assessment Carry out a full assessment of the woman and her baby every hour. At each assessment include: maternal antenatal risk factors for fetal compromise fetal antenatal risk factors for fetal compromise new or developing intrapartum risk factors progress in labour including characteristics of contractions (frequency, strength and duration) fetal heart rate monitoring, including changes to the fetal heart rate pattern.Discuss with the woman any changes identified since the last review, and the implications of these changes. Include birthing companion(s) in these discussions if appropriate and if that is what the woman wants. Obtain an in-person review of every hourly assessment (see recommendation 1.3.5) by another clinician ("fresh eyes") for women on CTG, to be completed before the next assessment takes place. ## Intrapartum risk factors Be aware that intrapartum risk factors may increase the risk of fetal compromise, and that intrapartum risk factors that develop as labour progresses are particularly concerning. Offer continuous CTG monitoring for women who have or develop any of the following new intrapartum risk factors: contractions that last longer than 2 minutes, or 5 or more contractions in 10 minutes the presence meconium (see the section on the presence of meconium) maternal pyrexia (a temperature of 38°C or above on a single reading or 37.5°C or above on 2 consecutive occasions 1 hour apart). See the section on preventing early-onset neonatal infection before birth in the NICE guideline on neonatal infection: antibiotics for prevention and treatment suspected chorioamnionitis or sepsis (see the section on preventing early-onset neonatal infection before birth in the NICE guideline on neonatal infection: antibiotics for prevention and treatment) pain reported by the woman that appears, based on her description or her previous experience, to differ from the pain normally associated with contractions fresh vaginal bleeding that develops in labour blood-stained liquor not associated with vaginal examination, that is likely to be uterine in origin (and may indicate suspected antepartum haemorrhage) maternal pulse over 120 beats a minute on 2 occasions 30 minutes apart severe hypertension (a single reading of either systolic blood pressure of 160 mmHg or more or diastolic blood pressure of 110 mmHg or more, measured between contractions) hypertension (either systolic blood pressure of 140 mmHg or more or diastolic blood pressure of 90 mmHg or more on 2 consecutive readings taken 30 minutes apart, measured between contractions) a reading of 2+ of protein on urinalysis and a single reading of either raised systolic blood pressure (140 mmHg or more) or raised diastolic blood pressure (90 mmHg or more) confirmed delay in the first or second stage of labour (see the NICE guideline on intrapartum care for healthy women and babies) insertion of regional analgesia (for example, an epidural) use of oxytocin. Consider continuous CTG monitoring if, based on clinical assessment and multidisciplinary review, there are concerns about other intrapartum factors not listed above that may lead to fetal compromise. ## Presence of meconium When assessing risk at any time during labour, be aware that the presence of meconium: can indicate possible fetal compromise, and may lead to complications, such as meconium aspiration syndrome. Consider the character of the meconium as part of the overall clinical assessment, in conjunction with other antenatal or intrapartum risk factors, and discuss the option of CTG monitoring with the woman. Recognise that the type of monitoring method used is the woman's choice, and support her decision. Be aware that meconium is more common post-term, but should still trigger a full risk assessment and discussion with the woman about the option of CTG monitoring. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indications for continuous cardiotocography monitoring in labour . Loading. Please wait. # Use of cardiotocography for monitoring during labour Review the previous fetal heart rate monitoring results, including any previous CTG traces, as part of the hourly risk assessment and in conjunction with other antenatal or intrapartum risk factors (see the section on indications for continuous cardiotocography monitoring in labour) and determine if there are any changes in baseline fetal heart rate, variability or decelerations. If there are changes in the fetal heart rate pattern over time which indicate a change in the baby's condition, review antenatal or intrapartum risk factors for hypoxia. When reviewing a CTG trace, assess and document: contractions baseline fetal heart rate variability presence or absence of decelerations (and characteristics of decelerations if present) presence of accelerations. If there is a stable baseline fetal heart rate between 110 and 160 beats a minute and normal variability, continue usual care as the risk of fetal acidosis is low. Differentiate between the maternal and fetal heartbeats hourly, or more often if there are any concerns. If there are concerns about whether the maternal heart rate is being heard rather than the fetal heart rate, discuss with the woman the methods available to differentiate and support her decision on which method to use. Options include: fetal heart rate auscultation with a Pinard stethoscope bedside ultrasound scanning continuous maternal heart rate monitoring (using a pulse oximeter or the facility on the CTG equipment) fetal heart rate detection using a fetal scalp electrode which is attached to the baby's head (but be aware this may detect maternal heart rate if there is no fetal heartbeat, so should always be used in conjunction with maternal heart rate monitoring) simultaneous palpation of the woman's pulse while listening to the fetal heart rate. Be aware that it is particularly important to confirm the fetal heart rate in the second stage of labour, when it is easier to mistakenly auscultate maternal rather than fetal heart rate. If concerns about differentiation between the maternal and fetal heart rate remain, or if a fetal heart cannot be heard, obtain an urgent review by an obstetrician or senior midwife. Ensure that the CTG trace is of high quality and, if not, take action to improve the trace (for example, by repositioning the tocodynamometer, the transducer or by using a fetal scalp electrode). When reviewing CTG traces: evaluate changes on traces over time to ascertain changes in the baby's condition document any changes in the CTG trace from the previous review review the changes alongside any existing and new intrapartum risk factors think about the possible reasons for any changes, and take these and the whole clinical picture into account when planning ongoing care. ## Features of cardiotocography Categorise the 4 features of the cardiotocography trace (contractions, baseline fetal heart rate, variability, decelerations) as white, amber or red (indicating increasing levels of concern) and use alongside consideration of the presence of accelerations to classify the overall CTG trace (see recommendation 1.4.31). Use a tocodynamometer to record contraction frequency and length on the CTG trace. Use the following to work out the categorisation for contractions (see recommendation 1.4.31 to work out the overall categorisation for the CTG): white fewer than 5 contractions in 10 minutes amber -r more contractions in 10 minutes, leading to reduced resting time between contractions, or hypertonus. If decelerations are present, evaluate their timing related to contractions. If 5 or more contractions per 10 minutes are present: perform a full risk assessment take action to reduce contraction frequency as described in the section on underlying causes and conservative measures explain to the woman what is happening, and ensure that she has adequate pain relief. Determine baseline fetal heart rate by looking at the mean fetal heart rate, excluding accelerations and decelerations, over a period of 10 minutes when the fetal heart rate is stable. When deciding if there is any change in baseline fetal heart rate, compare it with earlier CTG traces or recordings of fetal heart rate. Use the following to work out the categorisation for baseline fetal heart rate (see recommendation 1.4.31 to work out the overall categorisation for the CTG): white stable baseline of 110 to 160 beats a minute amber increase in baseline fetal heart rate of 20 beats a minute or more from the start of labour or since the last review an hour ago, or to 109 beats a minute (but see recommendation 1.4.16), or unable to determine baseline red below 100 beats a minute, or above 160 beats a minute. When assessing baseline fetal heart rate, differentiate between fetal and maternal heartbeats and take the following into account: baseline fetal heart rate will usually be between 110 and 160 beats a minute lower baseline fetal heart rates are expected with post-term pregnancies, with higher baseline rates in preterm pregnancies a rise in baseline fetal heart rate may represent either developing infection or hypoxia (see the section on preventing early-onset neonatal infection before birth in the NICE guideline on neonatal infection: antibiotics for prevention and treatment) although a baseline fetal heart rate between 100 and 109 beats a minute is an amber feature, continue usual care if this has been stable throughout labour and there is normal variability and no variable or late decelerations. Determine variability by looking at the minor oscillations in the fetal heart rate, which usually occur at 3 to 5 cycles a minute. Measure it by estimating the difference in beats per minute between the highest heart rate and the lowest heart rate in a 1‑minute segment of the trace between contractions, excluding decelerations and accelerations. If there is an absence of variability, carry out a review of the whole clinical picture with a low threshold for expedited birth, as this is a very concerning feature. Use the following to work out the categorisation for fetal heart rate variability (see recommendation 1.4.31 to work out the overall categorisation for the CTG): white to 25 beats a minute amber fewer than 5 beats a minute for between 30 and 50 minutes, or more than 25 beats a minute for up to 10 minutes red fewer than 5 beats a minute for more than 50 minutes, or more than 25 beats a minute for more than 10 minutes, or sinusoidal. Take the following into account when assessing fetal heart rate variability: variability will usually be between 5 and 25 beats a minute intermittent periods of reduced variability are normal, especially during periods of quiescence ('sleep') certain medicines, such as opioids, may lead to a reduction in variability, but all other intrapartum risk factors should be carefully reviewed as a potential cause (for example, look for other features on the CTG such as a rise in the baseline fetal heart suggestive of another reason such as sepsis) increased variability refers to oscillations around the baseline fetal heart rate of more than 25 beats a minute, and shorter episodes lasting a few minutes may represent worsening fetal condition. Obtain an urgent review by an obstetrician or senior midwife and consider expediting birth if: there is an isolated reduction in variability to fewer than 5 beats per minute for more than 30 minutes when combined with antenatal or intrapartum risk factors, as this is associated with an increased risk of adverse neonatal outcomes, or there is a reduction in variability to fewer than 5 beats per minute combined with other CTG changes, particularly a rise in the baseline fetal heart rate, as this is a strong indicator for fetal compromise. Define decelerations as transient episodes when the fetal heart rate slows to below the baseline level by more than 15 beats a minute, with each episode lasting 15 seconds or more. An exception to this is that in a trace with reduced variability, decelerations may be 'shallow'. When assessing the significance of decelerations in fetal heart rate, consider: their timing (early, variable or late) in relation to the peaks and duration of the contractions the duration of the individual decelerations whether or not the fetal heart rate returns to the baseline heart rate how long they have been present for whether they occur with over 50% of contractions (defined as repetitive) the presence or absence of shouldering the variability within the deceleration. Regard the following as concerning characteristics of variable decelerations: lasting more than 60 seconds reduced variability within the deceleration failure or slow return to baseline fetal heart rate loss of previously present shouldering. Describe decelerations as 'early', 'variable' or 'late'. Do not use the terms 'typical' and 'atypical', as they can cause confusion. Use the following to work out the categorisation for decelerations in fetal heart rate (see recommendation 1.4.31 to work out the overall categorisation for the CTG): white no decelerations, or early decelerations, or variable decelerations that are not evolving to have concerning characteristics amber repetitive variable decelerations with any concerning characteristics for less than 30 minutes, or variable decelerations with any concerning characteristics for more than 30 minutes, or repetitive late decelerations for less than 30 minutes red repetitive variable decelerations with any concerning characteristics for more than 30 minutes, or repetitive late decelerations for more than 30 minutes, or acute bradycardia, or a single prolonged deceleration lasting 3 minutes or more. Take into account that the longer and later the individual decelerations, the higher the risk of fetal compromise (particularly if the decelerations are accompanied by a rise in the baseline, a tachycardia or reduced or increased variability). Start conservative measures and carry out an urgent obstetric review if there are decelerations lasting longer than 30 minutes in the presence of either a rise in the baseline heart rate or reduced variability. Take into account antenatal and intrapartum risk factors, such as suspected sepsis, the presence of meconium, slow progress of labour or the use of oxytocin, to determine whether there is a need for expedited birth. If variable decelerations persist and other CTG changes are present, obtain an urgent review by an obstetrician and a senior midwife, as there is a risk of fetal compromise and acidosis. If variable decelerations with no concerning characteristics and no other CTG changes, including no rise in the baseline fetal heart rate, are observed: be aware that these are very common, can be a normal feature in an otherwise uncomplicated labour and birth, and are usually a result of cord compression support the woman to change position or mobilise. Take the following into account when categorising early decelerations: they are uncommon, benign and usually associated with head compression they are not accompanied by any other CTG changes, such as reduced variability or a rise in the baseline fetal heart rate. Define accelerations as transient increases in fetal heart rate of 15 beats a minute or more, lasting 15 seconds or more. Take the following into account when assessing accelerations in fetal heart rate: the presence of fetal heart rate accelerations, even with reduced variability, is generally a sign that the baby is healthy the absence of accelerations on an otherwise normal CTG trace does not indicate fetal acidosis. Include CTG categorisation as part of the full assessment of the condition of the woman and baby. Be aware categorisation is a tool which quickly communicates the current state of the CTG and should be used together with antenatal and intrapartum risk factors, to assess changes over time. Categorise CTG traces as follows, based on whether each of the 4 features (contractions, baseline, variability, decelerations) have been scored as white, amber or red: normal no amber or red features (all 4 features are white) suspicious any 1 feature is amber pathological any 1 feature is red, or -r more features are amber. Take into account any change in the categorisation of the CTG alongside other antenatal and intrapartum risk factors for hypoxia. Discuss the change and its implications with the woman, and take into account her preferences when deciding how to proceed. Take into account that interpretation of CTG traces in the second stage of labour is more challenging than in the first stage of labour. Have a lower threshold for seeking a second opinion or assistance. Ensure the fetal heart rate is differentiated from the maternal heart rate at least once every 5 minutes. Consider monitoring the baby with a fetal scalp electrode if there is concern about confusing the heart rates, but if this cannot be achieved expedite birth (see recommendation 1.4.6). In the second stage of labour: if fetal heart rate accelerations are recorded, be aware that these are most likely to be maternal pulse (see recommendation 1.4.6 on steps to take to check whether the maternal or fetal heart rate is being detected) if fetal heart rate decelerations are recorded, look for other signs of hypoxia (for example, a rise in the baseline fetal heart rate or a reduction in variability). Take into account that onset of hypoxia is both more common and more rapid in the active second stage of labour. Take an increase in the baseline fetal heart rate of 20 beats a minute or more from the start of labour or since the last review an hour ago as a red feature in active second stage labour. If CTG concerns arise in the active second stage of labour: -btain an obstetric review consider discouraging pushing and stopping any oxytocin infusion to allow the baby to recover, unless birth is imminent agree and document a clear plan with time limits for the next review. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on use of cardiotocography for monitoring during labour . Loading. Please wait. # Making care decisions based on the cardiotocography trace Assess fetal wellbeing every hour, taking into account antenatal and intrapartum risk factors, in conjunction with interpretation of the CTG trace. Take the whole clinical picture into account when making decisions on how to manage the labour, including maternal observations, contraction frequency and labour progress. Discuss with the woman and her birth companion(s) what is happening, taking into account her individual circumstances and preferences, and support her decisions. If the CTG trace is categorised as normal: continue CTG (unless it was started because of concerns arising from intermittent auscultation and there are no ongoing antenatal or intrapartum risk factors) and usual care continue to perform a full risk assessment at least hourly and document the findings. If the CTG trace is categorised as suspicious and there are no other concerning risk factors: perform a full risk assessment, including a full set of maternal observations, taking into account the whole clinical picture, and document the findings note that if accelerations are present then fetal acidosis is unlikely if the CTG trace was previously normal, consider possible underlying reasons for the change undertake conservative measures as indicated (see the section on underlying causes and conservative measures). If the CTG trace is categorised as suspicious and there are additional intrapartum risk factors such as slow progress, sepsis or meconium: perform a full risk assessment, including a full set of maternal observations, taking into account the whole clinical picture, and document the findings consider possible underlying causes, and undertake conservative measures as indicated (see the section on underlying causes and conservative measures) -btain an urgent review by an obstetrician or a senior midwife consider: fetal scalp stimulation (see the section on fetal scalp stimulation), or expediting birth. If the CTG trace is categorised as pathological: -btain an urgent review by an obstetrician and a senior midwife exclude acute events (for example, cord prolapse, suspected placental abruption or suspected uterine rupture) that need immediate intervention perform a full risk assessment, including a full set of maternal observations, taking into account the whole clinical picture, and document the findings consider possible underlying causes and undertake conservative measures as indicated (see the section on underlying causes and conservative measures). If the CTG trace is still pathological after implementing conservative measures: -btain a further urgent review by an obstetrician and a senior midwife evaluate the whole clinical picture and consider expediting birth if there are evolving intrapartum risk factors for fetal compromise, have a very low threshold for expediting birth. If there is an acute bradycardia, or a single prolonged deceleration for 3 minutes or more: urgently seek obstetric review if there has been an acute event (for example, cord prolapse, suspected placental abruption or suspected uterine rupture), expedite the birth consider possible underlying causes and undertake conservative measures as indicated (see the section on underlying causes and conservative measures) make preparations for an urgent birth, including a request for paediatric or neonatal support. expedite the birth if the acute bradycardia persists for 9 minutes, or less if there are significant antenatal or intrapartum risk factors for fetal compromise.If the fetal heart rate recovers at any time up to 9 minutes, reassess any decision to expedite the birth, but take into account other antenatal and intrapartum risk factors and discuss this with the woman. If a decision is made to expedite birth, ensure the time at which urgent review was sought, and the time the decision was made, are documented. For a short explanation of why the committee made the 2022 recommendation and how it might affect practice, see the rationale and impact section on making care decisions based on the cardiotocography trace . Loading. Please wait. ## Underlying causes and conservative measures If there are any concerns about the baby's wellbeing, be aware of the possible underlying causes and start 1 or more of the following conservative measures based on an assessment of the most likely cause(s): maternal position (as this can affect uterine blood flow and cord compression), encourage the woman to mobilise, or adopt an alternative position, and to avoid being supine hypotension: do not offer intravenous fluids to treat fetal heart rate abnormalities unless the woman is hypotensive or has signs of sepsis if the woman is hypotensive secondary to an epidural top-up, start intravenous fluids, move her to a left lateral position and call an anaesthetist to review excessive contraction frequency: reduce contraction frequency by reducing or stopping oxytocin if it is being used -ffer a tocolytic drug (a suggested regimen is subcutaneous terbutaline 0.25 mg). Do not offer maternal facial oxygen therapy as part of conservative measures because it may harm the baby. However, it can be used if it is given for maternal issues such as hypoxia, or as part of preoxygenation before a potential anaesthetic. Do not offer amnioinfusion for intrauterine fetal resuscitation. # Fetal scalp stimulation If the CTG trace is suspicious with antenatal or intrapartum risk factors for fetal compromise, then consider digital fetal scalp stimulation. If this leads to an acceleration in fetal heart rate and a sustained improvement in the CTG trace, continue to monitor the fetal heart rate and clinical picture. Be aware that the absence of an acceleration in response to fetal scalp stimulation is a worrying sign that fetal compromise may be present, and that expedited birth may be necessary. # Fetal blood sampling NICE is unable to make a recommendation about fetal blood sampling because of limited evidence. For a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on fetal blood sampling . Full details of the evidence and the committee's discussion are in evidence review A: fetal blood sampling. Loading. Please wait. # Record keeping for cardiotocography To ensure accurate record keeping for CTG: make sure that date and time clocks on the cardiotocograph monitor are set correctly ensure the recording or paper speed is set at 1 cm a minute and that adequate paper is available label traces with the woman's name, date of birth, hospital number or NHS number and pulse at the start of monitoring, and the date of the CTG. Individual units should develop a system for recording relevant intrapartum events (for example, vaginal examination and siting of an epidural) in standard notes and/or on the cardiotocograph trace. Keep cardiotocograph traces for 25 years and, if possible, store them electronically. In cases where there is concern that the baby may have sustained a possible brain injury, photocopy cardiotocograph traces (if they are not available electronically) and store them indefinitely in case of possible adverse outcomes. Ensure that tracer systems are available for all cardiotocograph traces if stored separately from the woman's records. Develop tracer systems to ensure that cardiotocograph traces removed for any purpose (such as risk management or for teaching purposes) can always be located. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster. ## Early decelerations Repetitive and periodic slowing of the fetal heart rate with onset early in the contraction and return to baseline at the end of the contraction. These are uncommon. ## Hypertonus A contraction lasting 2 minutes or longer. ## Late decelerations Repetitive and periodic slowing of the fetal heart rate with onset mid to end of the contraction and the lowest point more than 20 seconds after the peak of the contraction, and ending after the contraction. ## Variable decelerations Intermittent and periodic slowing of the fetal heart rate with a variable time in relation to the contraction.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Information and supported decision-making Recommendations 1.1.1 to 1.1.4 ## Why the committee made the recommendations The committee agreed, based on their knowledge and expertise, that discussions about fetal monitoring should occur as part of antenatal care and be documented in the personalised care plan. Although healthcare professionals currently always provide advice to women in labour on options for fetal monitoring, they should also support the decision made by the woman about which method to use. ## How the recommendations might affect practice The recommendations will reinforce current practice. Return to recommendations # Assessment during labour and methods for fetal monitoring Recommendations 1.2.3, 1.2.5 to 1.2.7, 1.2.15 to 1.2.17, 1.2.19, 1.2.21 and 1.2.22 ## Why the committee made the recommendations Based on their knowledge and expertise, the committee emphasised that fetal heart rate monitoring is only a tool that provides information. It should be used as part of assessing the whole clinical picture including antenatal and intrapartum risk factors, not as a standalone diagnostic tool, and that multiple risk factors may lower the threshold for intervention. The committee discussed the initial assessment that should be carried out at the start of labour and agreed that a decision on the method of monitoring should be based on antenatal risk factors. These risk factors should have been identified and discussed with the woman during antenatal care and should already be recorded in her personalised care plan. However, the committee agreed it was important to advise women that the recommended method of fetal monitoring may change during labour (based on a clinical decision or because the woman changes her mind), but that for women at low risk, the use of cardiotocography (CTG) may lead to more interventions without evidence of benefit. The committee were aware that there was the possibility of confusion between the interpretation of antenatal and intrapartum CTG and so made a recommendation to clarify this. The committee were aware of incidences where telemetry was not available because transducers had not been plugged in to charge, or where CTG was not used effectively because of problems with signal loss, so they made recommendations to reduce such events based on their knowledge and experience. ## How the recommendations might affect practice The recommendations will reinforce current best practice and help ensure the full clinical picture is looked at. Return to recommendations # Indications for continuous cardiotocography monitoring in labour Recommendations 1.3.1, 1.3.4, 1.3.6, 1.3.7 and 1.3.9 to 1.3.12 ## Why the committee made the recommendations The committee agreed that a decision to use CTG monitoring may already have been discussed and recorded in a woman's personalised care plan, but that antenatal risk factors identified during pregnancy or labour, or new intrapartum risk factors would mean that CTG was advised to assess if there was developing fetal compromise. The committee were aware that the lists of antenatal and intrapartum risk factors covered all commonly recognised risk factors but clinical judgement would be needed to determine if there were other risk factors not listed which also might lead to consideration of CTG. The committee agreed that the presence of any meconium, not just significant meconium, should be taken into account when assessing the whole clinical picture and considering the use of CTG. ## How the recommendations might affect practice The recommendations will reinforce current practice. Return to recommendations # Use of cardiotocography for monitoring during labour Recommendations 1.4.2, 1.4.6 to 1.4.8, 1.4.10 to 1.4.12, 1.4.14, 1.4.17, 1.4.20, 1.4.26, 1.4.27, 1.4.31, 1.4.33 and 1.4.34 to 1.4.38 ## Why the committee made the recommendations Recommendations 1.4.2, 1.4.6 to 1.4.8 and 1.4.10: The committee used their knowledge and expertise and agreed that any changes in the CTG, including the fetal heart rate pattern, over time indicated that the baby may be suffering from hypoxia. They agreed this should be investigated, alongside a review of the clinical picture and antenatal or intrapartum risk factors, so that causes could be sought and action could be taken, if necessary. The committee agreed, based on their knowledge and expertise, to provide advice about the actions to take when it is difficult to distinguish between the maternal and fetal heart rate, as incorrect monitoring can lead to significant harm to the baby. Recommendations 1.4.11 to 1.4.12 and 1.4.14: The committee agreed, based on their knowledge and expertise, that as well as monitoring the fetal heart rate pattern, it was important to monitor and record contractions to determine if they were normal and, if not, to take action. Recommendations 1.4.17 and 1.4.20: The committee defined how variability should be measured. The committee were aware, based on their knowledge and expertise, that an absence of variability was concerning and so made a recommendation to address this. Recommendation 1.4.20: The committee were aware, based on their knowledge and expertise, that a reduction in variability is not specific for fetal hypoxia. However, it does indicate an increased risk of adverse neonatal outcome and therefore requires obstetric review when combined with antenatal or intrapartum risk factors for fetal compromise. If a reduction in variability is combined with other amber or red features on the CTG, it will be classified as pathological, and the committee have emphasised the need for urgent review in these circumstances. Recommendation 1.4.26 and 1.4.27: The committee wanted to emphasise, based on their knowledge and expertise, that decelerations lasting longer than 30 minutes combined with other CTG abnormalities should trigger an urgent obstetric review as this combination is particularly concerning for fetal compromise. Recommendations 1.4.31 and 1.4.33: The committee were aware, based on their knowledge and expertise, that too much reliance may be placed on the categorisation of CTG trace as a substitute for reviewing and communicating about the wider clinical picture. They stated that CTG categorisation was a tool that should be used alongside review of other antenatal and intrapartum risk factors and the wider clinical picture. Recommendations 1.4.34 to 1.4.38: The committee were aware, based on their knowledge and expertise, that in the second stage of labour it may be more difficult to differentiate the maternal and fetal heart rates, and that hypoxia may develop more rapidly, and so made new recommendations about this. ## How the recommendations might affect practice The recommendations will reinforce current practice. Return to recommendations # Making care decisions based on the cardiotocography trace Recommendation 1.5.10 ## Why the committee made the recommendation The committee advised, based on their knowledge and experience, that documentation of reviews and decisions was important. ## How the recommendation might affect practice The recommendation will reinforce current practice. Return to recommendation # Fetal blood sampling Recommendation 1.7.1 ## Why the committee made the recommendation There was recent but very limited evidence that fetal blood sampling does not improve outcomes for women and babies compared with CTG alone, or compared with CTG in combination with fetal scalp stimulation. The comparison with CTG alone showed that fetal blood sampling may increase the proportion of babies with an Apgar score less than 7 at 5 minutes, possibly because of a delay in expediting birth to allow the fetal blood sampling to be carried out. This harm was not seen in the comparison with CTG in combination with fetal scalp stimulation, although in this comparison the number of caesarean births was increased. The committee agreed that it was difficult to define whether this outcome was harmful or a benefit as it may indicate that a birth had been expedited appropriately. The committee were aware, based on their knowledge and experience, that the time taken to carry out fetal blood sampling can delay appropriate expedition of birth, and that it can be an unpleasant procedure for the woman, especially in the absence of an effective epidural. The committee therefore agreed that the risks of fetal blood sampling were not balanced by the benefits and agreed it was no longer appropriate to recommend fetal blood sampling and they considered making a recommendation to advise that it should not be used. However, the committee were aware of an ongoing research study comparing fetal scalp stimulation with fetal blood sampling on maternal and fetal outcomes (FIRSST study) and did not wish to make recommendations which may impact on the completion of this study. The committee therefore agreed to make a recommendation advising on the current lack of evidence to support fetal blood sampling. The committee noted that the FIRSST study is due to be completed at the end of 2024 and that on its completion the advice on use of fetal blood sampling may need to be reviewed again. As there was on ongoing study the committee did not make a research recommendation. ## How the recommendation might affect practice The recommendations may reduce resource use, both of staff time and equipment needed to carry out the sampling process. Return to recommendation# Context This guideline covers the care of healthy women who go into labour at term. Of the 625,000 live births in England and Wales in 2021, approximately 90% were single babies born at term (37+0 weeks onwards), and so the recommendations in this guideline will affect over half a million women every year. Wherever birth happens (at home, in a midwifery-led unit or in an obstetric unit) monitoring the wellbeing of the woman and baby during labour is an important part of intrapartum care. The recommendations in this guideline cover fetal assessment and monitoring, including intermittent auscultation and cardiotocography. Risk assessment to determine the most appropriate method of monitoring is covered, as well as the interpretation of cardiotocograph traces, and escalation when fetal hypoxia is suspected. This guideline replaces the fetal monitoring section in the NICE guideline on intrapartum care. Editorial changes have been made to highlight the need for continual risk assessment of the woman and the baby in labour and to simplify the interpretation and categorisation of the cardiotocography (CTG) trace. The new guidance highlights that a change in the categorisation of the CTG is an intrapartum risk factor but equally important are the development of other intrapartum risk factors such as sepsis, slow progress, the presence of meconium and uterine tachysystole, all of which are associated with a poor outcome for the baby. There is a recognition that contraction frequency needs to be carefully monitored and the presence of 5 or more contractions in 10 minutes needs action. The updated guidance also reminds healthcare professionals that intravenous fluids should not be used as part of the management of an abnormal CTG unless the woman is hypotensive, and that the guideline is only applicable to the categorisation of intrapartum CTGs. The evidence on fetal blood sampling has been reviewed for this update and the recommendations updated based on recent evidence.	{'Recommendations': 'People have the right to be involved in discussions and make informed decisions about their care, as described in NICE\'s information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information and supported decision-making\n\nFor more guidance on providing information, including providing accessible information, see the NICE guidelines on patient experience in adult NHS services and shared decision-making.\n\nDiscuss fetal monitoring options with a woman as part of her antenatal care and document the discussions and decisions in her personalised care plan. \n\nThroughout labour, provide women with information on the fetal monitoring method being advised and the reasons for this advice. \n\nSupport the woman\'s decision about fetal monitoring during labour. Include birthing companion(s) in these discussions if appropriate, and if that is what the woman wants. Document these discussions and decisions in the woman\'s notes. \n\nKeep women and their birthing companion(s) informed about what is happening if additional advice or review is being sought by the care team, for example from a senior midwife or obstetrician. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and supported decision-making\xa0.\n\nLoading. Please wait.\n\n# Assessment during labour and methods for fetal monitoring\n\n## General principles\n\nPerform and document a systematic assessment of the condition of the woman and unborn baby every hour, or more frequently if there are concerns. See the NICE guideline on intrapartum care for more information on the monitoring recommendations for different stages of labour. [2017, amended 2022]\n\nDiscuss the results of each hourly assessment with the woman and base recommendations about care in labour on her preferences and:\n\nher reports of the frequency, length and strength of her contractions\n\nany antenatal and intrapartum risk factors for fetal compromise\n\nthe current wellbeing of the woman and unborn baby\n\nhow labour is progressing.Include birthing companion(s) in these discussions if appropriate, and if that is what the woman wants. [2017, amended 2022]\n\nRemember that:\n\nfetal heart rate monitoring is a tool to provide guidance on fetal condition, and not a standalone diagnostic tool\n\nthe findings from monitoring need to be looked at together with the developing clinical picture for both woman and baby. \n\nEnsure one-to-one support is maintained by having a midwife remain with the woman throughout labour. If the midwife needs to leave the room or there needs to be a change in staff, ensure the woman knows this is happening. [2017, amended 2022]\n\n## Initial assessment\n\nPerform an initial assessment of antenatal risk factors for fetal compromise at the onset of labour to determine whether intermittent auscultation or cardiotocography (CTG) is offered as the initial method of fetal heart rate monitoring. Take into account the recommendations for fetal monitoring for women who are considered to be at higher risk of complications during labour because of existing medical conditions or obstetric complications (see the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies) or for women with multiple pregnancies (see the section on fetal monitoring during labour in twin pregnancy in the NICE guideline on twin and triplet pregnancy). \n\nConfirm with the woman which method of fetal monitoring has already been advised as part of their personalised care plan. \n\nExplain to the woman that risk assessment is a continual process, and the advised method of fetal heart rate monitoring may change throughout the course of labour. \n\nExplain to women that if there are no identified risk factors for fetal compromise:\n\nthere is a risk of increased interventions with continuous CTG monitoring compared with intermittent auscultation, which may outweigh the benefits and\n\nadvice she is given by her midwife or obstetrician on the method of fetal heart rate monitoring will take into account the whole clinical picture. [2017, amended 2022]\n\n## Intermittent auscultation\n\nOffer women with a low risk of complications, fetal heart rate monitoring with intermittent auscultation when in established first stage of labour. Do this as follows:\n\nuse either a Pinard stethoscope or doppler ultrasound\n\ncarry out intermittent auscultation immediately after a palpated contraction for at least 1\xa0minute, repeated at least once every 15\xa0minutes, and record it as a single rate on a partogram and in the woman\'s notes\n\nrecord accelerations and decelerations, if heard\n\npalpate (and record on the partogram) the maternal pulse hourly, or more often if there are any concerns, to ensure differentiation between the maternal and fetal heartbeats\n\nif no fetal heartbeat is detected, offer urgent real-time ultrasound assessment to check fetal viability. [2017, amended 2022]\n\nOnce the woman has signs of, or is in confirmed second stage of labour:\n\nperform intermittent auscultation immediately after a palpated contraction for at least 1\xa0minute, repeated at least once every 5\xa0minutes and record it as a single rate on a partogram and in the woman\'s notes\n\npalpate the woman\'s pulse simultaneously to differentiate between the maternal and fetal heart rates\n\nif there are concerns about differentiating between the 2 heart rates, seek help and consider changing the method of fetal heart rate monitoring (see recommendation 1.4.6). [2007, amended 2022]\n\nIf, on intermittent auscultation, there is an increase in the fetal heart rate (as plotted on the partogram) of 20\xa0beats a minute or more from the start of labour, or a deceleration is heard:\n\ncarry out intermittent auscultation more frequently (for example, after 3 consecutive contractions)\n\ncarry out a full review, taking into account the whole clinical picture including antenatal and existing or new intrapartum risk factors, maternal observations, contraction frequency (including hypertonus) and the progress of labour. [2017, amended 2022]\n\nIf fetal heart rate concerns are confirmed:\n\nsummon help\n\nadvise continuous CTG monitoring, and explain to the woman and her birth companion(s) why it is recommended, and the implications for her choices of type and place of care\n\ntransfer the woman from midwifery-led to obstetric-led care, providing that it is safe and appropriate to do so (follow the general principles for transfer of care in the NICE guideline on intrapartum care for healthy women and babies). [2017, amended 2022]\n\nReturn to intermittent auscultation if continuous CTG monitoring has been started because of concerns arising from intermittent auscultation but the CTG trace is normal after 20\xa0minutes, unless the woman decides to remain on continuous CTG monitoring. [2017, amended 2022]\n\nAdvise continuous CTG monitoring if:\n\nfetal heart rate concerns arise with intermittent auscultation and are ongoing, or\n\nintrapartum maternal or fetal risk factors develop (see the section on indications for continuous cardiotocography monitoring in labour). [2017, amended 2022]\n\n## Continuous cardiotocography\n\nDo not use the advice in this guideline to categorise antenatal CTG traces. \n\nUse the advice in this guideline to interpret and categorise intrapartum CTG traces, but when interpreting how the baby is coping with labour take into account maternal, fetal and labour factors as well as CTG changes. \n\nConsider a lower threshold for escalation when there are any antenatal or intrapartum risk factors that could lead to fetal compromise. \n\nEncourage and help women to be as mobile as possible, to find positions that are comfortable for them, and to change position as often as they wish. [2017, amended 2022]\n\nOffer continuous CTG monitoring as part of fetal assessment if any antenatal or intrapartum risk factors for fetal compromise are present. See the section on indications for continuous cardiotocography monitoring in labour. \n\nDiscuss with the woman and her birth companion(s) the reasons for offering continuous CTG monitoring, and explain that:\n\na combination of antenatal risk factors, intrapartum risk factors and continuous CTG monitoring are used to evaluate the baby\'s condition in labour\n\ncontinuous CTG monitoring is used to monitor the baby\'s heart rate and the labour contractions\n\nit may restrict her mobility and the option to labour in water\n\na normal CTG trace indicates that the baby is coping well with labour\n\nchanges to the baby\'s heart rate pattern during labour are common and do not necessarily cause concern, however they may represent developing fetal compromise so maintaining continuous CTG monitoring is advised if these occur\n\nif the CTG trace changes or is not normal there will be less certainty about the condition of the baby and so maintaining continuous CTG monitoring is advised, in conjunction with a full assessment including checks for developing intrapartum risk factors such as the presence of meconium, sepsis and slow progress in labour\n\nadvice about her care during labour and birth will be based on an assessment of several factors, including her preferences, her condition and the condition of her baby, as well as the findings from the CTG. [2017, amended 2022]\n\n## Telemetry\n\nEnsure wireless transducers are kept charged and maintained so that they are ready to use. \n\nSwitch from wireless to wired transducers as soon as possible if there is signal loss which is not resolved by reducing the distance between the base unit and the woman, in order to confirm whether or not there is a clinical problem. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment during labour and methods for fetal monitoring\xa0.\n\nLoading. Please wait.\n\n# Indications for continuous cardiotocography monitoring in labour\n\n## Antenatal risk factors\n\nOffer continuous cardiotocography (CTG) monitoring to women in labour if it is in their personalised care plan. \n\nOffer continuous CTG monitoring for women in labour who have any of the following antenatal maternal risk factors:\n\nprevious caesarean birth or other full thickness uterine scar\n\nany hypertensive disorder needing medication\n\nprolonged ruptured membranes (but women who are already in established labour at 24\xa0hours after their membranes ruptured do not need CTG unless there are other concerns)\n\nany vaginal blood loss other than a show\n\nsuspected chorioamnionitis or maternal sepsis\n\npre-existing diabetes (type\xa01 or type\xa02) and gestational diabetes requiring medication. [2014, amended 2022]\n\nOffer continuous CTG monitoring for women in labour who have any of the following antenatal fetal risk factors:\n\nnon-cephalic presentation (including breech, transverse, oblique and cord), including while a decision is made about mode of birth\n\nfetal growth restriction (estimated fetal weight below 3rd centile)\n\nsmall for gestational age (estimated fetal weight below 10th centile) with other high-risk features such as abnormal doppler scan results, reduced liquor volume or reduced growth velocity\n\nadvanced gestational age (more than 42+0\xa0weeks at the onset of established labour)\n\nanhydramnios or polyhydramnios\n\nreduced fetal movements in the 24 hours before the onset of regular contractions. [2014, amended 2022]\n\nConsider continuous CTG monitoring if, based on clinical assessment and multidisciplinary review, there are concerns about other antenatal factors not listed above that may lead to fetal compromise. \n\n## Ongoing risk assessment\n\nCarry out a full assessment of the woman and her baby every hour. At each assessment include:\n\nmaternal antenatal risk factors for fetal compromise\n\nfetal antenatal risk factors for fetal compromise\n\nnew or developing intrapartum risk factors\n\nprogress in labour including characteristics of contractions (frequency, strength and duration)\n\nfetal heart rate monitoring, including changes to the fetal heart rate pattern.Discuss with the woman any changes identified since the last review, and the implications of these changes. Include birthing companion(s) in these discussions if appropriate and if that is what the woman wants. [2017, amended 2022]\n\nObtain an in-person review of every hourly assessment (see recommendation 1.3.5) by another clinician ("fresh eyes") for women on CTG, to be completed before the next assessment takes place. \n\n## Intrapartum risk factors\n\nBe aware that intrapartum risk factors may increase the risk of fetal compromise, and that intrapartum risk factors that develop as labour progresses are particularly concerning. \n\nOffer continuous CTG monitoring for women who have or develop any of the following new intrapartum risk factors:\n\ncontractions that last longer than 2\xa0minutes, or 5 or more contractions in 10\xa0minutes\n\nthe presence meconium (see the section on the presence of meconium)\n\nmaternal pyrexia (a temperature of 38°C or above on a single reading or 37.5°C or above on 2 consecutive occasions 1\xa0hour apart). See the section on preventing early-onset neonatal infection before birth in the NICE guideline on neonatal infection: antibiotics for prevention and treatment\n\nsuspected chorioamnionitis or sepsis (see the section on preventing early-onset neonatal infection before birth in the NICE guideline on neonatal infection: antibiotics for prevention and treatment)\n\npain reported by the woman that appears, based on her description or her previous experience, to differ from the pain normally associated with contractions\n\nfresh vaginal bleeding that develops in labour\n\nblood-stained liquor not associated with vaginal examination, that is likely to be uterine in origin (and may indicate suspected antepartum haemorrhage)\n\nmaternal pulse over 120\xa0beats a minute on 2 occasions 30\xa0minutes apart\n\nsevere hypertension (a single reading of either systolic blood pressure of 160\xa0mmHg or more or diastolic blood pressure of 110\xa0mmHg or more, measured between contractions)\n\nhypertension (either systolic blood pressure of 140\xa0mmHg or more or diastolic blood pressure of 90\xa0mmHg or more on 2 consecutive readings taken 30\xa0minutes apart, measured between contractions)\n\na reading of 2+ of protein on urinalysis and a single reading of either raised systolic blood pressure (140\xa0mmHg or more) or raised diastolic blood pressure (90\xa0mmHg or more)\n\nconfirmed delay in the first or second stage of labour (see the NICE guideline on intrapartum care for healthy women and babies)\n\ninsertion of regional analgesia (for example, an epidural)\n\nuse of oxytocin. [2017, amended 2022]\n\nConsider continuous CTG monitoring if, based on clinical assessment and multidisciplinary review, there are concerns about other intrapartum factors not listed above that may lead to fetal compromise. \n\n## Presence of meconium\n\nWhen assessing risk at any time during labour, be aware that the presence of meconium:\n\ncan indicate possible fetal compromise, and\n\nmay lead to complications, such as meconium aspiration syndrome. \n\nConsider the character of the meconium as part of the overall clinical assessment, in conjunction with other antenatal or intrapartum risk factors, and discuss the option of CTG monitoring with the woman. Recognise that the type of monitoring method used is the woman\'s choice, and support her decision. \n\nBe aware that meconium is more common post-term, but should still trigger a full risk assessment and discussion with the woman about the option of CTG monitoring. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indications for continuous cardiotocography monitoring in labour\xa0.\n\nLoading. Please wait.\n\n# Use of cardiotocography for monitoring during labour\n\nReview the previous fetal heart rate monitoring results, including any previous CTG traces, as part of the hourly risk assessment and in conjunction with other antenatal or intrapartum risk factors (see the section on indications for continuous cardiotocography monitoring in labour) and determine if there are any changes in baseline fetal heart rate, variability or decelerations. [2017, amended 2022]\n\nIf there are changes in the fetal heart rate pattern over time which indicate a change in the baby\'s condition, review antenatal or intrapartum risk factors for hypoxia. \n\nWhen reviewing a CTG trace, assess and document:\n\ncontractions\n\nbaseline fetal heart rate\n\nvariability\n\npresence or absence of decelerations (and characteristics of decelerations if present)\n\npresence of accelerations. [2017, amended 2022]\n\nIf there is a stable baseline fetal heart rate between 110 and 160\xa0beats a minute and normal variability, continue usual care as the risk of fetal acidosis is low. \n\nDifferentiate between the maternal and fetal heartbeats hourly, or more often if there are any concerns. \n\nIf there are concerns about whether the maternal heart rate is being heard rather than the fetal heart rate, discuss with the woman the methods available to differentiate and support her decision on which method to use. Options include:\n\nfetal heart rate auscultation with a Pinard stethoscope\n\nbedside ultrasound scanning\n\ncontinuous maternal heart rate monitoring (using a pulse oximeter or the facility on the CTG equipment)\n\nfetal heart rate detection using a fetal scalp electrode which is attached to the baby\'s head (but be aware this may detect maternal heart rate if there is no fetal heartbeat, so should always be used in conjunction with maternal heart rate monitoring)\n\nsimultaneous palpation of the woman\'s pulse while listening to the fetal heart rate. \n\nBe aware that it is particularly important to confirm the fetal heart rate in the second stage of labour, when it is easier to mistakenly auscultate maternal rather than fetal heart rate. \n\nIf concerns about differentiation between the maternal and fetal heart rate remain, or if a fetal heart cannot be heard, obtain an urgent review by an obstetrician or senior midwife. \n\nEnsure that the CTG trace is of high quality and, if not, take action to improve the trace (for example, by repositioning the tocodynamometer, the transducer or by using a fetal scalp electrode). [2017, amended 2022]\n\nWhen reviewing CTG traces:\n\nevaluate changes on traces over time to ascertain changes in the baby\'s condition\n\ndocument any changes in the CTG trace from the previous review\n\nreview the changes alongside any existing and new intrapartum risk factors\n\nthink about the possible reasons for any changes, and take these and the whole clinical picture into account when planning ongoing care. \n\n## Features of cardiotocography\n\nCategorise the 4 features of the cardiotocography trace (contractions, baseline fetal heart rate, variability, decelerations) as white, amber or red (indicating increasing levels of concern) and use alongside consideration of the presence of accelerations to classify the overall CTG trace (see recommendation 1.4.31).\n\nUse a tocodynamometer to record contraction frequency and length on the CTG trace. \n\nUse the following to work out the categorisation for contractions (see recommendation 1.4.31 to work out the overall categorisation for the CTG):\n\nwhite\n\n\n\nfewer than 5\xa0contractions in 10\xa0minutes\n\n\n\namber\n\n\n\nor more contractions in 10\xa0minutes, leading to reduced resting time between contractions, or\n\nhypertonus. \n\n\n\nIf decelerations are present, evaluate their timing related to contractions. \n\nIf 5 or more contractions per 10\xa0minutes are present:\n\nperform a full risk assessment\n\ntake action to reduce contraction frequency as described in the section on underlying causes and conservative measures\n\nexplain to the woman what is happening, and ensure that she has adequate pain relief. \n\nDetermine baseline fetal heart rate by looking at the mean fetal heart rate, excluding accelerations and decelerations, over a period of 10\xa0minutes when the fetal heart rate is stable. When deciding if there is any change in baseline fetal heart rate, compare it with earlier CTG traces or recordings of fetal heart rate. \n\nUse the following to work out the categorisation for baseline fetal heart rate (see recommendation 1.4.31 to work out the overall categorisation for the CTG):\n\nwhite\n\n\n\nstable baseline of 110 to 160\xa0beats a minute\n\n\n\namber\n\n\n\nincrease in baseline fetal heart rate of 20\xa0beats a minute or more from the start of labour or since the last review an hour ago, or\n\nto 109\xa0beats a minute (but see recommendation 1.4.16), or\n\nunable to determine baseline\n\n\n\nred\n\n\n\nbelow 100\xa0beats a minute, or\n\nabove 160\xa0beats a minute. [2017, amended 2022]\n\n\n\nWhen assessing baseline fetal heart rate, differentiate between fetal and maternal heartbeats and take the following into account:\n\nbaseline fetal heart rate will usually be between 110 and 160\xa0beats a minute\n\nlower baseline fetal heart rates are expected with post-term pregnancies, with higher baseline rates in preterm pregnancies\n\na rise in baseline fetal heart rate may represent either developing infection or hypoxia (see the section on preventing early-onset neonatal infection before birth in the NICE guideline on neonatal infection: antibiotics for prevention and treatment)\n\nalthough a baseline fetal heart rate between 100 and 109\xa0beats a minute is an amber feature, continue usual care if this has been stable throughout labour and there is normal variability and no variable or late decelerations. [2017, amended 2022]\n\nDetermine variability by looking at the minor oscillations in the fetal heart rate, which usually occur at 3\xa0to 5\xa0cycles a minute. Measure it by estimating the difference in beats per minute between the highest heart rate and the lowest heart rate in a 1‑minute segment of the trace between contractions, excluding decelerations and accelerations. \n\nIf there is an absence of variability, carry out a review of the whole clinical picture with a low threshold for expedited birth, as this is a very concerning feature. \n\nUse the following to work out the categorisation for fetal heart rate variability (see recommendation 1.4.31 to work out the overall categorisation for the CTG):\n\nwhite\n\n\n\nto 25\xa0beats a minute\n\n\n\namber\n\n\n\nfewer than 5\xa0beats a minute for between 30\xa0and 50 minutes, or\n\nmore than 25\xa0beats a minute for up to 10\xa0minutes\n\n\n\nred\n\n\n\nfewer than 5 beats a minute for more than 50 minutes, or\n\nmore than 25\xa0beats a minute for more than 10\xa0minutes, or\n\nsinusoidal. [2017, amended 2022]\n\n\n\nTake the following into account when assessing fetal heart rate variability:\n\nvariability will usually be between 5 and 25\xa0beats a minute\n\nintermittent periods of reduced variability are normal, especially during periods of quiescence (\'sleep\')\n\ncertain medicines, such as opioids, may lead to a reduction in variability, but all other intrapartum risk factors should be carefully reviewed as a potential cause (for example, look for other features on the CTG such as a rise in the baseline fetal heart suggestive of another reason such as sepsis)\n\nincreased variability refers to oscillations around the baseline fetal heart rate of more than 25\xa0beats a minute, and shorter episodes lasting a few minutes may represent worsening fetal condition. [2017, amended 2022]\n\nObtain an urgent review by an obstetrician or senior midwife and consider expediting birth if:\n\nthere is an isolated reduction in variability to fewer than 5\xa0beats per minute for more than 30\xa0minutes when combined with antenatal or intrapartum risk factors, as this is associated with an increased risk of adverse neonatal outcomes, or\n\nthere is a reduction in variability to fewer than 5\xa0beats per minute combined with other CTG changes, particularly a rise in the baseline fetal heart rate, as this is a strong indicator for fetal compromise. \n\nDefine decelerations as transient episodes when the fetal heart rate slows to below the baseline level by more than 15\xa0beats a minute, with each episode lasting 15\xa0seconds or more. An exception to this is that in a trace with reduced variability, decelerations may be \'shallow\'. \n\nWhen assessing the significance of decelerations in fetal heart rate, consider:\n\ntheir timing (early, variable or late) in relation to the peaks and duration of the contractions\n\nthe duration of the individual decelerations\n\nwhether or not the fetal heart rate returns to the baseline heart rate\n\nhow long they have been present for\n\nwhether they occur with over 50% of contractions (defined as repetitive)\n\nthe presence or absence of shouldering\n\nthe variability within the deceleration. [2017, amended 2022]\n\nRegard the following as concerning characteristics of variable decelerations:\n\nlasting more than 60\xa0seconds\n\nreduced variability within the deceleration\n\nfailure or slow return to baseline fetal heart rate\n\nloss of previously present shouldering. [2017, amended 2022]\n\nDescribe decelerations as \'early\', \'variable\' or \'late\'. Do not use the terms \'typical\' and \'atypical\', as they can cause confusion. \n\nUse the following to work out the categorisation for decelerations in fetal heart rate (see recommendation 1.4.31 to work out the overall categorisation for the CTG):\n\nwhite\n\n\n\nno decelerations, or\n\nearly decelerations, or\n\nvariable decelerations that are not evolving to have concerning characteristics\n\n\n\namber\n\n\n\nrepetitive variable decelerations with any concerning characteristics for less than 30\xa0minutes, or\n\nvariable decelerations with any concerning characteristics for more than 30\xa0minutes, or\n\nrepetitive late decelerations for less than 30\xa0minutes\n\n\n\nred\n\n\n\nrepetitive variable decelerations with any concerning characteristics for more than 30\xa0minutes, or\n\nrepetitive late decelerations for more than 30\xa0minutes, or\n\nacute bradycardia, or a single prolonged deceleration lasting 3\xa0minutes or more. [2017, amended 2022]\n\n\n\nTake into account that the longer and later the individual decelerations, the higher the risk of fetal compromise (particularly if the decelerations are accompanied by a rise in the baseline, a tachycardia or reduced or increased variability). [2017, amended 2022]\n\nStart conservative measures and carry out an urgent obstetric review if there are decelerations lasting longer than 30\xa0minutes in the presence of either a rise in the baseline heart rate or reduced variability. Take into account antenatal and intrapartum risk factors, such as suspected sepsis, the presence of meconium, slow progress of labour or the use of oxytocin, to determine whether there is a need for expedited birth. \n\nIf variable decelerations persist and other CTG changes are present, obtain an urgent review by an obstetrician and a senior midwife, as there is a risk of fetal compromise and acidosis. \n\nIf variable decelerations with no concerning characteristics and no other CTG changes, including no rise in the baseline fetal heart rate, are observed:\n\nbe aware that these are very common, can be a normal feature in an otherwise uncomplicated labour and birth, and are usually a result of cord compression\n\nsupport the woman to change position or mobilise. [2017, amended 2022]\n\nTake the following into account when categorising early decelerations:\n\nthey are uncommon, benign and usually associated with head compression\n\nthey are not accompanied by any other CTG changes, such as reduced variability or a rise in the baseline fetal heart rate. [2017, amended 2022]\n\nDefine accelerations as transient increases in fetal heart rate of 15\xa0beats a minute or more, lasting 15\xa0seconds or more. \n\nTake the following into account when assessing accelerations in fetal heart rate:\n\nthe presence of fetal heart rate accelerations, even with reduced variability, is generally a sign that the baby is healthy\n\nthe absence of accelerations on an otherwise normal CTG trace does not indicate fetal acidosis. \n\nInclude CTG categorisation as part of the full assessment of the condition of the woman and baby. Be aware categorisation is a tool which quickly communicates the current state of the CTG and should be used together with antenatal and intrapartum risk factors, to assess changes over time. \n\nCategorise CTG traces as follows, based on whether each of the 4\xa0features (contractions, baseline, variability, decelerations) have been scored as white, amber or red:\n\nnormal\n\n\n\nno amber or red features (all 4\xa0features are white)\n\n\n\nsuspicious\n\n\n\nany 1\xa0feature is amber\n\n\n\npathological\n\n\n\nany 1\xa0feature is red, or\n\nor more features are amber. [2017, amended 2022]\n\n\n\nTake into account any change in the categorisation of the CTG alongside other antenatal and intrapartum risk factors for hypoxia. Discuss the change and its implications with the woman, and take into account her preferences when deciding how to proceed. \n\nTake into account that interpretation of CTG traces in the second stage of labour is more challenging than in the first stage of labour. Have a lower threshold for seeking a second opinion or assistance. \n\nEnsure the fetal heart rate is differentiated from the maternal heart rate at least once every 5\xa0minutes. Consider monitoring the baby with a fetal scalp electrode if there is concern about confusing the heart rates, but if this cannot be achieved expedite birth (see recommendation 1.4.6). \n\nIn the second stage of labour:\n\nif fetal heart rate accelerations are recorded, be aware that these are most likely to be maternal pulse (see recommendation 1.4.6 on steps to take to check whether the maternal or fetal heart rate is being detected)\n\nif fetal heart rate decelerations are recorded, look for other signs of hypoxia (for example, a rise in the baseline fetal heart rate or a reduction in variability). \n\nTake into account that onset of hypoxia is both more common and more rapid in the active second stage of labour. Take an increase in the baseline fetal heart rate of 20\xa0beats a minute or more from the start of labour or since the last review an hour ago as a red feature in active second stage labour. \n\nIf CTG concerns arise in the active second stage of labour:\n\nobtain an obstetric review\n\nconsider discouraging pushing and stopping any oxytocin infusion to allow the baby to recover, unless birth is imminent\n\nagree and document a clear plan with time limits for the next review. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on use of cardiotocography for monitoring during labour\xa0.\n\nLoading. Please wait.\n\n# Making care decisions based on the cardiotocography trace\n\nAssess fetal wellbeing every hour, taking into account antenatal and intrapartum risk factors, in conjunction with interpretation of the CTG trace. \n\nTake the whole clinical picture into account when making decisions on how to manage the labour, including maternal observations, contraction frequency and labour progress. \n\nDiscuss with the woman and her birth companion(s) what is happening, taking into account her individual circumstances and preferences, and support her decisions. \n\nIf the CTG trace is categorised as normal:\n\ncontinue CTG (unless it was started because of concerns arising from intermittent auscultation and there are no ongoing antenatal or intrapartum risk factors) and usual care\n\ncontinue to perform a full risk assessment at least hourly and document the findings. [2017, amended 2022]\n\nIf the CTG trace is categorised as suspicious and there are no other concerning risk factors:\n\nperform a full risk assessment, including a full set of maternal observations, taking into account the whole clinical picture, and document the findings\n\nnote that if accelerations are present then fetal acidosis is unlikely\n\nif the CTG trace was previously normal, consider possible underlying reasons for the change\n\nundertake conservative measures as indicated (see the section on underlying causes and conservative measures). [2017, amended 2022]\n\nIf the CTG trace is categorised as suspicious and there are additional intrapartum risk factors such as slow progress, sepsis or meconium:\n\nperform a full risk assessment, including a full set of maternal observations, taking into account the whole clinical picture, and document the findings\n\nconsider possible underlying causes, and undertake conservative measures as indicated (see the section on underlying causes and conservative measures)\n\nobtain an urgent review by an obstetrician or a senior midwife\n\nconsider:\n\n\n\nfetal scalp stimulation (see the section on fetal scalp stimulation), or\n\nexpediting birth. [2017, amended 2022]\n\n\n\nIf the CTG trace is categorised as pathological:\n\nobtain an urgent review by an obstetrician and a senior midwife\n\nexclude acute events (for example, cord prolapse, suspected placental abruption or suspected uterine rupture) that need immediate intervention\n\nperform a full risk assessment, including a full set of maternal observations, taking into account the whole clinical picture, and document the findings\n\nconsider possible underlying causes and undertake conservative measures as indicated (see the section on underlying causes and conservative measures). [2017, amended 2022]\n\nIf the CTG trace is still pathological after implementing conservative measures:\n\nobtain a further urgent review by an obstetrician and a senior midwife\n\nevaluate the whole clinical picture and consider expediting birth\n\nif there are evolving intrapartum risk factors for fetal compromise, have a very low threshold for expediting birth. [2017, amended 2022]\n\nIf there is an acute bradycardia, or a single prolonged deceleration for 3\xa0minutes or more:\n\nurgently seek obstetric review\n\nif there has been an acute event (for example, cord prolapse, suspected placental abruption or suspected uterine rupture), expedite the birth\n\nconsider possible underlying causes and undertake conservative measures as indicated (see the section on underlying causes and conservative measures)\n\nmake preparations for an urgent birth, including a request for paediatric or neonatal support.\n\nexpedite the birth if the acute bradycardia persists for 9\xa0minutes, or less if there are significant antenatal or intrapartum risk factors for fetal compromise.If the fetal heart rate recovers at any time up to 9\xa0minutes, reassess any decision to expedite the birth, but take into account other antenatal and intrapartum risk factors and discuss this with the woman. [2017, amended 2022]\n\nIf a decision is made to expedite birth, ensure the time at which urgent review was sought, and the time the decision was made, are documented. \n\nFor a short explanation of why the committee made the 2022 recommendation and how it might affect practice, see the rationale and impact section on making care decisions based on the cardiotocography trace\xa0.\n\nLoading. Please wait.\n\n## Underlying causes and conservative measures\n\nIf there are any concerns about the baby\'s wellbeing, be aware of the possible underlying causes and start 1 or more of the following conservative measures based on an assessment of the most likely cause(s):\n\nmaternal position (as this can affect uterine blood flow and cord compression), encourage the woman to mobilise, or adopt an alternative position, and to avoid being supine\n\nhypotension:\n\n\n\ndo not offer intravenous fluids to treat fetal heart rate abnormalities unless the woman is hypotensive or has signs of sepsis\n\nif the woman is hypotensive secondary to an epidural top-up, start intravenous fluids, move her to a left lateral position and call an anaesthetist to review\n\n\n\nexcessive contraction frequency:\n\n\n\nreduce contraction frequency by reducing or stopping oxytocin if it is being used\n\noffer a tocolytic drug (a suggested regimen is subcutaneous terbutaline 0.25\xa0mg). [2017, amended 2022]\n\n\n\nDo not offer maternal facial oxygen therapy as part of conservative measures because it may harm the baby. However, it can be used if it is given for maternal issues such as hypoxia, or as part of preoxygenation before a potential anaesthetic. [2017, amended 2022]\n\nDo not offer amnioinfusion for intrauterine fetal resuscitation. \n\n# Fetal scalp stimulation\n\nIf the CTG trace is suspicious with antenatal or intrapartum risk factors for fetal compromise, then consider digital fetal scalp stimulation. If this leads to an acceleration in fetal heart rate and a sustained improvement in the CTG trace, continue to monitor the fetal heart rate and clinical picture. [2017, amended 2022]\n\nBe aware that the absence of an acceleration in response to fetal scalp stimulation is a worrying sign that fetal compromise may be present, and that expedited birth may be necessary. [2017, amended 2022]\n\n# Fetal blood sampling\n\nNICE is unable to make a recommendation about fetal blood sampling because of limited evidence. \n\nFor a short explanation of why the committee made the recommendation and how it might affect practice, see the rationale and impact section on fetal blood sampling\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review\xa0A: fetal blood sampling.\n\nLoading. Please wait.\n\n# Record keeping for cardiotocography\n\nTo ensure accurate record keeping for CTG:\n\nmake sure that date and time clocks on the cardiotocograph monitor are set correctly\n\nensure the recording or paper speed is set at 1\xa0cm a minute and that adequate paper is available\n\nlabel traces with the woman\'s name, date of birth, hospital number or NHS number and pulse at the start of monitoring, and the date of the CTG. [2014, amended 2022]\n\nIndividual units should develop a system for recording relevant intrapartum events (for example, vaginal examination and siting of an epidural) in standard notes and/or on the cardiotocograph trace. [2014, amended 2022]\n\nKeep cardiotocograph traces for 25\xa0years and, if possible, store them electronically. [2007, amended 2014]\n\nIn cases where there is concern that the baby may have sustained a possible brain injury, photocopy cardiotocograph traces (if they are not available electronically) and store them indefinitely in case of possible adverse outcomes. [2007, amended 2022]\n\nEnsure that tracer systems are available for all cardiotocograph traces if stored separately from the woman\'s records. [2007, amended 2014]\n\nDevelop tracer systems to ensure that cardiotocograph traces removed for any purpose (such as risk management or for teaching purposes) can always be located. [2007, amended 2014]\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Early decelerations\n\nRepetitive and periodic slowing of the fetal heart rate with onset early in the contraction and return to baseline at the end of the contraction. These are uncommon.\n\n## Hypertonus\n\nA contraction lasting 2\xa0minutes or longer.\n\n## Late decelerations\n\nRepetitive and periodic slowing of the fetal heart rate with onset mid to end of the contraction and the lowest point more than 20\xa0seconds after the peak of the contraction, and ending after the contraction.\n\n## Variable decelerations\n\nIntermittent and periodic slowing of the fetal heart rate with a variable time in relation to the contraction.', 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Information and supported decision-making\n\nRecommendations 1.1.1 to 1.1.4\n\n## Why the committee made the recommendations\n\nThe committee agreed, based on their knowledge and expertise, that discussions about fetal monitoring should occur as part of antenatal care and be documented in the personalised care plan. Although healthcare professionals currently always provide advice to women in labour on options for fetal monitoring, they should also support the decision made by the woman about which method to use.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current practice.\n\nReturn to recommendations\n\n# Assessment during labour and methods for fetal monitoring\n\nRecommendations 1.2.3, 1.2.5 to 1.2.7, 1.2.15 to 1.2.17, 1.2.19, 1.2.21 and 1.2.22\n\n## Why the committee made the recommendations\n\nBased on their knowledge and expertise, the committee emphasised that fetal heart rate monitoring is only a tool that provides information. It should be used as part of assessing the whole clinical picture including antenatal and intrapartum risk factors, not as a standalone diagnostic tool, and that multiple risk factors may lower the threshold for intervention.\n\nThe committee discussed the initial assessment that should be carried out at the start of labour and agreed that a decision on the method of monitoring should be based on antenatal risk factors. These risk factors should have been identified and discussed with the woman during antenatal care and should already be recorded in her personalised care plan. However, the committee agreed it was important to advise women that the recommended method of fetal monitoring may change during labour (based on a clinical decision or because the woman changes her mind), but that for women at low risk, the use of cardiotocography (CTG) may lead to more interventions without evidence of benefit.\n\nThe committee were aware that there was the possibility of confusion between the interpretation of antenatal and intrapartum CTG and so made a recommendation to clarify this.\n\nThe committee were aware of incidences where telemetry was not available because transducers had not been plugged in to charge, or where CTG was not used effectively because of problems with signal loss, so they made recommendations to reduce such events based on their knowledge and experience.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current best practice and help ensure the full clinical picture is looked at.\n\nReturn to recommendations\n\n# Indications for continuous cardiotocography monitoring in labour\n\nRecommendations 1.3.1, 1.3.4, 1.3.6, 1.3.7 and 1.3.9 to 1.3.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that a decision to use CTG monitoring may already have been discussed and recorded in a woman's personalised care plan, but that antenatal risk factors identified during pregnancy or labour, or new intrapartum risk factors would mean that CTG was advised to assess if there was developing fetal compromise. The committee were aware that the lists of antenatal and intrapartum risk factors covered all commonly recognised risk factors but clinical judgement would be needed to determine if there were other risk factors not listed which also might lead to consideration of CTG.\n\nThe committee agreed that the presence of any meconium, not just significant meconium, should be taken into account when assessing the whole clinical picture and considering the use of CTG.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current practice.\n\nReturn to recommendations\n\n# Use of cardiotocography for monitoring during labour\n\nRecommendations 1.4.2, 1.4.6 to 1.4.8, 1.4.10 to 1.4.12, 1.4.14, 1.4.17, 1.4.20, 1.4.26, 1.4.27, 1.4.31, 1.4.33 and 1.4.34 to 1.4.38\n\n## Why the committee made the recommendations\n\nRecommendations 1.4.2, 1.4.6 to 1.4.8 and 1.4.10: The committee used their knowledge and expertise and agreed that any changes in the CTG, including the fetal heart rate pattern, over time indicated that the baby may be suffering from hypoxia. They agreed this should be investigated, alongside a review of the clinical picture and antenatal or intrapartum risk factors, so that causes could be sought and action could be taken, if necessary.\n\nThe committee agreed, based on their knowledge and expertise, to provide advice about the actions to take when it is difficult to distinguish between the maternal and fetal heart rate, as incorrect monitoring can lead to significant harm to the baby.\n\nRecommendations 1.4.11 to 1.4.12 and 1.4.14: The committee agreed, based on their knowledge and expertise, that as well as monitoring the fetal heart rate pattern, it was important to monitor and record contractions to determine if they were normal and, if not, to take action.\n\nRecommendations 1.4.17 and 1.4.20: The committee defined how variability should be measured. The committee were aware, based on their knowledge and expertise, that an absence of variability was concerning and so made a recommendation to address this.\n\nRecommendation 1.4.20: The committee were aware, based on their knowledge and expertise, that a reduction in variability is not specific for fetal hypoxia. However, it does indicate an increased risk of adverse neonatal outcome and therefore requires obstetric review when combined with antenatal or intrapartum risk factors for fetal compromise. If a reduction in variability is combined with other amber or red features on the CTG, it will be classified as pathological, and the committee have emphasised the need for urgent review in these circumstances.\n\nRecommendation 1.4.26 and 1.4.27: The committee wanted to emphasise, based on their knowledge and expertise, that decelerations lasting longer than 30\xa0minutes combined with other CTG abnormalities should trigger an urgent obstetric review as this combination is particularly concerning for fetal compromise.\n\nRecommendations 1.4.31 and 1.4.33: The committee were aware, based on their knowledge and expertise, that too much reliance may be placed on the categorisation of CTG trace as a substitute for reviewing and communicating about the wider clinical picture. They stated that CTG categorisation was a tool that should be used alongside review of other antenatal and intrapartum risk factors and the wider clinical picture.\n\nRecommendations 1.4.34 to 1.4.38: The committee were aware, based on their knowledge and expertise, that in the second stage of labour it may be more difficult to differentiate the maternal and fetal heart rates, and that hypoxia may develop more rapidly, and so made new recommendations about this.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current practice.\n\nReturn to recommendations\n\n# Making care decisions based on the cardiotocography trace\n\nRecommendation 1.5.10\n\n## Why the committee made the recommendation\n\nThe committee advised, based on their knowledge and experience, that documentation of reviews and decisions was important.\n\n## How the recommendation might affect practice\n\nThe recommendation will reinforce current practice.\n\nReturn to recommendation\n\n# Fetal blood sampling\n\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\n\nThere was recent but very limited evidence that fetal blood sampling does not improve outcomes for women and babies compared with CTG alone, or compared with CTG in combination with fetal scalp stimulation. The comparison with CTG alone showed that fetal blood sampling may increase the proportion of babies with an Apgar score less than 7 at 5\xa0minutes, possibly because of a delay in expediting birth to allow the fetal blood sampling to be carried out. This harm was not seen in the comparison with CTG in combination with fetal scalp stimulation, although in this comparison the number of caesarean births was increased. The committee agreed that it was difficult to define whether this outcome was harmful or a benefit as it may indicate that a birth had been expedited appropriately.\n\nThe committee were aware, based on their knowledge and experience, that the time taken to carry out fetal blood sampling can delay appropriate expedition of birth, and that it can be an unpleasant procedure for the woman, especially in the absence of an effective epidural. The committee therefore agreed that the risks of fetal blood sampling were not balanced by the benefits and agreed it was no longer appropriate to recommend fetal blood sampling and they considered making a recommendation to advise that it should not be used. However, the committee were aware of an ongoing research study comparing fetal scalp stimulation with fetal blood sampling on maternal and fetal outcomes (FIRSST study) and did not wish to make recommendations which may impact on the completion of this study. The committee therefore agreed to make a recommendation advising on the current lack of evidence to support fetal blood sampling. The committee noted that the FIRSST study is due to be completed at the end of 2024 and that on its completion the advice on use of fetal blood sampling may need to be reviewed again.\n\nAs there was on ongoing study the committee did not make a research recommendation.\n\n## How the recommendation might affect practice\n\nThe recommendations may reduce resource use, both of staff time and equipment needed to carry out the sampling process.\n\nReturn to recommendation", 'Context': 'This guideline covers the care of healthy women who go into labour at term. Of the 625,000 live births in England and Wales in 2021, approximately 90% were single babies born at term (37+0 weeks onwards), and so the recommendations in this guideline will affect over half a million women every year.\n\nWherever birth happens (at home, in a midwifery-led unit or in an obstetric unit) monitoring the wellbeing of the woman and baby during labour is an important part of intrapartum care. The recommendations in this guideline cover fetal assessment and monitoring, including intermittent auscultation and cardiotocography. Risk assessment to determine the most appropriate method of monitoring is covered, as well as the interpretation of cardiotocograph traces, and escalation when fetal hypoxia is suspected.\n\nThis guideline replaces the fetal monitoring section in the NICE guideline on intrapartum care. Editorial changes have been made to highlight the need for continual risk assessment of the woman and the baby in labour and to simplify the interpretation and categorisation of the cardiotocography (CTG) trace. The new guidance highlights that a change in the categorisation of the CTG is an intrapartum risk factor but equally important are the development of other intrapartum risk factors such as sepsis, slow progress, the presence of meconium and uterine tachysystole, all of which are associated with a poor outcome for the baby. There is a recognition that contraction frequency needs to be carefully monitored and the presence of 5 or more contractions in 10\xa0minutes needs action. The updated guidance also reminds healthcare professionals that intravenous fluids should not be used as part of the management of an abnormal CTG unless the woman is hypotensive, and that the guideline is only applicable to the categorisation of intrapartum CTGs. The evidence on fetal blood sampling has been reviewed for this update and the recommendations updated based on recent evidence.'}	https://www.nice.org.uk/guidance/ng229	This guideline covers methods for monitoring the wellbeing of the baby during labour. It includes risk assessment to determine the appropriate level of fetal monitoring, using clinical assessment in addition to fetal monitoring, and interpreting and acting on monitoring findings.
4f45ef4825d3964f48f8e67b6ef1ca1dc1eb5bdb	nice	Memokath 051 Ureter stent for ureteric obstruction	Memokath 051 Ureter stent for ureteric obstruction Evidence-based recommendations on Memokath 051 Ureter stent for ureteric obstruction. # Recommendations Memokath 051 Ureter stent is recommended as an option to manage ureteric obstruction in adults with: malignant ureteric obstruction and anticipated medium- or long-term survival after adjunctive therapy benign ureteric obstruction who cannot have or do not want reconstructive surgery any type of ureteric obstruction, and they cannot have or do not want a double‑J stent, or when repeat procedures are particularly high risk. Data should be collected prospectively on ureteric stent procedures, including details of patient selection, choice of stent placement procedure and stent used, and adverse events such as stent migration and encrustation rates. Why the committee made these recommendations NICE originally recommended Memokath 051 for ureteric obstruction for selected people. New clinical evidence from retrospective studies suggests that Memokath 051 relieves ureteric obstruction as well as other stents. For people with malignant ureteric obstruction, Memokath 051 may have advantages over some other treatments because it is a less invasive procedure than nephrostomy, with no need for hospital stay, and fewer stent replacements needed compared with other stents. Clinical experts also felt that it was important to have Memokath 051 as an option for other people, for example people who cannot have or do not want reconstructive surgery or a double-J stent, or when repeat procedures are particularly high risk. The cost modelling suggests Memokath 051 is likely to be cost saving compared with other stents. This is because it may not need to be replaced as often as other stents. But the cost savings are not certain because there's not enough good quality evidence. There is enough clinical evidence to continue recommending Memokath 051 for selected adults with ureteric obstruction. But prospective data is still needed to be certain about the cost savings of using it, compared with other stents.# The technology # Technology Memokath 051 Ureter stent is a biocompatible, thermo-expandable, nickel-titanium alloy ureteric stent. It is intended as an alternative to conventional ureteric stents for people with benign or malignant ureteric obstruction. The nickel-titanium alloy has a shape memory effect, which is designed to allow the stent to be more easily inserted and anchored into position. A spiral coil design aims to prevent endothelial ingrowth of the tumour or stricture into the stent so that it can be easily removed. Four different versions of the Memokath 051 stent are available (single or double cone, for either antegrade or retrograde insertion), each in several different lengths. Memokath 051 can be used to treat obstructions elsewhere in the urinary tract, but this is outside the scope of this evaluation. # Care pathway Ureteric obstruction can be treated by stenting the ureter, creating a nephrostomy or through reconstructive surgery. It must be treated quickly to avoid obstructive renal failure. Nephrostomy or stenting should be done as soon as possible (within 12 hours of diagnosis). For malignant obstruction, the NICE guideline on prostate cancer recommends decompression of the upper urinary tract by nephrostomy or inserting a double‑J stent. The NICE guideline on bladder cancer recommends nephrostomy or retrograde stenting (if technically feasible) for people with locally advanced or metastatic bladder cancer. The NICE guideline on acute kidney injury says that all people with upper urinary tract obstruction should be referred to a urologist. # Innovative aspects Memokath 051 can adapt to the natural curves of the urinary tract because of its tight spiral structure, which also makes it less likely that tissue grows between the coils. According to the company, compared with other stents, it is better tolerated, with fewer stent-related symptoms and complications. It reduces the need for stent replacement and the risk of tissue ingrowth. # Intended use Memokath 051 is intended for treating ureteric obstruction in adults with benign or malignant strictures. It is contraindicated for children. People with bleeding disorders or using anticoagulant medication are advised to check coagulation parameters, and the stent should not be implanted if their coagulation parameters are not within the range that would be suitable for surgical intervention. For a full list of contraindications and details on using Memokath 051, see the instructions for use. # Costs The cost of Memokath 051 used in the company's submission for the original guidance was £1,690 (excluding VAT). This included the Memokath 051 stent, a guidewire and a dilator-insertion sheath. The company confirmed that there is no change to the cost of Memokath 051 stents.For more details about the technology, see the website for Memokath 051 Ureter.# Evidence NICE commissioned an external assessment group (EAG) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website. # Clinical evidence from the original guidance ## Evidence came from 6 comparative studies and 10 single-arm studies The EAG identified 16 studies (6 comparative studies and 10 single-arm studies) including 6 publications of 5 studies submitted by the company at guidance review. The comparative studies all had a retrospective design, with a small sample size of up to 27 people (Akbarov et al. 2017) in each treatment arm. The single-arm studies were observational case series, with sample sizes ranging from 4 people (Boyvat et al. 2005) to 73 people (Papatsoris and Buchholz 2010). For full details of the clinical evidence, see section 3 of the original assessment report in the supporting documentation (Newcastle upon Tyne Hospitals and York Health Economics Consortium External Assessment Centre, 2017). ## Clinical success varied and its definition was not consistent Memokath 051 Ureter stent's clinical success rates ranged from 43% (Kim et al. 2014) to 100% (Granberg et al. 2010, Zaman et al. 2011). Results of the comparative studies suggested that the clinical success rate of Memokath 051 was comparable to double‑J stents (100% success rate in both arms; Granberg et al. 2010) and Resonance stents (82% and 86% respectively; Nam et al. 2015) but was lower than Allium stents (81% compared with 100%; Bolton et al. 2015), and UVENTA (43% compared with 82%; Kim et al. 2014). The definition of clinical success and how it was measured were not consistently reported in the studies. ## Evidence on the length of time that stents remain in place was limited Evidence from 2 comparative studies showed that Memokath 051 remained in place longer than double‑J stents (17 months compared with 4 months; NCT00166361, 2014) and UVENTA (14 months compared with 12 months; Kim et al. 2014). The average length of time in place using Memokath 051 was 11 months (Papatsoris and Buchholz 2010). ## Memokath 051 had higher stent migration and encrustation rates than other stents The evidence from the comparative studies suggested that stent migrations were higher with Memokath 051 than double‑J stents (11% against 0%; Maan et al. 2010) and UVENTA (43% against 6%; Kim et al. 2014). Encrustation rates were also higher with Memokath 051 than with double‑J stents (29% against 0%; NCT00166361, 2014) and Allium (19% against 0%; Bolton et al. 2015). The other most common adverse events included urinary tract infection (Akbarov et al. 2017, Klarskov et al. 2005, Papatsoris and Buchholz 2010, Zaman et al. 2011) and blockage or obstruction (Akbarov et al. 2017; Kim et al. 2014; Klarskov et al. 2005; NCT00166361 2014; Zaman et al. 2011). The EAG did a pooled analysis, the results of which suggested that the stent migration rate for Memokath 051 was 17.7% (13 studies) compared with 5.9% using UVENTA (1 study) and 0% using double‑J stents (2 studies) and Allium (1 study). The evidence was reviewed in 2021 and long-term retrospective data suggested higher complication rates with Memokath 051 than were previously reported, so NICE decided to update the guidance. # New clinical evidence ## New evidence comes from 7 studies including 1 systematic review and 2 comparative studies For the guidance update, the EAG considered 7 new studies including 2 abstracts: systematic review and meta-analysis (Khoo et al. 2018) retrospective non-randomised single-centre comparative studies (Choi et al. 2019, Khoo et al. 2021) retrospective single-arm single-centre studies (Bier et al. 2017, Diaz Romero et al. 2018, Elbaroni et al. 2020, Forster et al. 2021).For full details of the clinical evidence, see section 4 of the assessment report update in the supporting documentation (King's Technology Evaluation Centre , 2022). ## Evidence suggests clinical success is similar for Memokath 051 and mesh stent (UVENTA) in people with benign ureteral strictures Evidence from a comparative retrospective study of people with chronic benign ureteral strictures reported that primary success rates (maintaining patency without additional procedures) were 28.6% for Memokath 051 and 12.0% for UVENTA during the observation period (Choi et al. 2019). The overall success rates (success defined as maintaining patency after further salvage procedures) were 57.1% for Memokath 051 and 40.0% for UVENTA. The differences between the 2 stents were not statistically significant. This result is consistent with the original guidance, which showed Memokath 051 had similar clinical success rates to UVENTA in the population with benign ureteral strictures. ## Length of time the stent remains in place varies in the studies The new evidence suggested that the median duration of actual functional stent follow up (censored by stent failure, death or end of study) was 5.5 months for Memokath 051, 11.4 months for Allium and 11.7 months for Resonance. This is shorter than the 2 studies included in the previous guidance, which reported 14 months and 17 months of indwelling time (Kim et al. 2014; NCT00166361 2014). Results of single-arm studies reported a median indwelling time of 11.8 months (range 1 week to 70.8 months; Bier et al. 2017) and a median stent lifespan of 14.5 months and 13.4 months in people with malignant ureter obstruction and benign ureter obstruction respectively. ## Long-term data from a non-comparative study suggests high complication rates with Memokath 051 Forster et al. (2021) reported long-term outcomes using Memokath 051 in an NHS centre. Only 25 out of 100 people included did not have any complications during a 5‑year follow up. The common complications were stent migration (36%) and failed ipsilateral upper tract drainage (27%), which included blockage (14%), encrustation (11%) and lost renal function (2%). The study included a subgroup analysis of benign and malignant ureteric obstruction, and the overall complication rate was significantly higher in people with a benign obstruction (85.4%) than those with a malignant obstruction (62.7%). Stent migration was the most common complication in people with a benign obstruction (53.7%) and failed renal drainage was common in people with a malignant obstruction (30.5%). A comparative study with a 5.5‑month follow-up period for Memokath 051 suggested that it had higher migration, obstruction and infection rates than Resonance, regardless of whether it was a benign or malignant obstruction (Khoo et al. 2021). Duration of follow-up was censored by stent failure, patient death or end-of-study period. The study did not have long-term comparative data on the complication rates of different stents. # Cost evidence ## No new published economic studies were identified by the company or the EAG The original guidance included 3 economic studies, all of which compared the cost associated with using Memokath 051 with double‑J stents (Aintree University Hospital 2012; Gonzalez et al. 2011; Zaman et al. 2012). The results indicated that Memokath 051 was likely to be cost saving compared with double‑J stents, although the studies were poorly reported and included a heterogeneous group of people with varying types of obstruction and life expectancy. The company and EAG search did not identify any new published economic studies since the original guidance. The EAG considered the evidence from 4 new clinical studies including 2 UK studies (Forster et al. 2021, Khoo et al. 2021), 1 German study (Bier et al. 2017) and 1 Korean study (Choi et al. 2019) to be relevant for updating the risk of unplanned stent replacement in the economic model. ## Some changes were made to the company's model in the original guidance The company developed a simple cost model in the original guidance. The EAG thought that the company's cost model captured the key aspects of treatment, but that the way it dealt with certain structural issues was too simplistic, such as only including double‑J stents as a comparator. The EAG adapted the company's model and made the following main changes to the original guidance: extending the time horizon from 2.5 years to 5 years including reconstructive surgery and other metallic stents as comparators adding the ability to report a break-even time point between Memokath 051 and the comparators including the risk of urinary tract infections.Scenario analyses were also added to model the risk of unplanned Memokath 051 replacement. More details of the cost model are in sections 4.2.2 and 4.2.3 of the original assessment report in the supporting documentation (Newcastle upon Tyne Hospitals and York Health Economics Consortium External Assessment Centre, 2017). ## The EAG updated the cost parameters using new evidence The EAG considered that the original model structure and assumptions remained valid. It updated the model's parameters because of new evidence available: An increase in the monthly risk of unplanned stent replacement for Memokath 051 from 1.40% to 1.80% compared with double‑J, Allium, Resonance and reconstructive surgery. A decrease in the monthly risk of unplanned stent replacement for Memokath 051 from 4.40% to 3.57% compared with UVENTA for chronic benign ureteral strictures. The monthly risk of unplanned stent replacement remained unchanged for double‑J stents (0%). But the monthly risks of unplanned stent replacement were updated from: % to 5.54% for Allium % to 1.78% for Resonance % to 4.99% for UVENTA.The model assumed that if someone needed an unplanned stent replacement it automatically delayed the planned replacement by the length of time in situ (thus removing any double counting). For full details of the clinical parameters, see economic model parameters in section 9.2 of the assessment report update in the supporting documentation (KiTEC 2022). ## The EAG updated the costs for double-J stents, UVENTA and Resonance The cost of Memokath 051 and related consumables did not change. The EAG updated the cost of double‑J stents, UVENTA and Resonance according to the NHS Supply Chain reported unit prices. The cost of Allium was the same as the original guidance. The EAG also updated other costs such as staffing and follow-up visits using the most up-to-date data sources available. For full details of the cost sources, see economic model parameters in section 9.2 of the assessment report update in the supporting documentation (KiTEC, 2022). In the original guidance, a passport balloon dilator was needed when inserting Memokath 051, and the assumption was that a dilator was also needed when inserting UVENTA and Resonance stents. At consultation, the EAG ran a scenario analysis and found that removing the cost of a balloon dilator for Resonance had a minimal effect on overall costings and did not change the cost saving conclusion for Memokath 051. ## Updated EAG base-case results show Memokath 051 is cost saving compared with other stents but cost incurring compared with reconstructive surgery The EAG's updated base-case results showed that using Memokath 051 is cost saving per person over 5 years by: £1,926 compared with double‑J stents £6,260 compared with Resonance £8,813 compared with UVENTA £9,365 compared with Allium.But using Memokath 051 incurred an additional £1,321 per person over 5 years compared with reconstructive surgery. Memokath 051 was also cost incurring compared with reconstructive surgery in the original guidance (£467) but the size of the additional cost has increased. Base-case results were modelled over a 5‑year period, reflecting the indwelling duration for Memokath 051 after which planned replacement is needed. Risks of unplanned replacement were also applied for the full-time horizon of the model. ## Change in risk of stent replacement is the key cost driver The EAG's scenario analyses showed that, compared with UVENTA, Allium and Resonance, Memokath 051 was cost saving in all scenarios. Compared with double‑J stents, Memokath 051 was cost saving in all scenarios, except when the replacement cost of double‑J stents dropped to £717. Memokath 051 would be cost neutral if the replacement cost of a double‑J stent was £1,008. In addition, Memokath 051 would be cost incurring compared with double‑J stents if the monthly unplanned replacement risk was 2.81% over a 2‑year time horizon. Scenario analyses were done to investigate the impact of unplanned replacement of Memokath 051 at various timepoints in the stent lifespan, but it was found to still be cost saving compared with UVENTA, Allium and Resonance. For full details of the scenario analyses, see economic model parameters in section 9.3 and 9.4 of the assessment report update and appendix D of the addendum to the assessment report update in the supporting documentation (KiTEC, 2022). Compared with reconstructive surgery, Memokath 051 was cost incurring in all the scenarios, except when the reconstructive surgery cost was £12,656 and the Memokath 051 monthly follow-up cost was £21 (1 visit per year). The threshold at which Memokath 051 could be cost neutral was if the cost of reconstructive surgery was £9,287. Memokath 051 would be cost saving if its risk of replacement in the first 2 years was 1.8%, and it was not replaced in the remaining 3 years of a 5‑year time horizon, or it had a 1.8% monthly unplanned replacement risk over a 2‑year time horizon.# Committee discussion # Clinical effectiveness overview ## Memokath 051 is effective at relieving ureteric obstruction but comparative evidence remains limited The committee agreed that the new evidence supports the original guidance, suggesting that Memokath 051 Ureter stent had similar clinical success to other stents. But only 2 studies compared Memokath 051 with other stents. The clinical experts thought that, although there was new evidence, the evidence base has not improved substantially and the quality remained low. The committee concluded that, although there was new evidence reporting comparable clinical success rates with Memokath 051 and other stents, the comparative evidence remains limited. ## Memokath 051 could be less likely to cause bladder irritation symptoms and is well tolerated compared with double-J stents The patient expert explained that people living with ureteric stents commonly reported pain, discomfort and urinary tract infections, and that the impact of stenting on people's quality of life is important. The clinical experts explained that Memokath 051 is a metal stent and usually well tolerated. They added that people tend to have fewer of the bladder irritation symptoms that are commonly associated with double‑J stents, so have a better quality of life. However, there is no new evidence on patient-reported outcomes or quality of life. The committee concluded that Memokath 051 could be a treatment option with improved patient experience, but more data on patient-reported outcomes and quality of life is needed. # Side effects and adverse events ## Stent migration is common after Memokath 051 but the rate may be reduced by careful patient selection The new evidence suggested that stent migration is the most common complication with Memokath 051 (as was the case in the original guidance). The committee was aware that the latest evidence suggests that Memokath 051 is more likely to move than other types of stents. But clinical experts explained that this may have been a result of differences in patient selection, and they also explained that stent migration does not necessarily lead to complications because the migration may be caused by changes in the ureteric obstruction itself. Other possible reasons for stent migration include stents placed too close to the pelvi-ureteric junction, using a stent that is too long, or using a single cone Memokath 051 stent, which is more likely to migrate than a double cone stent. The committee heard from the clinical experts that migration rates may be reduced with Memokath 051 by selecting patients carefully (see section 4.7), and possibly by a move to using the double cone stent instead of single cone. # Other patient benefits or issues ## Equality considerations No new equality issues were identified during the guidance update development. Some ureteric obstructions are caused by tumours, and everyone with cancer is protected under the Equality Act 2010 from the point of diagnosis. People with ureteric strictures caused by tumours may benefit from having Memokath 051 available as an alternative to double‑J stents. This is because it may be associated with fewer replacement procedures and reduced adverse events, which would reduce their overall number of appointments and improve their quality of life as they undergo cancer treatments, or make them more comfortable and have more time out of hospital if they have a limited life expectancy. Memokath 051 may also provide an alternative treatment for people with ureteric strictures who cannot tolerate conventional stents or for whom they have failed, who would otherwise be nephrostomy-dependent and may be disabled under the Equality Act 2010. ## More information about treatment should be provided to people with ureteric obstruction Clinical and patient experts explained that most people who had stent procedures knew little about what kind of stent they were having. The clinical experts explained that stent choice often relies on the assessment of urethral obstruction during a stent procedure in the surgical suite. They agreed that a best-case scenario would be explaining treatment options and associated risks to a person before placement, then giving them information about the treatment afterwards, including what stent was used and possible adverse events. The committee concluded that more information should be given to people to explain their care. # Relevance to the NHS ## There is new evidence from UK studies but generalisability to the NHS may be limited The clinical experts explained that Memokath 051 is currently used in some NHS trusts. The committee noted that some new published evidence for Memokath 051 is from studies that were done in the UK. One of the clinical experts involved in 1 of the UK studies (Forster et al. 2021) explained that a wide range of people with benign and malignant ureteric obstruction was included in the study, and its inclusion criteria for Memokath 051 were more relaxed than clinical practice. Therefore, people included in the retrospective analysis may be different from those who would be selected for Memokath 051 in clinical practice. The committee concluded that the new evidence is limited in the generalisability to clinical practice across sites in the UK because of the variability in patient selection. # NHS considerations overview ## Resource savings are possible with Memokath 051 but patient selection is important to avoid adverse events The clinical experts said that different treatment options, including Memokath 051, are available in the NHS for people with ureteric obstruction. They considered that treatments need to be offered to people on an individual basis, guided by clinical assessment of individual circumstances. Important factors to consider include the cause of the obstruction and its length and location. Clinicians should also take into account the person's preference. For people with malignant ureteric obstruction, quality of life is often the most important factor in determining what treatment will be needed. Memokath 051's advantages over some other treatments available for ureteric obstruction in the NHS are that it is a less invasive procedure with no need for hospital stay, and fewer stent replacements are needed. For people with benign ureteric obstruction, Memokath 051 is an option if they cannot have, or prefer not to have, open surgical procedures such as reconstructive surgery. The clinical experts said that Memokath 051 should not be used in people with bladder cancer or bladder stones, or in people with pelvi-ureteric junction obstruction because of an increased risk of stent migration. It concluded that careful patient selection for Memokath 051 is important when treating ureteric obstruction. ## Regular follow-ups are needed after Memokath 051 is inserted The clinical experts said that people are monitored after stent insertion, but the way they are monitored varies. For instance, changes in the ureteric obstruction or stent position can be detected using different imaging examinations such as ultrasound or X‑ray. Using an X‑ray and an ultrasound scan together is considered the best way to detect stent migration. The committee concluded that regular follow-up visits are needed after Memokath 051 is inserted to monitor stent positioning. # Cost modelling overview ## Memokath 051 is cost saving compared with other stents but cost incurring compared with reconstructive surgery The committee understood that the original cost model was relevant to the decision problem because its model structure and key assumptions remained valid. The external assessment group (EAG) updated the clinical parameters, including the cost of Memokath 051 and comparators to reflect changes in the risk of stent replacement and adverse events. Its updated base case showed that Memokath 051 remained cost saving compared with Allium, double‑J stents, Resonance and UVENTA over 5 years (see section 3.16). But using Memokath 051 is likely to incur an additional cost of £1,321 per person over 5 years compared with reconstructive surgery. ## The cost case for Memokath 051 remains uncertain because of the limited evidence base The committee considered that the cost case remains uncertain because of the lack of good quality evidence. The risk of stent replacement was 1 of the key drivers of the estimated cost savings with Memokath 051 compared with other stents. The analysis was based on an assumption that the same stent would be used for replacement. The clinical experts advised that, in clinical practice, people would not necessarily have the same brand of stent for replacement because people's conditions may change and Memokath 051 may no longer be suitable for them. There was limited data on stent replacement, and this introduced some uncertainty in the cost case between Memokath 051 and other stents. The EAG's sensitivity analyses also identified other cost drivers including the length of time the stent is in place, replacement cost and follow-up costs. Memokath 051 remained cost saving in most of the scenarios compared with double‑J, UVENTA, Allium and Resonance but would be cost incurring compared with reconstructive surgery. The committee noted these were one-way sensitivity analyses, which may not fully address uncertainties in the cost model. It concluded that the cost case for Memokath 051 remained uncertain because of the limited evidence base. # Further research ## Prospective data on Memokath 051 and other ureteric stents is needed Given the limited evidence available, the original guidance committee noted that it would be beneficial to routinely collect data on all ureteric stent placement procedures. This was ideally in collaboration with a national professional society such as the British Association of Urological Surgeons. Clinical experts confirmed that an NHS registry for stent procedures has not been set up since the original guidance, and the evidence base remains limited with no prospective data available. The committee for this guidance update considered it important to further emphasise the need for collecting data using a national database or clinical registry on ureteric stent procedures. The prospective data collection should cover information about patient selection, choice of stent placement procedure and stent used, and adverse events such as stent migration and encrustation rates. It concluded that this should form part of its recommendations in section 1 of the guidance, and agreed that such data collection should be used to help inform the most appropriate patient population for Memokath 051.	{'Recommendations': "Memokath\xa0051 Ureter stent is recommended as an option to manage ureteric obstruction in adults with:\n\nmalignant ureteric obstruction and anticipated medium- or long-term survival after adjunctive therapy\n\nbenign ureteric obstruction who cannot have or do not want reconstructive surgery\n\nany type of ureteric obstruction, and they cannot have or do not want a double‑J stent, or when repeat procedures are particularly high risk.\n\nData should be collected prospectively on ureteric stent procedures, including details of patient selection, choice of stent placement procedure and stent used, and adverse events such as stent migration and encrustation rates.\n\nWhy the committee made these recommendations\n\nNICE originally recommended Memokath\xa0051 for ureteric obstruction for selected people.\n\nNew clinical evidence from retrospective studies suggests that Memokath\xa0051 relieves ureteric obstruction as well as other stents.\n\nFor people with malignant ureteric obstruction, Memokath\xa0051 may have advantages over some other treatments because it is a less invasive procedure than nephrostomy, with no need for hospital stay, and fewer stent replacements needed compared with other stents.\n\nClinical experts also felt that it was important to have Memokath\xa0051 as an option for other people, for example people who cannot have or do not want reconstructive surgery or a double-J stent, or when repeat procedures are particularly high risk.\n\nThe cost modelling suggests Memokath\xa0051 is likely to be cost saving compared with other stents. This is because it may not need to be replaced as often as other stents. But the cost savings are not certain because there's not enough good quality evidence.\n\nThere is enough clinical evidence to continue recommending Memokath\xa0051 for selected adults with ureteric obstruction. But prospective data is still needed to be certain about the cost savings of using it, compared with other stents.", 'The technology': "# Technology\n\nMemokath\xa0051 Ureter stent is a biocompatible, thermo-expandable, nickel-titanium alloy ureteric stent. It is intended as an alternative to conventional ureteric stents for people with benign or malignant ureteric obstruction. The nickel-titanium alloy has a shape memory effect, which is designed to allow the stent to be more easily inserted and anchored into position. A spiral coil design aims to prevent endothelial ingrowth of the tumour or stricture into the stent so that it can be easily removed. Four different versions of the Memokath\xa0051 stent are available (single or double cone, for either antegrade or retrograde insertion), each in several different lengths. Memokath\xa0051 can be used to treat obstructions elsewhere in the urinary tract, but this is outside the scope of this evaluation.\n\n# Care pathway\n\nUreteric obstruction can be treated by stenting the ureter, creating a nephrostomy or through reconstructive surgery. It must be treated quickly to avoid obstructive renal failure. Nephrostomy or stenting should be done as soon as possible (within 12\xa0hours of diagnosis). For malignant obstruction, the NICE guideline on prostate cancer recommends decompression of the upper urinary tract by nephrostomy or inserting a double‑J stent. The NICE guideline on bladder cancer recommends nephrostomy or retrograde stenting (if technically feasible) for people with locally advanced or metastatic bladder cancer. The NICE guideline on acute kidney injury says that all people with upper urinary tract obstruction should be referred to a urologist.\n\n# Innovative aspects\n\nMemokath\xa0051 can adapt to the natural curves of the urinary tract because of its tight spiral structure, which also makes it less likely that tissue grows between the coils. According to the company, compared with other stents, it is better tolerated, with fewer stent-related symptoms and complications. It reduces the need for stent replacement and the risk of tissue ingrowth.\n\n# Intended use\n\nMemokath\xa0051 is intended for treating ureteric obstruction in adults with benign or malignant strictures. It is contraindicated for children. People with bleeding disorders or using anticoagulant medication are advised to check coagulation parameters, and the stent should not be implanted if their coagulation parameters are not within the range that would be suitable for surgical intervention. For a full list of contraindications and details on using Memokath\xa0051, see the instructions for use.\n\n# Costs\n\nThe cost of Memokath\xa0051 used in the company's submission for the original guidance was £1,690 (excluding VAT). This included the Memokath 051 stent, a guidewire and a dilator-insertion sheath. The company confirmed that there is no change to the cost of Memokath\xa0051 stents.For more details about the technology, see the website for Memokath\xa0051 Ureter.", 'Evidence': "NICE commissioned an external assessment group (EAG) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence from the original guidance\n\n## Evidence came from 6 comparative studies and 10 single-arm studies\n\nThe EAG identified 16\xa0studies (6 comparative studies and 10 single-arm studies) including 6\xa0publications of 5\xa0studies submitted by the company at guidance review. The comparative studies all had a retrospective design, with a small sample size of up to 27\xa0people (Akbarov et al. 2017) in each treatment arm. The single-arm studies were observational case series, with sample sizes ranging from 4\xa0people (Boyvat et al. 2005) to 73\xa0people (Papatsoris and Buchholz 2010). For full details of the clinical evidence, see section\xa03 of the original assessment report in the supporting documentation (Newcastle upon Tyne Hospitals and York Health Economics Consortium External Assessment Centre, 2017).\n\n## Clinical success varied and its definition was not consistent\n\nMemokath\xa0051 Ureter stent's clinical success rates ranged from 43% (Kim et al. 2014) to 100% (Granberg et al. 2010, Zaman et al. 2011). Results of the comparative studies suggested that the clinical success rate of Memokath\xa0051 was comparable to double‑J stents (100% success rate in both arms; Granberg et al. 2010) and Resonance stents (82% and 86% respectively; Nam et al. 2015) but was lower than Allium stents (81% compared with 100%; Bolton et al. 2015), and UVENTA (43% compared with 82%; Kim et al. 2014). The definition of clinical success and how it was measured were not consistently reported in the studies.\n\n## Evidence on the length of time that stents remain in place was limited\n\nEvidence from 2 comparative studies showed that Memokath\xa0051 remained in place longer than double‑J stents (17\xa0months compared with 4\xa0months; NCT00166361, 2014) and UVENTA (14\xa0months compared with 12\xa0months; Kim et al. 2014). The average length of time in place using Memokath\xa0051 was 11\xa0months (Papatsoris and Buchholz 2010).\n\n## Memokath\xa0051 had higher stent migration and encrustation rates than other stents\n\nThe evidence from the comparative studies suggested that stent migrations were higher with Memokath\xa0051 than double‑J stents (11% against 0%; Maan et al. 2010) and UVENTA (43% against 6%; Kim et al. 2014). Encrustation rates were also higher with Memokath\xa0051 than with double‑J stents (29% against 0%; NCT00166361, 2014) and Allium (19% against 0%; Bolton et al. 2015). The other most common adverse events included urinary tract infection (Akbarov et al. 2017, Klarskov et al. 2005, Papatsoris and Buchholz 2010, Zaman et al. 2011) and blockage or obstruction (Akbarov et al. 2017; Kim et al. 2014; Klarskov et al. 2005; NCT00166361 2014; Zaman et al. 2011).\n\nThe EAG did a pooled analysis, the results of which suggested that the stent migration rate for Memokath\xa0051 was 17.7% (13\xa0studies) compared with 5.9% using UVENTA (1\xa0study) and 0% using double‑J stents (2\xa0studies) and Allium (1\xa0study).\n\nThe evidence was reviewed in 2021 and long-term retrospective data suggested higher complication rates with Memokath\xa0051 than were previously reported, so NICE decided to update the guidance.\n\n# New clinical evidence\n\n## New evidence comes from 7 studies including 1 systematic review and 2 comparative studies\n\nFor the guidance update, the EAG considered 7 new studies including 2\xa0abstracts:\n\nsystematic review and meta-analysis (Khoo et al. 2018)\n\nretrospective non-randomised single-centre comparative studies (Choi et al. 2019, Khoo et al. 2021)\n\nretrospective single-arm single-centre studies (Bier et al. 2017, Diaz Romero et al. 2018, Elbaroni et al. 2020, Forster et al. 2021).For full details of the clinical evidence, see section\xa04 of the assessment report update in the supporting documentation (King's Technology Evaluation Centre [KiTEC], 2022).\n\n## Evidence suggests clinical success is similar for Memokath\xa0051 and mesh stent (UVENTA) in people with benign ureteral strictures\n\nEvidence from a comparative retrospective study of people with chronic benign ureteral strictures reported that primary success rates (maintaining patency without additional procedures) were 28.6% for Memokath\xa0051 and 12.0% for UVENTA during the observation period (Choi et al. 2019). The overall success rates (success defined as maintaining patency after further salvage procedures) were 57.1% for Memokath\xa0051 and 40.0% for UVENTA. The differences between the 2\xa0stents were not statistically significant. This result is consistent with the original guidance, which showed Memokath\xa0051 had similar clinical success rates to UVENTA in the population with benign ureteral strictures.\n\n## Length of time the stent remains in place varies in the studies\n\nThe new evidence suggested that the median duration of actual functional stent follow up (censored by stent failure, death or end of study) was 5.5\xa0months for Memokath\xa0051, 11.4\xa0months for Allium and 11.7\xa0months for Resonance. This is shorter than the 2\xa0studies included in the previous guidance, which reported 14\xa0months and 17\xa0months of indwelling time (Kim et al. 2014; NCT00166361 2014). Results of single-arm studies reported a median indwelling time of 11.8\xa0months (range 1\xa0week to 70.8\xa0months; Bier et al. 2017) and a median stent lifespan of 14.5\xa0months and 13.4\xa0months in people with malignant ureter obstruction and benign ureter obstruction respectively.\n\n## Long-term data from a non-comparative study suggests high complication rates with Memokath\xa0051\n\nForster et al. (2021) reported long-term outcomes using Memokath\xa0051 in an NHS centre. Only 25 out of 100\xa0people included did not have any complications during a 5‑year follow up. The common complications were stent migration (36%) and failed ipsilateral upper tract drainage (27%), which included blockage (14%), encrustation (11%) and lost renal function (2%). The study included a subgroup analysis of benign and malignant ureteric obstruction, and the overall complication rate was significantly higher in people with a benign obstruction (85.4%) than those with a malignant obstruction (62.7%). Stent migration was the most common complication in people with a benign obstruction (53.7%) and failed renal drainage was common in people with a malignant obstruction (30.5%). A comparative study with a 5.5‑month follow-up period for Memokath\xa0051 suggested that it had higher migration, obstruction and infection rates than Resonance, regardless of whether it was a benign or malignant obstruction (Khoo et al. 2021). Duration of follow-up was censored by stent failure, patient death or end-of-study period. The study did not have long-term comparative data on the complication rates of different stents.\n\n# Cost evidence\n\n## No new published economic studies were identified by the company or the EAG\n\nThe original guidance included 3 economic studies, all of which compared the cost associated with using Memokath\xa0051 with double‑J stents (Aintree University Hospital 2012; Gonzalez et al. 2011; Zaman et al. 2012). The results indicated that Memokath\xa0051 was likely to be cost saving compared with double‑J stents, although the studies were poorly reported and included a heterogeneous group of people with varying types of obstruction and life expectancy.\n\nThe company and EAG search did not identify any new published economic studies since the original guidance. The EAG considered the evidence from 4 new clinical studies including 2 UK studies (Forster et al. 2021, Khoo et al. 2021), 1 German study (Bier et al. 2017) and 1 Korean study (Choi et al. 2019) to be relevant for updating the risk of unplanned stent replacement in the economic model.\n\n## Some changes were made to the company's model in the original guidance\n\nThe company developed a simple cost model in the original guidance. The EAG thought that the company's cost model captured the key aspects of treatment, but that the way it dealt with certain structural issues was too simplistic, such as only including double‑J stents as a comparator. The EAG adapted the company's model and made the following main changes to the original guidance:\n\nextending the time horizon from 2.5\xa0years to 5\xa0years\n\nincluding reconstructive surgery and other metallic stents as comparators\n\nadding the ability to report a break-even time point between Memokath\xa0051 and the comparators\n\nincluding the risk of urinary tract infections.Scenario analyses were also added to model the risk of unplanned Memokath\xa0051 replacement. More details of the cost model are in sections\xa04.2.2 and 4.2.3 of the original assessment report in the supporting documentation (Newcastle upon Tyne Hospitals and York Health Economics Consortium External Assessment Centre, 2017).\n\n## The EAG updated the cost parameters using new evidence\n\nThe EAG considered that the original model structure and assumptions remained valid. It updated the model's parameters because of new evidence available:\n\nAn increase in the monthly risk of unplanned stent replacement for Memokath\xa0051 from 1.40% to 1.80% compared with double‑J, Allium, Resonance and reconstructive surgery. A decrease in the monthly risk of unplanned stent replacement for Memokath\xa0051 from 4.40% to 3.57% compared with UVENTA for chronic benign ureteral strictures.\n\nThe monthly risk of unplanned stent replacement remained unchanged for double‑J stents (0%). But the monthly risks of unplanned stent replacement were updated from:\n\n% to 5.54% for Allium\n\n% to 1.78% for Resonance\n\n% to 4.99% for UVENTA.The model assumed that if someone needed an unplanned stent replacement it automatically delayed the planned replacement by the length of time in situ (thus removing any double counting). For full details of the clinical parameters, see economic model parameters in section\xa09.2 of the assessment report update in the supporting documentation (KiTEC 2022).\n\n## The EAG updated the costs for double-J stents, UVENTA and Resonance\n\nThe cost of Memokath\xa0051 and related consumables did not change. The EAG updated the cost of double‑J stents, UVENTA and Resonance according to the NHS Supply Chain reported unit prices. The cost of Allium was the same as the original guidance. The EAG also updated other costs such as staffing and follow-up visits using the most up-to-date data sources available. For full details of the cost sources, see economic model parameters in section\xa09.2 of the assessment report update in the supporting documentation (KiTEC, 2022). In the original guidance, a passport balloon dilator was needed when inserting Memokath 051, and the assumption was that a dilator was also needed when inserting UVENTA and Resonance stents. At consultation, the EAG ran a scenario analysis and found that removing the cost of a balloon dilator for Resonance had a minimal effect on overall costings and did not change the cost saving conclusion for Memokath\xa0051.\n\n## Updated EAG base-case results show Memokath\xa0051 is cost saving compared with other stents but cost incurring compared with reconstructive surgery\n\nThe EAG's updated base-case results showed that using Memokath\xa0051 is cost saving per person over 5\xa0years by:\n\n£1,926 compared with double‑J stents\n\n£6,260 compared with Resonance\n\n£8,813 compared with UVENTA\n\n£9,365 compared with Allium.But using Memokath\xa0051 incurred an additional £1,321 per person over 5\xa0years compared with reconstructive surgery. Memokath\xa0051 was also cost incurring compared with reconstructive surgery in the original guidance (£467) but the size of the additional cost has increased. Base-case results were modelled over a 5‑year period, reflecting the indwelling duration for Memokath\xa0051 after which planned replacement is needed. Risks of unplanned replacement were also applied for the full-time horizon of the model.\n\n## Change in risk of stent replacement is the key cost driver\n\nThe EAG's scenario analyses showed that, compared with UVENTA, Allium and Resonance, Memokath\xa0051 was cost saving in all scenarios. Compared with double‑J stents, Memokath\xa0051 was cost saving in all scenarios, except when the replacement cost of double‑J stents dropped to £717. Memokath\xa0051 would be cost neutral if the replacement cost of a double‑J stent was £1,008. In addition, Memokath\xa0051 would be cost incurring compared with double‑J stents if the monthly unplanned replacement risk was 2.81% over a 2‑year time horizon. Scenario analyses were done to investigate the impact of unplanned replacement of Memokath 051 at various timepoints in the stent lifespan, but it was found to still be cost saving compared with UVENTA, Allium and Resonance. For full details of the scenario analyses, see economic model parameters in section 9.3 and 9.4 of the assessment report update and appendix D of the addendum to the assessment report update in the supporting documentation (KiTEC, 2022).\n\nCompared with reconstructive surgery, Memokath\xa0051 was cost incurring in all the scenarios, except when the reconstructive surgery cost was £12,656 and the Memokath\xa0051 monthly follow-up cost was £21 (1\xa0visit per year). The threshold at which Memokath\xa0051 could be cost neutral was if the cost of reconstructive surgery was £9,287. Memokath\xa0051 would be cost saving if its risk of replacement in the first 2\xa0years was 1.8%, and it was not replaced in the remaining 3\xa0years of a 5‑year time horizon, or it had a 1.8% monthly unplanned replacement risk over a 2‑year time horizon.", 'Committee discussion': "# Clinical effectiveness overview\n\n## Memokath\xa0051 is effective at relieving ureteric obstruction but comparative evidence remains limited\n\nThe committee agreed that the new evidence supports the original guidance, suggesting that Memokath\xa0051 Ureter stent had similar clinical success to other stents. But only 2\xa0studies compared Memokath\xa0051 with other stents. The clinical experts thought that, although there was new evidence, the evidence base has not improved substantially and the quality remained low. The committee concluded that, although there was new evidence reporting comparable clinical success rates with Memokath\xa0051 and other stents, the comparative evidence remains limited.\n\n## Memokath\xa0051 could be less likely to cause bladder irritation symptoms and is well tolerated compared with double-J stents\n\nThe patient expert explained that people living with ureteric stents commonly reported pain, discomfort and urinary tract infections, and that the impact of stenting on people's quality of life is important. The clinical experts explained that Memokath\xa0051 is a metal stent and usually well tolerated. They added that people tend to have fewer of the bladder irritation symptoms that are commonly associated with double‑J stents, so have a better quality of life. However, there is no new evidence on patient-reported outcomes or quality of life. The committee concluded that Memokath\xa0051 could be a treatment option with improved patient experience, but more data on patient-reported outcomes and quality of life is needed.\n\n# Side effects and adverse events\n\n## Stent migration is common after Memokath\xa0051 but the rate may be reduced by careful patient selection\n\nThe new evidence suggested that stent migration is the most common complication with Memokath\xa0051 (as was the case in the original guidance). The committee was aware that the latest evidence suggests that Memokath\xa0051 is more likely to move than other types of stents. But clinical experts explained that this may have been a result of differences in patient selection, and they also explained that stent migration does not necessarily lead to complications because the migration may be caused by changes in the ureteric obstruction itself. Other possible reasons for stent migration include stents placed too close to the pelvi-ureteric junction, using a stent that is too long, or using a single cone Memokath\xa0051 stent, which is more likely to migrate than a double cone stent. The committee heard from the clinical experts that migration rates may be reduced with Memokath\xa0051 by selecting patients carefully (see section 4.7), and possibly by a move to using the double cone stent instead of single cone.\n\n# Other patient benefits or issues\n\n## Equality considerations\n\nNo new equality issues were identified during the guidance update development. Some ureteric obstructions are caused by tumours, and everyone with cancer is protected under the Equality Act\xa02010 from the point of diagnosis. People with ureteric strictures caused by tumours may benefit from having Memokath\xa0051 available as an alternative to double‑J stents. This is because it may be associated with fewer replacement procedures and reduced adverse events, which would reduce their overall number of appointments and improve their quality of life as they undergo cancer treatments, or make them more comfortable and have more time out of hospital if they have a limited life expectancy. Memokath\xa0051 may also provide an alternative treatment for people with ureteric strictures who cannot tolerate conventional stents or for whom they have failed, who would otherwise be nephrostomy-dependent and may be disabled under the Equality Act\xa02010.\n\n## More information about treatment should be provided to people with ureteric obstruction\n\nClinical and patient experts explained that most people who had stent procedures knew little about what kind of stent they were having. The clinical experts explained that stent choice often relies on the assessment of urethral obstruction during a stent procedure in the surgical suite. They agreed that a best-case scenario would be explaining treatment options and associated risks to a person before placement, then giving them information about the treatment afterwards, including what stent was used and possible adverse events. The committee concluded that more information should be given to people to explain their care.\n\n# Relevance to the NHS\n\n## There is new evidence from UK studies but generalisability to the NHS may be limited\n\nThe clinical experts explained that Memokath\xa0051 is currently used in some NHS trusts. The committee noted that some new published evidence for Memokath\xa0051 is from studies that were done in the UK. One of the clinical experts involved in 1 of the UK studies (Forster et al. 2021) explained that a wide range of people with benign and malignant ureteric obstruction was included in the study, and its inclusion criteria for Memokath\xa0051 were more relaxed than clinical practice. Therefore, people included in the retrospective analysis may be different from those who would be selected for Memokath\xa0051 in clinical practice. The committee concluded that the new evidence is limited in the generalisability to clinical practice across sites in the UK because of the variability in patient selection.\n\n# NHS considerations overview\n\n## Resource savings are possible with Memokath\xa0051 but patient selection is important to avoid adverse events\n\nThe clinical experts said that different treatment options, including Memokath\xa0051, are available in the NHS for people with ureteric obstruction. They considered that treatments need to be offered to people on an individual basis, guided by clinical assessment of individual circumstances. Important factors to consider include the cause of the obstruction and its length and location. Clinicians should also take into account the person's preference. For people with malignant ureteric obstruction, quality of life is often the most important factor in determining what treatment will be needed. Memokath\xa0051's advantages over some other treatments available for ureteric obstruction in the NHS are that it is a less invasive procedure with no need for hospital stay, and fewer stent replacements are needed. For people with benign ureteric obstruction, Memokath\xa0051 is an option if they cannot have, or prefer not to have, open surgical procedures such as reconstructive surgery. The clinical experts said that Memokath\xa0051 should not be used in people with bladder cancer or bladder stones, or in people with pelvi-ureteric junction obstruction because of an increased risk of stent migration. It concluded that careful patient selection for Memokath\xa0051 is important when treating ureteric obstruction.\n\n## Regular follow-ups are needed after Memokath\xa0051 is inserted\n\nThe clinical experts said that people are monitored after stent insertion, but the way they are monitored varies. For instance, changes in the ureteric obstruction or stent position can be detected using different imaging examinations such as ultrasound or X‑ray. Using an X‑ray and an ultrasound scan together is considered the best way to detect stent migration. The committee concluded that regular follow-up visits are needed after Memokath\xa0051 is inserted to monitor stent positioning.\n\n# Cost modelling overview\n\n## Memokath\xa0051 is cost saving compared with other stents but cost incurring compared with reconstructive surgery\n\nThe committee understood that the original cost model was relevant to the decision problem because its model structure and key assumptions remained valid. The external assessment group (EAG) updated the clinical parameters, including the cost of Memokath\xa0051 and comparators to reflect changes in the risk of stent replacement and adverse events. Its updated base case showed that Memokath\xa0051 remained cost saving compared with Allium, double‑J stents, Resonance and UVENTA over 5\xa0years (see section\xa03.16). But using Memokath\xa0051 is likely to incur an additional cost of £1,321 per person over 5\xa0years compared with reconstructive surgery.\n\n## The cost case for Memokath\xa0051 remains uncertain because of the limited evidence base\n\nThe committee considered that the cost case remains uncertain because of the lack of good quality evidence. The risk of stent replacement was 1 of the key drivers of the estimated cost savings with Memokath\xa0051 compared with other stents. The analysis was based on an assumption that the same stent would be used for replacement. The clinical experts advised that, in clinical practice, people would not necessarily have the same brand of stent for replacement because people's conditions may change and Memokath\xa0051 may no longer be suitable for them. There was limited data on stent replacement, and this introduced some uncertainty in the cost case between Memokath\xa0051 and other stents.\n\nThe EAG's sensitivity analyses also identified other cost drivers including the length of time the stent is in place, replacement cost and follow-up costs. Memokath\xa0051 remained cost saving in most of the scenarios compared with double‑J, UVENTA, Allium and Resonance but would be cost incurring compared with reconstructive surgery. The committee noted these were one-way sensitivity analyses, which may not fully address uncertainties in the cost model. It concluded that the cost case for Memokath\xa0051 remained uncertain because of the limited evidence base.\n\n# Further research\n\n## Prospective data on Memokath\xa0051 and other ureteric stents is needed\n\nGiven the limited evidence available, the original guidance committee noted that it would be beneficial to routinely collect data on all ureteric stent placement procedures. This was ideally in collaboration with a national professional society such as the British Association of Urological Surgeons. Clinical experts confirmed that an NHS registry for stent procedures has not been set up since the original guidance, and the evidence base remains limited with no prospective data available. The committee for this guidance update considered it important to further emphasise the need for collecting data using a national database or clinical registry on ureteric stent procedures. The prospective data collection should cover information about patient selection, choice of stent placement procedure and stent used, and adverse events such as stent migration and encrustation rates. It concluded that this should form part of its recommendations in section 1 of the guidance, and agreed that such data collection should be used to help inform the most appropriate patient population for Memokath\xa0051."}	https://www.nice.org.uk/guidance/mtg75	Evidence-based recommendations on Memokath 051 Ureter stent for ureteric obstruction.
e9434e48661002dc98d3b69c610e030369701386	nice	Optilume for treating recurrent bulbar urethral strictures	Optilume for treating recurrent bulbar urethral strictures Evidence-based recommendations on Optilume for treating recurrent bulbar urethral strictures. # Recommendations Optilume is recommended as an option to treat recurrent bulbar urethral strictures in adults only if comparative data is collected on: patient-reported outcome measures reintervention rates. Find out details of required outcomes in the section on further research. Why the committee made these recommendations Optilume done in an outpatient setting could reduce the waiting times for treatment of recurrent bulbar urethral strictures. The comparative clinical evidence shows that Optilume is effective in the short term (up to 2 years). But how effective and safe it is in the long term (up to 5 years) compared with standard endoscopic management is uncertain. So, more long-term data collection is needed on retreatment rates and patient-reported outcomes. The cost analysis shows that Optilume is cost saving at 5 years compared with standard care (urethral dilatation, urethrotomy and urethroplasty). The uncertainty about the likelihood of recurrence in the long term limits the reliability of the longer-term cost savings.# The technology # Technology Optilume is a urethral balloon coated with paclitaxel (3.5 microgram/mm2). It is indicated for managing urethral stricture disease in 'adult males'. It is designed to be used as a drug-coated dilation balloon for a urethral stricture that is 3 cm or less in length. Optilume is available in 6 sizes (3 cm and 5 cm length versions, both in 3 different diameters). It is passed over a guidewire under direct vision with or without fluoroscopy, and positioned along the length of the stricture. The balloon is then inflated with a provided pressure inflation device, using saline or water. The inflated device is kept in place for a minimum of 5 minutes, at the recommended pressure, to dilate the urethral stricture and allow uptake of paclitaxel. The pressure is measured in atmospheres, as per instructions for use. Optilume urethral drug-coated balloon received a CE mark in September 2020 as a class 3 medical device. # Care pathway Current treatment options for recurrent bulbar urethral strictures include endoscopic procedures, urethral dilatation, direct visual internal urethrotomy and urethroplasty. The choice of treatment is considered by a multidisciplinary team and is dependent on patient and clinician choice, and clinician expertise. People having urethroplasty in the UK have often had several previous endoscopic procedures. Optilume is intended to be an additional option for treating recurrent strictures that could delay or prevent the need for the more invasive urethroplasty surgery. # Innovative aspects Optilume combines balloon dilation of the urethra to widen the stricture with paclitaxel delivered to the tissue of the stricture. The aim of the paclitaxel is to prevent new tissue growth and reduce scar formation. # Intended use Optilume is intended as a second-line treatment for urethral strictures in people who have had at least 1 previous endoscopic procedure that has failed. The technology is used by trained consultants in urology, urology trainees and urology nurse specialists. It can be done using local anaesthesia as a day case or in an outpatient setting. # Costs Optilume is a single use device and costs £1,350 per unit (excluding VAT). More details about Optilume are available on the company's website.# Evidence NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website. # Clinical evidence ## The main clinical evidence comprises the 3 ROBUST studies, 1 of which is a randomised controlled trial The EAC included 4 publications, 1 unpublished trial report and 10 abstracts as evidence. All publications and abstracts related to 3 studies (ROBUST 1, ROBUST 2 and ROBUST 3). ROBUST 3 is an ongoing randomised controlled trial comparing Optilume with standard endoscopic management (direct visual internal urethrotomy or dilatation). ROBUST 1 and ROBUST 2 were single-arm non-comparative open-label studies. The ROBUST studies have included a total of 196 people, of which 148 have had Optilume. Fourteen studies identified by the company were excluded by the EAC because they did not include Optilume. For full details of the clinical evidence, see section 4 of the assessment report in the supporting documentation. ## ROBUST 3 is most relevant to the decision problem ROBUST 3 (n=127; 79 randomised to Optilume and 48 to standard endoscopic management) was most relevant to the decision problem. It is an ongoing multicentre single-blind randomised controlled trial being done in the US and Canada. It becomes open label 6 months after randomisation. Then, people are given the choice to cross over to the Optilume group if they have confirmed stricture recurrence. The study includes adult men with anterior strictures 3 cm or less in length and who have had 2 or more previous endoscopic treatments. People in the intervention group had predilatation before having Optilume. ## The other studies are non-comparative and at high risk of bias ROBUST 1 (n=53) and ROBUST 2 (n=16) included Optilume but had no comparator. ROBUST 1 was done in 4 Latin American centres and ROBUST 2 was done in 5 US centres. They both included adult men with anterior urethral strictures 3 cm or less in length. People in ROBUST 1 had to have had up to 4 previous endoscopic treatments. People in ROBUST 2 had to have had 2 or more previous endoscopic treatments. The EAC concluded that, for both studies, methodological issues reduced the reliability of the findings and recruitment created the potential for selection bias. There were also inconsistencies in defining the primary outcome for follow up in ROBUST 1. ## The ROBUST studies report that Optilume reduces objective outcomes related to stricture recurrence In ROBUST 3, compared with standard care, Optilume significantly improved anatomical success at 6 months (74.6% compared with 26.8%) and the stricture-free outcome without repeat interventions at 1 year (83.0% compared with 22.0%; p<0.0001). Also, maximum flow rate and postvoid residual both improved after Optilume compared with baseline. These results were supported by findings from ROBUST 1 and 2, with similar rates reported in the 4‑year follow-up data from ROBUST 1. ## The ROBUST studies report that Optilume improves quality-of-life outcomes Using the international prostate symptom score (IPSS) in ROBUST 3: with Optilume, there were large and sustained improvements in quality-of-life and IPSS responder-rate outcomes from baseline to 1 year in the control group, there was an initial large improvement at 3 months, but this started to deteriorate to near baseline levels by 1 year.ROBUST 1 and 2 reported a similar improvement with Optilume. This was sustained over 4 years in ROBUST 1. All ROBUST studies found a slight (but not statistically significant) improvement in the overall satisfaction domain of the international index of erectile function with Optilume up to 1‑year follow up. The Urethral Stricture Surgery-Patient Reported Outcome Measure was only reported in ROBUST 1 and 2, and decreased at 1‑year follow up compared with baseline in both. This indicated an improvement in voiding symptoms and quality of life. ## Optilume is safe to use Adverse events were reported in all 3 ROBUST studies. ROBUST 1 and 3 also assessed the safety of Optilume. Urinary tract infection and acute urinary retention were the most reported adverse events. Pharmacokinetic studies found systemic exposure to paclitaxel was minimal. Clinical experts using Optilume acknowledged that there is still limited data on paclitaxel use in the urinary tract for preventing stricture recurrence. Nevertheless, they advised the device was very well tolerated with minimum side effects. Five out of 6 experts said that adverse events happening later than 30 days after the procedure would be unlikely with Optilume. The EAC acknowledged the Medicines and Healthcare products Regulatory Agency safety concerns about the ongoing use of paclitaxel-coated balloons and implantable drug-eluting stents in peripheral artery disease. The systemic paclitaxel concentration after Optilume is low and paclitaxel is primarily localised to the urethra. The EAC concluded that, based on the available evidence, Optilume causes very few adverse events and does not raise safety concerns. For full details of the adverse events, see sections 5.2 and 6 of the assessment report in the supporting documentation. ## There is a lack of long-term comparative studies to confirm the long-term benefits of Optilume The 2‑year evidence showed that Optilume improved clinical and patient-reported outcomes, and is an effective treatment for recurrent bulbar urethral strictures. The results of ROBUST 1 suggested long-term efficacy at a 4‑year follow up but it only included 53 people and was non-comparative. So, there is a lack of long-term comparative data. However, ROBUST 3 is ongoing and will collect 5‑year follow-up data until December 2025. # Cost evidence ## The company's cost modelling finds Optilume to be cost saving compared with endoscopic management The company submitted a new analysis because none of the economic studies identified included Optilume as a comparator. A Markov model compared Optilume with endoscopic management for treating recurrent anterior urethral strictures 3 cm or less in length over a 5‑year time horizon. The model was based on data from ROBUST 3. Additional clinical and cost data was taken from the OPEN trial, a randomised controlled trial comparing urethrotomy with urethroplasty with a 2‑year follow up (Pickard et al. 2020). The company's base case showed a cost saving of £2,502 per person using Optilume. For full details of the cost evidence, see section 9 of the assessment report in the supporting documentation. ## The company's cost model is appropriate and the EAC only made minor changes to costs of training and readmission to hospital The EAC accepted the company's model structure, comparators, time horizon, and most of the assumptions and parameters. The EAC's initial base case was amended to 100% of day-case procedures. The clinical experts confirmed that Optilume is also being used in an outpatient setting. The EAC's base case was amended to 50% of day cases and 50% of outpatient procedures. The EAC made minor changes to the costs of training with Optilume and readmission to hospital. These changes had a small effect on the incremental cost saving. The cost saving in the EAC's base case increased to £2,510 per person using Optilume. ## Stricture recurrence rate is the key cost driver The key cost driver in the model was the probability of recurrence, and therefore the expected cost of retreatment. Cost savings were dependent on the savings from reduced repeat interventions being greater than the additional cost of treatment with Optilume when compared with standard endoscopic procedures. The probabilistic sensitivity analysis for the EAC's base case found that 94% of the 1,000 iterations resulted in cost saving. ## The EAC noted that there is some uncertainty around clinical evidence in relation to recurrence rates The EAC noted that the clinical evidence showed that Optilume improved clinical outcomes in the shorter term. However, there was some uncertainty around the extent and duration of the improvement in the longer term and how this translated to recurrence in the model. This was related to several factors including: There is only 1 comparative study available for Optilume (ROBUST 3), which is ongoing. The study is limited to 2‑year follow up, although ROBUST 1 had follow up to 4 years. There is not an agreed single outcome measure that defines recurrence. Standard endoscopic methods encompass several different procedures. ## Optilume remains cost saving at 5 years when using different clinical data inputs for the probability of recurrence The clinical experts agreed that there is not a single outcome measure for recurrence that is used consistently. Several additional scenarios using different clinical inputs for the probability of recurrence were provided. The company's and EAC's base cases used the IPSS score to indicate recurrence rates. The company included 2 additional scenarios: 1 using anatomical success from ROBUST 3 and 1 using patient-reported outcome measures from the OPEN trial. When using the EAC's base case, both scenarios decreased the cost saving from £2,510 to £1,127 and £995 respectively. The EAC included an additional scenario that explored using retreatment rates from ROBUST 3. This increased the cost saving from £2,510 to £3,340. All scenarios reported treatment with Optilume to be cost saving at 5 years. ## Optilume in an outpatient setting increases cost savings The company stated that Optilume can be done as a day case and in an outpatient setting. Its base case assumed that 50% of the procedures would be done as a day case and 50% in an outpatient setting. Based on expert advice, the EAC accepted this assumption, which resulted in a cost saving of £2,510. The EAC analysed the effect of varying the proportion of Optilume procedures done as a day case and in an outpatient setting. Results showed that increasing the proportion of day-case procedures decreased cost savings (100%, £1,877), while increasing the proportion of outpatient procedures increased cost savings (100%, £3,142). ## Using endoscopic methods to retreat recurrent strictures moderately decreases cost savings The company's model assumed people initially having Optilume or endoscopic methods would have retreatment using the same method. In practice, it is likely that people who do not have urethroplasty have a mix of sequential endoscopic treatments, including Optilume. This will depend on patient and clinician choice, and availability of resources. The EAC included an additional scenario allowing for a mix of Optilume and endoscopic procedures for retreatment. The results showed that increasing the proportion having retreatment using a standard endoscopic treatment resulted in a moderate decrease in total cost savings. ## An exploratory analysis that extended the time horizon to 20 years suggests that Optilume remains cost saving The company's base-case time horizon was 5 years. This was because there was a lack of long-term data and because the effect of Optilume would be greater in the initial years of using it. The company included an additional scenario using a 10‑year time horizon and the EAC investigated the effect of a longer time horizon of 20 years. Increasing the time horizon to 20 years had a small effect on the EAC's base case, increasing the cost saving from £2,510 to £3,175. The EAC noted that, because of the lack of longer-term comparative data, the results were uncertain.# Committee discussion # Clinical-effectiveness overview ## The evidence shows that Optilume is effective in the short term, but the long-term benefits are uncertain The committee noted that the clinical evidence showed Optilume to be effective in improving clinically relevant outcomes including anatomical success, peak flow rate and international prostate symptom score (IPSS) at 2 years. The single-arm study data suggested that Optilume remains effective at 4 years (unpublished data from ROBUST 1). The committee considered that the studies of Optilume seemed to be well conducted and that the results were plausible. It concluded that the results to date are promising, although long-term comparative evidence was needed to see if the short-term benefits would be sustained at 5 years. ## The evidence is broadly generalisable to NHS practice The committee had some concerns about the generalisability of the evidence to clinical practice in the NHS. None of the ROBUST studies included any centres in the UK. Optilume is proposed for second-line treatment after stricture recurrence, but people in ROBUST 3 had more than 2 endoscopic treatments before having Optilume. The clinical experts noted that this reflects NHS practice. In ROBUST 3, strictures were predilatated in the entire Optilume group and in 58% of the control group. The clinical experts confirmed that this is not standard practice for either procedure in the NHS but that using a guidewire could dilate the stricture slightly. The company stated that, from the available evidence, predilatation does not appear to have affected Optilume's effectiveness. The clinical experts also agreed that predilatation is unlikely to affect Optilume's drug delivery and the overall results of ROBUST 3. The committee concluded that the evidence is broadly generalisable to NHS practice. # Side effects and adverse events ## Evidence suggests that Optilume is safe and 5-year safety data will be collected in ROBUST 3 The most common adverse events reported in the literature were urinary tract infection and acute urinary retention. Biological, haematological and serological studies in ROBUST 1 and 3 identified no significant effects on health. The external assessment centre (EAC) considered Optilume to be safe based on the evidence and expert feedback. The company stated that paclitaxel is locally delivered and washed out with urine. There is very little systemic exposure, and paclitaxel is mostly cleared within a day and cannot be detected. The company also noted that it is in the process of collecting safety data for up to 5‑year follow up in ROBUST 3. The committee concluded that the data provided reasonable assurance that Optilume is safe to use and understood that longer-term safety data will be collected in ROBUST 3. ## A postmarket study is planned to assess the effect of Optilume on semen characteristics The committee acknowledged that the presence of paclitaxel in semen may potentially affect semen quality, testicular function and fertility. It queried how the clinical experts counsel people about fertility. The clinical experts advised that they tell people that there is a theoretical risk of altered semen characteristics. They explained that it is up to the person having Optilume whether to continue with the treatment. The clinical experts advise them to abstain from sexual activity for 2 weeks and use barrier contraception for 3 months. They noted that so far, this has not affected the decision making of the people who have had treatment with Optilume. A postmarket study (STREAM PMS) to assess semen characteristics after treatment with Optilume in men younger than 55 is currently enrolling participants. # Outcome measures ## There is more than 1 outcome measure for recurrence, but none is used consistently The clinical experts agreed that there is no single outcome measure for recurrence that is used consistently. ROBUST 3 is collecting both objective (anatomical success, freedom from repeat intervention, postvoid residual and maximum flow rate) and subjective outcomes for recurrence (IPSS and IPSS quality of life). The clinical experts noted that subjective symptom outcomes are the easiest way to assess whether there is a stricture. The objective outcomes need more invasive assessments. They are not measured until someone presents with symptoms. IPSS, maximum flow rates and postvoid residual outcomes can be used because they are indicators that there is reasonable bladder emptying. The clinical experts noted that IPSS is not a disease-specific patient-reported outcome for strictures but that it has relevance because strictures also affect flow rates. It assesses how bothered people are about their symptoms. The committee concluded that all the outcomes in ROBUST 3 are clinically relevant. It also concluded that the results from the ROBUST studies are in line with what the clinical experts have seen in clinical practice. # NHS considerations overview ## Optilume is not widely used in the NHS, but adoption is increasing Optilume has been available in the UK since June 2021. The company stated that 10 NHS trusts have adopted Optilume and 82 procedures have been completed. It also stated that several NHS trusts have put in a business case for it, and more NHS trusts are looking to do so. The committee concluded that there is clinical interest in, and a rise in the adoption of, Optilume within the NHS. ## Optilume can reduce waiting lists for urethroplasty and relieve pressure on the NHS The clinical experts stated that, before the COVID‑19 pandemic, waiting times for routine urethroplasty were 7 to 8 months. Waiting times are now more than 2 years. Standard endoscopic treatments are typically done as day cases under general anaesthesia, but some may incorporate a short inpatient stay. Optilume can be done more routinely in an outpatient setting under local anaesthesia. After the procedure, people empty their bladder and can go home. The clinical experts confirmed that no changes are needed to the existing infrastructure because urology units would already be set up to do flexible cystoscopy and urethrograms. Using Optilume in an outpatient setting could reduce the waiting lists substantially. The committee recognised that the NHS is under severe pressure post the pandemic. It concluded that Optilume has the potential to reduce waiting lists, and that this may not be fully captured in the cost analysis. # Equality considerations ## Optilume can be used in anyone with a stricture in their bulbar urethra The clinical experts noted that trans women, with or without gender reassignment, have a bulbar urethra. If a bulbar stricture occurs, this is managed in the same way as for cisgender men. They considered that the evidence is generalisable to this group. # Cost-modelling overview ## The cost model is robust and reflects NHS practice The EAC accepted the model structure from the company but graphically redesigned the model diagram to provide a clearer presentation of the structure. The committee agreed that the model reflected NHS practice but noted that there should be a clearer distinction between what is an event compared with a health state. The health states labelled 'cured' have been amended to 'asymptomatic' because strictures can recur and people then move into the 'symptomatic' health state. The committee concluded that the rationale for the model was sensible and that the model structure was now clearer. ## The EAC's base case assumes that the proportion of day-case and outpatient procedures with Optilume is equal The company's base case assumed that 50% of procedures would be done as a day case and 50% in an outpatient setting. The initial EAC's base case was amended to 100% of day-case procedures. The clinical experts confirmed that Optilume is also being used in an outpatient setting. The EAC's base case was amended to 50% of day-case and 50% of outpatient procedures. The clinical experts noted that this was a reasonable assumption and that there is a high likelihood of more procedures being done in an outpatient setting in the future. The committee accepted the EAC's base-case assumption and recognised this may be a conservative estimate with a trend toward increasing outpatient procedures. ## Optilume is cost saving compared with standard endoscopic methods but the evidence on recurrence rate is uncertain The EAC's base case showed that Optilume was cost saving compared with standard endoscopic methods. The key cost driver was the probability of recurrence. Using deterministic one-way sensitivity analysis, this was the only variable that could make the base-case cost incurring at 5 years. However, the probabilistic sensitivity analysis for the EAC's base case showed that 94% of the iterations were cost saving. Scenario analysis, including using different clinical outcomes for recurrence rates, also showed that Optilume was cost saving. The committee concluded that the results were robust and suggested that Optilume is likely to be cost saving. However, long-term comparative data on recurrence is needed to improve the certainty of the cost saving associated with Optilume at 5 years and beyond. # Further research ## Further research to address the long-term uncertainty should include 5-year efficacy and patient-reported outcome data One-year data from ROBUST 3 has been published but the trial is ongoing with a 5‑year follow up. The committee understood that the planned follow up will include patient-reported outcomes. But the committee also considered it important to request further evidence to be collected in the NHS. It considered that real-world evidence and observational studies are important to assess clinical and operational effectiveness alongside ROBUST 3. The committee noted that outcomes should include: patient-reported outcome measures including IPSS and quality of life -bjective outcome measures indicating stricture-free success such as reintervention rates.The clinical experts noted that a large European registry has been set up to collect objective outcomes for stricture recurrence prospectively for several technologies, including Optilume. This registry includes NHS trust hospitals and NHS patients.	{'Recommendations': 'Optilume is recommended as an option to treat recurrent bulbar urethral strictures in adults only if comparative data is collected on:\n\npatient-reported outcome measures\n\nreintervention rates.\n\nFind out details of required outcomes in the section on further research.\n\nWhy the committee made these recommendations\n\nOptilume done in an outpatient setting could reduce the waiting times for treatment of recurrent bulbar urethral strictures. The comparative clinical evidence shows that Optilume is effective in the short term (up to 2\xa0years). But how effective and safe it is in the long term (up to 5\xa0years) compared with standard endoscopic management is uncertain. So, more long-term data collection is needed on retreatment rates and patient-reported outcomes.\n\nThe cost analysis shows that Optilume is cost saving at 5\xa0years compared with standard care (urethral dilatation, urethrotomy and urethroplasty). The uncertainty about the likelihood of recurrence in the long term limits the reliability of the longer-term cost savings.', 'The technology': "# Technology\n\nOptilume is a urethral balloon coated with paclitaxel (3.5\xa0microgram/mm2). It is indicated for managing urethral stricture disease in 'adult males'. It is designed to be used as a drug-coated dilation balloon for a urethral stricture that is 3\xa0cm or less in length.\n\nOptilume is available in 6\xa0sizes (3\xa0cm and 5\xa0cm length versions, both in 3\xa0different diameters). It is passed over a guidewire under direct vision with or without fluoroscopy, and positioned along the length of the stricture. The balloon is then inflated with a provided pressure inflation device, using saline or water. The inflated device is kept in place for a minimum of 5\xa0minutes, at the recommended pressure, to dilate the urethral stricture and allow uptake of paclitaxel. The pressure is measured in atmospheres, as per instructions for use.\n\nOptilume urethral drug-coated balloon received a CE\xa0mark in September 2020 as a class\xa03 medical device.\n\n# Care pathway\n\nCurrent treatment options for recurrent bulbar urethral strictures include endoscopic procedures, urethral dilatation, direct visual internal urethrotomy and urethroplasty. The choice of treatment is considered by a multidisciplinary team and is dependent on patient and clinician choice, and clinician expertise. People having urethroplasty in the UK have often had several previous endoscopic procedures.\n\nOptilume is intended to be an additional option for treating recurrent strictures that could delay or prevent the need for the more invasive urethroplasty surgery.\n\n# Innovative aspects\n\nOptilume combines balloon dilation of the urethra to widen the stricture with paclitaxel delivered to the tissue of the stricture. The aim of the paclitaxel is to prevent new tissue growth and reduce scar formation.\n\n# Intended use\n\nOptilume is intended as a second-line treatment for urethral strictures in people who have had at least 1\xa0previous endoscopic procedure that has failed. The technology is used by trained consultants in urology, urology trainees and urology nurse specialists. It can be done using local anaesthesia as a day case or in an outpatient setting.\n\n# Costs\n\nOptilume is a single use device and costs £1,350 per unit (excluding VAT). More details about Optilume are available on the company's website.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises the 3\xa0ROBUST studies, 1\xa0of which is a randomised controlled trial\n\nThe EAC included 4\xa0publications, 1\xa0unpublished trial report and 10\xa0abstracts as evidence. All publications and abstracts related to 3\xa0studies (ROBUST\xa01, ROBUST\xa02 and ROBUST\xa03). ROBUST\xa03 is an ongoing randomised controlled trial comparing Optilume with standard endoscopic management (direct visual internal urethrotomy or dilatation). ROBUST\xa01 and ROBUST\xa02 were single-arm non-comparative open-label studies. The ROBUST studies have included a total of 196\xa0people, of which 148\xa0have had Optilume. Fourteen studies identified by the company were excluded by the EAC because they did not include Optilume. For full details of the clinical evidence, see section\xa04 of the assessment report in the supporting documentation.\n\n## ROBUST\xa03 is most relevant to the decision problem\n\nROBUST\xa03 (n=127; 79\xa0randomised to Optilume and 48\xa0to standard endoscopic management) was most relevant to the decision problem. It is an ongoing multicentre single-blind randomised controlled trial being done in the US and Canada. It becomes open label 6\xa0months after randomisation. Then, people are given the choice to cross over to the Optilume group if they have confirmed stricture recurrence. The study includes adult men with anterior strictures 3\xa0cm or less in length and who have had 2\xa0or more previous endoscopic treatments. People in the intervention group had predilatation before having Optilume.\n\n## The other studies are non-comparative and at high risk of bias\n\nROBUST\xa01 (n=53) and ROBUST\xa02 (n=16) included Optilume but had no comparator. ROBUST\xa01 was done in 4\xa0Latin American centres and ROBUST\xa02 was done in 5\xa0US centres. They both included adult men with anterior urethral strictures 3\xa0cm or less in length. People in ROBUST\xa01 had to have had up to 4\xa0previous endoscopic treatments. People in ROBUST\xa02 had to have had 2\xa0or more previous endoscopic treatments. The EAC concluded that, for both studies, methodological issues reduced the reliability of the findings and recruitment created the potential for selection bias. There were also inconsistencies in defining the primary outcome for follow up in ROBUST\xa01.\n\n## The ROBUST studies report that Optilume reduces objective outcomes related to stricture recurrence\n\nIn ROBUST\xa03, compared with standard care, Optilume significantly improved anatomical success at 6\xa0months (74.6% compared with 26.8%) and the stricture-free outcome without repeat interventions at 1\xa0year (83.0% compared with 22.0%; p<0.0001). Also, maximum flow rate and postvoid residual both improved after Optilume compared with baseline. These results were supported by findings from ROBUST\xa01 and\xa02, with similar rates reported in the 4‑year follow-up data from ROBUST\xa01.\n\n## The ROBUST studies report that Optilume improves quality-of-life outcomes\n\nUsing the international prostate symptom score (IPSS) in ROBUST\xa03:\n\nwith Optilume, there were large and sustained improvements in quality-of-life and IPSS responder-rate outcomes from baseline to 1\xa0year\n\nin the control group, there was an initial large improvement at 3\xa0months, but this started to deteriorate to near baseline levels by 1\xa0year.ROBUST\xa01 and\xa02 reported a similar improvement with Optilume. This was sustained over 4\xa0years in ROBUST\xa01. All ROBUST studies found a slight (but not statistically significant) improvement in the overall satisfaction domain of the international index of erectile function with Optilume up to 1‑year follow up. The Urethral Stricture Surgery-Patient Reported Outcome Measure was only reported in ROBUST\xa01 and\xa02, and decreased at 1‑year follow up compared with baseline in both. This indicated an improvement in voiding symptoms and quality of life.\n\n## Optilume is safe to use\n\nAdverse events were reported in all 3\xa0ROBUST studies. ROBUST\xa01 and\xa03 also assessed the safety of Optilume. Urinary tract infection and acute urinary retention were the most reported adverse events. Pharmacokinetic studies found systemic exposure to paclitaxel was minimal. Clinical experts using Optilume acknowledged that there is still limited data on paclitaxel use in the urinary tract for preventing stricture recurrence. Nevertheless, they advised the device was very well tolerated with minimum side effects. Five out of 6\xa0experts said that adverse events happening later than 30\xa0days after the procedure would be unlikely with Optilume. The EAC acknowledged the Medicines and Healthcare products Regulatory Agency safety concerns about the ongoing use of paclitaxel-coated balloons and implantable drug-eluting stents in peripheral artery disease. The systemic paclitaxel concentration after Optilume is low and paclitaxel is primarily localised to the urethra. The EAC concluded that, based on the available evidence, Optilume causes very few adverse events and does not raise safety concerns. For full details of the adverse events, see sections\xa05.2 and\xa06 of the assessment report in the supporting documentation.\n\n## There is a lack of long-term comparative studies to confirm the long-term benefits of Optilume\n\nThe 2‑year evidence showed that Optilume improved clinical and patient-reported outcomes, and is an effective treatment for recurrent bulbar urethral strictures. The results of ROBUST\xa01 suggested long-term efficacy at a 4‑year follow up but it only included 53\xa0people and was non-comparative. So, there is a lack of long-term comparative data. However, ROBUST\xa03 is ongoing and will collect 5‑year follow-up data until December 2025.\n\n# Cost evidence\n\n## The company's cost modelling finds Optilume to be cost saving compared with endoscopic management\n\nThe company submitted a new analysis because none of the economic studies identified included Optilume as a comparator. A Markov model compared Optilume with endoscopic management for treating recurrent anterior urethral strictures 3\xa0cm or less in length over a 5‑year time horizon. The model was based on data from ROBUST\xa03. Additional clinical and cost data was taken from the OPEN trial, a randomised controlled trial comparing urethrotomy with urethroplasty with a 2‑year follow up (Pickard et\xa0al. 2020). The company's base case showed a cost saving of £2,502 per person using Optilume. For full details of the cost evidence, see section\xa09 of the assessment report in the supporting documentation.\n\n## The company's cost model is appropriate and the EAC only made minor changes to costs of training and readmission to hospital\n\nThe EAC accepted the company's model structure, comparators, time horizon, and most of the assumptions and parameters. The EAC's initial base case was amended to 100% of day-case procedures. The clinical experts confirmed that Optilume is also being used in an outpatient setting. The EAC's base case was amended to 50% of day cases and 50% of outpatient procedures. The EAC made minor changes to the costs of training with Optilume and readmission to hospital. These changes had a small effect on the incremental cost saving. The cost saving in the EAC's base case increased to £2,510 per person using Optilume.\n\n## Stricture recurrence rate is the key cost driver\n\nThe key cost driver in the model was the probability of recurrence, and therefore the expected cost of retreatment. Cost savings were dependent on the savings from reduced repeat interventions being greater than the additional cost of treatment with Optilume when compared with standard endoscopic procedures. The probabilistic sensitivity analysis for the EAC's base case found that 94% of the 1,000 iterations resulted in cost saving.\n\n## The EAC noted that there is some uncertainty around clinical evidence in relation to recurrence rates\n\nThe EAC noted that the clinical evidence showed that Optilume improved clinical outcomes in the shorter term. However, there was some uncertainty around the extent and duration of the improvement in the longer term and how this translated to recurrence in the model. This was related to several factors including:\n\nThere is only 1\xa0comparative study available for Optilume (ROBUST\xa03), which is ongoing.\n\nThe study is limited to 2‑year follow up, although ROBUST\xa01 had follow up to 4\xa0years.\n\nThere is not an agreed single outcome measure that defines recurrence.\n\nStandard endoscopic methods encompass several different procedures.\n\n## Optilume remains cost saving at 5\xa0years when using different clinical data inputs for the probability of recurrence\n\nThe clinical experts agreed that there is not a single outcome measure for recurrence that is used consistently. Several additional scenarios using different clinical inputs for the probability of recurrence were provided. The company's and EAC's base cases used the IPSS score to indicate recurrence rates. The company included 2\xa0additional scenarios: 1\xa0using anatomical success from ROBUST\xa03 and 1\xa0using patient-reported outcome measures from the OPEN trial. When using the EAC's base case, both scenarios decreased the cost saving from £2,510 to £1,127 and £995 respectively. The EAC included an additional scenario that explored using retreatment rates from ROBUST\xa03. This increased the cost saving from £2,510 to £3,340. All scenarios reported treatment with Optilume to be cost saving at 5\xa0years.\n\n## Optilume in an outpatient setting increases cost savings\n\nThe company stated that Optilume can be done as a day case and in an outpatient setting. Its base case assumed that 50% of the procedures would be done as a day case and 50% in an outpatient setting. Based on expert advice, the EAC accepted this assumption, which resulted in a cost saving of £2,510. The EAC analysed the effect of varying the proportion of Optilume procedures done as a day case and in an outpatient setting. Results showed that increasing the proportion of day-case procedures decreased cost savings (100%, £1,877), while increasing the proportion of outpatient procedures increased cost savings (100%, £3,142).\n\n## Using endoscopic methods to retreat recurrent strictures moderately decreases cost savings\n\nThe company's model assumed people initially having Optilume or endoscopic methods would have retreatment using the same method. In practice, it is likely that people who do not have urethroplasty have a mix of sequential endoscopic treatments, including Optilume. This will depend on patient and clinician choice, and availability of resources. The EAC included an additional scenario allowing for a mix of Optilume and endoscopic procedures for retreatment. The results showed that increasing the proportion having retreatment using a standard endoscopic treatment resulted in a moderate decrease in total cost savings.\n\n## An exploratory analysis that extended the time horizon to 20\xa0years suggests that Optilume remains cost saving\n\nThe company's base-case time horizon was 5\xa0years. This was because there was a lack of long-term data and because the effect of Optilume would be greater in the initial years of using it. The company included an additional scenario using a 10‑year time horizon and the EAC investigated the effect of a longer time horizon of 20\xa0years. Increasing the time horizon to 20\xa0years had a small effect on the EAC's base case, increasing the cost saving from £2,510 to £3,175. The EAC noted that, because of the lack of longer-term comparative data, the results were uncertain.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## The evidence shows that Optilume is effective in the short term, but the long-term benefits are uncertain\n\nThe committee noted that the clinical evidence showed Optilume to be effective in improving clinically relevant outcomes including anatomical success, peak flow rate and international prostate symptom score (IPSS) at 2\xa0years. The single-arm study data suggested that Optilume remains effective at 4\xa0years (unpublished data from ROBUST\xa01). The committee considered that the studies of Optilume seemed to be well conducted and that the results were plausible. It concluded that the results to date are promising, although long-term comparative evidence was needed to see if the short-term benefits would be sustained at 5\xa0years.\n\n## The evidence is broadly generalisable to NHS practice\n\nThe committee had some concerns about the generalisability of the evidence to clinical practice in the NHS. None of the ROBUST studies included any centres in the UK. Optilume is proposed for second-line treatment after stricture recurrence, but people in ROBUST\xa03 had more than 2\xa0endoscopic treatments before having Optilume. The clinical experts noted that this reflects NHS practice. In ROBUST\xa03, strictures were predilatated in the entire Optilume group and in 58% of the control group. The clinical experts confirmed that this is not standard practice for either procedure in the NHS but that using a guidewire could dilate the stricture slightly. The company stated that, from the available evidence, predilatation does not appear to have affected Optilume's effectiveness. The clinical experts also agreed that predilatation is unlikely to affect Optilume's drug delivery and the overall results of ROBUST\xa03. The committee concluded that the evidence is broadly generalisable to NHS practice.\n\n# Side effects and adverse events\n\n## Evidence suggests that Optilume is safe and 5-year safety data will be collected in ROBUST\xa03\n\nThe most common adverse events reported in the literature were urinary tract infection and acute urinary retention. Biological, haematological and serological studies in ROBUST\xa01 and\xa03 identified no significant effects on health. The external assessment centre (EAC) considered Optilume to be safe based on the evidence and expert feedback. The company stated that paclitaxel is locally delivered and washed out with urine. There is very little systemic exposure, and paclitaxel is mostly cleared within a day and cannot be detected. The company also noted that it is in the process of collecting safety data for up to 5‑year follow up in ROBUST\xa03. The committee concluded that the data provided reasonable assurance that Optilume is safe to use and understood that longer-term safety data will be collected in ROBUST\xa03.\n\n## A postmarket study is planned to assess the effect of Optilume on semen characteristics\n\nThe committee acknowledged that the presence of paclitaxel in semen may potentially affect semen quality, testicular function and fertility. It queried how the clinical experts counsel people about fertility. The clinical experts advised that they tell people that there is a theoretical risk of altered semen characteristics. They explained that it is up to the person having Optilume whether to continue with the treatment. The clinical experts advise them to abstain from sexual activity for 2\xa0weeks and use barrier contraception for 3\xa0months. They noted that so far, this has not affected the decision making of the people who have had treatment with Optilume. A postmarket study (STREAM\xa0PMS) to assess semen characteristics after treatment with Optilume in men younger than\xa055 is currently enrolling participants.\n\n# Outcome measures\n\n## There is more than 1\xa0outcome measure for recurrence, but none is used consistently\n\nThe clinical experts agreed that there is no single outcome measure for recurrence that is used consistently. ROBUST\xa03 is collecting both objective (anatomical success, freedom from repeat intervention, postvoid residual and maximum flow rate) and subjective outcomes for recurrence (IPSS and IPSS quality of life). The clinical experts noted that subjective symptom outcomes are the easiest way to assess whether there is a stricture. The objective outcomes need more invasive assessments. They are not measured until someone presents with symptoms. IPSS, maximum flow rates and postvoid residual outcomes can be used because they are indicators that there is reasonable bladder emptying. The clinical experts noted that IPSS is not a disease-specific patient-reported outcome for strictures but that it has relevance because strictures also affect flow rates. It assesses how bothered people are about their symptoms. The committee concluded that all the outcomes in ROBUST\xa03 are clinically relevant. It also concluded that the results from the ROBUST studies are in line with what the clinical experts have seen in clinical practice.\n\n# NHS considerations overview\n\n## Optilume is not widely used in the NHS, but adoption is increasing\n\nOptilume has been available in the UK since June 2021. The company stated that 10\xa0NHS trusts have adopted Optilume and 82\xa0procedures have been completed. It also stated that several NHS trusts have put in a business case for it, and more NHS trusts are looking to do so. The committee concluded that there is clinical interest in, and a rise in the adoption of, Optilume within the NHS.\n\n## Optilume can reduce waiting lists for urethroplasty and relieve pressure on the NHS\n\nThe clinical experts stated that, before the COVID‑19 pandemic, waiting times for routine urethroplasty were 7\xa0to 8\xa0months. Waiting times are now more than 2\xa0years. Standard endoscopic treatments are typically done as day cases under general anaesthesia, but some may incorporate a short inpatient stay. Optilume can be done more routinely in an outpatient setting under local anaesthesia. After the procedure, people empty their bladder and can go home. The clinical experts confirmed that no changes are needed to the existing infrastructure because urology units would already be set up to do flexible cystoscopy and urethrograms. Using Optilume in an outpatient setting could reduce the waiting lists substantially. The committee recognised that the NHS is under severe pressure post the pandemic. It concluded that Optilume has the potential to reduce waiting lists, and that this may not be fully captured in the cost analysis.\n\n# Equality considerations\n\n## Optilume can be used in anyone with a stricture in their bulbar urethra\n\nThe clinical experts noted that trans women, with or without gender reassignment, have a bulbar urethra. If a bulbar stricture occurs, this is managed in the same way as for cisgender men. They considered that the evidence is generalisable to this group.\n\n# Cost-modelling overview\n\n## The cost model is robust and reflects NHS practice\n\nThe EAC accepted the model structure from the company but graphically redesigned the model diagram to provide a clearer presentation of the structure. The committee agreed that the model reflected NHS practice but noted that there should be a clearer distinction between what is an event compared with a health state. The health states labelled 'cured' have been amended to 'asymptomatic' because strictures can recur and people then move into the 'symptomatic' health state. The committee concluded that the rationale for the model was sensible and that the model structure was now clearer.\n\n## The EAC's base case assumes that the proportion of day-case and outpatient procedures with Optilume is equal\n\nThe company's base case assumed that 50% of procedures would be done as a day case and 50% in an outpatient setting. The initial EAC's base case was amended to 100% of day-case procedures. The clinical experts confirmed that Optilume is also being used in an outpatient setting. The EAC's base case was amended to 50% of day-case and 50% of outpatient procedures. The clinical experts noted that this was a reasonable assumption and that there is a high likelihood of more procedures being done in an outpatient setting in the future. The committee accepted the EAC's base-case assumption and recognised this may be a conservative estimate with a trend toward increasing outpatient procedures.\n\n## Optilume is cost saving compared with standard endoscopic methods but the evidence on recurrence rate is uncertain\n\nThe EAC's base case showed that Optilume was cost saving compared with standard endoscopic methods. The key cost driver was the probability of recurrence. Using deterministic one-way sensitivity analysis, this was the only variable that could make the base-case cost incurring at 5\xa0years. However, the probabilistic sensitivity analysis for the EAC's base case showed that 94% of the iterations were cost saving. Scenario analysis, including using different clinical outcomes for recurrence rates, also showed that Optilume was cost saving. The committee concluded that the results were robust and suggested that Optilume is likely to be cost saving. However, long-term comparative data on recurrence is needed to improve the certainty of the cost saving associated with Optilume at 5\xa0years and beyond.\n\n# Further research\n\n## Further research to address the long-term uncertainty should include 5-year efficacy and patient-reported outcome data\n\nOne-year data from ROBUST\xa03 has been published but the trial is ongoing with a 5‑year follow up. The committee understood that the planned follow up will include patient-reported outcomes. But the committee also considered it important to request further evidence to be collected in the NHS. It considered that real-world evidence and observational studies are important to assess clinical and operational effectiveness alongside ROBUST\xa03. The committee noted that outcomes should include:\n\npatient-reported outcome measures including IPSS and quality of life\n\nobjective outcome measures indicating stricture-free success such as reintervention rates.The clinical experts noted that a large European registry has been set up to collect objective outcomes for stricture recurrence prospectively for several technologies, including Optilume. This registry includes NHS trust hospitals and NHS patients."}	https://www.nice.org.uk/guidance/mtg73	Evidence-based recommendations on Optilume for treating recurrent bulbar urethral strictures.
8a039162eddaf453a18fbb72c49ff4df580e1ac3	nice	GreenLight XPS for treating benign prostatic hyperplasia	GreenLight XPS for treating benign prostatic hyperplasia Evidence-based recommendations on GreenLight XPS for benign prostatic hyperplasia. # Recommendations GreenLight XPS is recommended as an option to treat benign prostatic hyperplasia (BPH) in adults. Data should continue to be collected on cost-saving outcomes for GreenLight XPS compared with other treatments in people who may be considered high risk. This includes people with larger prostates and a higher risk of bleeding. Why the committee made these recommendations NICE previously recommended GreenLight XPS for BPH in people in non-high-risk groups. But it asked for more data on people in high-risk groups (previously defined as people with urinary retention, prostates over 100 ml in volume, and a higher risk of bleeding). Clinical experts advised that urinary retention is now not considered high risk in practice. In the remaining high-risk groups, clinical evidence suggests that GreenLight XPS is as effective as transurethral resection of the prostate (TURP) in treating BPH symptoms. GreenLight XPS is associated with a reduction in hospital stay and less postoperative catheterisation. Sexual function is also more likely to be maintained after the procedure. The cost modelling suggests GreenLight XPS is likely to be cost saving compared with TURP and holmium laser enucleation of the prostate (HoLEP). By how much depends on day case proportions, length of stay and procedure length. Although there is enough clinical evidence to recommend GreenLight XPS for people with BPH, including those in high-risk groups, further data is still needed to be more certain about cost savings in people with larger prostates and a higher risk of bleeding.# The technology # Technology GreenLight XPS (Boston Scientific) is a 180 W, 532 nm wavelength laser system intended to treat benign prostatic hyperplasia (BPH). It works by removing excess prostate tissue using laser vaporisation (a procedure known as photoselective vaporisation of the prostate ). A laser fibre is passed through a cystoscope to vaporise the enlarged prostate, leaving a clear urethral channel. In 'coagulation' mode, GreenLight XPS can also seal (cauterise) any bleeding vessels that may result from PVP. The GreenLight XPS system consists of a reusable laser console and a single-use fibre optic delivery device. It uses a proprietary MoXy liquid-cooled laser fibre, which is designed to handle high power and reduce fibre degradation. The procedure can be done either as a day case or on an inpatient basis. It is carried out under general or spinal anaesthetic. Using GreenLight XPS requires training, and the NHS has a mentorship scheme. # Care pathway Current surgical treatment for BPH when conservative management has been unsuccessful, or is not appropriate, is in NICE's guideline on managing lower urinary tract symptoms in men and includes: monopolar or bipolar transurethral resection of the prostate (TURP). See NICE's medical technologies guidance on the PLASMA system for transurethral resection and haemostasis of the prostate transurethral vaporisation of the prostate (TUVP) holmium laser enucleation of the prostate (HoLEP) transurethral incision of the prostate (TUIP; only in prostates smaller than 30 ml) -pen prostatectomy (only in prostates larger than 80 ml). Other surgical approaches include: prostatic urethral lift (see NICE's medical technologies guidance on UroLift for treating lower urinary tract symptoms of benign prostatic hyperplasia) PLASMA (see NICE's medical technologies guidance on the PLASMA system for transurethral resection and haemostasis of the prostate) water vapour thermal therapy (see NICE's medical technologies guidance on Rezum for treating lower urinary tract symptoms secondary to benign prostatic hyperplasia) photoselective laser vaporisation techniques. # Innovative aspects GreenLight XPS uses a proprietary MoXy laser fibre, which is actively cooled using a flow of saline to improve fibre durability. Because the laser operates at a shorter wavelength (532 nm) than other laser systems, it is absorbed by oxyhaemoglobin, vaporising the tissue without leaving fragments behind. GreenLight XPS can also seal (cauterise) any bleeding vessels which result from PVP in 'coagulation' mode. # Intended use GreenLight XPS is intended for PVP to treat BPH. It is contraindicated for people with prostate cancer. For a full list of contraindications and details on using GreenLight XPS, see the instructions for use. # Costs The company said that it usually provides the GreenLight XPS laser to the NHS for free, as part of a contractual arrangement in which the NHS agrees to buy a minimum number of laser fibres over a specified time period at an average price of £500 per fibre (excluding VAT). The company also said that if more than 1 fibre is needed per person, it will provide it for free.For more details, see the webpage for GreenLight XPS at the Boston Scientific website.# Evidence NICE commissioned an external assessment group (EAG) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website. # Clinical evidence from the original guidance ## The GOLIATH trial shows GreenLight XPS is as clinically effective as TURP The company submissions included 3 publications of a single trial (the GOLIATH study: Bachmann et al. 2014, Bachmann et al. 2015, Thomas et al. 2015), which compared GreenLight XPS with transurethral resection of the prostate (TURP). GOLIATH was a European multicentre randomised controlled trial in 281 people aged between 40 years and 80 years with a prostate volume less than 100 ml who were not on active anticoagulation therapy. Results showed no statistically significant difference in benign prostatic hyperplasia (BPH) symptom improvement (measured on the International Prostate Symptom Score or as maximum urinary flow ) between GreenLight XPS and TURP up to 2 years. Using GreenLight XPS resulted in a significantly shorter duration of catheterisation and shorter lengths of stay. The committee at the time of the original guidance concluded that GreenLight XPS was as effective as TURP in treating BPH in non-high-risk groups. ## There was not enough evidence in the high-risk population at the time of the original guidance The EAG identified 10 studies in total, including 2 from the 3 that the company submitted, that were relevant to the high-risk groups. High risk was defined in the previous guidance as people with a higher risk of bleeding (such as those on anticoagulants), larger prostates (over 100 ml) and urinary retention. Five of these studies included comparative clinical data. There were significant improvements from baseline in all clinical outcomes (p<0.001). The clinical experts said that GreenLight XPS may be a safe alternative to TURP in this population. However, the committee agreed that there was not enough evidence to show any notable differences in effectiveness or adverse events using GreenLight XPS in the high-risk population compared with TURP and holmium laser enucleation of the prostate (HoLEP). The committee therefore concluded in the original guidance that multicentre prospective studies with GreenLight XPS were needed in this population. Following a review of the evidence base in 2019, NICE decided to update the guidance to consider the new evidence on its use in high-risk groups since the original guidance. # New clinical evidence ## The EAG prioritised 37 studies out of 58 new publications For the guidance update, the EAG considered a total of 58 new studies relevant to the decision problem. Because of the size of the evidence base, the EAG prioritised 37 of these studies: randomised controlled trial (RCT) comparing standard GreenLight XPS 180 W photoselective vaporisation of the prostate (PVP) with GreenLight XPS ejaculatory hood-sparing technique (Abolazm et al. 2020) propensity-matched cohorts (Azizi et al. 2017, Castellani et al. 2018, Cimino et al. 2017) non-randomised, non-propensity-matched comparative studies (Cindolo et al. 2017, Gondran-Tellier et al. 2021, Hibon et al. 2017, Mathieu et al. 2017, Mattevi et al. 2020, Mesnard et al. 2021, Reimann et al. 2019) cohort studies that stratified by patient risk (Campobasso et al. 2020, Eken and Soyupak 2018, Goueli et al. 2017, Knapp et al. 2017, Lee et al. 2016, Meskawi et al. 2019, Meskawi et al. 2017, Waters et al. 2021) or procedure setting (Xu et al. 2021) single arm studies that reported on rare adverse events (Aboutaleb et al. 2018, Berquet et al. 2015, Castellucci et al. 2020, Chen and Chiang 2016, Ferrari et al. 2021b, Gasmi et al. 2021, Ghahhari et al. 2021, Ghahhari et al. 2018, Law et al. 2021, Liu et al. 2020, Rajih et al. 2017, Reimann et al. 2018, Tao et al. 2019, Thomas et al. 2019, Trail et al. 2021, Trujilo et al. 2021, Zhou et al. 2017).For full details of the clinical evidence, see section 3 of the assessment report update in the supporting documentation (Newcastle EAG 2022). ## There was no new randomised evidence comparing GreenLight XPS with TURP or HoLEP No new RCTs comparing GreenLight XPS with TURP or HoLEP were identified at guidance update. The GOLIATH trial remained the only randomised controlled evidence comparing GreenLight XPS with TURP. There was no randomised evidence comparing GreenLight XPS with HoLEP. At guidance update, 6 observational studies compared GreenLight XPS with TURP. The EAG said that further randomised comparative studies in people at high risk exclusively may not be ethical. This is because of the increased risk of bleeding, complications and longer hospital stays associated with TURP. ## Evidence suggests clinical benefits with GreenLight XPS, including in high-risk groups The new evidence suggested that, when compared with TURP, GreenLight XPS was associated with a significantly shorter hospital stay, significantly shorter postoperative catheterisation period and significantly higher preservation of ejaculatory function at 12 months (Reimann et al. 2019, Cimino et al. 2017, Mattevi et al. 2017, Gondran-Tellier et al. 2021, Mathieu et al. 2017). While most of this new evidence included people at high risk (50 of 58 studies), only 4 reported on high-risk populations exclusively. Two were comparative studies (Gondran-Tellier et al. 2021, Mesnard et al. 2021) and 2 were retrospective cohorts (Meskawi et al. 2017, Eken and Soyupak 2018). An additional 4 cohort studies stratified by anticoagulation status (Lee et al. 2016, Knapp et al. 2017, Meskawi et al. 2019, Eken and Soyupak et al. 2018). Details of these studies are in section 4.2 of the assessment report update in the supporting documentation (NICE 2022). # Cost evidence ## Published economic evidence reports cost benefits using GreenLight XPS The original guidance included 2 published cost-effectiveness studies, both of which compared GreenLight XPS with TURP (Thomas 2015, Bunejam-Gual 2014). Both studies suggested that reduced length of stay, or an increased proportion of procedures done as day cases would be associated with a cost saving when using GreenLight XPS. The EAG identified 6 economic studies published since the original guidance. None was done in the UK. Two studies reported GreenLight XPS to be cost saving against TURP (Masucci et al. 2018, Ulchaker and Martinson 2018), one reported GreenLight XPS to be more costly but more effective than TURP (Caicedo et al. 2019). Two studies reported TURP to be more cost effective (Erman et al. 2018, Ulchaker and Martinson 2018) and 1 reported cost savings when compared with HoLEP or ThuLEP in people with a prostate volume greater than 80 ml (Mathieu et al. 2017). For full details of the cost evidence, see section 9 of the assessment report update in the supporting documentation (Newcastle EAG 2022). ## The EAG updated the original decision tree cost model In the original guidance the company developed a decision tree model, which was used to inform the committee's recommendation. These compared the cost consequences of using GreenLight XPS with: monopolar or bipolar TURP in a non-high-risk BPH population (people who did not have urinary retention, not taking anticoagulation therapy or with prostates less than 100 ml) HoLEP in a high-risk BPH population (people with urinary retention, taking anticoagulation therapy or with prostates larger than 100 ml).The model used a 6‑month time horizon. The EAG corrected some minor errors and updated the model costs and clinical parameters, including: shortening the length of stay, reducing the calculated cost for HoLEP and removing excess bed day costs. For full details, see the assessment report update in the supporting documentation (Newcastle EAG 2022). ## The updated decision tree model suggests that GreenLight XPS is cost saving compared with TURP but cost incurring compared with HoLEP With the updated clinical and cost parameters, the EAG's base case results suggested that GreenLight XPS remains cost saving by £70 per person compared with TURP, but is cost incurring when compared with HoLEP (an additional cost of £114 per person). The latter was because of reduced capital costs associated with increased use per year of HoLEP in the updated model. Base case estimates assume 4% of TURP procedures and 36% of GreenLight XPS procedures were done as a day case procedure. The key driver of the cost saving was the proportion of procedures that could be carried out as day cases. The EAG's threshold analysis suggested that GreenLight XPS would be cost incurring if the proportion of day case procedures for TURP or HoLEP was above 43.6% and 56% respectively. This is assuming the proportion of GreenLight XPS procedures done as day cases stayed at 68%. The EAG and clinical experts agreed that these thresholds were clinically unlikely in the NHS. ## The company presented a new Markov model, which included a high-risk population scenario The company submitted a new cost model during the guidance update. It had a Markov model structure, which allowed for retreatment, and had a 4‑year time horizon. The model included everyone who needed treatment for BPH and had a high-risk group scenario, which was informed by the results of an unpublished systematic review. The EAG considered the unpublished systematic review to be low quality and the results of the review not robust because of methodological concerns. Details of the EAG's critique are in the economic model parameters of section 9.4 of the assessment report update in the supporting documentation (Newcastle EAG 2022). During the consultation, the systematic review was published (Burtt et al. 2022). The EAG reviewed and critiqued the published review. It considered that the publication provided no additional new evidence and the main methodological concerns remained. The EAG concluded that the published review was not sufficiently robust to inform a cost model for the high-risk population. ## The EAG modelled all people treated for BPH because there was limited comparative evidence in high-risk groups Given these limitations the EAG judged that the GOLIATH trial remained the most robust comparative evidence and that there was no new prospective comparative evidence specifically on using GreenLight XPS in high-risk populations, since the original guidance. The EAG considered that modelling all people whose BPH was treated, including those in high-risk groups, was more appropriate and more generalisable to the NHS. The EAG made some changes in the model costs and clinical parameters, including: extending the time horizon to 5 years, reducing the capital cost of HoLEP, and increasing the length of stay. Full details are in the assessment report update in the supporting documentation (Newcastle EAG 2022). ## The revised EAG base case results from the Markov model show that GreenLight XPS is cost saving compared with TURP or HoLEP The EAG's revised base case analysis for the Markov model showed that GreenLight XPS is cost saving, per person, by £304.83 compared with TURP and £269.52 compared with HoLEP. The EAG did a limited probabilistic sensitivity analysis, varying just 2 parameters, because of the lack of data. Base case cost savings were driven by the duration of procedures and the length of stay after procedures. Threshold analyses suggested that GreenLight XPS would become cost incurring if TURP and HoLEP were done in less than 43.7 minutes and 60.0 minutes respectively (relative to 49.6 minutes for GreenLight XPS). GreenLight XPS would also become cost incurring if the length of hospital stay after TURP or HoLEP was less than 1.5 days and 0.9 days respectively (relative to 1.6 days for GreenLight XPS). The clinical experts agreed that the scenarios of length of stay or proportion of day cases that would make GreenLight XPS cost incurring are unlikely in the NHS. ## Additional scenario analyses varying length of stay explore the size of cost savings using GreenLight XPS compared with TURP and HoLEP There was no comparative data on length of stay. The company estimated a length of stay of 0.7 days for GreenLight XPS based on a single arm, single-centre study in Canada (Ajib et al. 2018). The EAG applied a 1.6‑day length of stay derived from NHS activity data (hospital episode data). Both data sources had limitations (see details in table 22 of the assessment report update in the supporting documentation, Newcastle EAG 2022). After the public consultation, the EAG did additional analyses to consider the possible size of cost savings with GreenLight XPS by applying different values for length of stay. One scenario was informed by a clinical expert's opinion that length of stay with GreenLight XPS was 1 day. Length of stay with HoLEP and TURP was kept at 1.6 days and 2.3 days respectively. Two additional scenarios were informed by the British Association of Urological Surgeons Bladder Outflow Obstruction Audit data (2019), which reported mean lengths of stay (for people with and without a catheter pre-operatively, respectively) of: days and 1.13 days for GreenLight XPS days and 1.48 days for HoLEP days and 2.20 days for mTURP days and 1.63 days for bTURP.The results of these analyses showed GreenLight XPS remained cost saving by between £236 and £489 against TURP and by between £357 and £452 against HoLEP.# Committee discussion # Clinical-effectiveness overview ## GreenLight XPS is effective and has clinical benefits for the general population The committee concluded that the new clinical evidence on GreenLight XPS showed its effectiveness in relieving the lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Evidence also suggested that, compared with transurethral resection of the prostate (TURP), GreenLight XPS was associated with significantly shorter hospital stays, significantly shorter postoperative catheterisation, and significantly higher preservation of ejaculatory function at 12 months. The clinical experts confirmed that, in their experience, GreenLight XPS is an effective treatment option for people with BPH. The committee noted that there are no randomised trials that directly compare GreenLight XPS with holmium laser enucleation of the prostate (HoLEP), and no new randomised trials with TURP (other than the GOLIATH study). But it was satisfied that the available trial evidence, alongside real-world evidence and expert opinion, showed the clinical benefits associated with GreenLight XPS in practice. ## There is new evidence in high-risk populations, but comparative evidence is limited The committee noted that most of the evidence included people considered high risk, but there was little comparative data in these groups exclusively. The external assessment group (EAG) highlighted the possible ethical challenges in getting randomised comparative evidence in these high-risk groups. The committee agreed that a large volume of evidence has been published after the original guidance but the comparative evidence in high-risk populations remains limited. ## Clinicians do not consider people with urinary retention to have a higher risk of complications Clinical experts described how the risk profile of people with BPH has changed in practice since the previous guidance. They explained that urinary retention is common in people being treated for BPH (up to 50% of the population). The committee was satisfied that GreenLight XPS has been used for treating BPH in people with urinary retention, who are not now considered as a high-risk group in practice. ## GreenLight XPS is considered to be a safe and effective treatment option for people with a higher risk of bleeding and large prostates The clinical experts said that they considered GreenLight XPS to be a safe treatment option for people with a higher risk of bleeding or who were taking anticoagulants. They estimated that 20% of people having GreenLight XPS were in this high-risk group. The clinical experts said that anticoagulants can usually be taken through GreenLight XPS surgery, unlike with TURP. They said this means people who were at risk of bleeding could be referred across hospitals for treatment with GreenLight XPS. The clinical experts also advised that treatment for people with large prostates may be more varied because of laser technology availability and clinicians' experience. All of them considered that using GreenLight XPS to treat BPH was safe with prostates up to 100 ml in volume. They agreed that up to 150 ml was appropriate for GreenLight XPS if the clinician was experienced. People with prostates bigger than 150 ml are more likely to be considered for HoLEP treatment. The committee understood prostate size was a key factor in how long the procedure may take, so patient selection and the clinician's experience were important considerations in this high-risk group. The committee was satisfied that the evidence showed the clinical effectiveness of GreenLight XPS in BPH in larger prostates and people with a high risk of bleeding but concluded that more comparative evidence on the use of GreenLight XPS in these groups is needed. # Side effects and adverse events ## Risk of bleeding is low with GreenLight XPS Evidence from 12 studies reported that between 0% and 2.2% of people needed blood transfusions intraoperatively and 0.6% and 0.8% within 30 days. Seventeen studies recorded 0.1% to 5.6% of people with capsular perforation. Six studies reported no adverse events. The clinical experts explained that GreenLight XPS was rarely associated with postoperative bleeding. They said that continuous bladder irrigation (to prevent clot formation) was not normally needed after GreenLight XPS surgery, which reduces nursing requirements and improves the patient experience. Three-way catheters can help identify any issues with secondary bleeds, but clinical experts reported bleed risk to be low. The committee was satisfied that the risk of bleeding is low with GreenLight XPS. ## Fibre breakage is rare and does not affect the person having treatment The company said that fibre breakage was rare, and that it had modified the device to promote the cooling of the fibres, to minimise breakage. The EAG confirmed that there were no concerns over device safety and no adverse events related to patient harm. The clinical experts agreed that fibre breakage was rare (around 1 in 200 cases) and was not associated with patient harm. They explained that fibre breakage is more likely when a clinician first starts to use the device because they may position the fibre too close to the tissue. The committee was satisfied that there were no patient or clinician safety concerns about fibre breakage. # Relevance to the NHS ## GreenLight XPS is available for treating BPH in the NHS The company confirmed that GreenLight XPS is used in 26 specialist centres in the UK. The clinical experts explained that GreenLight XPS is used routinely in people needing surgical treatment for BPH, including those in the high-risk groups (people with large prostates or with a higher risk of bleeding). GreenLight XPS is one of the technologies covered by the MedTech funding mandate in 2022 to 2023. # NHS considerations overview ## GreenLight XPS can be done as a day case procedure, but some people need to stay overnight The evidence reported that 68% of GreenLight XPS procedures were done as a day case (Trail et al. 2021). The clinical experts said that in their experience most people having GreenLight XPS are seen as a day case and do not need hospital admission. One said that, compared with TURP or HoLEP, GreenLight XPS is more likely to be a day case procedure. But they added that it depended on individual circumstances, such as the size of their prostate gland, social reasons, and the use of anaesthetics, which may mean some people needed an overnight stay. ## Service set up is important when optimising day case proportions and length of stay Clinical experts explained that NHS urology centres varied in how services were set up. For example, some hospitals have extended opening hours to support day case surgery for GreenLight XPS but other centres require hospital admission. The committee understood that how services were set up could explain the large variations in length of stay and proportion of day cases across the centres. It agreed that willingness to set up day case services would be important to optimise the potential savings with GreenLight XPS. ## There may be benefits to GreenLight XPS with respect to learning curves and training The clinical experts explained that urologists need specialist training to use GreenLight XPS. But they suggested that it may be quicker to learn than TURP or HoLEP. The clinical experts also highlighted the importance of minimum procedure levels across centres to ensure skills are maintained. ## Laser equipment and safety training are required, but the costs are negligible The clinical experts said that laser treatment is available across urology departments for treating conditions such as kidney stones and BPH. Urologists are routinely trained in laser techniques and laser safety. Using GreenLight XPS requires laser equipment, including goggles. The cost of the equipment was not included in the cost model. The EAG considered that laser equipment is reusable, with a long lifespan and that costs would be negligible. The committee was satisfied that this would not be a significant additional cost requirement for services. # Equality considerations ## Two people who identify as women have had GreenLight XPS The committee was told that 2 people who identified as women and retained a prostate had GreenLight XPS treatment. No change in technique or concerns in carrying out the procedure in this population were reported. # Cost modelling overview ## GreenLight XPS is estimated to be cost saving compared with standard treatments but by how much is uncertain The EAG's cost modelling results from the Markov model showed that GreenLight XPS is likely to be cost saving compared with TURP by £305 per person over 5 years. They showed that it was also likely to be cost saving compared with HoLEP by £270 per person over 5 years. The estimates applied to all people with BPH, including those considered to be high risk. The EAG considered the model to accurately reflect treatment complication and retreatment costs but that the size of the cost savings was uncertain in high-risk groups because of a lack of comparative evidence. The clinical experts also advised that modelling high-risk populations collectively may not be appropriate or generalisable to clinical practice. The committee agreed that the EAG's approach to modelling using the GOLIATH data was appropriate. It concluded that using GreenLight XPS is likely to be cost saving but by how much is uncertain, particularly for high-risk groups. # Main cost drivers in the Markov model ## Length of stay affects GreenLight XPS's cost case Length of stay was one of the key drivers of the estimated cost savings with GreenLight XPS compared with standard treatments such as TURP in the Markov model. GreenLight XPS becomes cost incurring if the length of stay with TURP is reduced to a level similar to GreenLight XPS. Length of stay was not a key driver in the original guidance, because the decision tree model presented it as the proportion of day cases, which was the key driver (see the assessment report update in the supporting documentation, Newcastle EAG 2022). The clinical experts said that people having GreenLight XPS are likely to be discharged on the same day and are not usually admitted to hospital after the procedure. However, the length of stay is likely to be influenced by personal factors and hospital infrastructure (see section 4.9). The clinical experts agreed that the scenarios for length of stay or proportion of day cases that would make GreenLight XPS cost incurring are unlikely in clinical practice in the NHS. However, given there is uncertainty in the size of the cost saving from length of stay in the cost model, the committee suggested data should continue to be collected on cost-saving outcomes such as length of stay when treating people who may be considered high risk (including those with larger prostates and a higher risk of bleeding). ## Length of procedure affects GreenLight XPS's cost case The economic analysis included an assumed average procedure length of 49.6 minutes for GreenLight XPS, 66 minutes for TURP and 80 minutes for HoLEP. The clinical experts considered these procedure durations to be reasonable. However, they advised that duration is affected by prostate size and the clinician's experience. The clinical experts said that using GreenLight XPS for larger prostates might extend procedure duration. This could reduce the cost saving of using GreenLight XPS compared with TURP or HoLEP. However, it should be noted that there is a lack of data on procedural duration. The committee agreed that more data, including audit data, would be helpful to inform the uncertainty in the cost benefit of length of procedure across the comparators for the high-risk population (including those with larger prostates and a higher risk of bleeding). # Further data collection ## The committee would like to see more robust comparative evidence in high-risk groups The committee agreed that more data on the resource impact of GreenLight XPS compared with other treatments is needed in the high-risk groups (including those with larger prostates and higher risk of bleeding). It recommended collecting more data to address the cost-saving outcomes, including the length of hospital stay and the procedure duration, in high-risk groups.	{'Recommendations': 'GreenLight\xa0XPS is recommended as an option to treat benign prostatic hyperplasia (BPH) in adults.\n\nData should continue to be collected on cost-saving outcomes for GreenLight\xa0XPS compared with other treatments in people who may be considered high risk. This includes people with larger prostates and a higher risk of bleeding.\n\nWhy the committee made these recommendations\n\nNICE previously recommended GreenLight\xa0XPS for BPH in people in non-high-risk groups. But it asked for more data on people in high-risk groups (previously defined as people with urinary retention, prostates over 100\xa0ml in volume, and a higher risk of bleeding).\n\nClinical experts advised that urinary retention is now not considered high risk in practice. In the remaining high-risk groups, clinical evidence suggests that GreenLight\xa0XPS is as effective as transurethral resection of the prostate (TURP) in treating BPH symptoms. GreenLight\xa0XPS is associated with a reduction in hospital stay and less postoperative catheterisation. Sexual function is also more likely to be maintained after the procedure.\n\nThe cost modelling suggests GreenLight\xa0XPS is likely to be cost saving compared with TURP and holmium laser enucleation of the prostate (HoLEP). By how much depends on day case proportions, length of stay and procedure length.\n\nAlthough there is enough clinical evidence to recommend GreenLight\xa0XPS for people with BPH, including those in high-risk groups, further data is still needed to be more certain about cost savings in people with larger prostates and a higher risk of bleeding.', 'The technology': "# Technology\n\nGreenLight\xa0XPS (Boston Scientific) is a 180\xa0W, 532\xa0nm wavelength laser system intended to treat benign prostatic hyperplasia (BPH). It works by removing excess prostate tissue using laser vaporisation (a procedure known as photoselective vaporisation of the prostate [PVP]). A laser fibre is passed through a cystoscope to vaporise the enlarged prostate, leaving a clear urethral channel. In 'coagulation' mode, GreenLight\xa0XPS can also seal (cauterise) any bleeding vessels that may result from PVP.\n\nThe GreenLight\xa0XPS system consists of a reusable laser console and a single-use fibre optic delivery device. It uses a proprietary MoXy liquid-cooled laser fibre, which is designed to handle high power and reduce fibre degradation.\n\nThe procedure can be done either as a day case or on an inpatient basis. It is carried out under general or spinal anaesthetic. Using GreenLight\xa0XPS requires training, and the NHS has a mentorship scheme.\n\n# Care pathway\n\nCurrent surgical treatment for BPH when conservative management has been unsuccessful, or is not appropriate, is in NICE's guideline on managing lower urinary tract symptoms in men and includes:\n\nmonopolar or bipolar transurethral resection of the prostate (TURP). See NICE's medical technologies guidance on the PLASMA system for transurethral resection and haemostasis of the prostate\n\ntransurethral vaporisation of the prostate (TUVP)\n\nholmium laser enucleation of the prostate (HoLEP)\n\ntransurethral incision of the prostate (TUIP; only in prostates smaller than 30\xa0ml)\n\nopen prostatectomy (only in prostates larger than 80\xa0ml).\n\nOther surgical approaches include:\n\nprostatic urethral lift (see NICE's medical technologies guidance on UroLift for treating lower urinary tract symptoms of benign prostatic hyperplasia)\n\nPLASMA (see NICE's medical technologies guidance on the PLASMA system for transurethral resection and haemostasis of the prostate)\n\nwater vapour thermal therapy (see NICE's medical technologies guidance on Rezum for treating lower urinary tract symptoms secondary to benign prostatic hyperplasia)\n\nphotoselective laser vaporisation techniques.\n\n# Innovative aspects\n\nGreenLight\xa0XPS uses a proprietary MoXy laser fibre, which is actively cooled using a flow of saline to improve fibre durability. Because the laser operates at a shorter wavelength (532\xa0nm) than other laser systems, it is absorbed by oxyhaemoglobin, vaporising the tissue without leaving fragments behind. GreenLight\xa0XPS can also seal (cauterise) any bleeding vessels which result from PVP in 'coagulation' mode.\n\n# Intended use\n\nGreenLight\xa0XPS is intended for PVP to treat BPH. It is contraindicated for people with prostate cancer. For a full list of contraindications and details on using GreenLight\xa0XPS, see the instructions for use.\n\n# Costs\n\nThe company said that it usually provides the GreenLight\xa0XPS laser to the NHS for free, as part of a contractual arrangement in which the NHS agrees to buy a minimum number of laser fibres over a specified time period at an average price of £500 per fibre (excluding VAT). The company also said that if more than 1\xa0fibre is needed per person, it will provide it for free.For more details, see the webpage for GreenLight\xa0XPS at the Boston Scientific website.", 'Evidence': "NICE commissioned an external assessment group (EAG) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence from the original guidance\n\n## The GOLIATH trial shows GreenLight\xa0XPS is as clinically effective as TURP\n\nThe company submissions included 3 publications of a single trial (the GOLIATH study: Bachmann et al. 2014, Bachmann et al. 2015, Thomas et al. 2015), which compared GreenLight\xa0XPS with transurethral resection of the prostate (TURP). GOLIATH was a European multicentre randomised controlled trial in 281 people aged between 40\xa0years and 80\xa0years with a prostate volume less than 100\xa0ml who were not on active anticoagulation therapy. Results showed no statistically significant difference in benign prostatic hyperplasia (BPH) symptom improvement (measured on the International Prostate Symptom Score [IPSS] or as maximum urinary flow [Qmax]) between GreenLight\xa0XPS and TURP up to 2\xa0years. Using GreenLight\xa0XPS resulted in a significantly shorter duration of catheterisation and shorter lengths of stay. The committee at the time of the original guidance concluded that GreenLight\xa0XPS was as effective as TURP in treating BPH in non-high-risk groups.\n\n## There was not enough evidence in the high-risk population at the time of the original guidance\n\nThe EAG identified 10 studies in total, including 2 from the 3 that the company submitted, that were relevant to the high-risk groups. High risk was defined in the previous guidance as people with a higher risk of bleeding (such as those on anticoagulants), larger prostates (over 100\xa0ml) and urinary retention. Five of these studies included comparative clinical data. There were significant improvements from baseline in all clinical outcomes (p<0.001). The clinical experts said that GreenLight\xa0XPS may be a safe alternative to TURP in this population. However, the committee agreed that there was not enough evidence to show any notable differences in effectiveness or adverse events using GreenLight\xa0XPS in the high-risk population compared with TURP and holmium laser enucleation of the prostate (HoLEP). The committee therefore concluded in the original guidance that multicentre prospective studies with GreenLight\xa0XPS were needed in this population.\n\nFollowing a review of the evidence base in 2019, NICE decided to update the guidance to consider the new evidence on its use in high-risk groups since the original guidance.\n\n# New clinical evidence\n\n## The EAG prioritised 37 studies out of 58 new publications\n\nFor the guidance update, the EAG considered a total of 58 new studies relevant to the decision problem. Because of the size of the evidence base, the EAG prioritised 37 of these studies:\n\nrandomised controlled trial (RCT) comparing standard GreenLight\xa0XPS 180\xa0W photoselective vaporisation of the prostate (PVP) with GreenLight\xa0XPS ejaculatory hood-sparing technique (Abolazm et al. 2020)\n\npropensity-matched cohorts (Azizi et al. 2017, Castellani et al. 2018, Cimino et al. 2017)\n\nnon-randomised, non-propensity-matched comparative studies (Cindolo et al. 2017, Gondran-Tellier et al. 2021, Hibon et al. 2017, Mathieu et al. 2017, Mattevi et al. 2020, Mesnard et al. 2021, Reimann et al. 2019)\n\ncohort studies that stratified by patient risk (Campobasso et al. 2020, Eken and Soyupak 2018, Goueli et al. 2017, Knapp et al. 2017, Lee et al. 2016, Meskawi et al. 2019, Meskawi et al. 2017, Waters et al. 2021) or procedure setting (Xu et al. 2021)\n\nsingle arm studies that reported on rare adverse events (Aboutaleb et al. 2018, Berquet et al. 2015, Castellucci et al. 2020, Chen and Chiang 2016, Ferrari et al. 2021b, Gasmi et al. 2021, Ghahhari et al. 2021, Ghahhari et al. 2018, Law et al. 2021, Liu et al. 2020, Rajih et al. 2017, Reimann et al. 2018, Tao et al. 2019, Thomas et al. 2019, Trail et al. 2021, Trujilo et al. 2021, Zhou et al. 2017).For full details of the clinical evidence, see section 3 of the assessment report update in the supporting documentation (Newcastle EAG 2022).\n\n## There was no new randomised evidence comparing GreenLight\xa0XPS with TURP or HoLEP\n\nNo new RCTs comparing GreenLight\xa0XPS with TURP or HoLEP were identified at guidance update. The GOLIATH trial remained the only randomised controlled evidence comparing GreenLight\xa0XPS with TURP. There was no randomised evidence comparing GreenLight\xa0XPS with HoLEP. At guidance update, 6 observational studies compared GreenLight\xa0XPS with TURP. The EAG said that further randomised comparative studies in people at high risk exclusively may not be ethical. This is because of the increased risk of bleeding, complications and longer hospital stays associated with TURP.\n\n## Evidence suggests clinical benefits with GreenLight\xa0XPS, including in high-risk groups\n\nThe new evidence suggested that, when compared with TURP, GreenLight\xa0XPS was associated with a significantly shorter hospital stay, significantly shorter postoperative catheterisation period and significantly higher preservation of ejaculatory function at 12\xa0months (Reimann et al. 2019, Cimino et al. 2017, Mattevi et al. 2017, Gondran-Tellier et al. 2021, Mathieu et al. 2017). While most of this new evidence included people at high risk (50 of 58 studies), only 4 reported on high-risk populations exclusively. Two were comparative studies (Gondran-Tellier et al. 2021, Mesnard et al. 2021) and 2 were retrospective cohorts (Meskawi et al. 2017, Eken and Soyupak 2018). An additional 4 cohort studies stratified by anticoagulation status (Lee et al. 2016, Knapp et al. 2017, Meskawi et al. 2019, Eken and Soyupak et al. 2018). Details of these studies are in section 4.2 of the assessment report update in the supporting documentation (NICE 2022).\n\n# Cost evidence\n\n## Published economic evidence reports cost benefits using GreenLight\xa0XPS\n\nThe original guidance included 2 published cost-effectiveness studies, both of which compared GreenLight\xa0XPS with TURP (Thomas 2015, Bunejam-Gual 2014). Both studies suggested that reduced length of stay, or an increased proportion of procedures done as day cases would be associated with a cost saving when using GreenLight\xa0XPS.\n\nThe EAG identified 6 economic studies published since the original guidance. None was done in the UK. Two studies reported GreenLight\xa0XPS to be cost saving against TURP (Masucci et al. 2018, Ulchaker and Martinson 2018), one reported GreenLight\xa0XPS to be more costly but more effective than TURP (Caicedo et al. 2019). Two studies reported TURP to be more cost effective (Erman et al. 2018, Ulchaker and Martinson 2018) and 1 reported cost savings when compared with HoLEP or ThuLEP in people with a prostate volume greater than 80\xa0ml (Mathieu et al. 2017). For full details of the cost evidence, see section 9 of the assessment report update in the supporting documentation (Newcastle EAG 2022).\n\n## The EAG updated the original decision tree cost model\n\nIn the original guidance the company developed a decision tree model, which was used to inform the committee's recommendation. These compared the cost consequences of using GreenLight\xa0XPS with:\n\nmonopolar or bipolar TURP in a non-high-risk BPH population (people who did not have urinary retention, not taking anticoagulation therapy or with prostates less than 100\xa0ml)\n\nHoLEP in a high-risk BPH population (people with urinary retention, taking anticoagulation therapy or with prostates larger than 100\xa0ml).The model used a 6‑month time horizon. The EAG corrected some minor errors and updated the model costs and clinical parameters, including: shortening the length of stay, reducing the calculated cost for HoLEP and removing excess bed day costs. For full details, see the assessment report update in the supporting documentation (Newcastle EAG 2022).\n\n## The updated decision tree model suggests that GreenLight\xa0XPS is cost saving compared with TURP but cost incurring compared with HoLEP\n\nWith the updated clinical and cost parameters, the EAG's base case results suggested that GreenLight\xa0XPS remains cost saving by £70 per person compared with TURP, but is cost incurring when compared with HoLEP (an additional cost of £114 per person). The latter was because of reduced capital costs associated with increased use per year of HoLEP in the updated model. Base case estimates assume 4% of TURP procedures and 36% of GreenLight\xa0XPS procedures were done as a day case procedure. The key driver of the cost saving was the proportion of procedures that could be carried out as day cases. The EAG's threshold analysis suggested that GreenLight\xa0XPS would be cost incurring if the proportion of day case procedures for TURP or HoLEP was above 43.6% and 56% respectively. This is assuming the proportion of GreenLight XPS procedures done as day cases stayed at 68%. The EAG and clinical experts agreed that these thresholds were clinically unlikely in the NHS.\n\n## The company presented a new Markov model, which included a high-risk population scenario\n\nThe company submitted a new cost model during the guidance update. It had a Markov model structure, which allowed for retreatment, and had a 4‑year time horizon. The model included everyone who needed treatment for BPH and had a high-risk group scenario, which was informed by the results of an unpublished systematic review. The EAG considered the unpublished systematic review to be low quality and the results of the review not robust because of methodological concerns. Details of the EAG's critique are in the economic model parameters of section 9.4 of the assessment report update in the supporting documentation (Newcastle EAG 2022).\n\nDuring the consultation, the systematic review was published (Burtt et al. 2022). The EAG reviewed and critiqued the published review. It considered that the publication provided no additional new evidence and the main methodological concerns remained. The EAG concluded that the published review was not sufficiently robust to inform a cost model for the high-risk population.\n\n## The EAG modelled all people treated for BPH because there was limited comparative evidence in high-risk groups\n\nGiven these limitations the EAG judged that the GOLIATH trial remained the most robust comparative evidence and that there was no new prospective comparative evidence specifically on using GreenLight\xa0XPS in high-risk populations, since the original guidance. The EAG considered that modelling all people whose BPH was treated, including those in high-risk groups, was more appropriate and more generalisable to the NHS. The EAG made some changes in the model costs and clinical parameters, including: extending the time horizon to 5\xa0years, reducing the capital cost of HoLEP, and increasing the length of stay. Full details are in the assessment report update in the supporting documentation (Newcastle EAG 2022).\n\n## The revised EAG base case results from the Markov model show that GreenLight\xa0XPS is cost saving compared with TURP or HoLEP\n\nThe EAG's revised base case analysis for the Markov model showed that GreenLight\xa0XPS is cost saving, per person, by £304.83 compared with TURP and £269.52 compared with HoLEP. The EAG did a limited probabilistic sensitivity analysis, varying just 2 parameters, because of the lack of data. Base case cost savings were driven by the duration of procedures and the length of stay after procedures. Threshold analyses suggested that GreenLight\xa0XPS would become cost incurring if TURP and HoLEP were done in less than 43.7\xa0minutes and 60.0\xa0minutes respectively (relative to 49.6\xa0minutes for GreenLight\xa0XPS). GreenLight\xa0XPS would also become cost incurring if the length of hospital stay after TURP or HoLEP was less than 1.5\xa0days and 0.9\xa0days respectively (relative to 1.6\xa0days for GreenLight\xa0XPS). The clinical experts agreed that the scenarios of length of stay or proportion of day cases that would make GreenLight\xa0XPS cost incurring are unlikely in the NHS.\n\n## Additional scenario analyses varying length of stay explore the size of cost savings using GreenLight\xa0XPS compared with TURP and HoLEP\n\nThere was no comparative data on length of stay. The company estimated a length of stay of 0.7\xa0days for GreenLight\xa0XPS based on a single arm, single-centre study in Canada (Ajib et al. 2018). The EAG applied a 1.6‑day length of stay derived from NHS activity data (hospital episode data). Both data sources had limitations (see details in table 22 of the assessment report update in the supporting documentation, Newcastle EAG 2022). After the public consultation, the EAG did additional analyses to consider the possible size of cost savings with GreenLight\xa0XPS by applying different values for length of stay. One scenario was informed by a clinical expert's opinion that length of stay with GreenLight\xa0XPS was 1\xa0day. Length of stay with HoLEP and TURP was kept at 1.6\xa0days and 2.3\xa0days respectively. Two additional scenarios were informed by the British Association of Urological Surgeons Bladder Outflow Obstruction Audit data (2019), which reported mean lengths of stay (for people with and without a catheter pre-operatively, respectively) of:\n\ndays and 1.13\xa0days for GreenLight\xa0XPS\n\ndays and 1.48\xa0days for HoLEP\n\ndays and 2.20\xa0days for mTURP\n\ndays and 1.63\xa0days for bTURP.The results of these analyses showed GreenLight\xa0XPS remained cost saving by between £236 and £489 against TURP and by between £357 and £452 against HoLEP.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## GreenLight\xa0XPS is effective and has clinical benefits for the general population\n\nThe committee concluded that the new clinical evidence on GreenLight\xa0XPS showed its effectiveness in relieving the lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Evidence also suggested that, compared with transurethral resection of the prostate (TURP), GreenLight\xa0XPS was associated with significantly shorter hospital stays, significantly shorter postoperative catheterisation, and significantly higher preservation of ejaculatory function at 12\xa0months. The clinical experts confirmed that, in their experience, GreenLight\xa0XPS is an effective treatment option for people with BPH. The committee noted that there are no randomised trials that directly compare GreenLight\xa0XPS with holmium laser enucleation of the prostate (HoLEP), and no new randomised trials with TURP (other than the GOLIATH study). But it was satisfied that the available trial evidence, alongside real-world evidence and expert opinion, showed the clinical benefits associated with GreenLight\xa0XPS in practice.\n\n## There is new evidence in high-risk populations, but comparative evidence is limited\n\nThe committee noted that most of the evidence included people considered high risk, but there was little comparative data in these groups exclusively. The external assessment group (EAG) highlighted the possible ethical challenges in getting randomised comparative evidence in these high-risk groups. The committee agreed that a large volume of evidence has been published after the original guidance but the comparative evidence in high-risk populations remains limited.\n\n## Clinicians do not consider people with urinary retention to have a higher risk of complications\n\nClinical experts described how the risk profile of people with BPH has changed in practice since the previous guidance. They explained that urinary retention is common in people being treated for BPH (up to 50% of the population). The committee was satisfied that GreenLight\xa0XPS has been used for treating BPH in people with urinary retention, who are not now considered as a high-risk group in practice.\n\n## GreenLight\xa0XPS is considered to be a safe and effective treatment option for people with a higher risk of bleeding and large prostates\n\nThe clinical experts said that they considered GreenLight\xa0XPS to be a safe treatment option for people with a higher risk of bleeding or who were taking anticoagulants. They estimated that 20% of people having GreenLight\xa0XPS were in this high-risk group. The clinical experts said that anticoagulants can usually be taken through GreenLight\xa0XPS surgery, unlike with TURP. They said this means people who were at risk of bleeding could be referred across hospitals for treatment with GreenLight\xa0XPS. The clinical experts also advised that treatment for people with large prostates may be more varied because of laser technology availability and clinicians' experience. All of them considered that using GreenLight\xa0XPS to treat BPH was safe with prostates up to 100\xa0ml in volume. They agreed that up to 150\xa0ml was appropriate for GreenLight\xa0XPS if the clinician was experienced. People with prostates bigger than 150\xa0ml are more likely to be considered for HoLEP treatment. The committee understood prostate size was a key factor in how long the procedure may take, so patient selection and the clinician's experience were important considerations in this high-risk group. The committee was satisfied that the evidence showed the clinical effectiveness of GreenLight\xa0XPS in BPH in larger prostates and people with a high risk of bleeding but concluded that more comparative evidence on the use of GreenLight\xa0XPS in these groups is needed.\n\n# Side effects and adverse events\n\n## Risk of bleeding is low with GreenLight\xa0XPS\n\nEvidence from 12 studies reported that between 0% and 2.2% of people needed blood transfusions intraoperatively and 0.6% and 0.8% within 30\xa0days. Seventeen studies recorded 0.1% to 5.6% of people with capsular perforation. Six studies reported no adverse events. The clinical experts explained that GreenLight\xa0XPS was rarely associated with postoperative bleeding. They said that continuous bladder irrigation (to prevent clot formation) was not normally needed after GreenLight\xa0XPS surgery, which reduces nursing requirements and improves the patient experience. Three-way catheters can help identify any issues with secondary bleeds, but clinical experts reported bleed risk to be low. The committee was satisfied that the risk of bleeding is low with GreenLight\xa0XPS.\n\n## Fibre breakage is rare and does not affect the person having treatment\n\nThe company said that fibre breakage was rare, and that it had modified the device to promote the cooling of the fibres, to minimise breakage. The EAG confirmed that there were no concerns over device safety and no adverse events related to patient harm. The clinical experts agreed that fibre breakage was rare (around 1 in 200 cases) and was not associated with patient harm. They explained that fibre breakage is more likely when a clinician first starts to use the device because they may position the fibre too close to the tissue. The committee was satisfied that there were no patient or clinician safety concerns about fibre breakage.\n\n# Relevance to the NHS\n\n## GreenLight\xa0XPS is available for treating BPH in the NHS\n\nThe company confirmed that GreenLight\xa0XPS is used in 26 specialist centres in the UK. The clinical experts explained that GreenLight\xa0XPS is used routinely in people needing surgical treatment for BPH, including those in the high-risk groups (people with large prostates or with a higher risk of bleeding). GreenLight\xa0XPS is one of the technologies covered by the MedTech funding mandate in 2022 to 2023.\n\n# NHS considerations overview\n\n## GreenLight\xa0XPS can be done as a day case procedure, but some people need to stay overnight\n\nThe evidence reported that 68% of GreenLight\xa0XPS procedures were done as a day case (Trail et al. 2021). The clinical experts said that in their experience most people having GreenLight\xa0XPS are seen as a day case and do not need hospital admission. One said that, compared with TURP or HoLEP, GreenLight\xa0XPS is more likely to be a day case procedure. But they added that it depended on individual circumstances, such as the size of their prostate gland, social reasons, and the use of anaesthetics, which may mean some people needed an overnight stay.\n\n## Service set up is important when optimising day case proportions and length of stay\n\nClinical experts explained that NHS urology centres varied in how services were set up. For example, some hospitals have extended opening hours to support day case surgery for GreenLight\xa0XPS but other centres require hospital admission. The committee understood that how services were set up could explain the large variations in length of stay and proportion of day cases across the centres. It agreed that willingness to set up day case services would be important to optimise the potential savings with GreenLight\xa0XPS.\n\n## There may be benefits to GreenLight\xa0XPS with respect to learning curves and training\n\nThe clinical experts explained that urologists need specialist training to use GreenLight\xa0XPS. But they suggested that it may be quicker to learn than TURP or HoLEP. The clinical experts also highlighted the importance of minimum procedure levels across centres to ensure skills are maintained.\n\n## Laser equipment and safety training are required, but the costs are negligible\n\nThe clinical experts said that laser treatment is available across urology departments for treating conditions such as kidney stones and BPH. Urologists are routinely trained in laser techniques and laser safety. Using GreenLight\xa0XPS requires laser equipment, including goggles. The cost of the equipment was not included in the cost model. The EAG considered that laser equipment is reusable, with a long lifespan and that costs would be negligible. The committee was satisfied that this would not be a significant additional cost requirement for services.\n\n# Equality considerations\n\n## Two people who identify as women have had GreenLight\xa0XPS\n\nThe committee was told that 2 people who identified as women and retained a prostate had GreenLight\xa0XPS treatment. No change in technique or concerns in carrying out the procedure in this population were reported.\n\n# Cost modelling overview\n\n## GreenLight\xa0XPS is estimated to be cost saving compared with standard treatments but by how much is uncertain\n\nThe EAG's cost modelling results from the Markov model showed that GreenLight\xa0XPS is likely to be cost saving compared with TURP by £305 per person over 5\xa0years. They showed that it was also likely to be cost saving compared with HoLEP by £270 per person over 5\xa0years. The estimates applied to all people with BPH, including those considered to be high risk. The EAG considered the model to accurately reflect treatment complication and retreatment costs but that the size of the cost savings was uncertain in high-risk groups because of a lack of comparative evidence. The clinical experts also advised that modelling high-risk populations collectively may not be appropriate or generalisable to clinical practice. The committee agreed that the EAG's approach to modelling using the GOLIATH data was appropriate. It concluded that using GreenLight\xa0XPS is likely to be cost saving but by how much is uncertain, particularly for high-risk groups.\n\n# Main cost drivers in the Markov model\n\n## Length of stay affects GreenLight\xa0XPS's cost case\n\nLength of stay was one of the key drivers of the estimated cost savings with GreenLight\xa0XPS compared with standard treatments such as TURP in the Markov model. GreenLight\xa0XPS becomes cost incurring if the length of stay with TURP is reduced to a level similar to GreenLight\xa0XPS. Length of stay was not a key driver in the original guidance, because the decision tree model presented it as the proportion of day cases, which was the key driver (see the assessment report update in the supporting documentation, Newcastle EAG 2022). The clinical experts said that people having GreenLight\xa0XPS are likely to be discharged on the same day and are not usually admitted to hospital after the procedure. However, the length of stay is likely to be influenced by personal factors and hospital infrastructure (see section 4.9). The clinical experts agreed that the scenarios for length of stay or proportion of day cases that would make GreenLight\xa0XPS cost incurring are unlikely in clinical practice in the NHS. However, given there is uncertainty in the size of the cost saving from length of stay in the cost model, the committee suggested data should continue to be collected on cost-saving outcomes such as length of stay when treating people who may be considered high risk (including those with larger prostates and a higher risk of bleeding).\n\n## Length of procedure affects GreenLight\xa0XPS's cost case\n\nThe economic analysis included an assumed average procedure length of 49.6\xa0minutes for GreenLight\xa0XPS, 66\xa0minutes for TURP and 80\xa0minutes for HoLEP. The clinical experts considered these procedure durations to be reasonable. However, they advised that duration is affected by prostate size and the clinician's experience. The clinical experts said that using GreenLight\xa0XPS for larger prostates might extend procedure duration. This could reduce the cost saving of using GreenLight\xa0XPS compared with TURP or HoLEP. However, it should be noted that there is a lack of data on procedural duration. The committee agreed that more data, including audit data, would be helpful to inform the uncertainty in the cost benefit of length of procedure across the comparators for the high-risk population (including those with larger prostates and a higher risk of bleeding).\n\n# Further data collection\n\n## The committee would like to see more robust comparative evidence in high-risk groups\n\nThe committee agreed that more data on the resource impact of GreenLight\xa0XPS compared with other treatments is needed in the high-risk groups (including those with larger prostates and higher risk of bleeding). It recommended collecting more data to address the cost-saving outcomes, including the length of hospital stay and the procedure duration, in high-risk groups."}	https://www.nice.org.uk/guidance/mtg74	Evidence-based recommendations on GreenLight XPS for benign prostatic hyperplasia.
ee381c047e2779d897bedc960f40fed5e893eaf0	nice	Subarachnoid haemorrhage caused by a ruptured aneurysm: diagnosis and management	Subarachnoid haemorrhage caused by a ruptured aneurysm: diagnosis and management This guideline covers diagnosing and treating an aneurysmal (caused by a ruptured aneurysm) subarachnoid haemorrhage and its complications. It provides recommendations to improve diagnosis and ensure that the most effective treatments are offered. It includes guidance on follow-up care and information for people (aged 16 and over) who have had an aneurysmal subarachnoid haemorrhage, their families and carers. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Assessment and diagnosis NICE has also produced a visual summary of the recommendations on diagnosis. ## Assessment and referral for diagnostic investigations Be aware that urgent investigation to confirm a diagnosis of subarachnoid haemorrhage facilitates early treatment to prevent rebleeding from a ruptured aneurysm and minimises disability and death. When carrying out an initial assessment in a person who presents with unexplained acute severe headache: have a high index of suspicion for subarachnoid haemorrhage take a careful history to establish the rate of onset and time to peak intensity of the headache. Bear in mind that: A 'thunderclap' headache (a sudden severe headache, typically peaking in intensity within 1 to 5 minutes) is a red-flag symptom of subarachnoid haemorrhage. Thunderclap headache is associated with other conditions or causes such as migraine, cough, coitus or exertion. Most people with a thunderclap headache do not have a subarachnoid haemorrhage, but this should not deter further investigation if subarachnoid haemorrhage is suspected. People with subarachnoid haemorrhage can present with a range of non-specific symptoms and signs and are at greater risk of a diagnosis being missed. Other symptoms and signs of subarachnoid haemorrhage include, but are not limited to: neck pain or stiffness photophobia nausea and vomiting new symptoms or signs of altered brain function (such as reduced consciousness, seizure or focal neurological deficit) limited or painful neck flexion on examination. If a person with a possible subarachnoid haemorrhage finds it difficult to describe their symptoms, for example because of a learning disability, language problem or altered consciousness, ask anyone who witnessed the onset of symptoms for a description (without delaying referral). Refer people with suspected subarachnoid haemorrhage seen outside of acute hospital settings to an emergency department immediately for further assessment. Ensure that people with suspected subarachnoid haemorrhage seen in acute hospital settings such as emergency departments are reviewed urgently by a senior clinical decision-maker to assess the person and think about alternative diagnoses. Refer the person for an urgent non-contrast CT head scan if review in secondary care by a senior clinical decision-maker confirms unexplained thunderclap headache, or other signs and symptoms that suggest subarachnoid haemorrhage. Be aware that the diagnostic accuracy of CT head scans is highest within 6 hours of symptom onset. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment and referral for diagnostic investigations . Full details of the evidence and the committee's discussion are in evidence review A: symptoms and signs and evidence review B: diagnostic accuracy of investigations. Loading. Please wait. ## Pain relief and neurological assessment Ensure that people with a suspected or confirmed subarachnoid haemorrhage are given effective pain relief, including opioid analgesia if needed. Document administration of opioid analgesia in the person's healthcare record. When conducting a neurological assessment, check the person's care record and if opioid analgesia has been given, take into account its sedating and pupillary effects. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain relief and neurological assessment . Full details of the evidence and the committee's discussion are in evidence review D: medical management strategies. Loading. Please wait. ## Diagnosing a subarachnoid haemorrhage Diagnose a subarachnoid haemorrhage if the non-contrast CT head scan shows blood in the subarachnoid space. If a CT head scan done within 6 hours of symptom onset and reported and documented by a radiologist shows no evidence of a subarachnoid haemorrhage: do not routinely offer a lumbar puncture think about alternative diagnoses and seek advice from a specialist. If a CT head scan done more than 6 hours after symptom onset shows no evidence of a subarachnoid haemorrhage, consider a lumbar puncture. Allow at least 12 hours after symptom onset before doing a lumbar puncture to diagnose a subarachnoid haemorrhage. Diagnose a subarachnoid haemorrhage if the lumbar puncture sample shows evidence of elevated bilirubin (xanthochromia) on spectrophotometry. Think about alternative diagnoses if the lumbar puncture sample shows no evidence of elevated bilirubin (xanthochromia) on spectrophotometry. Urgently discuss with a specialist neurosurgical centre the need for transfer of care of a person with a diagnosis of subarachnoid haemorrhage to a specialist neurosurgical centre. Do not use a subarachnoid haemorrhage severity score in isolation to determine the need for, or timing of, transfer of care to a specialist neurosurgical centre. Be aware that the risk of rebleeding is highest within 24 hours of the onset of symptoms. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosing a subarachnoid haemorrhage . Full details of the evidence and the committee's discussion are in evidence review B: diagnostic accuracy of investigations and evidence review C: severity scoring systems. Loading. Please wait. ## Detecting an aneurysm Offer CT angiography of the head without delay to people with a confirmed diagnosis of subarachnoid haemorrhage to identify the cause of the bleeding and to guide treatment. Diagnose an aneurysmal subarachnoid haemorrhage if: CT angiography of the head shows an intracranial arterial aneurysm and the pattern of subarachnoid blood is compatible with aneurysm rupture. Seek specialist opinion without delay from an interventional neuroradiologist and neurosurgeon if: CT angiography of the head shows an intracranial arterial aneurysm and the pattern of subarachnoid blood is not compatible with aneurysm rupture. If CT angiography of the head does not identify the cause of the subarachnoid haemorrhage and an aneurysm is still suspected, consider digital subtraction angiography (DSA), or magnetic resonance angiography (MRA) if DSA is contraindicated. Diagnose an aneurysmal subarachnoid haemorrhage if: DSA or MRA shows an intracranial arterial aneurysm and the pattern of subarachnoid blood is compatible with aneurysm rupture. Think about other diagnoses if DSA or MRA does not show an intracranial arterial aneurysm. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on detecting an aneurysm . Full details of the evidence and the committee's discussion are in evidence review K: diagnostic imaging strategies. Loading. Please wait. # Managing a confirmed aneurysmal subarachnoid haemorrhage ## Medical management Consider enteral nimodipine for people with a confirmed subarachnoid haemorrhage. Only use intravenous nimodipine within a specialist setting and if enteral treatment is not suitable. Manage the risk of venous thromboembolism in people with an aneurysmal subarachnoid haemorrhage in line with the NICE guideline on venous thromboembolism in over 16s. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on medical management . Full details of the evidence and the committee's discussion are in evidence review D: medical management strategies. Loading. Please wait. ## Managing the culprit aneurysm An interventional neuroradiologist and a neurosurgeon should discuss the options for managing the culprit aneurysm, taking into account the person's clinical condition, the characteristics of the aneurysm, and the amount and location of subarachnoid blood. They should document a proposed treatment plan based on the following options: endovascular coiling neurosurgical clipping no interventional procedure, with monitoring to check for clinical improvement and reassess the options for treatment. Do not use a subarachnoid haemorrhage severity score in isolation to determine the suitability of any management option. If interventional treatment to secure the aneurysm is an option, offer: endovascular coiling or neurosurgical clipping if endovascular coiling is not suitable. Discuss the proposed treatment plan and any alternative options with the person, and their family or carers if appropriate, then agree and document a final treatment plan (see recommendations 1.5.5 to 1.5.7). If interventional treatment is planned, ensure that it is carried out at the earliest opportunity to prevent rebleeding. Be aware that the risk of rebleeding is highest within 24 hours of the onset of symptoms. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing the culprit aneurysm . Full details of the evidence and the committee's discussion are in evidence review L: interventions to prevent rebleeding, evidence review C: severity scoring systems and evidence review M: timing of interventions to prevent rebleeding. Loading. Please wait. NICE interventional procedures guidance on endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms NICE interventional procedures guidance on coil embolisation of ruptured intracranial aneurysms. # Monitoring and managing complications ## Monitoring and investigating for deterioration Do not use transcranial doppler monitoring to guide clinical management of an aneurysmal subarachnoid haemorrhage except in the context of clinical research. For people with unexplained neurological deterioration after a subarachnoid haemorrhage, offer a non-contrast CT head scan as the first diagnostic investigation to determine the cause. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring and investigating for deterioration . Full details of the evidence and the committee's discussion are in evidence review E: monitoring for raised intracranial pressure and vasospasm. Loading. Please wait. ## Hydrocephalus Base a diagnosis of acute or chronic hydrocephalus on the person's symptoms and signs, and on a comparison of current and previous CT or other brain imaging. Consider drainage or diversion of cerebrospinal fluid for people with neurological deterioration caused by acute hydrocephalus. For people with persistent or progressive symptoms and a clinical diagnosis of chronic hydrocephalus, consider drainage or permanent diversion of cerebrospinal fluid. If there is uncertainty about the likely benefit of permanent diversion, consider a trial of temporary drainage to assess the need for permanent diversion. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on hydrocephalus . Full details of the evidence and the committee's discussion are in evidence review G: detecting hydrocephalus and evidence review H: managing hydrocephalus. Loading. Please wait. ## Delayed cerebral ischaemia Ensure euvolaemia (normal blood volume) in people with delayed cerebral ischaemia after an aneurysmal subarachnoid haemorrhage and consider treatment with a vasopressor if symptoms persist. Bear in mind that clinical improvement from vasopressor treatment may be temporary. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on delayed cerebral ischaemia . Full details of the evidence and the committee's discussion are in evidence review F: management of delayed cerebral ischaemia. Loading. Please wait. # Follow-up care ## Follow-up care plan Agree and document a plan for follow-up care with the person after their aneurysmal subarachnoid haemorrhage. Give a paper copy of the plan to the person (and their family or carers if appropriate) and include details of who to contact at the specialist centre for ongoing advice and support. Include the follow-up care plan in the person's medical record and discharge correspondence. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up care plan . Full details of the evidence and the committee's discussion are in evidence review S: patient information. Loading. Please wait. ## Rehabilitation Offer rehabilitation after aneurysmal subarachnoid haemorrhage in line with the NICE guidelines on stroke rehabilitation in adults and rehabilitation after critical illness in adults. ## Follow-up neuroimaging Consider follow-up neuroimaging for people who have had an aneurysmal subarachnoid haemorrhage, taking into account the extent of their recovery and the suitability of further imaging. Base the choice of imaging modality, and the frequency and duration of imaging follow-up, on the: type and outcome of any neurointervention or neurosurgery on the initial aneurysm presence of any non-culprit aneurysms estimated risk of further bleeding risks of planned investigations and any subsequent interventions person's preference. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up neuroimaging . Full details of the evidence and the committee's discussion are in evidence review O: imaging strategies for follow-up. Loading. Please wait. ## Managing non-culprit (unruptured) aneurysms A multidisciplinary team (MDT) that includes an interventional neuroradiologist and a neurosurgeon should evaluate the options for managing non-culprit (unruptured) aneurysms, including: endovascular coiling neurosurgical clipping conservative management and follow-up monitoring. When evaluating the options for managing a non-culprit aneurysm, the MDT should take into account: the size and location of the aneurysm the estimated lifetime risk of the aneurysm rupturing the estimated risk of each treatment option any comorbidities the person's preferences. Discuss the proposed management plan and any alternative options with the person (and their family or carers as appropriate). Base the discussion on the factors listed in recommendation 1.4.6. Agree and document a final management plan. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing non-culprit (unruptured) aneurysms . Full details of the evidence and the committee's discussion are in evidence review P: non-culprit aneurysms. Loading. Please wait. NICE medical technologies guidance on Pipeline Flex embolisation device with Shield Technology for the treatment of complex intracranial aneurysms NICE interventional procedures guidance on endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms NICE interventional procedures guidance on coil embolisation of unruptured intracranial aneurysms. ## Managing other conditions after discharge from hospital Manage blood pressure in people aged 18 and over who have had an aneurysmal subarachnoid haemorrhage in line with the NICE guideline on hypertension in adults. Do not withhold treatment with antiplatelets or anticoagulants solely on the basis of an aneurysmal subarachnoid haemorrhage if the culprit aneurysm has been secured by coiling or clipping. Balance the risks and benefits of treatment with an antiplatelet or anticoagulant, taking into account specialist assessment of the risk of a future subarachnoid haemorrhage. Encourage people who smoke to stop, and consider smoking cessation support as set out in the recommendations on stop-smoking interventions in the NICE guideline on tobacco. Assess, diagnose and manage headaches in people who have had an aneurysmal subarachnoid haemorrhage in line with the NICE guideline on headaches in over 12s. Be aware that headaches in people with a history of aneurysmal subarachnoid haemorrhage: are common and generally benign may be due to chronic hydrocephalus if the person has additional symptoms or signs such as gait disturbance, incontinence, incoordination or cognitive impairment. Manage seizures in people who have recovered from an aneurysmal subarachnoid haemorrhage in line with the NICE guideline on epilepsies in children, young people and adults. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing other conditions after discharge from hospital . Full details of the evidence and the committee's discussion are in evidence review Q: long-term medicines for reducing the risk of subsequent subarachnoid haemorrhage and evidence review R: long-term medication for managing the consequences of subarachnoid haemorrhage. Loading. Please wait. ## Investigations to detect aneurysms in relatives Explain to people (and their families if appropriate) who have had an aneurysmal subarachnoid haemorrhage and are concerned about possible aneurysms in their relatives that: routine testing to check for aneurysms in relatives has not been shown to save lives or prevent aneurysmal subarachnoid haemorrhages testing for relatives is based on an assessment of the relative's own risk testing is usually limited to people with at least 2 first-degree relatives (father, mother, sister or brother) who have had an aneurysmal subarachnoid haemorrhage.Tell people where they can find more information about testing for relatives, such as the NHS webpage on diagnosis of brain aneurysm. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on investigations to detect aneurysms in relatives . Full details of the evidence and the committee's discussion are evidence review T: investigating relatives of people with aneurysmal subarachnoid haemorrhage. Loading. Please wait. # Information and support Follow the recommendations in the section on enabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services, including: establishing the most effective way of communicating with the person and providing information in a format that is accessible to them avoiding jargon, using words the person will understand and explaining unfamiliar words. When making decisions with people about their treatment and care, follow the NICE guideline on shared decision making. When supporting people who may lack capacity to make decisions about their treatment and care, follow the NICE guideline on decision making and mental capacity. Adapt written and verbal information about aneurysmal subarachnoid haemorrhage to the needs and preferences of the person (and their family or carers if appropriate). ## At diagnosis Explain to the person (and their family or carers if appropriate) what an aneurysmal subarachnoid haemorrhage is and what the treatment options are, including their benefits and risks. ## During the hospital stay Give the person (and their family or carers if appropriate) information about complications that can happen after an aneurysmal subarachnoid haemorrhage, such as: a build-up of fluid on the brain (hydrocephalus) a reduced supply of blood to the brain (delayed cerebral ischaemia) speech or communication difficulties physical disabilities seizures. Tell the person (and their family or carers if appropriate) that common symptoms reported by people who have had a subarachnoid haemorrhage include: headaches, fatigue and sleep disturbances anxiety, low moods and increased irritability problems with memory and cognitive function changes to smell, taste, hearing or vision. Give people who wish to receive it (and their family or carers if appropriate) information about their estimated future risk of another subarachnoid haemorrhage. Base the information on specialist assessment by the MDT of the person's medical circumstances, including: the effectiveness of the treatment of the ruptured aneurysm the presence and growth of additional aneurysms their smoking status. Give the person advice on returning to their usual activities including work, exercise, driving and sexual activity. ## At discharge Check that the person has been given advice about wound care and medicines, a copy of their follow-up care plan and details of who to contact at their specialist centre if they have questions or concerns. Give them details of local and national support groups. ## At follow-up Discuss the person's return to their usual activities (see recommendation 1.5.9). For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support . Full details of the evidence and the committee's discussion are in evidence review S: patient information and evidence review N: risk of subsequent subarachnoid haemorrhage. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a particular way for this guideline. ## Senior clinical decision-maker A clinician with the necessary training and experience to assess people with suspected subarachnoid haemorrhage, confirm subarachnoid haemorrhage symptoms and signs, and refer people for further investigation. This may be a consultant, a staff-grade, associate-specialist or specialty doctor, or a doctor in a training grade who has been delegated to do this because they have the necessary competencies.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Timing of CT head scans What is the relative accuracy of CT head scans at different time intervals, for example 12 hours or 24 hours after symptom onset, to diagnose subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on diagnosing a subarachnoid haemorrhage . Full details of the evidence and the committee's discussion are in evidence review B: diagnostic accuracy of investigations. Loading. Please wait. ## Predictors of death and disability What variables predict death or disability for people with aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on diagnosing a subarachnoid haemorrhage . Full details of the evidence and the committee's discussion are in evidence review C: severity scoring systems. Loading. Please wait. ## Nimodipine What is the clinical and cost effectiveness of nimodipine in the management of aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on nimodipine . Full details of the evidence and the committee's discussion are in evidence review D: medical management strategies. Loading. Please wait. ## Novel endovascular interventions What is the clinical and cost effectiveness of novel endovascular techniques and devices such as coated coils, endoluminal flow diverters and intrasaccular devices to treat aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on managing the culprit aneurysm . Full details of the evidence and the committee's discussion are in evidence review L: interventions to prevent re-bleeding. Loading. Please wait. ## Risk stratification tool to estimate risk of recurrence What is the utility of a risk stratification tool to estimate the risk of subsequent aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on information and support . Full details of the evidence and the committee's discussion are in evidence review N: risk of subsequent subarachnoid haemorrhage. Loading. Please wait. # Other recommendations for research ## Interventions for aneurysmal subarachnoid haemorrhage in people with major neurological deficit What is the outcome of intervention to prevent rebleeding in people who present with or rapidly develop severe neurological deficits as a consequence of acute aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on managing the culprit aneurysm . Full details of the evidence and the committee's discussion are in evidence review L: interventions to prevent re-bleeding. Loading. Please wait. ## Managing acute hydrocephalus What is the most clinically and cost-effective method of cerebrospinal fluid drainage or diversion (for example shunt surgery, external ventricular drain surgery or lumbar drain) for symptomatic acute hydrocephalus? For a short explanation of why the committee made this recommendation for research, see the rationale section on hydrocephalus . Full details of the evidence and the committee's discussion are in evidence review H: managing hydrocephalus. Loading. Please wait. ## Transcranial doppler monitoring What is the clinical and cost effectiveness of routine transcranial doppler monitoring to guide clinical management of aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on monitoring and investigating for deterioration . Full details of the evidence and the committee's discussion are in evidence review E: monitoring for raised intracranial pressure and vasospasm. Loading. Please wait. ## Intracranial hypertension What is the impact of routine monitoring of intracranial hypertension on subsequent management and outcome in people with aneurysmal subarachnoid haemorrhage who are unconscious or ventilated on an intensive care unit? For a short explanation of why the committee made this recommendation for research, see the rationale section on intracranial hypertension . Full details of the evidence and the committee's discussion are in evidence review I: detecting intracranial hypertension and evidence review J: managing intracranial hypertension. Loading. Please wait. ## Intra-arterial therapies to manage delayed cerebral ischaemia What is the impact of intra-arterial therapies to manage delayed cerebral ischaemia on outcome in people with aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on delayed cerebral ischaemia . Full details of the evidence and the committee's discussion are in evidence review F: management of delayed cerebral ischaemia. Loading. Please wait. ## Vasopressors to manage delayed cerebral ischaemia What is the clinical and cost effectiveness of vasopressors to manage delayed cerebral ischaemia in people with aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on delayed cerebral ischaemia . Full details of the evidence and the committee's discussion are in evidence review F: management of delayed cerebral ischaemia. Loading. Please wait. ## Blood pressure targets What is the clinical and cost effectiveness of a lower blood pressure treatment target relative to the standard blood pressure treatment target for people with aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on managing other conditions after discharge from hospital . Full details of the evidence and the committee's discussion are in evidence review Q: long-term medicines for reducing the risk of subsequent subarachnoid haemorrhage. Loading. Please wait. ## Investigations for relatives What is the clinical and cost effectiveness of investigations to detect intracranial arterial aneurysms in first-degree relatives of people who have had an aneurysmal subarachnoid haemorrhage? For a short explanation of why the committee made this recommendation for research, see the rationale section on investigations to detect aneurysms in relatives . Full details of the evidence and the committee's discussion are in evidence review T: investigating relatives of people with aneurysmal subarachnoid haemorrhage. Loading. Please wait.# Rationale and impact These sections briefly explain why the committee made the recommendations and how they might affect practice. # Assessment and referral for diagnostic investigation Recommendations 1.1.1 to 1.1.7 ## Why the committee made the recommendations People with a suspected subarachnoid haemorrhage can present with a wide range of symptoms and signs. There was little evidence to indicate which symptoms or signs specifically point to a diagnosis of subarachnoid haemorrhage. The committee agreed that the consequences of a missed diagnosis may be severe and include disability and death. Urgent investigation is required to confirm a diagnosis of subarachnoid haemorrhage and facilitate early treatment to prevent rebleeding from the ruptured aneurysm. Clinicians should therefore be alert to the possibility of subarachnoid haemorrhage in people presenting with unexplained acute severe headache, reduced consciousness, seizure, focal neurological deficit or other suggestive symptoms. Some people present with non-specific symptoms, such as nausea and vomiting, photophobia, or neck pain or stiffness. In these cases, a diagnosis of subarachnoid haemorrhage is more likely to be missed. The committee's experience indicated that a 'thunderclap' headache is a presenting symptom in most people with a subarachnoid haemorrhage. However, they noted that this type of headache is a common presentation in emergency departments and around 10% of people who present with this symptom have a diagnosis of subarachnoid haemorrhage confirmed; the majority are diagnosed with other conditions, for example, migraine. The committee agreed that other symptoms and signs are also commonly seen in people with a subarachnoid haemorrhage. These can be used, together with clinical judgement, to support clinical assessment and guide decisions on further diagnostic investigations. The committee noted that these symptoms and signs of subarachnoid haemorrhage can also be caused by a number of other conditions. Therefore, a senior clinician should confirm the assessment of subarachnoid haemorrhage and arrange immediate referral for further investigation. There is good evidence showing that non-contrast CT head scans carried out within 6 hours of symptom onset are highly accurate and can be used to rule out a diagnosis of subarachnoid haemorrhage, therefore avoiding the need for further investigation with a lumbar puncture. CT head scans done more than 6 hours after symptom onset are less accurate (see the section on diagnosing a subarachnoid haemorrhage for more information). Evidence on decision tools, including the Ottawa Subarachnoid Haemorrhage Rule for Headache Evaluation, showed that these tools have a high level of accuracy in ruling out subarachnoid haemorrhage, but are less accurate at ruling it in, with a large number of false-positive identifications. Although these tools are beneficial in ensuring that no cases are missed, over-reliance on them risks harm from unnecessary imaging and invasive investigations. The committee noted that the tools use a broad range of symptoms and signs that are not specific to subarachnoid haemorrhage. ## How the recommendations might affect practice The recommendations may be useful for non-specialist clinicians, but are not expected to lead to significant changes in practice. Non-contrast CT head scans are the usual first-line investigation for suspected subarachnoid haemorrhage, and this is not expected to change. Return to recommendations # Pain relief and neurological assessment Recommendations 1.1.8 and 1.1.9 ## Why the committee made the recommendations Although there was limited evidence on the use of specific analgesia or sedation, the committee agreed that pain in adults with aneurysmal subarachnoid haemorrhage should be managed with analgesics in line with standard clinical practice. Headache is usually treated with simple analgesics such as paracetamol, escalating to opioids as needed. The committee agreed that the sedative and pupillary effect of opioid analgesics should be taken into account when doing a neurological assessment, but should not preclude their use. ## How the recommendations might affect practice The recommendations generally reflect current practice and are not likely to result in changes. Return to recommendations # Diagnosing a subarachnoid haemorrhage Recommendations 1.1.10 to 1.1.17 ## Why the committee made the recommendations The committee looked at evidence on non-contrast CT head scans, lumbar puncture and MRI. In the studies, the CT scans were reviewed by either a general radiologist or a neuroradiologist. There was good evidence showing that CT head scans done within 6 hours of symptom onset have a high diagnostic accuracy. Taking into account the invasive risks of lumbar puncture, the difficulty of monitoring patients during MRI and the costs of both procedures, the committee concluded that these procedures should not be routinely offered if a CT head scan, done within 6 hours of symptom onset and reported and documented by an appropriately experienced radiologist, shows no evidence of a subarachnoid haemorrhage. In these circumstances alternative diagnoses should be considered and advice sought from a specialist, for example in neurosurgery, neuroradiology, neurology or stroke medicine. If the CT head scan is done more than 6 hours after symptom onset, the evidence showed that diagnostic accuracy is reduced and false-negative results are more likely. The committee therefore agreed that further investigation with a lumbar puncture should be considered if a CT head scan done more than 6 hours after ictus does not confirm the diagnosis of subarachnoid haemorrhage. When a lumbar puncture is indicated, the committee agreed that it should be done at least 12 hours after symptom onset, when bilirubin formation is sufficient to be detected reliably. The committee considered that the diagnostic accuracy of earlier lumbar puncture (to detect blood in the cerebrospinal fluid) is likely to be low because it can take several hours for blood to appear in the lumbar subarachnoid sac. There was limited evidence on the relative accuracy of non-contrast CT head scanning at various time intervals greater than 6 hours after symptom onset, so the committee made a recommendation for research on timing of CT head scans. If subarachnoid haemorrhage is diagnosed, the committee noted that an urgent decision is needed on whether to transfer the person to specialist care. The committee decided to make a consensus recommendation to stress the importance of an urgent discussion with a specialist neurosurgical centre. Although evidence on a number of severity scores showed an association with morbidity and mortality, there was inconsistency across the scores and the evidence was not sufficient to recommend the use of any score on its own. The committee agreed that, although severity scoring can be a useful clinical descriptor, decisions on transfer should be based on a holistic patient assessment rather than a severity score on its own, to avoid inappropriate withholding of specialist neurosurgical care from people whose score indicates a poor clinical condition. The committee noted that evidence to support the prognostic accuracy of the severity scores was weak and made a recommendation for research on predictors of death and disability. ## How the recommendations might affect practice Centres that routinely perform lumbar puncture after a negative CT head scan may see a reduction in the use of lumbar puncture in people with an early negative CT head scan. Reliance on severity scoring to determine transfer to specialist centres may reduce, leading to more people appropriately being transferred for treatment. Return to recommendations # Detecting an aneurysm Recommendations 1.1.18 to 1.1.23 ## Why the committee made the recommendations Evidence showed that CT angiography has a high level of accuracy in identifying aneurysms causing subarachnoid haemorrhage but evidence for the diagnostic accuracy of magnetic resonance angiography (MRA) was less compelling. CT angiography is the quickest to perform, is non-invasive, does not usually necessitate sedation or general anaesthesia and is available in most centres. MRA and DSA are more complex and time-consuming procedures that need specialist input and have a higher risk of complications. DSA is regarded as the 'gold standard' investigation and is currently commonly carried out when CT angiography is negative but there is a high suspicion of aneurysmal subarachnoid haemorrhage, whereas the complexities involved in obtaining high-quality MRA images make this less beneficial. The committee agreed that DSA should be reserved for instances when CT angiography has not detected a suspected aneurysm. ## How the recommendations might affect practice The recommendations largely reflect current practice and are not expected to lead to changes. Return to recommendations # Medical management Recommendations 1.2.1 to 1.2.3 ## Why the committee made the recommendations Although limited evidence showed some reductions in mortality, rebleeding, disability and delayed cerebral ischaemia with nimodipine, most of the evidence available was graded as low or very low quality, predominately due to imprecision of outcome data, and risk of bias. There was a high risk of uncertainty around a number of outcomes due to significant statistical imprecision around the summary effect estimates, with wide confidence intervals crossing the thresholds for clinical significance. The committee noted that the studies in the evidence review were conducted in the 1980s, with a lack of more recent evidence. In most of the studies, nimodipine was commenced up to 96 hours after ictus and continued for up to 3 weeks before neurosurgical management. Therefore, the committee had reservations about the applicability of this evidence to current practice, in which people with aneurysmal subarachnoid haemorrhage are frequently treated by endovascular coiling within 48 hours of ictus. The committee could not be sure that the benefits from nimodipine are maintained with current treatments to secure the ruptured aneurysm, but they agreed that, without evidence of significant harms, a recommendation to consider nimodipine was appropriate in the acute management of aneurysmal subarachnoid haemorrhage. The committee noted that the use of nimodipine is entrenched in clinical practice and was surprised at the lack of more compelling contemporary evidence for the use of enteral nimodipine in the management of aneurysmal subarachnoid haemorrhage. The lack of recent evidence influenced their decision to make a weak recommendation for the use of nimodipine. The committee also made a recommendation for research on nimodipine to determine its place in current practice. Most of the evidence related to the use of oral nimodipine but some was drawn from studies that included intravenous nimodipine. The committee were aware that intravenous nimodipine has a high cost and were uncertain whether it is likely to be cost effective in patients who are unconscious or ventilated, or unable to swallow. The committee were also aware that some clinicians recommend administration of crushed nimodipine tablets to these patients via a nasogastric tube to avoid the need to use intravenous nimodipine. The committee noted that intravenous nimodipine may be useful for patients in whom poor absorption of the drug is suspected. Based on these observations and their experience, the committee agreed that intravenous nimodipine should be reserved for patients in whom enteral administration is not suitable. The committee noted that NICE's guideline on reducing the risk of hospital-acquired venous thromboembolism (VTE) includes assessment of bleeding risk and alternatives to pharmacological VTE prophylaxis, and is therefore suitable for people admitted to hospital with a subarachnoid haemorrhage before their aneurysm is secured and after it is secured. Evidence on tranexamic acid in the management of aneurysmal subarachnoid haemorrhage was mixed, and most was from small studies from the 1970s and 1980s. Some of the evidence suggested that short courses of intravenous tranexamic acid started immediately after diagnosis and before a planned intervention (endovascular coiling or neurosurgical clipping) reduce the risks of rebleeding. However, there was no evidence showing that they reduce death or disability. The committee were aware that short-course tranexamic acid is occasionally used in current practice if interventional treatment to secure the aneurysm is suitable but not available within a short time frame. However, the committee agreed that the administration of tranexamic acid should not delay interventional treatment to secure the aneurysm. ## How the recommendations might affect practice The recommendation is not expected to substantially change the current practice of giving nimodipine after an aneurysmal subarachnoid haemorrhage. The recommendation is not expected to change current practice. Return to recommendations # Managing the culprit aneurysm Recommendations 1.2.4 to 1.2.8 ## Why the committee made the recommendations The committee noted that around half of people who survive an aneurysmal subarachnoid haemorrhage will have a second bleed from the culprit aneurysm within weeks, and the mortality from a second bleed can exceed 50%. Interventional treatment with endovascular coiling or neurosurgical clipping, if suitable, can secure the aneurysm and prevent rebleeding. The committee acknowledged that interventional treatment is not suitable for some people who have a major neurological deficit after an aneurysmal subarachnoid haemorrhage, and that the costs of long-term nursing care or rehabilitation can be considerable. Very little evidence was found for this group, so the committee made a recommendation for research on interventions for aneurysmal subarachnoid haemorrhage in people with major neurological deficit. Severity scoring systems might help clinicians identify people for whom intervention is likely to be justified, but none of the severity scoring systems currently in use reliably predicts morbidity and mortality in people with aneurysmal subarachnoid haemorrhage. In addition, the committee agreed that clinical state and severity score can vary over time, especially soon after symptom onset. Decisions on clinical management should therefore be based on a holistic patient assessment rather than solely on a severity score. Factors that should be considered by clinicians and discussed with the patient include: neurological status, performance status and comorbidities. The evidence was not sufficient to determine the clinical effectiveness of endovascular coiling compared with neurosurgical clipping, although a small amount of evidence suggested that endovascular coiling might be more beneficial. Endovascular coiling is less invasive and potentially safer, so the committee agreed that it should be offered as the first option, taking factors such as aneurysm characteristics and the amount and location of subarachnoid blood into account. The committee agreed that neurosurgical clipping should be considered if endovascular coiling is not a suitable treatment option. They stressed that any procedure to secure the aneurysm should be performed without delay to minimise the risk of rebleeding. Newer, more expensive interventional technologies are being used but there is little evidence on their effectiveness, so the committee made a recommendation for research on novel endovascular interventions. ## How the recommendations might affect practice Endovascular coiling accounts for around 75% of interventions done in current practice and the recommendation is not expected to change this. Most interventions are carried out within 48 hours of admission. However, this may vary according to the availability of interventional neuroradiologists and vascular neurosurgeons, and the capacity of neurosurgical centres. For people admitted during weekends, endovascular coiling should be available from the same interventional neuroradiology teams who will provide thrombectomy for stroke, in line with the recommendations on thrombectomy in the NICE guideline on stroke and transient ischaemic attack in over 16s. However, provision of neurosurgical clipping during weekends may necessitate changes to services such as the setting up of appropriate networks. Return to recommendations # Monitoring and investigating for deterioration Recommendations 1.3.1 and 1.3.2 ## Why the committee made the recommendations There was no evidence on the routine use of direct intracranial pressure monitoring for raised intracranial pressure. Very limited evidence from 1 study on transcranial doppler monitoring for vasospasm suggested an increase in mortality, morbidity and length of hospital stay compared with no transcranial doppler monitoring. The committee agreed that these outcomes were unlikely to be directly caused by the transcranial doppler monitoring. However, they were concerned that such monitoring might influence subsequent decisions, for example about investigations or interventions, and so indirectly affect outcomes. They therefore agreed that transcranial doppler monitoring should only be used in the context of clinical research. The committee noted that there is increasing enthusiasm for the use of this modality and made a recommendation for research on transcranial doppler monitoring. There was no evidence on the investigation of unexplained neurological deterioration in people with aneurysmal subarachnoid haemorrhage. The committee agreed that in current practice unexplained neurological deterioration is initially investigated with a non-contrast CT scan, which can indicate the cause of deterioration including ventricular enlargement suggestive of hydrocephalus, cerebral ischaemia, intracranial haematoma or evidence of rebleeding. ## How the recommendations might affect practice In current practice the use of transcranial doppler monitoring varies widely. The recommendation is likely to stop this type of monitoring in centres that use it in routine practice. CT head scans are used to investigate unexplained neurological deterioration in current practice and the recommendation will not affect this. Return to recommendations # Hydrocephalus Recommendations 1.3.3 to 1.3.5 ## Why the committee made the recommendations There was no evidence on diagnosing acute hydrocephalus. Based on their experience, the committee agreed that hydrocephalus is suspected on the basis of symptoms and signs of raised intracranial pressure such as an altered level of consciousness or neurological deterioration, and that the diagnosis should be confirmed by comparing a CT head scan with previous CT or other head scans to show an increase in the size of the ventricular system. The committee agreed that MRI offers no advantage over CT for diagnosing hydrocephalus in people with aneurysmal subarachnoid haemorrhage, is more expensive and is a difficult procedure for people who are unwell. The committee noted that acute hydrocephalus can lead to severe disability or death if not treated promptly by drainage or diversion of cerebrospinal fluid. There was no evidence on the effectiveness of different techniques for drainage or diversion in acute hydrocephalus. The committee agreed that either drainage or diversion could be considered. They also made a recommendation for research on managing acute hydrocephalus. There was little evidence to inform recommendations on diagnosing and managing chronic hydrocephalus. Based on their experience, the committee agreed that chronic hydrocephalus is uncommon and typically presents several weeks or months after an aneurysmal subarachnoid haemorrhage, with reduced consciousness, gait disturbance or other neurological symptoms. As with acute hydrocephalus, the committee agreed that chronic hydrocephalus is suspected based on symptoms and signs and a diagnosis should be confirmed based on a comparison of current CT head scans with previous CT or other head scans. In current clinical practice most people with persisting or progressive symptoms and radiological evidence of ventricular dilatation are offered drainage of cerebrospinal fluid, which improves symptoms in the majority. If the likelihood of symptom improvement is uncertain, some clinicians advocate a trial of temporary drainage, for example, serial lumbar punctures, before considering permanent diversion of cerebrospinal fluid. The committee agreed with this approach. The committee discussed making a recommendation for research on chronic hydrocephalus but concluded that research in this area might not be feasible within a reasonable time frame and have little impact on clinical practice. ## How the recommendations might affect practice The recommendations reflect current practice. Return to recommendations # Intracranial hypertension Recommendation for research ## Why the committee did not make a recommendation There was little evidence on diagnosing and treating intracranial hypertension. The committee agreed that the diagnostic accuracies of transcranial doppler and ultrasound measurement of optic nerve sheath diameter are too low for reliable detection of intracranial hypertension when compared with direct intracranial pressure measurement. The committee also acknowledged that there is no evidence that interventions to lower intracranial pressure improve clinical outcome. The committee agreed that raised intracranial pressure is common in people with aneurysmal subarachnoid haemorrhage, but intracranial hypertension that impedes blood flow to the brain and contributes to brain injury is generally only seen in the most severely ill. These people are usually unconscious or need ventilation in an intensive care unit. They are a heterogeneous population and management varies widely, with some clinicians advocating routine monitoring of intracranial pressure to guide intervention (such as drainage of cerebrospinal fluid, hypertonic saline or vasopressor therapy) to lower intracranial pressure and maintain cerebral perfusion. Other clinicians favour management without intracranial pressure monitoring. Intracranial pressure can be monitored by inserting an intracranial pressure bolt or using an external ventricular drain inserted to manage acute hydrocephalus. The committee acknowledged that insertion of a pressure bolt is associated with risk, and monitoring of intracranial pressure will only improve outcome if it leads to effective intervention. The committee debated the variation in current practice and were not able to reach a consensus on the role of interventions to diagnose and treat intracranial hypertension, and so they made a recommendation for research. Return to recommendation for research # Delayed cerebral ischaemia Recommendation 1.3.6 ## Why the committee made the recommendation There was very little evidence on delayed cerebral ischaemia so the committee based the recommendation on their clinical experience. They noted that current practice for managing delayed cerebral ischaemia is to maintain cerebral blood flow to prevent or limit cerebral infarction. Intravenous fluid is usually given to ensure euvolemia and if symptoms persist a vasopressor is administered to raise systemic blood pressure. The committee agreed with this approach, but added that the improvements seen after these measures may be temporary, and there was no evidence of impact on longer-term outcomes. Treatment for people whose condition is not improved by vasopressor therapy varies widely. Some clinicians recommend cerebral angiography and intra-arterial therapies, including intra-arterial vasodilators and angioplasty. However, the committee were unable to reach a consensus on the use of intra-arterial therapies. They made recommendations for research on intra-arterial therapies to manage delayed cerebral ischaemia and vasopressors to manage delayed cerebral ischaemia. ## How the recommendation might affect practice The recommendation reflects current practice. Return to recommendation # Follow-up care plan Recommendations 1.4.1 and 1.4.2 ## Why the committee made the recommendations Evidence from surveys and interviews with people who had an aneurysmal subarachnoid haemorrhage showed that those who did not receive clear information about their medical care after discharge felt anxious and 'abandoned'. Those who were given this information, together with details of who to contact for ongoing advice, said they felt more supported. The committee agreed that the follow-up care plan should be included in the person's medical record and discharge correspondence. ## How the recommendations might affect practice The amount and quality of information given to people about follow-up care after an aneurysmal subarachnoid haemorrhage varies. This recommendation can be expected to improve the provision of this information. Return to recommendations # Follow-up neuroimaging Recommendation 1.4.4 ## Why the committee made the recommendation No clinical evidence was found on follow-up neuroimaging. Based on their knowledge and experience, the committee agreed that there is a risk of aneurysm recurrence, progression of non-culprit aneurysms and formation of new aneurysms. They agreed that follow-up imaging should be considered, based on the person's clinical situation and risk factors. ## How the recommendation might affect practice The recommendation reflects current practice. Return to recommendation # Managing non-culprit (unruptured) aneurysms Recommendations 1.4.5 to 1.4.7 ## Why the committee made the recommendations There was not enough good evidence to enable the committee to recommend a preferred management option for non-culprit aneurysms, although they agreed that the risk of a non-culprit aneurysm rupturing is higher in people who have had an aneurysmal subarachnoid haemorrhage than those who have not. Based on their experience, the committee agreed that the overall probability of a non-culprit aneurysm rupturing is low, so interventional treatment of all non-culprit aneurysms is unlikely to be a cost-effective strategy. They agreed that conservative management usually includes monitoring of the aneurysm with MRA to detect changes in the aneurysm's size or shape. The committee were in agreement that the frequency of monitoring should be based on a balance between the risks of aneurysm rupture and the risks of interventional treatment, and take into account multidisciplinary team, neuroradiological and neurosurgical opinion, and the person's preferences. The committee's experience was that people with unruptured aneurysms who are offered conservative management are often anxious about the possibility of a future rupture. They therefore recommended that all treatment options be discussed with the person. ## How the recommendations might affect practice Current management of unruptured aneurysms varies. The recommendations are not expected to lead to substantial changes in practice. Return to recommendations # Managing other conditions after discharge from hospital Recommendations 1.4.8 to 1.4.14 ## Why the committee made the recommendations Uncontrolled hypertension is recognised to be a risk factor for aneurysmal subarachnoid haemorrhage and may pose a greater risk to people with a history of this type of stroke. The committee agreed that blood pressure should be controlled in line with the NICE guideline on hypertension in adults. There was no evidence on long-term blood pressure control specifically for people with a history of aneurysmal subarachnoid haemorrhage, so the committee made a recommendation for research on blood pressure targets. There was little evidence about the effect of an antiplatelet or anticoagulant on the risk of recurrent intracranial bleeding. The committee agreed that, in their experience, these medicines are safe for people with a secured aneurysm following an aneurysmal subarachnoid haemorrhage. For people with a higher risk of recurrence, specialist advice should be sought to judge the balance between the risk of recurrent or new intracranial bleeding and the risk of athero-embolic events. The committee noted that smoking can be a risk factor for an initial subarachnoid haemorrhage. They agreed that smoking cessation interventions, in addition to benefiting general health, may also reduce the risk of recurrent subarachnoid haemorrhage. The committee agreed, based on their experience, that people who develop headaches after recovering from an aneurysmal subarachnoid haemorrhage can become anxious and worry that their headache indicates new aneurysmal bleeding or a complication of the treatment they had for their aneurysm. This can lead to morbidity, multiple presentations to healthcare professionals and unnecessary investigations. There was no evidence on specific long-term medicines to relieve headaches as a consequence of subarachnoid haemorrhage. The committee agreed that headache should be assessed, diagnosed and managed in line with NICE's guideline on headaches in over 12s. The committee agreed, based on their experience, that headaches are common and generally benign in people who have had a subarachnoid haemorrhage, but in some people may indicate chronic hydrocephalus. The committee agreed that people who have had an aneurysmal subarachnoid haemorrhage have an increased risk of seizures and epilepsy. There was no evidence on the use of long-term antiseizure medicines to prevent or relieve seizures in this population. They agreed that seizures after an aneurysmal subarachnoid haemorrhage should be treated in line with NICE's guidance on diagnosing and managing epilepsies. ## How the recommendations might affect practice The recommendations on hypertension, smoking, headaches and seizures are not expected to change practice. The recommendations on managing conditions treated with antiplatelets or anticoagulants may reduce delays in prescribing these medicines for people who have had a successfully treated aneurysmal subarachnoid haemorrhage. Although specialist input may be needed, this is not expected to have a large impact on services. Return to recommendations # Investigations to detect aneurysms in relatives Recommendation 1.4.15 ## Why the committee made the recommendation No evidence was found on investigating relatives for intracranial aneurysms. The committee recognised that first-degree relatives of people who have had an aneurysmal subarachnoid haemorrhage are at higher risk of intracranial arterial aneurysm than the general population. The committee agreed that investigating for aneurysms in first-degree relatives may produce health benefits but could also lead to harm, including unnecessary anxiety and a consequent increase in visits to GPs and emergency departments. Moreover, the optimal timing and frequency of investigations to detect and monitor intracranial aneurysms in first-degree relatives is unknown. The committee were aware that the NHS does not currently support routine screening for intracranial arterial aneurysms in relatives and any change in NHS policy could have a significant resource impact. The committee acknowledged that in current practice investigation is typically only recommended for people thought to have a significant risk of having a brain aneurysm that could rupture at some point in the future, and this would usually only apply to people with 2 or more first-degree relatives who have had an aneurysmal subarachnoid haemorrhage. This reflects the advice given on the NHS website on screening for brain aneurysms. The committee agreed that the lack of evidence for routine testing of relatives and current practice on testing should be explained to people who have had a subarachnoid haemorrhage, and their families as appropriate. Given the importance of this issue and the lack of evidence, the committee made a recommendation for research on investigations for relatives. ## How the recommendation might affect practice The recommendation is not expected to lead to a change in practice. Return to recommendation # Information and support Recommendations 1.5.1 to 1.5.11 ## Why the committee made the recommendations Evidence from studies using surveys and interviews with people who have had an aneurysmal subarachnoid haemorrhage showed that they value information that is clear, concise and tailored to their own needs. Participants in the studies highlighted how difficult it was to remember information given to them verbally at the time of hospital admission and the need to have this information in a written form that they can take home at discharge. They also stressed the importance of information about their medical care and what to expect after discharge, including common symptoms, possible complications and where they can get advice and support. The committee used their experience to agree topics that should be included, as a minimum, in the information given. They highlighted the importance of ease of access to information for people throughout their care pathway. In the committee's experience, some people want information about the risk of recurrence of subarachnoid haemorrhage and some do not. They agreed that discussions should include the effect of individual variables on the person's risk of recurrence. The committee discussed the lack of a validated risk tool to inform estimates of individual risk and made a recommendation for research on a risk stratification tool to estimate risk of recurrence. ## How the recommendations might affect practice The content, delivery and quality of information given to people with aneurysmal subarachnoid haemorrhage varies widely. The recommendations are expected to encourage discussion that is tailored to the person's preferences. Return to recommendations# Context Subarachnoid haemorrhage is a bleed into the fluid-filled subarachnoid space around the brain and spinal cord. Spontaneous subarachnoid haemorrhage accounts for 5% of all strokes and is estimated to occur in 2 to 20 people per 100,000 per year. In around 80% of people, the bleed arises from rupture of an intracranial arterial aneurysm. Aneurysmal subarachnoid haemorrhage is slightly more common in women than men, and can occur across a wide range of ages with a median age at presentation between 50 and 60. The main symptom of subarachnoid haemorrhage is a sudden and severe 'thunderclap' headache but there may also be neck stiffness, altered consciousness or seizures. The condition is more easily diagnosed in people presenting with severe symptoms, unconsciousness or sudden onset acute headache but some people with subarachnoid haemorrhage present with less severe or non-specific symptoms and signs. A high index of suspicion and holistic clinical assessment are therefore required to avoid missed diagnoses. Urgent investigation to confirm a diagnosis of subarachnoid haemorrhage facilitates treatment to prevent rebleeding from the ruptured aneurysm and reduces disability and death. Although outcomes for people with subarachnoid haemorrhage have slowly improved, the risk of death remains high and those who survive are often severely disabled. This guideline aims to improve the speed and accuracy of diagnosis and the effectiveness of treatment. It provides recommendations based on current evidence covering initial assessment, diagnostic investigations, treatment options, management of complications and follow-up care. It also identifies areas where evidence is lacking and recommends research to help inform future guidance.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessment and diagnosis\n\nNICE has also produced a visual summary of the recommendations on diagnosis.\n\n## Assessment and referral for diagnostic investigations\n\nBe aware that urgent investigation to confirm a diagnosis of subarachnoid haemorrhage facilitates early treatment to prevent rebleeding from a ruptured aneurysm and minimises disability and death.\n\nWhen carrying out an initial assessment in a person who presents with unexplained acute severe headache:\n\nhave a high index of suspicion for subarachnoid haemorrhage\n\ntake a careful history to establish the rate of onset and time to peak intensity of the headache.\n\nBear in mind that:\n\nA 'thunderclap' headache (a sudden severe headache, typically peaking in intensity within 1\xa0to 5\xa0minutes) is a red-flag symptom of subarachnoid haemorrhage.\n\nThunderclap headache is associated with other conditions or causes such as migraine, cough, coitus or exertion. Most people with a thunderclap headache do not have a subarachnoid haemorrhage, but this should not deter further investigation if subarachnoid haemorrhage is suspected.\n\nPeople with subarachnoid haemorrhage can present with a range of non-specific symptoms and signs and are at greater risk of a diagnosis being missed. Other symptoms and signs of subarachnoid haemorrhage include, but are not limited to:\n\n\n\nneck pain or stiffness\n\nphotophobia\n\nnausea and vomiting\n\nnew symptoms or signs of altered brain function (such as reduced consciousness, seizure or focal neurological deficit)\n\nlimited or painful neck flexion on examination.\n\n\n\nIf a person with a possible subarachnoid haemorrhage finds it difficult to describe their symptoms, for example because of a learning disability, language problem or altered consciousness, ask anyone who witnessed the onset of symptoms for a description (without delaying referral).\n\nRefer people with suspected subarachnoid haemorrhage seen outside of acute hospital settings to an emergency department immediately for further assessment.\n\nEnsure that people with suspected subarachnoid haemorrhage seen in acute hospital settings such as emergency departments are reviewed urgently by a senior clinical decision-maker to assess the person and think about alternative diagnoses.\n\nRefer the person for an urgent non-contrast CT head scan if review in secondary care by a senior clinical decision-maker confirms unexplained thunderclap headache, or other signs and symptoms that suggest subarachnoid haemorrhage. Be aware that the diagnostic accuracy of CT head scans is highest within 6\xa0hours of symptom onset.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment and referral for diagnostic investigations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: symptoms and signs and evidence review B: diagnostic accuracy of investigations.\n\nLoading. Please wait.\n\n## Pain relief and neurological assessment\n\nEnsure that people with a suspected or confirmed subarachnoid haemorrhage are given effective pain relief, including opioid analgesia if needed. Document administration of opioid analgesia in the person's healthcare record.\n\nWhen conducting a neurological assessment, check the person's care record and if opioid analgesia has been given, take into account its sedating and pupillary effects.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain relief and neurological assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: medical management strategies.\n\nLoading. Please wait.\n\n## Diagnosing a subarachnoid haemorrhage\n\nDiagnose a subarachnoid haemorrhage if the non-contrast CT head scan shows blood in the subarachnoid space.\n\nIf a CT head scan done within 6\xa0hours of symptom onset and reported and documented by a radiologist shows no evidence of a subarachnoid haemorrhage:\n\ndo not routinely offer a lumbar puncture\n\nthink about alternative diagnoses and seek advice from a specialist.\n\nIf a CT head scan done more than 6\xa0hours after symptom onset shows no evidence of a subarachnoid haemorrhage, consider a lumbar puncture.\n\nAllow at least 12\xa0hours after symptom onset before doing a lumbar puncture to diagnose a subarachnoid haemorrhage.\n\nDiagnose a subarachnoid haemorrhage if the lumbar puncture sample shows evidence of elevated bilirubin (xanthochromia) on spectrophotometry.\n\nThink about alternative diagnoses if the lumbar puncture sample shows no evidence of elevated bilirubin (xanthochromia) on spectrophotometry.\n\nUrgently discuss with a specialist neurosurgical centre the need for transfer of care of a person with a diagnosis of subarachnoid haemorrhage to a specialist neurosurgical centre.\n\nDo not use a subarachnoid haemorrhage severity score in isolation to determine the need for, or timing of, transfer of care to a specialist neurosurgical centre. Be aware that the risk of rebleeding is highest within 24\xa0hours of the onset of symptoms.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosing a subarachnoid haemorrhage\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: diagnostic accuracy of investigations and evidence review C: severity scoring systems.\n\nLoading. Please wait.\n\n## Detecting an aneurysm\n\nOffer CT angiography of the head without delay to people with a confirmed diagnosis of subarachnoid haemorrhage to identify the cause of the bleeding and to guide treatment.\n\nDiagnose an aneurysmal subarachnoid haemorrhage if:\n\nCT angiography of the head shows an intracranial arterial aneurysm and\n\nthe pattern of subarachnoid blood is compatible with aneurysm rupture.\n\nSeek specialist opinion without delay from an interventional neuroradiologist and neurosurgeon if:\n\nCT angiography of the head shows an intracranial arterial aneurysm and\n\nthe pattern of subarachnoid blood is not compatible with aneurysm rupture.\n\nIf CT angiography of the head does not identify the cause of the subarachnoid haemorrhage and an aneurysm is still suspected, consider digital subtraction angiography (DSA), or magnetic resonance angiography (MRA) if DSA is contraindicated.\n\nDiagnose an aneurysmal subarachnoid haemorrhage if:\n\nDSA or MRA shows an intracranial arterial aneurysm and\n\nthe pattern of subarachnoid blood is compatible with aneurysm rupture.\n\nThink about other diagnoses if DSA or MRA does not show an intracranial arterial aneurysm.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on detecting an aneurysm\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: diagnostic imaging strategies.\n\nLoading. Please wait.\n\n# Managing a confirmed aneurysmal subarachnoid haemorrhage\n\n## Medical management\n\nConsider enteral nimodipine for people with a confirmed subarachnoid haemorrhage.\n\nOnly use intravenous nimodipine within a specialist setting and if enteral treatment is not suitable.\n\nManage the risk of venous thromboembolism in people with an aneurysmal subarachnoid haemorrhage in line with the NICE guideline on venous thromboembolism in over 16s.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on medical management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: medical management strategies.\n\nLoading. Please wait.\n\n## Managing the culprit aneurysm\n\nAn interventional neuroradiologist and a neurosurgeon should discuss the options for managing the culprit aneurysm, taking into account the person's clinical condition, the characteristics of the aneurysm, and the amount and location of subarachnoid blood. They should document a proposed treatment plan based on the following options:\n\nendovascular coiling\n\nneurosurgical clipping\n\nno interventional procedure, with monitoring to check for clinical improvement and reassess the options for treatment.\n\nDo not use a subarachnoid haemorrhage severity score in isolation to determine the suitability of any management option.\n\nIf interventional treatment to secure the aneurysm is an option, offer:\n\nendovascular coiling or\n\nneurosurgical clipping if endovascular coiling is not suitable.\n\nDiscuss the proposed treatment plan and any alternative options with the person, and their family or carers if appropriate, then agree and document a final treatment plan (see recommendations 1.5.5 to 1.5.7).\n\nIf interventional treatment is planned, ensure that it is carried out at the earliest opportunity to prevent rebleeding. Be aware that the risk of rebleeding is highest within 24\xa0hours of the onset of symptoms.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing the culprit aneurysm\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: interventions to prevent rebleeding, evidence review C: severity scoring systems and evidence review M: timing of interventions to prevent rebleeding.\n\nLoading. Please wait.\n\nNICE interventional procedures guidance on endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms\n\nNICE interventional procedures guidance on coil embolisation of ruptured intracranial aneurysms.\n\n# Monitoring and managing complications\n\n## Monitoring and investigating for deterioration\n\nDo not use transcranial doppler monitoring to guide clinical management of an aneurysmal subarachnoid haemorrhage except in the context of clinical research.\n\nFor people with unexplained neurological deterioration after a subarachnoid haemorrhage, offer a non-contrast CT head scan as the first diagnostic investigation to determine the cause.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring and investigating for deterioration\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: monitoring for raised intracranial pressure and vasospasm.\n\nLoading. Please wait.\n\n## Hydrocephalus\n\nBase a diagnosis of acute or chronic hydrocephalus on the person's symptoms and signs, and on a comparison of current and previous CT or other brain imaging.\n\nConsider drainage or diversion of cerebrospinal fluid for people with neurological deterioration caused by acute hydrocephalus.\n\nFor people with persistent or progressive symptoms and a clinical diagnosis of chronic hydrocephalus, consider drainage or permanent diversion of cerebrospinal fluid. If there is uncertainty about the likely benefit of permanent diversion, consider a trial of temporary drainage to assess the need for permanent diversion.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on hydrocephalus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: detecting hydrocephalus and evidence review H: managing hydrocephalus.\n\nLoading. Please wait.\n\n## Delayed cerebral ischaemia\n\nEnsure euvolaemia (normal blood volume) in people with delayed cerebral ischaemia after an aneurysmal subarachnoid haemorrhage and consider treatment with a vasopressor if symptoms persist. Bear in mind that clinical improvement from vasopressor treatment may be temporary.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on delayed cerebral ischaemia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: management of delayed cerebral ischaemia.\n\nLoading. Please wait.\n\n# Follow-up care\n\n## Follow-up care plan\n\nAgree and document a plan for follow-up care with the person after their aneurysmal subarachnoid haemorrhage. Give a paper copy of the plan to the person (and their family or carers if appropriate) and include details of who to contact at the specialist centre for ongoing advice and support.\n\nInclude the follow-up care plan in the person's medical record and discharge correspondence.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up care plan\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review S: patient information.\n\nLoading. Please wait.\n\n## Rehabilitation\n\nOffer rehabilitation after aneurysmal subarachnoid haemorrhage in line with the NICE guidelines on stroke rehabilitation in adults and rehabilitation after critical illness in adults.\n\n## Follow-up neuroimaging\n\nConsider follow-up neuroimaging for people who have had an aneurysmal subarachnoid haemorrhage, taking into account the extent of their recovery and the suitability of further imaging. Base the choice of imaging modality, and the frequency and duration of imaging follow-up, on the:\n\ntype and outcome of any neurointervention or neurosurgery on the initial aneurysm\n\npresence of any non-culprit aneurysms\n\nestimated risk of further bleeding\n\nrisks of planned investigations and any subsequent interventions\n\nperson's preference.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up neuroimaging\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review O: imaging strategies for follow-up.\n\nLoading. Please wait.\n\n## Managing non-culprit (unruptured) aneurysms\n\nA multidisciplinary team (MDT) that includes an interventional neuroradiologist and a neurosurgeon should evaluate the options for managing non-culprit (unruptured) aneurysms, including:\n\nendovascular coiling\n\nneurosurgical clipping\n\nconservative management and follow-up monitoring.\n\nWhen evaluating the options for managing a non-culprit aneurysm, the MDT should take into account:\n\nthe size and location of the aneurysm\n\nthe estimated lifetime risk of the aneurysm rupturing\n\nthe estimated risk of each treatment option\n\nany comorbidities\n\nthe person's preferences.\n\nDiscuss the proposed management plan and any alternative options with the person (and their family or carers as appropriate). Base the discussion on the factors listed in recommendation\xa01.4.6. Agree and document a final management plan.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing non-culprit (unruptured) aneurysms\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review P: non-culprit aneurysms.\n\nLoading. Please wait.\n\nNICE medical technologies guidance on Pipeline Flex embolisation device with Shield Technology for the treatment of complex intracranial aneurysms\n\nNICE interventional procedures guidance on endovascular insertion of an intrasaccular wire-mesh blood-flow disruption device for intracranial aneurysms\n\nNICE interventional procedures guidance on coil embolisation of unruptured intracranial aneurysms.\n\n## Managing other conditions after discharge from hospital\n\nManage blood pressure in people aged\xa018 and over who have had an aneurysmal subarachnoid haemorrhage in line with the NICE guideline on hypertension in adults.\n\nDo not withhold treatment with antiplatelets or anticoagulants solely on the basis of an aneurysmal subarachnoid haemorrhage if the culprit aneurysm has been secured by coiling or clipping.\n\nBalance the risks and benefits of treatment with an antiplatelet or anticoagulant, taking into account specialist assessment of the risk of a future subarachnoid haemorrhage.\n\nEncourage people who smoke to stop, and consider smoking cessation support as set out in the recommendations on stop-smoking interventions in the NICE guideline on tobacco.\n\nAssess, diagnose and manage headaches in people who have had an aneurysmal subarachnoid haemorrhage in line with the NICE guideline on headaches in over 12s.\n\nBe aware that headaches in people with a history of aneurysmal subarachnoid haemorrhage:\n\nare common and generally benign\n\nmay be due to chronic hydrocephalus if the person has additional symptoms or signs such as gait disturbance, incontinence, incoordination or cognitive impairment.\n\nManage seizures in people who have recovered from an aneurysmal subarachnoid haemorrhage in line with the NICE guideline on epilepsies in children, young people and adults.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing other conditions after discharge from hospital\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review Q: long-term medicines for reducing the risk of subsequent subarachnoid haemorrhage and evidence review R: long-term medication for managing the consequences of subarachnoid haemorrhage.\n\nLoading. Please wait.\n\n## Investigations to detect aneurysms in relatives\n\nExplain to people (and their families if appropriate) who have had an aneurysmal subarachnoid haemorrhage and are concerned about possible aneurysms in their relatives that:\n\nroutine testing to check for aneurysms in relatives has not been shown to save lives or prevent aneurysmal subarachnoid haemorrhages\n\ntesting for relatives is based on an assessment of the relative's own risk\n\ntesting is usually limited to people with at least 2 first-degree relatives (father, mother, sister or brother) who have had an aneurysmal subarachnoid haemorrhage.Tell people where they can find more information about testing for relatives, such as the NHS webpage on diagnosis of brain aneurysm.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on investigations to detect aneurysms in relatives\xa0.\n\nFull details of the evidence and the committee's discussion are evidence review T: investigating relatives of people with aneurysmal subarachnoid haemorrhage.\n\nLoading. Please wait.\n\n# Information and support\n\nFollow the recommendations in the section on enabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services, including:\n\nestablishing the most effective way of communicating with the person and providing information in a format that is accessible to them\n\navoiding jargon, using words the person will understand and explaining unfamiliar words.\n\nWhen making decisions with people about their treatment and care, follow the NICE guideline on shared decision making.\n\nWhen supporting people who may lack capacity to make decisions about their treatment and care, follow the NICE guideline on decision making and mental capacity.\n\nAdapt written and verbal information about aneurysmal subarachnoid haemorrhage to the needs and preferences of the person (and their family or carers if appropriate).\n\n## At diagnosis\n\nExplain to the person (and their family or carers if appropriate) what an aneurysmal subarachnoid haemorrhage is and what the treatment options are, including their benefits and risks.\n\n## During the hospital stay\n\nGive the person (and their family or carers if appropriate) information about complications that can happen after an aneurysmal subarachnoid haemorrhage, such as:\n\na build-up of fluid on the brain (hydrocephalus)\n\na reduced supply of blood to the brain (delayed cerebral ischaemia)\n\nspeech or communication difficulties\n\nphysical disabilities\n\nseizures.\n\nTell the person (and their family or carers if appropriate) that common symptoms reported by people who have had a subarachnoid haemorrhage include:\n\nheadaches, fatigue and sleep disturbances\n\nanxiety, low moods and increased irritability\n\nproblems with memory and cognitive function\n\nchanges to smell, taste, hearing or vision.\n\nGive people who wish to receive it (and their family or carers if appropriate) information about their estimated future risk of another subarachnoid haemorrhage. Base the information on specialist assessment by the MDT of the person's medical circumstances, including:\n\nthe effectiveness of the treatment of the ruptured aneurysm\n\nthe presence and growth of additional aneurysms\n\ntheir smoking status.\n\nGive the person advice on returning to their usual activities including work, exercise, driving and sexual activity.\n\n## At discharge\n\nCheck that the person has been given advice about wound care and medicines, a copy of their follow-up care plan and details of who to contact at their specialist centre if they have questions or concerns. Give them details of local and national support groups.\n\n## At follow-up\n\nDiscuss the person's return to their usual activities (see recommendation\xa01.5.9).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review S: patient information and evidence review N: risk of subsequent subarachnoid haemorrhage.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Senior clinical decision-maker\n\nA clinician with the necessary training and experience to assess people with suspected subarachnoid haemorrhage, confirm subarachnoid haemorrhage symptoms and signs, and refer people for further investigation. This may be a consultant, a staff-grade, associate-specialist or specialty doctor, or a doctor in a training grade who has been delegated to do this because they have the necessary competencies.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Timing of CT head scans\n\nWhat is the relative accuracy of CT head scans at different time intervals, for example 12\xa0hours or 24\xa0hours after symptom onset, to diagnose subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on diagnosing a subarachnoid haemorrhage\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: diagnostic accuracy of investigations.\n\nLoading. Please wait.\n\n## Predictors of death and disability\n\nWhat variables predict death or disability for people with aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on diagnosing a subarachnoid haemorrhage\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: severity scoring systems.\n\nLoading. Please wait.\n\n## Nimodipine\n\nWhat is the clinical and cost effectiveness of nimodipine in the management of aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on nimodipine\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: medical management strategies.\n\nLoading. Please wait.\n\n## Novel endovascular interventions\n\nWhat is the clinical and cost effectiveness of novel endovascular techniques and devices such as coated coils, endoluminal flow diverters and intrasaccular devices to treat aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing the culprit aneurysm\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: interventions to prevent re-bleeding.\n\nLoading. Please wait.\n\n## Risk stratification tool to estimate risk of recurrence\n\nWhat is the utility of a risk stratification tool to estimate the risk of subsequent aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review N: risk of subsequent subarachnoid haemorrhage.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Interventions for aneurysmal subarachnoid haemorrhage in people with major neurological deficit\n\nWhat is the outcome of intervention to prevent rebleeding in people who present with or rapidly develop severe neurological deficits as a consequence of acute aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing the culprit aneurysm\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: interventions to prevent re-bleeding.\n\nLoading. Please wait.\n\n## Managing acute hydrocephalus\n\nWhat is the most clinically and cost-effective method of cerebrospinal fluid drainage or diversion (for example shunt surgery, external ventricular drain surgery or lumbar drain) for symptomatic acute hydrocephalus?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on hydrocephalus\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: managing hydrocephalus.\n\nLoading. Please wait.\n\n## Transcranial doppler monitoring\n\nWhat is the clinical and cost effectiveness of routine transcranial doppler monitoring to guide clinical management of aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on monitoring and investigating for deterioration\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: monitoring for raised intracranial pressure and vasospasm.\n\nLoading. Please wait.\n\n## Intracranial hypertension\n\nWhat is the impact of routine monitoring of intracranial hypertension on subsequent management and outcome in people with aneurysmal subarachnoid haemorrhage who are unconscious or ventilated on an intensive care unit?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on intracranial hypertension\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: detecting intracranial hypertension and evidence review J: managing intracranial hypertension.\n\nLoading. Please wait.\n\n## Intra-arterial therapies to manage delayed cerebral ischaemia\n\nWhat is the impact of intra-arterial therapies to manage delayed cerebral ischaemia on outcome in people with aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on delayed cerebral ischaemia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: management of delayed cerebral ischaemia.\n\nLoading. Please wait.\n\n## Vasopressors to manage delayed cerebral ischaemia\n\nWhat is the clinical and cost effectiveness of vasopressors to manage delayed cerebral ischaemia in people with aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on delayed cerebral ischaemia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: management of delayed cerebral ischaemia.\n\nLoading. Please wait.\n\n## Blood pressure targets\n\nWhat is the clinical and cost effectiveness of a lower blood pressure treatment target relative to the standard blood pressure treatment target for people with aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on managing other conditions after discharge from hospital\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review Q: long-term medicines for reducing the risk of subsequent subarachnoid haemorrhage.\n\nLoading. Please wait.\n\n## Investigations for relatives\n\nWhat is the clinical and cost effectiveness of investigations to detect intracranial arterial aneurysms in first-degree relatives of people who have had an aneurysmal subarachnoid haemorrhage?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on investigations to detect aneurysms in relatives\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review T: investigating relatives of people with aneurysmal subarachnoid haemorrhage.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Assessment and referral for diagnostic investigation\n\nRecommendations 1.1.1 to 1.1.7\n\n## Why the committee made the recommendations\n\nPeople with a suspected subarachnoid haemorrhage can present with a wide range of symptoms and signs. There was little evidence to indicate which symptoms or signs specifically point to a diagnosis of subarachnoid haemorrhage. The committee agreed that the consequences of a missed diagnosis may be severe and include disability and death. Urgent investigation is required to confirm a diagnosis of subarachnoid haemorrhage and facilitate early treatment to prevent rebleeding from the ruptured aneurysm. Clinicians should therefore be alert to the possibility of subarachnoid haemorrhage in people presenting with unexplained acute severe headache, reduced consciousness, seizure, focal neurological deficit or other suggestive symptoms. Some people present with non-specific symptoms, such as nausea and vomiting, photophobia, or neck pain or stiffness. In these cases, a diagnosis of subarachnoid haemorrhage is more likely to be missed.\n\nThe committee's experience indicated that a 'thunderclap' headache is a presenting symptom in most people with a subarachnoid haemorrhage. However, they noted that this type of headache is a common presentation in emergency departments and around 10% of people who present with this symptom have a diagnosis of subarachnoid haemorrhage confirmed; the majority are diagnosed with other conditions, for example, migraine. The committee agreed that other symptoms and signs are also commonly seen in people with a subarachnoid haemorrhage. These can be used, together with clinical judgement, to support clinical assessment and guide decisions on further diagnostic investigations. The committee noted that these symptoms and signs of subarachnoid haemorrhage can also be caused by a number of other conditions. Therefore, a senior clinician should confirm the assessment of subarachnoid haemorrhage and arrange immediate referral for further investigation.\n\nThere is good evidence showing that non-contrast CT head scans carried out within 6\xa0hours of symptom onset are highly accurate and can be used to rule out a diagnosis of subarachnoid haemorrhage, therefore avoiding the need for further investigation with a lumbar puncture. CT head scans done more than 6\xa0hours after symptom onset are less accurate (see the section on diagnosing a subarachnoid haemorrhage for more information).\n\nEvidence on decision tools, including the Ottawa Subarachnoid Haemorrhage Rule for Headache Evaluation, showed that these tools have a high level of accuracy in ruling out subarachnoid haemorrhage, but are less accurate at ruling it in, with a large number of false-positive identifications. Although these tools are beneficial in ensuring that no cases are missed, over-reliance on them risks harm from unnecessary imaging and invasive investigations. The committee noted that the tools use a broad range of symptoms and signs that are not specific to subarachnoid haemorrhage.\n\n## How the recommendations might affect practice\n\nThe recommendations may be useful for non-specialist clinicians, but are not expected to lead to significant changes in practice. Non-contrast CT head scans are the usual first-line investigation for suspected subarachnoid haemorrhage, and this is not expected to change.\n\nReturn to recommendations\n\n# Pain relief and neurological assessment\n\nRecommendations 1.1.8 and 1.1.9\n\n## Why the committee made the recommendations\n\nAlthough there was limited evidence on the use of specific analgesia or sedation, the committee agreed that pain in adults with aneurysmal subarachnoid haemorrhage should be managed with analgesics in line with standard clinical practice. Headache is usually treated with simple analgesics such as paracetamol, escalating to opioids as needed. The committee agreed that the sedative and pupillary effect of opioid analgesics should be taken into account when doing a neurological assessment, but should not preclude their use.\n\n## How the recommendations might affect practice\n\nThe recommendations generally reflect current practice and are not likely to result in changes.\n\nReturn to recommendations\n\n# Diagnosing a subarachnoid haemorrhage\n\nRecommendations 1.1.10 to 1.1.17\n\n## Why the committee made the recommendations\n\nThe committee looked at evidence on non-contrast CT head scans, lumbar puncture and MRI. In the studies, the CT scans were reviewed by either a general radiologist or a neuroradiologist. There was good evidence showing that CT head scans done within 6\xa0hours of symptom onset have a high diagnostic accuracy. Taking into account the invasive risks of lumbar puncture, the difficulty of monitoring patients during MRI and the costs of both procedures, the committee concluded that these procedures should not be routinely offered if a CT head scan, done within 6\xa0hours of symptom onset and reported and documented by an appropriately experienced radiologist, shows no evidence of a subarachnoid haemorrhage. In these circumstances alternative diagnoses should be considered and advice sought from a specialist, for example in neurosurgery, neuroradiology, neurology or stroke medicine.\n\nIf the CT head scan is done more than 6\xa0hours after symptom onset, the evidence showed that diagnostic accuracy is reduced and false-negative results are more likely. The committee therefore agreed that further investigation with a lumbar puncture should be considered if a CT head scan done more than 6\xa0hours after ictus does not confirm the diagnosis of subarachnoid haemorrhage.\n\nWhen a lumbar puncture is indicated, the committee agreed that it should be done at least 12\xa0hours after symptom onset, when bilirubin formation is sufficient to be detected reliably. The committee considered that the diagnostic accuracy of earlier lumbar puncture (to detect blood in the cerebrospinal fluid) is likely to be low because it can take several hours for blood to appear in the lumbar subarachnoid sac.\n\nThere was limited evidence on the relative accuracy of non-contrast CT head scanning at various time intervals greater than 6\xa0hours after symptom onset, so the committee made a recommendation for research on timing of CT head scans.\n\nIf subarachnoid haemorrhage is diagnosed, the committee noted that an urgent decision is needed on whether to transfer the person to specialist care. The committee decided to make a consensus recommendation to stress the importance of an urgent discussion with a specialist neurosurgical centre.\n\nAlthough evidence on a number of severity scores showed an association with morbidity and mortality, there was inconsistency across the scores and the evidence was not sufficient to recommend the use of any score on its own. The committee agreed that, although severity scoring can be a useful clinical descriptor, decisions on transfer should be based on a holistic patient assessment rather than a severity score on its own, to avoid inappropriate withholding of specialist neurosurgical care from people whose score indicates a poor clinical condition.\n\nThe committee noted that evidence to support the prognostic accuracy of the severity scores was weak and made a recommendation for research on predictors of death and disability.\n\n## How the recommendations might affect practice\n\nCentres that routinely perform lumbar puncture after a negative CT head scan may see a reduction in the use of lumbar puncture in people with an early negative CT head scan. Reliance on severity scoring to determine transfer to specialist centres may reduce, leading to more people appropriately being transferred for treatment.\n\nReturn to recommendations\n\n# Detecting an aneurysm\n\nRecommendations 1.1.18 to 1.1.23\n\n## Why the committee made the recommendations\n\nEvidence showed that CT angiography has a high level of accuracy in identifying aneurysms causing subarachnoid haemorrhage but evidence for the diagnostic accuracy of magnetic resonance angiography (MRA) was less compelling. CT angiography is the quickest to perform, is non-invasive, does not usually necessitate sedation or general anaesthesia and is available in most centres. MRA and DSA are more complex and time-consuming procedures that need specialist input and have a higher risk of complications. DSA is regarded as the 'gold standard' investigation and is currently commonly carried out when CT angiography is negative but there is a high suspicion of aneurysmal subarachnoid haemorrhage, whereas the complexities involved in obtaining high-quality MRA images make this less beneficial. The committee agreed that DSA should be reserved for instances when CT angiography has not detected a suspected aneurysm.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current practice and are not expected to lead to changes.\n\nReturn to recommendations\n\n# Medical management\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nAlthough limited evidence showed some reductions in mortality, rebleeding, disability and delayed cerebral ischaemia with nimodipine, most of the evidence available was graded as low or very low quality, predominately due to imprecision of outcome data, and risk of bias. There was a high risk of uncertainty around a number of outcomes due to significant statistical imprecision around the summary effect estimates, with wide confidence intervals crossing the thresholds for clinical significance.\n\nThe committee noted that the studies in the evidence review were conducted in the 1980s, with a lack of more recent evidence. In most of the studies, nimodipine was commenced up to 96\xa0hours after ictus and continued for up to 3\xa0weeks before neurosurgical management. Therefore, the committee had reservations about the applicability of this evidence to current practice, in which people with aneurysmal subarachnoid haemorrhage are frequently treated by endovascular coiling within 48\xa0hours of ictus. The committee could not be sure that the benefits from nimodipine are maintained with current treatments to secure the ruptured aneurysm, but they agreed that, without evidence of significant harms, a recommendation to consider nimodipine was appropriate in the acute management of aneurysmal subarachnoid haemorrhage.\n\nThe committee noted that the use of nimodipine is entrenched in clinical practice and was surprised at the lack of more compelling contemporary evidence for the use of enteral nimodipine in the management of aneurysmal subarachnoid haemorrhage. The lack of recent evidence influenced their decision to make a weak recommendation for the use of nimodipine. The committee also made a recommendation for research on nimodipine to determine its place in current practice.\n\nMost of the evidence related to the use of oral nimodipine but some was drawn from studies that included intravenous nimodipine. The committee were aware that intravenous nimodipine has a high cost and were uncertain whether it is likely to be cost effective in patients who are unconscious or ventilated, or unable to swallow. The committee were also aware that some clinicians recommend administration of crushed nimodipine tablets to these patients via a nasogastric tube to avoid the need to use intravenous nimodipine. The committee noted that intravenous nimodipine may be useful for patients in whom poor absorption of the drug is suspected. Based on these observations and their experience, the committee agreed that intravenous nimodipine should be reserved for patients in whom enteral administration is not suitable.\n\nThe committee noted that NICE's guideline on reducing the risk of hospital-acquired venous thromboembolism (VTE) includes assessment of bleeding risk and alternatives to pharmacological VTE prophylaxis, and is therefore suitable for people admitted to hospital with a subarachnoid haemorrhage before their aneurysm is secured and after it is secured.\n\nEvidence on tranexamic acid in the management of aneurysmal subarachnoid haemorrhage was mixed, and most was from small studies from the 1970s and 1980s. Some of the evidence suggested that short courses of intravenous tranexamic acid started immediately after diagnosis and before a planned intervention (endovascular coiling or neurosurgical clipping) reduce the risks of rebleeding. However, there was no evidence showing that they reduce death or disability.\n\nThe committee were aware that short-course tranexamic acid is occasionally used in current practice if interventional treatment to secure the aneurysm is suitable but not available within a short time frame. However, the committee agreed that the administration of tranexamic acid should not delay interventional treatment to secure the aneurysm.\n\n## How the recommendations might affect practice\n\nThe recommendation is not expected to substantially change the current practice of giving nimodipine after an aneurysmal subarachnoid haemorrhage.\n\nThe recommendation is not expected to change current practice.\n\nReturn to recommendations\n\n# Managing the culprit aneurysm\n\nRecommendations 1.2.4 to 1.2.8\n\n## Why the committee made the recommendations\n\nThe committee noted that around half of people who survive an aneurysmal subarachnoid haemorrhage will have a second bleed from the culprit aneurysm within weeks, and the mortality from a second bleed can exceed 50%. Interventional treatment with endovascular coiling or neurosurgical clipping, if suitable, can secure the aneurysm and prevent rebleeding.\n\nThe committee acknowledged that interventional treatment is not suitable for some people who have a major neurological deficit after an aneurysmal subarachnoid haemorrhage, and that the costs of long-term nursing care or rehabilitation can be considerable. Very little evidence was found for this group, so the committee made a recommendation for research on interventions for aneurysmal subarachnoid haemorrhage in people with major neurological deficit.\n\nSeverity scoring systems might help clinicians identify people for whom intervention is likely to be justified, but none of the severity scoring systems currently in use reliably predicts morbidity and mortality in people with aneurysmal subarachnoid haemorrhage. In addition, the committee agreed that clinical state and severity score can vary over time, especially soon after symptom onset. Decisions on clinical management should therefore be based on a holistic patient assessment rather than solely on a severity score. Factors that should be considered by clinicians and discussed with the patient include: neurological status, performance status and comorbidities.\n\nThe evidence was not sufficient to determine the clinical effectiveness of endovascular coiling compared with neurosurgical clipping, although a small amount of evidence suggested that endovascular coiling might be more beneficial. Endovascular coiling is less invasive and potentially safer, so the committee agreed that it should be offered as the first option, taking factors such as aneurysm characteristics and the amount and location of subarachnoid blood into account. The committee agreed that neurosurgical clipping should be considered if endovascular coiling is not a suitable treatment option. They stressed that any procedure to secure the aneurysm should be performed without delay to minimise the risk of rebleeding.\n\nNewer, more expensive interventional technologies are being used but there is little evidence on their effectiveness, so the committee made a recommendation for research on novel endovascular interventions.\n\n## How the recommendations might affect practice\n\nEndovascular coiling accounts for around 75% of interventions done in current practice and the recommendation is not expected to change this. Most interventions are carried out within 48\xa0hours of admission. However, this may vary according to the availability of interventional neuroradiologists and vascular neurosurgeons, and the capacity of neurosurgical centres. For people admitted during weekends, endovascular coiling should be available from the same interventional neuroradiology teams who will provide thrombectomy for stroke, in line with the recommendations on thrombectomy in the NICE guideline on stroke and transient ischaemic attack in over 16s. However, provision of neurosurgical clipping during weekends may necessitate changes to services such as the setting up of appropriate networks.\n\nReturn to recommendations\n\n# Monitoring and investigating for deterioration\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nThere was no evidence on the routine use of direct intracranial pressure monitoring for raised intracranial pressure. Very limited evidence from 1\xa0study on transcranial doppler monitoring for vasospasm suggested an increase in mortality, morbidity and length of hospital stay compared with no transcranial doppler monitoring. The committee agreed that these outcomes were unlikely to be directly caused by the transcranial doppler monitoring. However, they were concerned that such monitoring might influence subsequent decisions, for example about investigations or interventions, and so indirectly affect outcomes. They therefore agreed that transcranial doppler monitoring should only be used in the context of clinical research. The committee noted that there is increasing enthusiasm for the use of this modality and made a recommendation for research on transcranial doppler monitoring.\n\nThere was no evidence on the investigation of unexplained neurological deterioration in people with aneurysmal subarachnoid haemorrhage. The committee agreed that in current practice unexplained neurological deterioration is initially investigated with a non-contrast CT scan, which can indicate the cause of deterioration including ventricular enlargement suggestive of hydrocephalus, cerebral ischaemia, intracranial haematoma or evidence of rebleeding.\n\n## How the recommendations might affect practice\n\nIn current practice the use of transcranial doppler monitoring varies widely. The recommendation is likely to stop this type of monitoring in centres that use it in routine practice. CT head scans are used to investigate unexplained neurological deterioration in current practice and the recommendation will not affect this.\n\nReturn to recommendations\n\n# Hydrocephalus\n\nRecommendations 1.3.3 to 1.3.5\n\n## Why the committee made the recommendations\n\nThere was no evidence on diagnosing acute hydrocephalus. Based on their experience, the committee agreed that hydrocephalus is suspected on the basis of symptoms and signs of raised intracranial pressure such as an altered level of consciousness or neurological deterioration, and that the diagnosis should be confirmed by comparing a CT head scan with previous CT or other head scans to show an increase in the size of the ventricular system. The committee agreed that MRI offers no advantage over CT for diagnosing hydrocephalus in people with aneurysmal subarachnoid haemorrhage, is more expensive and is a difficult procedure for people who are unwell.\n\nThe committee noted that acute hydrocephalus can lead to severe disability or death if not treated promptly by drainage or diversion of cerebrospinal fluid. There was no evidence on the effectiveness of different techniques for drainage or diversion in acute hydrocephalus. The committee agreed that either drainage or diversion could be considered. They also made a recommendation for research on managing acute hydrocephalus.\n\nThere was little evidence to inform recommendations on diagnosing and managing chronic hydrocephalus. Based on their experience, the committee agreed that chronic hydrocephalus is uncommon and typically presents several weeks or months after an aneurysmal subarachnoid haemorrhage, with reduced consciousness, gait disturbance or other neurological symptoms. As with acute hydrocephalus, the committee agreed that chronic hydrocephalus is suspected based on symptoms and signs and a diagnosis should be confirmed based on a comparison of current CT head scans with previous CT or other head scans.\n\nIn current clinical practice most people with persisting or progressive symptoms and radiological evidence of ventricular dilatation are offered drainage of cerebrospinal fluid, which improves symptoms in the majority. If the likelihood of symptom improvement is uncertain, some clinicians advocate a trial of temporary drainage, for example, serial lumbar punctures, before considering permanent diversion of cerebrospinal fluid. The committee agreed with this approach.\n\nThe committee discussed making a recommendation for research on chronic hydrocephalus but concluded that research in this area might not be feasible within a reasonable time frame and have little impact on clinical practice.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nReturn to recommendations\n\n# Intracranial hypertension\n\nRecommendation for research\n\n## Why the committee did not make a recommendation\n\nThere was little evidence on diagnosing and treating intracranial hypertension. The committee agreed that the diagnostic accuracies of transcranial doppler and ultrasound measurement of optic nerve sheath diameter are too low for reliable detection of intracranial hypertension when compared with direct intracranial pressure measurement. The committee also acknowledged that there is no evidence that interventions to lower intracranial pressure improve clinical outcome.\n\nThe committee agreed that raised intracranial pressure is common in people with aneurysmal subarachnoid haemorrhage, but intracranial hypertension that impedes blood flow to the brain and contributes to brain injury is generally only seen in the most severely ill. These people are usually unconscious or need ventilation in an intensive care unit. They are a heterogeneous population and management varies widely, with some clinicians advocating routine monitoring of intracranial pressure to guide intervention (such as drainage of cerebrospinal fluid, hypertonic saline or vasopressor therapy) to lower intracranial pressure and maintain cerebral perfusion. Other clinicians favour management without intracranial pressure monitoring.\n\nIntracranial pressure can be monitored by inserting an intracranial pressure bolt or using an external ventricular drain inserted to manage acute hydrocephalus. The committee acknowledged that insertion of a pressure bolt is associated with risk, and monitoring of intracranial pressure will only improve outcome if it leads to effective intervention.\n\nThe committee debated the variation in current practice and were not able to reach a consensus on the role of interventions to diagnose and treat intracranial hypertension, and so they made a recommendation for research.\n\nReturn to recommendation for research\n\n# Delayed cerebral ischaemia\n\nRecommendation 1.3.6\n\n## Why the committee made the recommendation\n\nThere was very little evidence on delayed cerebral ischaemia so the committee based the recommendation on their clinical experience. They noted that current practice for managing delayed cerebral ischaemia is to maintain cerebral blood flow to prevent or limit cerebral infarction. Intravenous fluid is usually given to ensure euvolemia and if symptoms persist a vasopressor is administered to raise systemic blood pressure. The committee agreed with this approach, but added that the improvements seen after these measures may be temporary, and there was no evidence of impact on longer-term outcomes. Treatment for people whose condition is not improved by vasopressor therapy varies widely. Some clinicians recommend cerebral angiography and intra-arterial therapies, including intra-arterial vasodilators and angioplasty. However, the committee were unable to reach a consensus on the use of intra-arterial therapies. They made recommendations for research on intra-arterial therapies to manage delayed cerebral ischaemia and vasopressors to manage delayed cerebral ischaemia.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nReturn to recommendation\n\n# Follow-up care plan\n\nRecommendations 1.4.1 and 1.4.2\n\n## Why the committee made the recommendations\n\nEvidence from surveys and interviews with people who had an aneurysmal subarachnoid haemorrhage showed that those who did not receive clear information about their medical care after discharge felt anxious and 'abandoned'. Those who were given this information, together with details of who to contact for ongoing advice, said they felt more supported. The committee agreed that the follow-up care plan should be included in the person's medical record and discharge correspondence.\n\n## How the recommendations might affect practice\n\nThe amount and quality of information given to people about follow-up care after an aneurysmal subarachnoid haemorrhage varies. This recommendation can be expected to improve the provision of this information.\n\nReturn to recommendations\n\n# Follow-up neuroimaging\n\nRecommendation 1.4.4\n\n## Why the committee made the recommendation\n\nNo clinical evidence was found on follow-up neuroimaging. Based on their knowledge and experience, the committee agreed that there is a risk of aneurysm recurrence, progression of non-culprit aneurysms and formation of new aneurysms. They agreed that follow-up imaging should be considered, based on the person's clinical situation and risk factors.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nReturn to recommendation\n\n# Managing non-culprit (unruptured) aneurysms\n\nRecommendations 1.4.5 to 1.4.7\n\n## Why the committee made the recommendations\n\nThere was not enough good evidence to enable the committee to recommend a preferred management option for non-culprit aneurysms, although they agreed that the risk of a non-culprit aneurysm rupturing is higher in people who have had an aneurysmal subarachnoid haemorrhage than those who have not. Based on their experience, the committee agreed that the overall probability of a non-culprit aneurysm rupturing is low, so interventional treatment of all non-culprit aneurysms is unlikely to be a cost-effective strategy. They agreed that conservative management usually includes monitoring of the aneurysm with MRA to detect changes in the aneurysm's size or shape. The committee were in agreement that the frequency of monitoring should be based on a balance between the risks of aneurysm rupture and the risks of interventional treatment, and take into account multidisciplinary team, neuroradiological and neurosurgical opinion, and the person's preferences.\n\nThe committee's experience was that people with unruptured aneurysms who are offered conservative management are often anxious about the possibility of a future rupture. They therefore recommended that all treatment options be discussed with the person.\n\n## How the recommendations might affect practice\n\nCurrent management of unruptured aneurysms varies. The recommendations are not expected to lead to substantial changes in practice.\n\nReturn to recommendations\n\n# Managing other conditions after discharge from hospital\n\nRecommendations 1.4.8 to 1.4.14\n\n## Why the committee made the recommendations\n\nUncontrolled hypertension is recognised to be a risk factor for aneurysmal subarachnoid haemorrhage and may pose a greater risk to people with a history of this type of stroke. The committee agreed that blood pressure should be controlled in line with the NICE guideline on hypertension in adults.\n\nThere was no evidence on long-term blood pressure control specifically for people with a history of aneurysmal subarachnoid haemorrhage, so the committee made a recommendation for research on blood pressure targets.\n\nThere was little evidence about the effect of an antiplatelet or anticoagulant on the risk of recurrent intracranial bleeding. The committee agreed that, in their experience, these medicines are safe for people with a secured aneurysm following an aneurysmal subarachnoid haemorrhage. For people with a higher risk of recurrence, specialist advice should be sought to judge the balance between the risk of recurrent or new intracranial bleeding and the risk of athero-embolic events.\n\nThe committee noted that smoking can be a risk factor for an initial subarachnoid haemorrhage. They agreed that smoking cessation interventions, in addition to benefiting general health, may also reduce the risk of recurrent subarachnoid haemorrhage.\n\nThe committee agreed, based on their experience, that people who develop headaches after recovering from an aneurysmal subarachnoid haemorrhage can become anxious and worry that their headache indicates new aneurysmal bleeding or a complication of the treatment they had for their aneurysm. This can lead to morbidity, multiple presentations to healthcare professionals and unnecessary investigations. There was no evidence on specific long-term medicines to relieve headaches as a consequence of subarachnoid haemorrhage. The committee agreed that headache should be assessed, diagnosed and managed in line with NICE's guideline on headaches in over 12s.\n\nThe committee agreed, based on their experience, that headaches are common and generally benign in people who have had a subarachnoid haemorrhage, but in some people may indicate chronic hydrocephalus.\n\nThe committee agreed that people who have had an aneurysmal subarachnoid haemorrhage have an increased risk of seizures and epilepsy. There was no evidence on the use of long-term antiseizure medicines to prevent or relieve seizures in this population. They agreed that seizures after an aneurysmal subarachnoid haemorrhage should be treated in line with NICE's guidance on diagnosing and managing epilepsies.\n\n## How the recommendations might affect practice\n\nThe recommendations on hypertension, smoking, headaches and seizures are not expected to change practice. The recommendations on managing conditions treated with antiplatelets or anticoagulants may reduce delays in prescribing these medicines for people who have had a successfully treated aneurysmal subarachnoid haemorrhage. Although specialist input may be needed, this is not expected to have a large impact on services.\n\nReturn to recommendations\n\n# Investigations to detect aneurysms in relatives\n\nRecommendation 1.4.15\n\n## Why the committee made the recommendation\n\nNo evidence was found on investigating relatives for intracranial aneurysms. The committee recognised that first-degree relatives of people who have had an aneurysmal subarachnoid haemorrhage are at higher risk of intracranial arterial aneurysm than the general population. The committee agreed that investigating for aneurysms in first-degree relatives may produce health benefits but could also lead to harm, including unnecessary anxiety and a consequent increase in visits to GPs and emergency departments. Moreover, the optimal timing and frequency of investigations to detect and monitor intracranial aneurysms in first-degree relatives is unknown.\n\nThe committee were aware that the NHS does not currently support routine screening for intracranial arterial aneurysms in relatives and any change in NHS policy could have a significant resource impact.\n\nThe committee acknowledged that in current practice investigation is typically only recommended for people thought to have a significant risk of having a brain aneurysm that could rupture at some point in the future, and this would usually only apply to people with 2 or more first-degree relatives who have had an aneurysmal subarachnoid haemorrhage. This reflects the advice given on the NHS website on screening for brain aneurysms.\n\nThe committee agreed that the lack of evidence for routine testing of relatives and current practice on testing should be explained to people who have had a subarachnoid haemorrhage, and their families as appropriate. Given the importance of this issue and the lack of evidence, the committee made a recommendation for research on investigations for relatives.\n\n## How the recommendation might affect practice\n\nThe recommendation is not expected to lead to a change in practice.\n\nReturn to recommendation\n\n# Information and support\n\nRecommendations 1.5.1 to 1.5.11\n\n## Why the committee made the recommendations\n\nEvidence from studies using surveys and interviews with people who have had an aneurysmal subarachnoid haemorrhage showed that they value information that is clear, concise and tailored to their own needs. Participants in the studies highlighted how difficult it was to remember information given to them verbally at the time of hospital admission and the need to have this information in a written form that they can take home at discharge. They also stressed the importance of information about their medical care and what to expect after discharge, including common symptoms, possible complications and where they can get advice and support.\n\nThe committee used their experience to agree topics that should be included, as a minimum, in the information given. They highlighted the importance of ease of access to information for people throughout their care pathway.\n\nIn the committee's experience, some people want information about the risk of recurrence of subarachnoid haemorrhage and some do not. They agreed that discussions should include the effect of individual variables on the person's risk of recurrence. The committee discussed the lack of a validated risk tool to inform estimates of individual risk and made a recommendation for research on a risk stratification tool to estimate risk of recurrence.\n\n## How the recommendations might affect practice\n\nThe content, delivery and quality of information given to people with aneurysmal subarachnoid haemorrhage varies widely. The recommendations are expected to encourage discussion that is tailored to the person's preferences.\n\nReturn to recommendations", 'Context': "Subarachnoid haemorrhage is a bleed into the fluid-filled subarachnoid space around the brain and spinal cord. Spontaneous subarachnoid haemorrhage accounts for 5% of all strokes and is estimated to occur in 2 to 20\xa0people per 100,000 per year. In around 80% of people, the bleed arises from rupture of an intracranial arterial aneurysm. Aneurysmal subarachnoid haemorrhage is slightly more common in women than men, and can occur across a wide range of ages with a median age at presentation between 50 and 60.\n\nThe main symptom of subarachnoid haemorrhage is a sudden and severe 'thunderclap' headache but there may also be neck stiffness, altered consciousness or seizures. The condition is more easily diagnosed in people presenting with severe symptoms, unconsciousness or sudden onset acute headache but some people with subarachnoid haemorrhage present with less severe or non-specific symptoms and signs. A high index of suspicion and holistic clinical assessment are therefore required to avoid missed diagnoses.\n\nUrgent investigation to confirm a diagnosis of subarachnoid haemorrhage facilitates treatment to prevent rebleeding from the ruptured aneurysm and reduces disability and death. Although outcomes for people with subarachnoid haemorrhage have slowly improved, the risk of death remains high and those who survive are often severely disabled. This guideline aims to improve the speed and accuracy of diagnosis and the effectiveness of treatment. It provides recommendations based on current evidence covering initial assessment, diagnostic investigations, treatment options, management of complications and follow-up care. It also identifies areas where evidence is lacking and recommends research to help inform future guidance."}	https://www.nice.org.uk/guidance/ng228	This guideline covers diagnosing and treating an aneurysmal (caused by a ruptured aneurysm) subarachnoid haemorrhage and its complications. It provides recommendations to improve diagnosis and ensure that the most effective treatments are offered. It includes guidance on follow-up care and information for people (aged 16 and over) who have had an aneurysmal subarachnoid haemorrhage, their families and carers.
ec9ae2251391f03b66b79721f17431ce0d91b970	nice	Fractures (complex): assessment and management	Fractures (complex): assessment and management This guideline covers assessing and managing pelvic fractures, open fractures and severe ankle fractures (known as pilon fractures and intra-articular distal tibia fractures) in pre-hospital settings (including ambulance services), emergency departments and major trauma centres. It aims to reduce deaths and long-term health problems by improving the quality of emergency and urgent care. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Recommendations apply to both children (under 16s) and adults (16 or over) unless otherwise specified. Some recommendations on management depend on whether the growth plate of the injured bone has closed (skeletal maturity). The age at which this happens varies. In practice, healthcare professionals use clinical judgement to determine skeletal maturity. When a recommendation depends on skeletal maturity this is clearly indicated. # Pre-hospital settings For recommendations on managing airways, recognising and managing chest trauma, controlling external haemorrhage and fluid replacement, see the NICE guideline on major trauma. ## Initial pharmacological management of pain For recommendations on pain assessment in people with suspected complex fractures, see the NICE guideline on major trauma. For recommendations on the initial pharmacological management of pain in people with suspected open fractures, see the NICE guideline on major trauma. For recommendations on the initial pharmacological management of pain in people with suspected high‑energy pelvic fractures, see the NICE guideline on major trauma. For recommendations on the initial pharmacological management of pain in adults with suspected low‑energy pelvic fractures, see the NICE guideline on hip fracture. For recommendations on the initial pharmacological management of pain in adults with suspected pilon fractures and children with suspected intra‑articular distal tibia fractures, see the NICE guideline on non-complex fractures. ## Using a pelvic binder If active bleeding is suspected from a pelvic fracture following blunt high‑energy trauma: apply a purpose‑made pelvic binder, or consider an improvised pelvic binder but only if a purpose‑made binder does not fit. ## Initial management of open fractures before wound excision Do not irrigate open fractures of the long bones, hindfoot or midfoot in pre‑hospital settings. Consider a saline‑soaked dressing covered with an occlusive layer for open fractures in pre‑hospital settings. In the pre‑hospital setting, consider administering prophylactic intravenous antibiotics as soon as possible and preferably within 1 hour of injury to people with open fractures without delaying transport to hospital. ## Splinting long bone fractures of the leg in the pre‑hospital setting In the pre‑hospital setting, consider the following for people with suspected long bone fractures of the legs: a traction splint or adjacent leg as a splint if the suspected fracture is above the knee a vacuum splint for all other suspected long bone fractures. ## Destination for people with suspected fractures Transport people with suspected open fractures: directly to a major trauma centre (In some locations or circumstances, intermediate care in a trauma unit might be needed for urgent treatment, in line with agreed practice within the regional trauma network.) or specialist centre that can provide orthoplastic care if a long bone, hindfoot or midfoot are involved, or to the nearest trauma unit or emergency department if the suspected fracture is in the hand, wrist or toes, unless there are pre‑hospital triage indications for direct transport to a major trauma centre. Transport people with suspected pelvic fractures: to the nearest hospital if suspected pelvic fracture is the only pre‑hospital triage indication directly to a major trauma centre (in some locations or circumstances, intermediate care in a trauma unit might be needed for urgent treatment, in line with agreed practice within the regional trauma network) if they also have other pre‑hospital triage indications for major trauma. # Hospital settings See recommendations 1.1.2 to 1.1.6 for advice on initial management of pain. ## Vascular injury Use hard signs (lack of palpable pulse, continued blood loss, or expanding haematoma) to diagnose vascular injury. Do not rely on capillary return or Doppler signal to exclude vascular injury. Perform immediate surgical exploration if hard signs of vascular injury persist after any necessary restoration of limb alignment and joint reduction. In people with a devascularised limb following long bone fracture, use a vascular shunt as the first surgical intervention before skeletal stabilisation and definitive vascular reconstruction. Do not delay revascularisation for angiography in people with complex fractures. For humeral supracondylar fractures in children (under 16s) without a palpable radial pulse but with a well‑perfused hand, consider observation rather than immediate vascular intervention. ## Compartment syndrome In people with fractures of the tibia, maintain awareness of compartment syndrome for 48 hours after injury or fixation by: regularly assessing and recording clinical symptoms and signs in hospital considering continuous compartment pressure monitoring in hospital when clinical symptoms and signs cannot be readily identified (for example, because the person is unconscious or has a nerve block) advising people how to self‑monitor for symptoms of compartment syndrome, when they leave hospital. ## Whole-body CT of multiple injuries Use whole‑body CT (consisting of a vertex‑to‑toes scanogram followed by CT from vertex to mid‑thigh) in adults (16 or over) with blunt major trauma and suspected multiple injuries. Patients should not be repositioned during whole‑body CT. Use clinical findings and the scanogram to direct CT of the limbs in adults (16 or over) with limb trauma. Do not routinely use whole‑body CT to image children (under 16s). Use clinical judgement to limit CT to the body areas where assessment is needed. ## Pelvic fractures The NICE guideline on major trauma: service delivery contains a recommendation for ambulance and hospital trust boards, medical directors and senior managers on transfer between emergency departments. Immediately transfer people with haemodynamic instability from pelvic or acetabular fractures to a major trauma centre for definitive treatment of active bleeding. Transfer people with pelvic or acetabular fractures needing specialist pelvic reconstruction to a major trauma centre or specialist centre within 24 hours of injury. Immediately transfer people with a failed closed reduction of a native hip joint to a specialist centre if there is insufficient expertise for open reduction at the receiving hospital. Use CT for first-line imaging in adults (16 or over) with suspected high‑energy pelvic fractures. For first‑line imaging in children (under 16s) with suspected high‑energy pelvic fractures: use CT rather than X‑ray when CT of the abdomen or pelvis is already indicated for assessing other injuries consider CT rather than X‑ray when CT of the abdomen or pelvis is not indicated for assessing other injuries.Use clinical judgement to limit CT to the body areas where assessment is needed. The NICE guideline on major trauma: service delivery contains a recommendation for ambulance and hospital trust boards, medical directors and senior managers on interventional radiology and definitive open surgery. For first‑line invasive treatment of active arterial pelvic bleeding, use: interventional radiology if emergency laparotomy is not needed for abdominal injuries pelvic packing if emergency laparotomy is needed for abdominal injuries. For people with suspected pelvic fractures and pelvic binders, remove the binder as soon as possible if: there is no pelvic fracture, or a pelvic fracture is identified as mechanically stable, or the binder is not controlling the mechanical stability of the fracture, or there is no further bleeding or coagulation is normal.Remove all pelvic binders within 24 hours of application. Before removing the pelvic binder, agree with a pelvic surgeon how a mechanically unstable fracture should be managed. Do not log roll people with suspected pelvic fractures before pelvic imaging unless: an occult penetrating injury is suspected in a person with haemodynamic instability log rolling is needed to clear the airway (for example, suction is ineffective in a person who is vomiting). When log rolling, pay particular attention to haemodynamic stability. ## Open fractures Do not irrigate open fractures of the long bones, hindfoot or midfoot in the emergency department before wound excision. Consider a saline‑soaked dressing covered with an occlusive layer (if not already applied) for open fractures in the emergency department before wound excision. In the emergency department, administer prophylactic intravenous antibiotics immediately to people with open fractures if not already given. Do not base the decision whether to perform limb salvage or amputation on an injury severity tool score. Perform emergency amputation when: a limb is the source of uncontrollable life‑threatening bleeding, or a limb is salvageable but attempted preservation would pose an unacceptable risk to the person's life, or a limb is deemed unsalvageable after orthoplastic assessment.Include the person and their family members or carers (as appropriate) in a full discussion of the options if this is possible. Base the decision whether to perform limb salvage or delayed primary amputation on multidisciplinary assessment involving an orthopaedic surgeon, a plastic surgeon, a rehabilitation specialist and the person and their family members or carers (as appropriate). When indicated, perform the delayed primary amputation within 72 hours of injury. Surgery to achieve wound excision, fixation and cover of open fractures of the long bone, hindfoot or midfoot should be performed concurrently by consultants in orthopaedic and plastic surgery (a combined orthoplastic approach). Perform wound excision: immediately for highly contaminated open fractures within 12 hours of injury for high‑energy open fractures (likely Gustilo–Anderson classification type IIIA or type IIIB) that are not highly contaminated within 24 hours of injury for all other open fractures. Perform fixation and definitive soft tissue cover: at the same time as wound excision if the next orthoplastic list allows this within the time to wound excision recommended in 1.2.28, or within 72 hours of injury if definitive soft tissue cover cannot be performed at the time of wound excision. When internal fixation is used, perform definitive soft tissue cover at the same time. Use a temporary dressing that avoids wound desiccation and minimises the number of dressing changes after wound excision if immediate definitive soft tissue cover has not been performed . For a short explanation of why the committee made the 2022 recommendation and how it might affect practice, see the rationale and impact section on temporary dressings for open fractures after wound excision but before definitive tissue cover . Full details of the evidence and the committee's discussion are in evidence review A: negative pressure wound therapy for temporary closure of open fractures. Loading. Please wait. ## Pilon fractures in adults (skeletally mature) Create a definitive management plan and perform initial surgery (temporary or definitive) within 24 hours of injury in adults (skeletally mature) with displaced pilon fractures. If a definitive management plan and initial surgery cannot be performed at the receiving hospital within 24 hours of injury, transfer adults (skeletally mature) with displaced pilon fractures to an orthoplastic centre (ideally this would be emergency department to emergency department transfer to avoid delay). Immediately transfer adults (skeletally mature) with displaced pilon fractures to an orthoplastic centre if there are wound complications. ## Intra-articular distal tibia fractures in children (skeletally immature) Create a definitive management plan involving a children's orthopaedic trauma specialist within 24 hours of diagnosis in children (skeletally immature) with intra‑articular distal tibia fractures. If a definitive management plan and surgery cannot be performed at the receiving hospital, transfer children (skeletally immature) with intra‑articular distal tibia fractures to a centre with a children's orthopaedic trauma specialist (ideally this would be emergency department to emergency department transfer to avoid delay). # Documentation The NICE guideline on major trauma: service delivery contains recommendations for ambulance and hospital trust boards, senior managers and commissioners on documentation within a trauma network. Follow a structured process when handing over care within the emergency department (including shift changes) and to other departments. Ensure that the handover is documented. Ensure that all patient documentation, including images and reports, goes with patients when they are transferred to other departments or centres. Produce a written summary, which gives the diagnosis, management plan and expected outcome, and: is aimed at and sent to the patient's GP within 24 hours of admission includes a summary written in plain English that is understandable by patients, family members and carers is readily available in the patient's records. ## Photographic documentation of open fracture wounds All trusts receiving patients with open fractures must have information governance policies in place that enable staff to take and use photographs of open fracture wounds for clinical decision‑making 24 hours a day. Protocols must also cover the handling and storage of photographic images of open fracture wounds. Consider photographing open fracture wounds when they are first exposed for clinical care, before wound excision and at other key stages of management. Keep any photographs of open fracture wounds in the patient's records. ## Documentation of neurovascular status When assessing neurovascular status in a person with a limb injury, document for both limbs: which nerves and nerve function have been assessed and when the findings, including: sensibility motor function using the Medical Research Council (MRC) grading system which pulses have been assessed and when how circulation has been assessed when pulses are not accessible. Document and time each repeated assessment. # Information and support for patients, family members and carers The NICE guideline on major trauma: service delivery contains a recommendation for ambulance and hospital trust boards, senior managers and commissioners on providing information and support for patients, family members and carers. ## Providing support When communicating with patients, family members and carers: manage expectations and avoid misinformation answer questions and provide information honestly, within the limits of your knowledge do not speculate and avoid being overly optimistic or pessimistic when discussing information on further investigations, diagnosis or prognosis ask if there are any other questions. The trauma team structure should include a clear point of contact for providing information to patients, their family members and carers. If possible, ask the patient if they want someone (family member, carer or friend) with them. Reassure people while they are having procedures for fractures under local and regional anaesthesia. Allocate a dedicated member of staff to contact the next of kin and provide support for unaccompanied children and vulnerable adults. Contact the mental health team as soon as possible for patients who have a pre-existing psychological or psychiatric condition that might have contributed to their injury, or a mental health problem that might affect their wellbeing or care in hospital. For a child or vulnerable adult with a complex fracture, enable their family members or carers to remain within eyesight if appropriate. Work with family members and carers of children and vulnerable adults to provide information and support. Take into account the age, developmental stage and cognitive function of the child or vulnerable adult. Include siblings of an injured child when offering support to family members and carers. ## Providing information Explain to patients, family members and carers, what is happening and why it is happening. Provide: information on known injuries details of immediate investigations and treatment, and if possible include time schedules. Offer people with fractures the opportunity to see images of their injury, taken before and after treatment. Provide people with fractures with both verbal and written information on the following when the management plan is agreed or changed: expected outcomes of treatment, including time to returning to usual activities and the likelihood of permanent effects on quality of life (such as pain, loss of function and psychological effects) amputation, if this is a possibility activities they can do to help themselves home care options, if needed rehabilitation, including whom to contact and how (this should include information on the importance of active patient participation for achieving goals and the expectations of rehabilitation) mobilisation and weight‑bearing, including upper limb load bearing for arm fractures. Document all key communications with patients, family members and carers about the management plan. Ensure that all health and social care practitioners have access to information previously given to people with fractures to enable consistent information to be provided. For patients who are being transferred from an emergency department to another centre, provide verbal and written information that includes: the reason for the transfer the location of the receiving centre and the patient's destination within the receiving centre the name and contact details of the person responsible for the patient's care at the receiving centre the name and contact details of the person who was responsible for the patient's care at the initial hospital. # Training and skills ## These recommendations are for ambulance and hospital trust boards, medical directors and senior managers within trauma networks. Ensure that each healthcare professional within the trauma service has the training and skills to deliver, safely and effectively, the interventions they are required to give, in line with the NICE guideline on non-complex fractures, complex fractures, major trauma, major trauma services and spinal injury assessment. Enable each healthcare professional who delivers care to people with fractures to have up‑to‑date training in the interventions they are required to give. # Terms used in this guideline ## Delayed primary amputation A procedure that is carried out when amputation is chosen as preferable to attempting reconstructive surgery for limb salvage, but not performed as an emergency operation. ## Orthoplastic centre A hospital with a dedicated, combined service for orthopaedic and plastic surgery in which consultants from both specialties work simultaneously to treat open fractures as part of regular, scheduled, combined orthopaedic and plastic surgery operating lists. Consultants are supported by combined review clinics and specialist nursing teams. ## Wound excision Also known as debridement, this refers to the separation of tissues that are contaminated or non-viable from those that are healthy and viable.# Recommendations for research The guideline committee has made the following key recommendations for research. # Temporary dressings for up to 72 hours between wound excision and definitive soft tissue cover What is the most clinically and cost effective temporary (up to 72 hours) dressing (including negative pressure dressings) for open fractures after wound excision for: minimising the number of dressing changes or supplementary dressings minimising the number of associated bedding changes acceptability for patients, for example, in terms of minimising pain minimising nursing time. For a short explanation of why the committee made this recommendation for research, see the rationale section on temporary dressings for open fractures after wound excision but before definitive tissue cover . Full details of the evidence and the committee's discussion are in evidence review A: negative pressure wound therapy for temporary closure of open fractures. Loading. Please wait. # Cystourethrogram How accurate is the first CT scan with contrast (trauma scan) for detecting bladder injuries in people with suspected bladder injuries after a traumatic incident? ## Why this is important Bladder injuries usually occur in people with high‑energy pelvic fractures after a traumatic incident. Currently people with suspected bladder injuries have a CT scan with intravenous contrast (a trauma scan) to diagnose non‑bladder injuries. People who do not have injuries needing urgent treatment may then either be given another CT scan or a fluoroscopic cystogram to check for bladder injury. People with injuries needing urgent treatment (for example, bleeding or a neurological injury) are taken to the resuscitation room after the initial CT scan (trauma scan). Once the person's condition is stabilised they are taken to either the CT or fluoroscopy suite for a retrograde cystogram to check for bladder injury. The guideline committee agreed that these strategies are accurate for the diagnosis of bladder injuries, but felt that there were advantages to a strategy that did not involve a second set of images. The guideline committee was interested in whether the first CT scan with intravenous contrast (trauma scan) could accurately diagnose bladder injuries. # Pilon fractures In adults with closed pilon fractures, what method of fixation provides the best clinical and cost effectiveness outcomes as assessed by function and incidence of major complications at 2 years (stratified for timing of definitive surgery early versus later )? ## Why this is important Pilon fractures involve a significant proportion of the weight‑bearing surface of the distal tibia. The damaged joint surface is vulnerable to degeneration. Therefore, the injury can lead to long‑term disability, most commonly arthritis with pain and stiffness. Surgery can improve outcomes, allowing reduction and fixation of the fracture and early movement of the ankle joint. However, it has a high incidence of serious complications, particularly related to the vulnerability of the soft tissues around the ankle. The potential for life‑changing adverse consequences of both the injury and its treatment is known, but the best management strategy to minimise these consequences is unclear.# Rationale and impact This section briefly explains why the committee made the recommendation dated 2022 and how it might affect practice. # Temporary dressings for open fractures after wound excision but before definitive soft tissue cover Recommendation 1.2.31 ## Why the committee made the recommendation The evidence showed that use of negative pressure wound therapy (NPWT) after wound excision if immediate definitive soft tissue cover has not been performed is not more clinically effective than other dressings and is unlikely to be cost effective. However, the committee agreed that most of the evidence related to the use of NPWT as a therapy rather than as a temporary dressing (which is what it is used for in the UK) and therefore most of the long-term outcomes were not relevant to the UK context. Furthermore, the cost effectiveness of NPWT is unclear. They agreed that, on that basis, it was not appropriate to make a 'do not routinely use' recommendation. The committee agreed that, in their experience, compared to other dressings, NPWT could: reduce the number of times dressings are changed or supplemented and reduce the number of associated bedding changes, thereby saving nursing time reduce the pain and discomfort of changing or supplementing dressings, thereby improving patient satisfaction. They also noted that NPWT is useful for wounds that are heavily exuding where other dressings may need to be changed or supplemented more often. The committee agreed that there are several types of dressing that can remain in situ until definitive soft tissue cover is performed up to 72 hours later. NPWT is not the only choice. They also agreed it was important to ensure the correct application of dressings. The committee agreed to replace the 2016 recommendation on NPWT with a recommendation to apply a temporary dressing that avoids wound desiccation and minimises dressing changes. They were not able to recommend specific dressings because the evidence they considered only related to NPWT, so they discussed whether to make a recommendation for research on specific temporary dressing for open fractures after wound excision but before definitive soft tissue cover. Since they could not be sure that this evidence did not already exist (because it was not searched for as part of this update) they agreed to ask stakeholders at consultation. Stakeholders did not raise any objection and so the committee proceeded to make a recommendation for research on temporary dressings. ## How the recommendations might affect practice NPWT is widely used as a temporary dressing for open fractures before definitive soft tissue cover, however other temporary dressings can be effective in providing temporary coverage and may be more cost-effective. The updated recommendation stipulates the use of a temporary dressing that prevents desiccation and minimises the number of dressing changes. This may reduce the use of NPWT. Return to recommendation# Context Complex fractures make up the minority of the 1.8 million fractures that occur in England each year, but are associated with considerable morbidity and are a large burden on healthcare resources. The treatment of complex fractures is often complicated and usually involves multiple healthcare professionals and specialists. This guideline covers the triage, initial and acute stage assessment and management, imaging, referral to specialist care and treatment of complex fractures in children (under 16s) and adults (16 or over). It includes recommendations in the following key clinical areas: management in pre‑hospital settings immediate destination for people with suspected complex fractures initial assessment and management in acute care imaging and haemorrhage control of pelvic fractures management of open fractures management plan and referral for adults with pilon fractures and children with intra‑articular distal tibia fractures documentation information and support for people with complex fractures and their families and carers. The guideline does not address all potential situations for every individual complex fracture. It is based around topics that should be considered as representative of an evidence‑based guide to the general management of complex fractures. It provides recommendations on open fractures, pelvic fractures, pilon fractures in adults and intra‑articular distal tibia fractures in children. It does not cover the prevention and follow‑up of complex fractures, and the management and follow‑up of dislocations and conditions such as osteoporosis and osteoarthritis. The guideline does not cover non‑complex fractures, skull fractures, hip fractures and spinal injuries. These are covered by other NICE guidelines.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nRecommendations apply to both children (under 16s) and adults (16 or over) unless otherwise specified. Some recommendations on management depend on whether the growth plate of the injured bone has closed (skeletal maturity). The age at which this happens varies. In practice, healthcare professionals use clinical judgement to determine skeletal maturity. When a recommendation depends on skeletal maturity this is clearly indicated.\n\n# Pre-hospital settings\n\nFor recommendations on managing airways, recognising and managing chest trauma, controlling external haemorrhage and fluid replacement, see the NICE guideline on major trauma. \n\n## Initial pharmacological management of pain\n\nFor recommendations on pain assessment in people with suspected complex fractures, see the NICE guideline on major trauma. \n\nFor recommendations on the initial pharmacological management of pain in people with suspected open fractures, see the NICE guideline on major trauma. \n\nFor recommendations on the initial pharmacological management of pain in people with suspected high‑energy pelvic fractures, see the NICE guideline on major trauma. \n\nFor recommendations on the initial pharmacological management of pain in adults with suspected low‑energy pelvic fractures, see the NICE guideline on hip fracture. \n\nFor recommendations on the initial pharmacological management of pain in adults with suspected pilon fractures and children with suspected intra‑articular distal tibia fractures, see the NICE guideline on non-complex fractures. \n\n## Using a pelvic binder\n\nIf active bleeding is suspected from a pelvic fracture following blunt high‑energy trauma:\n\napply a purpose‑made pelvic binder, or\n\nconsider an improvised pelvic binder but only if a purpose‑made binder does not fit. \n\n## Initial management of open fractures before wound excision\n\nDo not irrigate open fractures of the long bones, hindfoot or midfoot in pre‑hospital settings. \n\nConsider a saline‑soaked dressing covered with an occlusive layer for open fractures in pre‑hospital settings. \n\nIn the pre‑hospital setting, consider administering prophylactic intravenous antibiotics as soon as possible and preferably within 1\xa0hour of injury to people with open fractures without delaying transport to hospital. [2016, amended 2017]\n\n## Splinting long bone fractures of the leg in the pre‑hospital setting\n\nIn the pre‑hospital setting, consider the following for people with suspected long bone fractures of the legs:\n\na traction splint or adjacent leg as a splint if the suspected fracture is above the knee\n\na vacuum splint for all other suspected long bone fractures. \n\n## Destination for people with suspected fractures\n\nTransport people with suspected open fractures:\n\ndirectly to a major trauma centre (In some locations or circumstances, intermediate care in a trauma unit might be needed for urgent treatment, in line with agreed practice within the regional trauma network.) or specialist centre that can provide orthoplastic care if a long bone, hindfoot or midfoot are involved, or\n\nto the nearest trauma unit or emergency department if the suspected fracture is in the hand, wrist or toes, unless there are pre‑hospital triage indications for direct transport to a major trauma centre. \n\nTransport people with suspected pelvic fractures:\n\nto the nearest hospital if suspected pelvic fracture is the only pre‑hospital triage indication\n\ndirectly to a major trauma centre (in some locations or circumstances, intermediate care in a trauma unit might be needed for urgent treatment, in line with agreed practice within the regional trauma network) if they also have other pre‑hospital triage indications for major trauma. \n\n# Hospital settings\n\nSee recommendations 1.1.2 to 1.1.6 for advice on initial management of pain.\n\n## Vascular injury\n\nUse hard signs (lack of palpable pulse, continued blood loss, or expanding haematoma) to diagnose vascular injury. \n\nDo not rely on capillary return or Doppler signal to exclude vascular injury. \n\nPerform immediate surgical exploration if hard signs of vascular injury persist after any necessary restoration of limb alignment and joint reduction. \n\nIn people with a devascularised limb following long bone fracture, use a vascular shunt as the first surgical intervention before skeletal stabilisation and definitive vascular reconstruction. \n\nDo not delay revascularisation for angiography in people with complex fractures. \n\nFor humeral supracondylar fractures in children (under 16s) without a palpable radial pulse but with a well‑perfused hand, consider observation rather than immediate vascular intervention. \n\n## Compartment syndrome\n\nIn people with fractures of the tibia, maintain awareness of compartment syndrome for 48\xa0hours after injury or fixation by:\n\nregularly assessing and recording clinical symptoms and signs in hospital\n\nconsidering continuous compartment pressure monitoring in hospital when clinical symptoms and signs cannot be readily identified (for example, because the person is unconscious or has a nerve block)\n\nadvising people how to self‑monitor for symptoms of compartment syndrome, when they leave hospital. \n\n## Whole-body CT of multiple injuries\n\nUse whole‑body CT (consisting of a vertex‑to‑toes scanogram followed by CT from vertex to mid‑thigh) in adults (16 or over) with blunt major trauma and suspected multiple injuries. Patients should not be repositioned during whole‑body CT. \n\nUse clinical findings and the scanogram to direct CT of the limbs in adults (16 or over) with limb trauma. \n\nDo not routinely use whole‑body CT to image children (under 16s). Use clinical judgement to limit CT to the body areas where assessment is needed. \n\n## Pelvic fractures\n\nThe NICE guideline on major trauma: service delivery contains a recommendation for ambulance and hospital trust boards, medical directors and senior managers on transfer between emergency departments.\n\nImmediately transfer people with haemodynamic instability from pelvic or acetabular fractures to a major trauma centre for definitive treatment of active bleeding. \n\nTransfer people with pelvic or acetabular fractures needing specialist pelvic reconstruction to a major trauma centre or specialist centre within 24\xa0hours of injury. \n\nImmediately transfer people with a failed closed reduction of a native hip joint to a specialist centre if there is insufficient expertise for open reduction at the receiving hospital. \n\nUse CT for first-line imaging in adults (16 or over) with suspected high‑energy pelvic fractures. \n\nFor first‑line imaging in children (under 16s) with suspected high‑energy pelvic fractures:\n\nuse CT rather than X‑ray when CT of the abdomen or pelvis is already indicated for assessing other injuries\n\nconsider CT rather than X‑ray when CT of the abdomen or pelvis is not indicated for assessing other injuries.Use clinical judgement to limit CT to the body areas where assessment is needed. \n\nThe NICE guideline on major trauma: service delivery contains a recommendation for ambulance and hospital trust boards, medical directors and senior managers on interventional radiology and definitive open surgery.\n\nFor first‑line invasive treatment of active arterial pelvic bleeding, use:\n\ninterventional radiology if emergency laparotomy is not needed for abdominal injuries\n\npelvic packing if emergency laparotomy is needed for abdominal injuries. \n\nFor people with suspected pelvic fractures and pelvic binders, remove the binder as soon as possible if:\n\nthere is no pelvic fracture, or\n\na pelvic fracture is identified as mechanically stable, or\n\nthe binder is not controlling the mechanical stability of the fracture, or\n\nthere is no further bleeding or coagulation is normal.Remove all pelvic binders within 24\xa0hours of application. \n\nBefore removing the pelvic binder, agree with a pelvic surgeon how a mechanically unstable fracture should be managed. \n\nDo not log roll people with suspected pelvic fractures before pelvic imaging unless:\n\nan occult penetrating injury is suspected in a person with haemodynamic instability\n\nlog rolling is needed to clear the airway (for example, suction is ineffective in a person who is vomiting). When log rolling, pay particular attention to haemodynamic stability.\n\n## Open fractures\n\nDo not irrigate open fractures of the long bones, hindfoot or midfoot in the emergency department before wound excision. \n\nConsider a saline‑soaked dressing covered with an occlusive layer (if not already applied) for open fractures in the emergency department before wound excision. \n\nIn the emergency department, administer prophylactic intravenous antibiotics immediately to people with open fractures if not already given. \n\nDo not base the decision whether to perform limb salvage or amputation on an injury severity tool score. \n\nPerform emergency amputation when:\n\na limb is the source of uncontrollable life‑threatening bleeding, or\n\na limb is salvageable but attempted preservation would pose an unacceptable risk to the person's life, or\n\na limb is deemed unsalvageable after orthoplastic assessment.Include the person and their family members or carers (as appropriate) in a full discussion of the options if this is possible. \n\nBase the decision whether to perform limb salvage or delayed primary amputation on multidisciplinary assessment involving an orthopaedic surgeon, a plastic surgeon, a rehabilitation specialist and the person and their family members or carers (as appropriate). \n\nWhen indicated, perform the delayed primary amputation within 72\xa0hours of injury. \n\nSurgery to achieve wound excision, fixation and cover of open fractures of the long bone, hindfoot or midfoot should be performed concurrently by consultants in orthopaedic and plastic surgery (a combined orthoplastic approach). \n\nPerform wound excision:\n\nimmediately for highly contaminated open fractures\n\nwithin 12\xa0hours of injury for high‑energy open fractures (likely Gustilo–Anderson classification type IIIA or type IIIB) that are not highly contaminated\n\nwithin 24\xa0hours of injury for all other open fractures. \n\nPerform fixation and definitive soft tissue cover:\n\nat the same time as wound excision if the next orthoplastic list allows this within the time to wound excision recommended in 1.2.28, or\n\nwithin 72\xa0hours of injury if definitive soft tissue cover cannot be performed at the time of wound excision. \n\nWhen internal fixation is used, perform definitive soft tissue cover at the same time. \n\nUse a temporary dressing that avoids wound desiccation and minimises the number of dressing changes after wound excision if immediate definitive soft tissue cover has not been performed .\n\nFor a short explanation of why the committee made the 2022 recommendation and how it might affect practice, see the rationale and impact section on temporary dressings for open fractures after wound excision but before definitive tissue cover\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: negative pressure wound therapy for temporary closure of open fractures.\n\nLoading. Please wait.\n\n## Pilon fractures in adults (skeletally mature)\n\nCreate a definitive management plan and perform initial surgery (temporary or definitive) within 24\xa0hours of injury in adults (skeletally mature) with displaced pilon fractures. \n\nIf a definitive management plan and initial surgery cannot be performed at the receiving hospital within 24\xa0hours of injury, transfer adults (skeletally mature) with displaced pilon fractures to an orthoplastic centre (ideally this would be emergency department to emergency department transfer to avoid delay). \n\nImmediately transfer adults (skeletally mature) with displaced pilon fractures to an orthoplastic centre if there are wound complications. \n\n## Intra-articular distal tibia fractures in children (skeletally immature)\n\nCreate a definitive management plan involving a children's orthopaedic trauma specialist within 24\xa0hours of diagnosis in children (skeletally immature) with intra‑articular distal tibia fractures. \n\nIf a definitive management plan and surgery cannot be performed at the receiving hospital, transfer children (skeletally immature) with intra‑articular distal tibia fractures to a centre with a children's orthopaedic trauma specialist (ideally this would be emergency department to emergency department transfer to avoid delay). \n\n# Documentation\n\nThe NICE guideline on major trauma: service delivery contains recommendations for ambulance and hospital trust boards, senior managers and commissioners on documentation within a trauma network.\n\nFollow a structured process when handing over care within the emergency department (including shift changes) and to other departments. Ensure that the handover is documented. \n\nEnsure that all patient documentation, including images and reports, goes with patients when they are transferred to other departments or centres. \n\nProduce a written summary, which gives the diagnosis, management plan and expected outcome, and:\n\nis aimed at and sent to the patient's GP within 24\xa0hours of admission\n\nincludes a summary written in plain English that is understandable by patients, family members and carers\n\nis readily available in the patient's records. \n\n## Photographic documentation of open fracture wounds\n\nAll trusts receiving patients with open fractures must have information governance policies in place that enable staff to take and use photographs of open fracture wounds for clinical decision‑making 24\xa0hours a day. Protocols must also cover the handling and storage of photographic images of open fracture wounds. \n\nConsider photographing open fracture wounds when they are first exposed for clinical care, before wound excision and at other key stages of management. \n\nKeep any photographs of open fracture wounds in the patient's records. \n\n## Documentation of neurovascular status\n\nWhen assessing neurovascular status in a person with a limb injury, document for both limbs:\n\nwhich nerves and nerve function have been assessed and when\n\nthe findings, including:\n\n\n\nsensibility\n\nmotor function using the Medical Research Council (MRC) grading system\n\n\n\nwhich pulses have been assessed and when\n\nhow circulation has been assessed when pulses are not accessible. Document and time each repeated assessment. \n\n# Information and support for patients, family members and carers\n\nThe NICE guideline on major trauma: service delivery contains a recommendation for ambulance and hospital trust boards, senior managers and commissioners on providing information and support for patients, family members and carers.\n\n## Providing support\n\nWhen communicating with patients, family members and carers:\n\nmanage expectations and avoid misinformation\n\nanswer questions and provide information honestly, within the limits of your knowledge\n\ndo not speculate and avoid being overly optimistic or pessimistic when discussing information on further investigations, diagnosis or prognosis\n\nask if there are any other questions. \n\nThe trauma team structure should include a clear point of contact for providing information to patients, their family members and carers. \n\nIf possible, ask the patient if they want someone (family member, carer or friend) with them. \n\nReassure people while they are having procedures for fractures under local and regional anaesthesia. \n\nAllocate a dedicated member of staff to contact the next of kin and provide support for unaccompanied children and vulnerable adults. \n\nContact the mental health team as soon as possible for patients who have a pre-existing psychological or psychiatric condition that might have contributed to their injury, or a mental health problem that might affect their wellbeing or care in hospital. \n\nFor a child or vulnerable adult with a complex fracture, enable their family members or carers to remain within eyesight if appropriate. \n\nWork with family members and carers of children and vulnerable adults to provide information and support. Take into account the age, developmental stage and cognitive function of the child or vulnerable adult. \n\nInclude siblings of an injured child when offering support to family members and carers. \n\n## Providing information\n\nExplain to patients, family members and carers, what is happening and why it is happening. Provide:\n\ninformation on known injuries\n\ndetails of immediate investigations and treatment, and if possible include time schedules. \n\nOffer people with fractures the opportunity to see images of their injury, taken before and after treatment. \n\nProvide people with fractures with both verbal and written information on the following when the management plan is agreed or changed:\n\nexpected outcomes of treatment, including time to returning to usual activities and the likelihood of permanent effects on quality of life (such as pain, loss of function and psychological effects)\n\namputation, if this is a possibility\n\nactivities they can do to help themselves\n\nhome care options, if needed\n\nrehabilitation, including whom to contact and how (this should include information on the importance of active patient participation for achieving goals and the expectations of rehabilitation)\n\nmobilisation and weight‑bearing, including upper limb load bearing for arm fractures. \n\nDocument all key communications with patients, family members and carers about the management plan. \n\nEnsure that all health and social care practitioners have access to information previously given to people with fractures to enable consistent information to be provided. \n\nFor patients who are being transferred from an emergency department to another centre, provide verbal and written information that includes:\n\nthe reason for the transfer\n\nthe location of the receiving centre and the patient's destination within the receiving centre\n\nthe name and contact details of the person responsible for the patient's care at the receiving centre\n\nthe name and contact details of the person who was responsible for the patient's care at the initial hospital. \n\n# Training and skills\n\n## These recommendations are for ambulance and hospital trust boards, medical directors and senior managers within trauma networks.\n\nEnsure that each healthcare professional within the trauma service has the training and skills to deliver, safely and effectively, the interventions they are required to give, in line with the NICE guideline on non-complex fractures, complex fractures, major trauma, major trauma services and spinal injury assessment. \n\nEnable each healthcare professional who delivers care to people with fractures to have up‑to‑date training in the interventions they are required to give. \n\n# Terms used in this guideline\n\n## Delayed primary amputation\n\nA procedure that is carried out when amputation is chosen as preferable to attempting reconstructive surgery for limb salvage, but not performed as an emergency operation.\n\n## Orthoplastic centre\n\nA hospital with a dedicated, combined service for orthopaedic and plastic surgery in which consultants from both specialties work simultaneously to treat open fractures as part of regular, scheduled, combined orthopaedic and plastic surgery operating lists. Consultants are supported by combined review clinics and specialist nursing teams.\n\n## Wound excision\n\nAlso known as debridement, this refers to the separation of tissues that are contaminated or non-viable from those that are healthy and viable.", 'Recommendations for research': "The guideline committee has made the following key recommendations for research.\n\n# Temporary dressings for up to 72 hours between wound excision and definitive soft tissue cover\n\nWhat is the most clinically and cost effective temporary (up to 72\xa0hours) dressing (including negative pressure dressings) for open fractures after wound excision for:\n\nminimising the number of dressing changes or supplementary dressings\n\nminimising the number of associated bedding changes\n\nacceptability for patients, for example, in terms of minimising pain\n\nminimising nursing time.\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on temporary dressings for open fractures after wound excision but before definitive tissue cover\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: negative pressure wound therapy for temporary closure of open fractures.\n\nLoading. Please wait.\n\n# Cystourethrogram\n\nHow accurate is the first CT scan with contrast (trauma scan) for detecting bladder injuries in people with suspected bladder injuries after a traumatic incident?\n\n## Why this is important\n\nBladder injuries usually occur in people with high‑energy pelvic fractures after a traumatic incident. Currently people with suspected bladder injuries have a CT scan with intravenous contrast (a trauma scan) to diagnose non‑bladder injuries. People who do not have injuries needing urgent treatment may then either be given another CT scan or a fluoroscopic cystogram to check for bladder injury. People with injuries needing urgent treatment (for example, bleeding or a neurological injury) are taken to the resuscitation room after the initial CT scan (trauma scan). Once the person's condition is stabilised they are taken to either the CT or fluoroscopy suite for a retrograde cystogram to check for bladder injury. The guideline committee agreed that these strategies are accurate for the diagnosis of bladder injuries, but felt that there were advantages to a strategy that did not involve a second set of images. The guideline committee was interested in whether the first CT scan with intravenous contrast (trauma scan) could accurately diagnose bladder injuries.\n\n# Pilon fractures\n\nIn adults with closed pilon fractures, what method of fixation provides the best clinical and cost effectiveness outcomes as assessed by function and incidence of major complications at 2\xa0years (stratified for timing of definitive surgery early [under 36\xa0hours] versus later [over 36\xa0hours])?\n\n## Why this is important\n\nPilon fractures involve a significant proportion of the weight‑bearing surface of the distal tibia. The damaged joint surface is vulnerable to degeneration. Therefore, the injury can lead to long‑term disability, most commonly arthritis with pain and stiffness. Surgery can improve outcomes, allowing reduction and fixation of the fracture and early movement of the ankle joint. However, it has a high incidence of serious complications, particularly related to the vulnerability of the soft tissues around the ankle. The potential for life‑changing adverse consequences of both the injury and its treatment is known, but the best management strategy to minimise these consequences is unclear.", 'Rationale and impact': "This section briefly explains why the committee made the recommendation dated 2022 and how it might affect practice.\n\n# Temporary dressings for open fractures after wound excision but before definitive soft tissue cover\n\nRecommendation 1.2.31\n\n## Why the committee made the recommendation\n\nThe evidence showed that use of negative pressure wound therapy (NPWT) after wound excision if immediate definitive soft tissue cover has not been performed is not more clinically effective than other dressings and is unlikely to be cost effective. However, the committee agreed that most of the evidence related to the use of NPWT as a therapy rather than as a temporary dressing (which is what it is used for in the UK) and therefore most of the long-term outcomes were not relevant to the UK context. Furthermore, the cost effectiveness of NPWT is unclear. They agreed that, on that basis, it was not appropriate to make a 'do not routinely use' recommendation.\n\nThe committee agreed that, in their experience, compared to other dressings, NPWT could:\n\nreduce the number of times dressings are changed or supplemented and reduce the number of associated bedding changes, thereby saving nursing time\n\nreduce the pain and discomfort of changing or supplementing dressings, thereby improving patient satisfaction.\n\nThey also noted that NPWT is useful for wounds that are heavily exuding where other dressings may need to be changed or supplemented more often.\n\nThe committee agreed that there are several types of dressing that can remain in situ until definitive soft tissue cover is performed up to 72 hours later. NPWT is not the only choice. They also agreed it was important to ensure the correct application of dressings.\n\nThe committee agreed to replace the 2016 recommendation on NPWT with a recommendation to apply a temporary dressing that avoids wound desiccation and minimises dressing changes.\n\nThey were not able to recommend specific dressings because the evidence they considered only related to NPWT, so they discussed whether to make a recommendation for research on specific temporary dressing for open fractures after wound excision but before definitive soft tissue cover. Since they could not be sure that this evidence did not already exist (because it was not searched for as part of this update) they agreed to ask stakeholders at consultation. Stakeholders did not raise any objection and so the committee proceeded to make a recommendation for research on temporary dressings.\n\n## How the recommendations might affect practice\n\nNPWT is widely used as a temporary dressing for open fractures before definitive soft tissue cover, however other temporary dressings can be effective in providing temporary coverage and may be more cost-effective. The updated recommendation stipulates the use of a temporary dressing that prevents desiccation and minimises the number of dressing changes. This may reduce the use of NPWT.\n\nReturn to recommendation", 'Context': 'Complex fractures make up the minority of the 1.8\xa0million fractures that occur in England each year, but are associated with considerable morbidity and are a large burden on healthcare resources. The treatment of complex fractures is often complicated and usually involves multiple healthcare professionals and specialists.\n\nThis guideline covers the triage, initial and acute stage assessment and management, imaging, referral to specialist care and treatment of complex fractures in children (under 16s) and adults (16 or over). It includes recommendations in the following key clinical areas:\n\nmanagement in pre‑hospital settings\n\nimmediate destination for people with suspected complex fractures\n\ninitial assessment and management in acute care\n\nimaging and haemorrhage control of pelvic fractures\n\nmanagement of open fractures\n\nmanagement plan and referral for adults with pilon fractures and children with intra‑articular distal tibia fractures\n\ndocumentation\n\ninformation and support for people with complex fractures and their families and carers.\n\nThe guideline does not address all potential situations for every individual complex fracture. It is based around topics that should be considered as representative of an evidence‑based guide to the general management of complex fractures. It provides recommendations on open fractures, pelvic fractures, pilon fractures in adults and intra‑articular distal tibia fractures in children. It does not cover the prevention and follow‑up of complex fractures, and the management and follow‑up of dislocations and conditions such as osteoporosis and osteoarthritis.\n\nThe guideline does not cover non‑complex fractures, skull fractures, hip fractures and spinal injuries. These are covered by other NICE guidelines.'}	https://www.nice.org.uk/guidance/ng37	This guideline covers assessing and managing pelvic fractures, open fractures and severe ankle fractures (known as pilon fractures and intra-articular distal tibia fractures) in pre-hospital settings (including ambulance services), emergency departments and major trauma centres. It aims to reduce deaths and long-term health problems by improving the quality of emergency and urgent care.
5b140b145affbd88af4d34498a3f6a2db869b891	nice	Tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis	Tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis Evidence-based recommendations on tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis. This involves inserting a catheter under the skin in the abdomen to drain excess fluid when needed, at home or in community care. The aim is to reduce the need for hospital admissions and improve quality of life. # Recommendations Evidence on the safety of long-term tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis is limited but shows well-recognised complications. Evidence on the efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do long-term tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers as appropriate) clear information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection, continued community care support and follow up should be done by a multidisciplinary team experienced in managing the condition. The team should include a hepatologist, a specialist community nurse and specialist level palliative care. NICE encourages further research into long-term tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis.# The condition, current treatments and procedure # The condition Refractory ascites is a common complication of cirrhosis of the liver. Build-up of fluid causes difficulty in breathing, fatigue, nausea, poor appetite, acid reflux, abdominal pain and infection. Mortality at 2 years in people with refractory ascites is 50% or more, and 5‑year survival is normally less than 20%. # Current treatments Treatment options for symptomatic relief include dietary sodium and fluid restriction, diuretics, large-volume paracentesis (a temporary drain inserted into the abdomen to drain the ascitic fluid) with albumin infusion, or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS). If the cause of liver failure and ascites cannot be treated or treatment fails, liver transplantation may be used in some people. If TIPSS or liver transplantation is not suitable, long-term ascitic drainage peritoneal catheters are a palliative treatment option. # The procedure The procedure is usually done as a day case with local anaesthesia, with or without sedation. Ultrasound, fluoroscopy or both are used to guide catheter insertion and placement. A guidewire introducer needle is inserted percutaneously into the peritoneal cavity and ascitic fluid is aspirated. A guidewire is then inserted through the introducer and into the peritoneal cavity. A fenestrated drainage catheter is tunnelled subcutaneously from a second incision away from the guidewire insertion site. It is then inserted over the guidewire into the peritoneal cavity using a dilator and peel-away sheath. A polystyrene cuff on the catheter is positioned inside the subcutaneous tunnel. The dilator and guidewire are removed and the catheter insertion site and exit sites are sutured. Antibiotics may be offered during and after the procedure. A lockable drainage line is connected to a valve at the outer end of the catheter to allow the ascitic fluid to be drained into a vacuum bottle or a drainage bag. Before hospital discharge, the ascites is normally drained to dryness and albumin replacement is given. After this procedure, ascites drainage is done in the community or at home without giving replacement albumin. This is typically supervised by district nurses. People can drain small amounts of ascitic fluid repeatedly from their peritoneal cavity into vacuum bottles. The volume of fluid drained and how often it is done can be adjusted according to their needs.	{'Recommendations': "Evidence on the safety of long-term tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis is limited but shows well-recognised complications. Evidence on the efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do long-term tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers as appropriate) clear information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection, continued community care support and follow up should be done by a multidisciplinary team experienced in managing the condition. The team should include a hepatologist, a specialist community nurse and specialist level palliative care.\n\nNICE encourages further research into long-term tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis.", 'The condition, current treatments and procedure': '# The condition\n\nRefractory ascites is a common complication of cirrhosis of the liver. Build-up of fluid causes difficulty in breathing, fatigue, nausea, poor appetite, acid reflux, abdominal pain and infection. Mortality at 2\xa0years in people with refractory ascites is 50% or more, and 5‑year survival is normally less than 20%.\n\n# Current treatments\n\nTreatment options for symptomatic relief include dietary sodium and fluid restriction, diuretics, large-volume paracentesis (a temporary drain inserted into the abdomen to drain the ascitic fluid) with albumin infusion, or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS). If the cause of liver failure and ascites cannot be treated or treatment fails, liver transplantation may be used in some people. If TIPSS or liver transplantation is not suitable, long-term ascitic drainage peritoneal catheters are a palliative treatment option.\n\n# The procedure\n\nThe procedure is usually done as a day case with local anaesthesia, with or without sedation. Ultrasound, fluoroscopy or both are used to guide catheter insertion and placement. A guidewire introducer needle is inserted percutaneously into the peritoneal cavity and ascitic fluid is aspirated. A guidewire is then inserted through the introducer and into the peritoneal cavity. A fenestrated drainage catheter is tunnelled subcutaneously from a second incision away from the guidewire insertion site. It is then inserted over the guidewire into the peritoneal cavity using a dilator and peel-away sheath. A polystyrene cuff on the catheter is positioned inside the subcutaneous tunnel. The dilator and guidewire are removed and the catheter insertion site and exit sites are sutured. Antibiotics may be offered during and after the procedure.\n\nA lockable drainage line is connected to a valve at the outer end of the catheter to allow the ascitic fluid to be drained into a vacuum bottle or a drainage bag. Before hospital discharge, the ascites is normally drained to dryness and albumin replacement is given. After this procedure, ascites drainage is done in the community or at home without giving replacement albumin. This is typically supervised by district nurses.\n\nPeople can drain small amounts of ascitic fluid repeatedly from their peritoneal cavity into vacuum bottles. The volume of fluid drained and how often it is done can be adjusted according to their needs.'}	https://www.nice.org.uk/guidance/ipg746	Evidence-based recommendations on tunnelled peritoneal drainage catheter insertion for refractory ascites in cirrhosis. This involves inserting a catheter under the skin in the abdomen to drain excess fluid when needed, at home or in community care. The aim is to reduce the need for hospital admissions and improve quality of life.
61bfb4961a0ffdfbf404c117e703f9ac90daedac	nice	Ab interno canaloplasty for open-angle glaucoma	Ab interno canaloplasty for open-angle glaucoma Evidence-based recommendations on ab interno canaloplasty for open-angle glaucoma. This involves widening the channel that drains fluid from the eye. The aim is to reduce pressure in the eye. # Recommendations Evidence on the safety of ab interno canaloplasty for open-angle glaucoma shows no major safety concerns. Evidence on the efficacy is limited in quality and quantity, particularly in the long term. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. Clinicians wanting to do ab interno canaloplasty for open-angle glaucoma should: Inform the clinical governance leads in their healthcare organisation. Give people (and their families and carers, as appropriate) clear information to support shared decision making, including NICE's information for the public. Ensure that people (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these. Audit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion). Enter details about everyone having ab interno canaloplasty for open-angle glaucoma onto a suitable registry and review local clinical outcomes. Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve. Healthcare organisations should: Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure. Regularly review data on outcomes and safety for this procedure. Patient selection and treatment should be done by glaucoma specialists with training and experience in the technique. Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme. Further research should report: details of patient selection, including concurrent procedures, severity of glaucoma and concomitant therapy long-term efficacy and safety outcomes.# The condition, current treatments and procedure # The condition Glaucoma is usually a chronic condition that is typically associated with raised intraocular pressure (IOP). The most common type of glaucoma in the UK is primary open-angle glaucoma. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic. But, as the condition progresses, it can cause visual impairment and, if untreated, blindness. In the healthy eye, aqueous humor drains through the trabecular meshwork (into Schlemm's canal) and through the uveoscleral outflow pathway. In glaucoma, this drainage becomes impaired, either from resistance in the trabecular meshwork pathway (primary open-angle glaucoma) or from obstruction by the iris (primary closed-angle glaucoma). # Current treatments Treatment usually involves eye drops containing medicines that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, deep sclerectomy, trabeculotomy, stenting, canaloplasty or laser trabeculoplasty may be used. # The procedure Ab interno canaloplasty aims to reduce IOP by improving the drainage of aqueous fluid from the eye in people with open-angle glaucoma. It is usually done under local anaesthesia, but general anaesthesia can be used. Unlike traditional (ab externo) canaloplasty, which is done by cutting through the conjunctiva and sclera, ab interno canaloplasty uses an internal approach through a clear corneal or limbal incision. A microcatheter is introduced into the canal through a small opening in the trabecular meshwork and advanced around its entire circumference. As the catheter tip is withdrawn, viscoelastic fluid is injected into the canal to dilate it. The microcatheter is then removed. The viscoelastic fluid disperses down the collector channels of the eye within 2 to 3 days. The aim is to permanently dilate the canal to allow increased drainage of aqueous humor from the eye and thereby lower IOP. Some devices allow canaloplasty to be done sequentially with trabeculotomy as part of a single operation. Canaloplasty is often done concurrently with phacoemulsification (cataract surgery).	{'Recommendations': "Evidence on the safety of ab interno canaloplasty for open-angle glaucoma shows no major safety concerns. Evidence on the efficacy is limited in quality and quantity, particularly in the long term. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do ab interno canaloplasty for open-angle glaucoma should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive people (and their families and carers, as appropriate) clear information to support shared decision making, including NICE's information for the public.\n\nEnsure that people (and their families and carers, as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of everyone having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nEnter details about everyone having ab interno canaloplasty for open-angle glaucoma onto a suitable registry and review local clinical outcomes.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection and treatment should be done by glaucoma specialists with training and experience in the technique.\n\nReport any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nFurther research should report:\n\ndetails of patient selection, including concurrent procedures, severity of glaucoma and concomitant therapy\n\nlong-term efficacy and safety outcomes.", 'The condition, current treatments and procedure': "# The condition\n\nGlaucoma is usually a chronic condition that is typically associated with raised intraocular pressure (IOP). The most common type of glaucoma in the UK is primary open-angle glaucoma. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic. But, as the condition progresses, it can cause visual impairment and, if untreated, blindness.\n\nIn the healthy eye, aqueous humor drains through the trabecular meshwork (into Schlemm's canal) and through the uveoscleral outflow pathway. In glaucoma, this drainage becomes impaired, either from resistance in the trabecular meshwork pathway (primary open-angle glaucoma) or from obstruction by the iris (primary closed-angle glaucoma).\n\n# Current treatments\n\nTreatment usually involves eye drops containing medicines that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, deep sclerectomy, trabeculotomy, stenting, canaloplasty or laser trabeculoplasty may be used.\n\n# The procedure\n\nAb interno canaloplasty aims to reduce IOP by improving the drainage of aqueous fluid from the eye in people with open-angle glaucoma. It is usually done under local anaesthesia, but general anaesthesia can be used. Unlike traditional (ab externo) canaloplasty, which is done by cutting through the conjunctiva and sclera, ab interno canaloplasty uses an internal approach through a clear corneal or limbal incision. A microcatheter is introduced into the canal through a small opening in the trabecular meshwork and advanced around its entire circumference. As the catheter tip is withdrawn, viscoelastic fluid is injected into the canal to dilate it. The microcatheter is then removed. The viscoelastic fluid disperses down the collector channels of the eye within 2\xa0to 3\xa0days. The aim is to permanently dilate the canal to allow increased drainage of aqueous humor from the eye and thereby lower IOP. Some devices allow canaloplasty to be done sequentially with trabeculotomy as part of a single operation. Canaloplasty is often done concurrently with phacoemulsification (cataract surgery)."}	https://www.nice.org.uk/guidance/ipg745	Evidence-based recommendations on ab interno canaloplasty for open-angle glaucoma. This involves widening the channel that drains fluid from the eye. The aim is to reduce pressure in the eye.

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